Sample records for lung epithelia model

  1. Water Permeability Adjusts Resorption in Lung Epithelia to Increased Apical Surface Liquid Volumes.

    PubMed

    Schmidt, Hanna; Michel, Christiane; Braubach, Peter; Fauler, Michael; Neubauer, Daniel; Thompson, Kristin E; Frick, Manfred; Mizaikoff, Boris; Dietl, Paul; Wittekindt, Oliver H

    2017-03-01

    The apical surface liquid (ASL) layer covers the airways and forms a first line of defense against pathogens. Maintenance of ASL volume by airway epithelia is essential for maintaining lung function. The proteolytic activation of epithelial Na + channels is believed to be the dominating mechanism to cope with increases in ASL volumes. Alternative mechanisms, in particular increases in epithelial osmotic water permeability (P osm ), have so far been regarded as rather less important. However, most studies mainly addressed immediate effects upon apical volume expansion (AVE) and increases in ASL. This study addresses the response of lung epithelia to long-term AVE. NCI-H441 cells and primary human tracheal epithelial cells, both cultivated in air-liquid interface conditions, were used as models for the lung epithelium. AVE was established by adding isotonic solution to the apical surface of differentiated lung epithelia, and time course of ASL volume restoration was assessed by the deuterium oxide dilution method. Concomitant ion transport was investigated in Ussing chambers. We identified a low resorptive state immediately after AVE, which coincided with proteolytic ion transport activation within 10-15 minutes after AVE. The main clearance of excess ASL occurred during a delayed (hours after AVE) high resorptive state, which did not correlate with ion transport activation. Instead, high resorptive state onset coincided with an increase in P osm , which depended on aquaporin up-regulation. In summary, our data demonstrate that, aside from ion transport activation, modulation of P osm is a major mechanism to compensate for long-term AVE in lung epithelia.

  2. Phenylbutyrate counteracts Shigella mediated downregulation of cathelicidin in rabbit lung and intestinal epithelia: a potential therapeutic strategy.

    PubMed

    Sarker, Protim; Ahmed, Sultan; Tiash, Snigdha; Rekha, Rokeya Sultana; Stromberg, Roger; Andersson, Jan; Bergman, Peter; Gudmundsson, Gudmundur H; Agerberth, Birgitta; Raqib, Rubhana

    2011-01-01

    Cathelicidins and defensins are endogenous antimicrobial peptides (AMPs) that are downregulated in the mucosal epithelia of the large intestine in shigellosis. Oral treatment of Shigella infected rabbits with sodium butyrate (NaB) reduces clinical severity and counteracts the downregulation of cathelicidin (CAP-18) in the large intestinal epithelia. To develop novel regimen for treating infectious diseases by inducing innate immunity, we selected sodium 4-phenylbutyrate (PB), a registered drug for a metabolic disorder as a potential therapeutic candidate in a rabbit model of shigellosis. Since acute respiratory infections often cause secondary complications during shigellosis, the systemic effect of PB and NaB on CAP-18 expression in respiratory epithelia was also evaluated. The readouts were clinical outcomes, CAP-18 expression in mucosa of colon, rectum, lung and trachea (immunohistochemistry and real-time PCR) and release of the CAP-18 peptide/protein in stool (Western blot). Significant downregulation of CAP-18 expression in the epithelia of rectum and colon, the site of Shigella infection was confirmed. Interestingly, reduced expression of CAP-18 was also noticed in the epithelia of lung and trachea, indicating a systemic effect of the infection. This suggests a causative link to acute respiratory infections during shigellosis. Oral treatment with PB resulted in reduced clinical illness and upregulation of CAP-18 in the epithelium of rectum. Both PB and NaB counteracted the downregulation of CAP-18 in lung epithelium. The drug effect is suggested to be systemic as intravenous administration of NaB could also upregulate CAP-18 in the epithelia of lung, rectum and colon. Our results suggest that PB has treatment potential in human shigellosis. Enhancement of CAP-18 in the mucosal epithelia of the respiratory tract by PB or NaB is a novel discovery. This could mediate protection from secondary respiratory infections that frequently are the lethal causes in

  3. Phenylbutyrate Counteracts Shigella Mediated Downregulation of Cathelicidin in Rabbit Lung and Intestinal Epithelia: A Potential Therapeutic Strategy

    PubMed Central

    Sarker, Protim; Ahmed, Sultan; Tiash, Snigdha; Rekha, Rokeya Sultana; Stromberg, Roger; Andersson, Jan; Bergman, Peter; Gudmundsson, Gudmundur H.

    2011-01-01

    Background Cathelicidins and defensins are endogenous antimicrobial peptides (AMPs) that are downregulated in the mucosal epithelia of the large intestine in shigellosis. Oral treatment of Shigella infected rabbits with sodium butyrate (NaB) reduces clinical severity and counteracts the downregulation of cathelicidin (CAP-18) in the large intestinal epithelia. Aims To develop novel regimen for treating infectious diseases by inducing innate immunity, we selected sodium 4-phenylbutyrate (PB), a registered drug for a metabolic disorder as a potential therapeutic candidate in a rabbit model of shigellosis. Since acute respiratory infections often cause secondary complications during shigellosis, the systemic effect of PB and NaB on CAP-18 expression in respiratory epithelia was also evaluated. Methods The readouts were clinical outcomes, CAP-18 expression in mucosa of colon, rectum, lung and trachea (immunohistochemistry and real-time PCR) and release of the CAP-18 peptide/protein in stool (Western blot). Principal findings Significant downregulation of CAP-18 expression in the epithelia of rectum and colon, the site of Shigella infection was confirmed. Interestingly, reduced expression of CAP-18 was also noticed in the epithelia of lung and trachea, indicating a systemic effect of the infection. This suggests a causative link to acute respiratory infections during shigellosis. Oral treatment with PB resulted in reduced clinical illness and upregulation of CAP-18 in the epithelium of rectum. Both PB and NaB counteracted the downregulation of CAP-18 in lung epithelium. The drug effect is suggested to be systemic as intravenous administration of NaB could also upregulate CAP-18 in the epithelia of lung, rectum and colon. Conclusion Our results suggest that PB has treatment potential in human shigellosis. Enhancement of CAP-18 in the mucosal epithelia of the respiratory tract by PB or NaB is a novel discovery. This could mediate protection from secondary respiratory

  4. Biophysical Model of Ion Transport across Human Respiratory Epithelia Allows Quantification of Ion Permeabilities

    PubMed Central

    Garcia, Guilherme J.M.; Boucher, Richard C.; Elston, Timothy C.

    2013-01-01

    Lung health and normal mucus clearance depend on adequate hydration of airway surfaces. Because transepithelial osmotic gradients drive water flows, sufficient hydration of the airway surface liquid depends on a balance between ion secretion and absorption by respiratory epithelia. In vitro experiments using cultures of primary human nasal epithelia and human bronchial epithelia have established many of the biophysical processes involved in airway surface liquid homeostasis. Most experimental studies, however, have focused on the apical membrane, despite the fact that ion transport across respiratory epithelia involves both cellular and paracellular pathways. In fact, the ion permeabilities of the basolateral membrane and paracellular pathway remain largely unknown. Here we use a biophysical model for water and ion transport to quantify ion permeabilities of all pathways (apical, basolateral, paracellular) in human nasal epithelia cultures using experimental (Ussing Chamber and microelectrode) data reported in the literature. We derive analytical formulas for the steady-state short-circuit current and membrane potential, which are for polarized epithelia the equivalent of the Goldman-Hodgkin-Katz equation for single isolated cells. These relations allow parameter estimation to be performed efficiently. By providing a method to quantify all the ion permeabilities of respiratory epithelia, the model may aid us in understanding the physiology that regulates normal airway surface hydration. PMID:23442922

  5. Biophysical model of ion transport across human respiratory epithelia allows quantification of ion permeabilities.

    PubMed

    Garcia, Guilherme J M; Boucher, Richard C; Elston, Timothy C

    2013-02-05

    Lung health and normal mucus clearance depend on adequate hydration of airway surfaces. Because transepithelial osmotic gradients drive water flows, sufficient hydration of the airway surface liquid depends on a balance between ion secretion and absorption by respiratory epithelia. In vitro experiments using cultures of primary human nasal epithelia and human bronchial epithelia have established many of the biophysical processes involved in airway surface liquid homeostasis. Most experimental studies, however, have focused on the apical membrane, despite the fact that ion transport across respiratory epithelia involves both cellular and paracellular pathways. In fact, the ion permeabilities of the basolateral membrane and paracellular pathway remain largely unknown. Here we use a biophysical model for water and ion transport to quantify ion permeabilities of all pathways (apical, basolateral, paracellular) in human nasal epithelia cultures using experimental (Ussing Chamber and microelectrode) data reported in the literature. We derive analytical formulas for the steady-state short-circuit current and membrane potential, which are for polarized epithelia the equivalent of the Goldman-Hodgkin-Katz equation for single isolated cells. These relations allow parameter estimation to be performed efficiently. By providing a method to quantify all the ion permeabilities of respiratory epithelia, the model may aid us in understanding the physiology that regulates normal airway surface hydration. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  6. CFTR is required for maximal transepithelial liquid transport in pig alveolar epithelia.

    PubMed

    Li, Xiaopeng; Comellas, Alejandro P; Karp, Philip H; Ernst, Sarah E; Moninger, Thomas O; Gansemer, Nicholas D; Taft, Peter J; Pezzulo, Alejandro A; Rector, Michael V; Rossen, Nathan; Stoltz, David A; McCray, Paul B; Welsh, Michael J; Zabner, Joseph

    2012-07-01

    A balance between alveolar liquid absorption and secretion is critical for maintaining optimal alveolar subphase liquid height and facilitating gas exchange in the alveolar space. However, the role of cystic fibrosis transmembrane regulator protein (CFTR) in this homeostatic process has remained elusive. Using a newly developed porcine model of cystic fibrosis, in which CFTR is absent, we investigated ion transport properties and alveolar liquid transport in isolated type II alveolar epithelial cells (T2AECs) cultured at the air-liquid interface. CFTR was distributed exclusively to the apical surface of cultured T2AECs. Alveolar epithelia from CFTR(-/-) pigs failed to increase liquid absorption in response to agents that increase cAMP, whereas cAMP-stimulated liquid absorption in CFTR(+/-) epithelia was similar to that in CFTR(+/+) epithelia. Expression of recombinant CFTR restored stimulated liquid absorption in CFTR(-/-) T2AECs but had no effect on CFTR(+/+) epithelia. In ex vivo studies of nonperfused lungs, stimulated liquid absorption was defective in CFTR(-/-) alveolar epithelia but similar between CFTR(+/+) and CFTR(+/-) epithelia. When epithelia were studied at the air-liquid interface, elevating cAMP levels increased subphase liquid height in CFTR(+/+) but not in CFTR(-/-) T2AECs. Our findings demonstrate that CFTR is required for maximal liquid absorption under cAMP stimulation, but it is not the rate-limiting factor. Furthermore, our data define a role for CFTR in liquid secretion by T2AECs. These insights may help to develop new treatment strategies for pulmonary edema and respiratory distress syndrome, diseases in which lung liquid transport is disrupted.

  7. Differential Transmission of HIV Traversing Fetal Oral/Intestinal Epithelia and Adult Oral Epithelia

    PubMed Central

    Herrera, Rossana; Veluppillai, Piri; Greenspan, Deborah; Soros, Vanessa; Greene, Warner C.; Levy, Jay A.; Palefsky, Joel M.

    2012-01-01

    While human immunodeficiency virus (HIV) transmission through the adult oral route is rare, mother-to-child transmission (MTCT) through the neonatal/infant oral and/or gastrointestinal route is common. To study the mechanisms of cell-free and cell-associated HIV transmission across adult oral and neonatal/infant oral/intestinal epithelia, we established ex vivo organ tissue model systems of adult and fetal origin. Given the similarity of neonatal and fetal oral epithelia with respect to epithelial stratification and density of HIV-susceptible immune cells, we used fetal oral the epithelium as a model for neonatal/infant oral epithelium. We found that cell-free HIV traversed fetal oral and intestinal epithelia and infected HIV-susceptible CD4+ T lymphocytes, Langerhans/dendritic cells, and macrophages. To study the penetration of cell-associated virus into fetal oral and intestinal epithelia, HIV-infected macrophages and lymphocytes were added to the surfaces of fetal oral and intestinal epithelia. HIV-infected macrophages, but not lymphocytes, transmigrated across fetal oral epithelia. HIV-infected macrophages and, to a lesser extent, lymphocytes transmigrated across fetal intestinal epithelia. In contrast to the fetal oral/intestinal epithelia, cell-free HIV transmigration through adult oral epithelia was inefficient and virions did not infect intraepithelial and subepithelial HIV-susceptible cells. In addition, HIV-infected macrophages and lymphocytes did not transmigrate through intact adult oral epithelia. Transmigration of cell-free and cell-associated HIV across the fetal oral/intestinal mucosal epithelium may serve as an initial mechanism for HIV MTCT. PMID:22205732

  8. Comparative biology of rAAV transduction in ferret, pig and human airway epithelia.

    PubMed

    Liu, X; Luo, M; Guo, C; Yan, Z; Wang, Y; Engelhardt, J F

    2007-11-01

    Differences between rodent and human airway cell biology have made it difficult to translate recombinant adeno-associated virus (rAAV)-mediated gene therapies to the lung for cystic fibrosis (CF). As new ferret and pig models for CF become available, knowledge about host cell/vector interactions in these species will become increasingly important for testing potential gene therapies. To this end, we have compared the transduction biology of three rAAV serotypes (AAV1, 2 and 5) in human, ferret, pig and mouse-polarized airway epithelia. Our results indicate that apical transduction of ferret and pig airway epithelia with these rAAV serotypes closely mirrors that observed in human epithelia (rAAV1>rAAV2 congruent withrAAV5), while transduction of mouse epithelia was significantly different (rAAV1>rAAV5>rAAV2). Similarly, ferret, pig and human epithelia also shared serotype-specific differences in the polarity (apical vs basolateral) and proteasome dependence of rAAV transduction. Despite these parallels, N-linked sialic acid receptors were required for rAAV1 and rAAV5 transduction of human and mouse airway epithelia, but not ferret or pig airway epithelia. Hence, although the airway tropisms of rAAV serotypes 1, 2 and 5 are conserved better among ferret, pig and human as compared to mouse, viral receptors/co-receptors appear to maintain considerable species diversity.

  9. Actions of Hydrogen Sulfide on Sodium Transport Processes across Native Distal Lung Epithelia (Xenopus laevis)

    PubMed Central

    Erb, Alexandra; Althaus, Mike

    2014-01-01

    Hydrogen sulfide (H2S) is well known as a highly toxic environmental chemical threat. Prolonged exposure to H2S can lead to the formation of pulmonary edema. However, the mechanisms of how H2S facilitates edema formation are poorly understood. Since edema formation can be enhanced by an impaired clearance of electrolytes and, consequently, fluid across the alveolar epithelium, it was questioned whether H2S may interfere with transepithelial electrolyte absorption. Electrolyte absorption was electrophysiologically measured across native distal lung preparations (Xenopus laevis) in Ussing chambers. The exposure of lung epithelia to H2S decreased net transepithelial electrolyte absorption. This was due to an impairment of amiloride-sensitive sodium transport. H2S inhibited the activity of the Na+/K+-ATPase as well as lidocaine-sensitive potassium channels located in the basolateral membrane of the epithelium. Inhibition of these transport molecules diminishes the electrochemical gradient which is necessary for transepithelial sodium absorption. Since sodium absorption osmotically facilitates alveolar fluid clearance, interference of H2S with the epithelial transport machinery provides a mechanism which enhances edema formation in H2S-exposed lungs. PMID:24960042

  10. Loss of anion transport without increased sodium absorption characterizes newborn porcine cystic fibrosis airway epithelia

    PubMed Central

    Chen, Jeng-Haur; Stoltz, David A.; Karp, Philip H.; Ernst, Sarah E.; Pezzulo, Alejandro A.; Moninger, Thomas O.; Rector, Michael V.; Reznikov, Leah R.; Launspach, Janice L.; Chaloner, Kathryn; Zabner, Joseph; Welsh, Michael J.

    2011-01-01

    SUMMARY Defective transepithelial electrolyte transport is thought to initiate cystic fibrosis (CF) lung disease. Yet, how loss of CFTR affects electrolyte transport remains uncertain. CFTR−/− pigs spontaneously develop lung disease resembling human CF. At birth, their airways exhibit a bacterial host defense defect, but are not inflamed. Therefore, we studied ion transport in newborn nasal and tracheal/bronchial epithelia in tissue, cultures, and in vivo. CFTR−/− epithelia showed markedly reduced Cl− and HCO3− transport. However, in contrast to a widely held view, lack of CFTR did not increase transepithelial Na+ or liquid absorption or reduce periciliary liquid depth. Like human CF, CFTR−/− pigs showed increased amiloride-sensitive voltage and current, but lack of apical Cl− conductance caused the change, not increased Na+ transport. These results indicate that CFTR provides the predominant transcellular pathway for Cl− and HCO3− in porcine airway epithelia, and reduced anion permeability may initiate CF airway disease. PMID:21145458

  11. Transduction of ferret airway epithelia using a pre-treatment and lentiviral gene vector.

    PubMed

    Cmielewski, Patricia; Farrow, Nigel; Donnelley, Martin; McIntyre, Chantelle; Penny-Dimri, Jahan; Kuchel, Tim; Parsons, David

    2014-11-21

    The safety and efficiency of gene therapies for cystic fibrosis (CF) need to be assessed in pre-clinical models. Using the normal ferret, this study sought to determine whether ferret airway epithelia could be transduced with a lysophosphatidylcholine (LPC) pre-treatment followed by a VSV-G pseudotyped HIV-1 based lentiviral (LV) vector, in preparation for future studies in CF ferrets. Six normal ferrets (7 -8 weeks old) were treated with a 150 μL LPC pre-treatment, followed one hour later by a 500 μL LV vector dose containing the LacZ transgene. LacZ gene expression in the conducting airways and lung was assessed by X-gal staining after 7 days. The presence of transduction in the lung, as well as off-target transduction in the liver, spleen and gonads, were assessed by qPCR. The levels of LV vector p24 protein bio-distribution in blood sera were assessed by ELISA at 0, 1, 3, 5 and 7 days. The dosing protocol was well tolerated. LacZ gene expression was observed en face in the trachea of all animals. Histology showed that ciliated and basal cells were transduced in the trachea, with rare LacZ transduced single cells noted in lung. p24 levels was not detectable in the sera of 5 of the 6 animals. The LacZ gene was not detected in the lung tissue and no off-target transduction was detected by qPCR. This study shows that ferret airway epithelia are transducible using our unique two-step pre-treatment and LV vector dosing protocol. We have identified a number of unusual anatomical factors that are likely to influence the level of transduction that can be achieved in ferret airways. The ability to transduce ferret airway epithelium is a promising step towards therapeutic LV-CFTR testing in a CF ferret model.

  12. Prenatal fine particulate exposure associated with reduced childhood lung function and nasal epithelia GSTP1 hypermethylation: Sex-specific effects.

    PubMed

    Lee, Alison G; Le Grand, Blake; Hsu, Hsiao-Hsien Leon; Chiu, Yueh-Hsiu Mathilda; Brennan, Kasey J; Bose, Sonali; Rosa, Maria José; Brunst, Kelly J; Kloog, Itai; Wilson, Ander; Schwartz, Joel; Morgan, Wayne; Coull, Brent A; Wright, Robert O; Baccarelli, Andrea A; Wright, Rosalind J

    2018-04-27

    In utero exposure to particulate matter with an aerodynamic diameter of less than 2.5 μm (PM 2.5 ) has been linked to child lung function. Overlapping evidence suggests that child sex and exposure timing may modify effects and associations may be mediated through glutathione S-transferase P1 (GSTP1) methylation. We prospectively examined associations among prenatal PM 2.5 exposure and child lung function and GSTP1 methylation in an urban pregnancy cohort study. We employed a validated satellite-based spatiotemporally resolved prediction model to estimate daily prenatal PM 2.5 exposure over gestation. We used Baysian distributed lag interaction models (BDLIMs) to identify sensitive windows for prenatal PM 2.5 exposure on child lung function and nasal epithelia GSTP1 methylation at age 7 years, and to examine effect modification by child sex. BDLIMs identified a sensitive window for prenatal PM 2.5 exposure at 35-40 weeks gestation [cumulative effect estimate (CEE) = - 0.10, 95%CI = - 0.19 to - 0.01, per μg/m 3 increase in PM 2.5 ] and at 36-40 weeks (CEE = - 0.12, 95%CI = - 0.20 to - 0.01) on FEV 1 and FVC, respectively, in boys. BDLIMs also identified a sensitive window of exposure at 37-40 weeks gestation between higher prenatal PM 2.5 exposure and increased GSTP1 percent methylation. The association between higher GSTP1 percent methylation and decreased FEV1 was borderline significant in the sample as a whole (β = - 0.37, SE = 0.20, p = 0.06) and in boys in stratified analyses (β = - 0.56, SE = 0.29, p = 0.05). Prenatal PM 2.5 exposure in late pregnancy was associated with impaired early childhood lung function and hypermethylation of GSTPI in DNA isolated from nasal epithelial cells. There was a trend towards higher GSTP1 percent methylation being associated with reduced FEV1. All findings were most evident among boys.

  13. Wood combustion particles induce adverse effects to normal and diseased airway epithelia.

    PubMed

    Krapf, Manuel; Künzi, Lisa; Allenbach, Sandrine; Bruns, Emily A; Gavarini, Ilaria; El-Haddad, Imad; Slowik, Jay G; Prévôt, André S H; Drinovec, Luka; Močnik, Griša; Dümbgen, Lutz; Salathe, Matthias; Baumlin, Nathalie; Sioutas, Constantinos; Baltensperger, Urs; Dommen, Josef; Geiser, Marianne

    2017-04-19

    Residential wood burning is a major source of poorly characterized, deleterious particulate matter, whose composition and toxicity may vary with wood type, burning condition and photochemical age. The causative link between ambient wood particle constituents and observed adverse health effects is currently lacking. Here we investigate the relationship between chemical properties of primary and atmospherically aged wood combustion particles and acute toxicity in human airway epithelial cells. Emissions from a log wood burner were diluted and injected into a smog chamber for photochemical aging. After concentration-enrichment and removal of oxidizing gases, directly emitted and atmospherically aged particles were deposited on cell cultures at the air-liquid interface for 2 hours in an aerosol deposition chamber mimicking physiological conditions in lungs. Cell models were fully differentiated normal and diseased (cystic fibrosis and asthma) human bronchial epithelia (HBE) and the bronchial epithelial cell line BEAS-2B. Cell responses were assessed at 24 hours after aerosol exposure. Atmospherically relevant doses of wood combustion particles significantly increased cell death in all but the asthma cell model. Expression of oxidative stress markers increased in HBE from all donors. Increased cell death and inflammatory responses could not be assigned to a single chemical fraction of the particles. Exposure to primary and aged wood combustion particles caused adverse effects to airway epithelia, apparently induced by several interacting components.

  14. Motile cilia of human airway epithelia contain hedgehog signaling components that mediate noncanonical hedgehog signaling.

    PubMed

    Mao, Suifang; Shah, Alok S; Moninger, Thomas O; Ostedgaard, Lynda S; Lu, Lin; Tang, Xiao Xiao; Thornell, Ian M; Reznikov, Leah R; Ernst, Sarah E; Karp, Philip H; Tan, Ping; Keshavjee, Shaf; Abou Alaiwa, Mahmoud H; Welsh, Michael J

    2018-02-06

    Differentiated airway epithelia produce sonic hedgehog (SHH), which is found in the thin layer of liquid covering the airway surface. Although previous studies showed that vertebrate HH signaling requires primary cilia, as airway epithelia mature, the cells lose primary cilia and produce hundreds of motile cilia. Thus, whether airway epithelia have apical receptors for SHH has remained unknown. We discovered that motile cilia on airway epithelial cells have HH signaling proteins, including patched and smoothened. These cilia also have proteins affecting cAMP-dependent signaling, including Gα i and adenylyl cyclase 5/6. Apical SHH decreases intracellular levels of cAMP, which reduces ciliary beat frequency and pH in airway surface liquid. These results suggest that apical SHH may mediate noncanonical HH signaling through motile cilia to dampen respiratory defenses at the contact point between the environment and the lung, perhaps counterbalancing processes that stimulate airway defenses. Copyright © 2018 the Author(s). Published by PNAS.

  15. Drosophila as a Model for Human Diseases-Focus on Innate Immunity in Barrier Epithelia.

    PubMed

    Bergman, P; Seyedoleslami Esfahani, S; Engström, Y

    2017-01-01

    Epithelial immunity protects the host from harmful microbial invaders but also controls the beneficial microbiota on epithelial surfaces. When this delicate balance between pathogen and symbiont is disturbed, clinical disease often occurs, such as in inflammatory bowel disease, cystic fibrosis, or atopic dermatitis, which all can be in part linked to impairment of barrier epithelia. Many innate immune receptors, signaling pathways, and effector molecules are evolutionarily conserved between human and Drosophila. This review describes the current knowledge on Drosophila as a model for human diseases, with a special focus on innate immune-related disorders of the gut, lung, and skin. The discovery of antimicrobial peptides, the crucial role of Toll and Toll-like receptors, and the evolutionary conservation of signaling to the immune systems of both human and Drosophila are described in a historical perspective. Similarities and differences between human and Drosophila are discussed; current knowledge on receptors, signaling pathways, and effectors are reviewed, including antimicrobial peptides, reactive oxygen species, as well as autophagy. We also give examples of human diseases for which Drosophila appears to be a useful model. In addition, the limitations of the Drosophila model are mentioned. Finally, we propose areas for future research, which include using the Drosophila model for drug screening, as a validation tool for novel genetic mutations in humans and for exploratory research of microbiota-host interactions, with relevance for infection, wound healing, and cancer. © 2017 Elsevier Inc. All rights reserved.

  16. Mechanical stress induces lung fibrosis by epithelial-mesenchymal transition.

    PubMed

    Cabrera-Benítez, Nuria E; Parotto, Matteo; Post, Martin; Han, Bing; Spieth, Peter M; Cheng, Wei-Erh; Valladares, Francisco; Villar, Jesús; Liu, Mingayo; Sato, Masaaki; Zhang, Haibo; Slutsky, Arthur S

    2012-02-01

    Many mechanically ventilated patients with acute respiratory distress syndrome develop pulmonary fibrosis. Stresses induced by mechanical ventilation may explain the development of fibrosis by a number of mechanisms (e.g., damage the alveolar epithelium, biotrauma). The objective of this study was t test the hypothesis that mechanical ventilation plays an important role in the pathogenesis of lung fibrosis. C57BL/6 mice were randomized into four groups: healthy controls; hydrochloric acid aspiration alone; vehicle control solution followed 24 hrs later by mechanical ventilation (peak inspiratory pressure 22 cm H(2)O and positive end-expiratory pressure 2 cm H(2)O for 2 hrs); and acid aspiration followed 24 hrs later by mechanical ventilation. The animals were monitored for up to 15 days after acid aspiration. To explore the direct effects of mechanical stress on lung fibrotic formation, human lung epithelial cells (BEAS-2B) were exposed to mechanical stretch for up to 48 hrs. Impaired lung mechanics after mechanical ventilation was associated with increased lung hydroxyproline content, and increased expression of transforming growth factor-β, β-catenin, and mesenchymal markers (α-smooth muscle actin and vimentin) at both the gene and protein levels. Expression of epithelial markers including cytokeratin-8, E-cadherin, and prosurfactant protein B decreased. Lung histology demonstrated fibrosis formation and potential epithelia-mesenchymal transition. In vitro direct mechanical stretch of BEAS-2B cells resulted in similar fibrotic and epithelia-mesenchymal transition formation. Mechanical stress induces lung fibrosis, and epithelia-mesenchymal transition may play an important role in mediating the ventilator-induced lung fibrosis.

  17. Expression of mutant Sftpcin murine alveolar epithelia drives spontaneous lung fibrosis.

    PubMed

    Nureki, Shin-Ichi; Tomer, Yaniv; Venosa, Alessandro; Katzen, Jeremy; Russo, Scott J; Jamil, Sarita; Barrett, Matthew; Nguyen, Vivian; Kopp, Meghan; Mulugeta, Surafel; Beers, Michael F

    2018-06-19

    Epithelial cell dysfunction is postulated as an important component in the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). Mutations in the Surfactant Protein C [SP-C] gene [SFTPC], an alveolar type 2 (AT2) cell restricted protein, have been found in sporadic and familial IPF. To causally link these events, we developed a knock-in mouse model capable of regulated expression of an IPF-associated Isoleucine to Threonine substitution at codon 73 [I73T] in Sftpc (SP-CI73T). Tamoxifen treated SP-CI73T cohorts developed rapid increases in SftpcI73T mRNA and misprocessed proSP-CI73T protein accompanied by increased early mortality (days 7-14). This acute phase was marked by diffuse parenchymal lung injury, tissue infiltration by monocytes, polycellular alveolitis, and elevations in bronchoalveolar lavage and AT2 mRNA contents of select inflammatory cytokines. Resolution of alveolitis (2-4 weeks), commensurate with a rise in TGFB1, was followed by aberrant remodeling marked by collagen deposition, AT2 cell hyperplasia, a-SMA positive cells, and restrictive lung physiology. The translational relevance of the model was supported by detection of multiple IPF biomarkers previously reported in human cohorts. These data provide proof of principle that mutant SP-C expression in vivo causes spontaneous lung fibrosis strengthening the role of AT2 dysfunction as a key upstream driver of IPF pathogenesis.

  18. The 34th Annual Fall Meeting of the American Physiological Society and the International Conference on Hydrogen Ion Transport in Epithelia.

    ERIC Educational Resources Information Center

    Physiologist, 1983

    1983-01-01

    Provided are abstracts of papers presented at the annual American Physiological Society meeting and International Conference on Hydrogen Ion Transport in Epithelia. Papers are grouped by such topic areas as lung fluid balance, renal cardiovascular integration, smooth muscle physiology, neuroendocrines (pituitary), exercise physiology, mechanics of…

  19. Toll-Like Receptor 4 Engagement Mediates Prolyl Endopeptidase Release from Airway Epithelia via Exosomes.

    PubMed

    Szul, Tomasz; Bratcher, Preston E; Fraser, Kyle B; Kong, Michele; Tirouvanziam, Rabindra; Ingersoll, Sarah; Sztul, Elizabeth; Rangarajan, Sunil; Blalock, J Edwin; Xu, Xin; Gaggar, Amit

    2016-03-01

    Proteases are important regulators of pulmonary remodeling and airway inflammation. Recently, we have characterized the enzyme prolyl endopeptidase (PE), a serine peptidase, as a critical protease in the generation of the neutrophil chemoattractant tripeptide Pro-Gly-Pro (PGP) from collagen. However, PE has been characterized as a cytosolic enzyme, and the mechanism mediating PE release extracellularly remains unknown. We examined the role of exosomes derived from airway epithelia as a mechanism for PE release and the potential extracellular signals that regulate the release of these exosomes. We demonstrate a specific regulatory pathway of exosome release from airway epithelia and identify PE as novel exosome cargo. LPS stimulation of airway epithelial cells induces release of PE-containing exosomes, which is significantly attenuated by small interfering RNA depletion of Toll-like receptor 4 (TLR4). These differences were recapitulated upon intratracheal LPS administration in mice competent versus deficient for TLR4 signaling. Finally, sputum samples from subjects with cystic fibrosis colonized with Pseudomonas aeruginosa demonstrate elevated exosome content and increased PE levels. This TLR4-based mechanism highlights the first report of nonstochastic release of exosomes in the lung and couples TLR4 activation with matrikine generation. The increased quantity of these proteolytic exosomes in the airways of subjects with chronic lung disease highlights a new mechanism of injury and inflammation in the pathogenesis of pulmonary disorders.

  20. Chloride transporting capability of Calu-3 epithelia following persistent knockdown of the cystic fibrosis transmembrane conductance regulator, CFTR

    PubMed Central

    MacVinish, L J; Cope, G; Ropenga, A; Cuthbert, A W

    2007-01-01

    Background and purpose: Calu-3 cells are derived from serous cells of human lung submucosal glands, a prime target for therapy in cystic fibrosis (CF). Calu-3 cells can be cultured to form epithelia capable of transepithelial transport of chloride. A CF Calu-3 cell is not available. Experimental approach: A retroviral vector was used to cause persistent down regulation of CFTR using siRNA methodology, in Calu-3 cells. A Calu-3 cell line with CFTR content less than 5% of the original line has been established. Epithelia grown using the modified cells have been used in comparative studies of transporting capability. Key results: All aspects of cAMP activated chloride secretion were attenuated in the epithelia with reduced CFTR content. However transporting capability was reduced less than the CFTR content. From studies with the CFTR channel inhibitor, GlyH-101, it was concluded that wild type Calu-3 cells have a reserve of CFTR channels not located in the membrane, but available for replacement, while in the modified Calu-3 cell line there was little or no reserve. Lubiprostone, a putative ClC-2 activator, increased transepithelial chloride secretion in both modified and wild type Calu-3 epithelia. Modified Calu-3 epithelia with the residual CFTR currents blocked with GlyH-101 responded equally well to lubiprostone as those without the blocking agent. Conclusions and implications: It appears that lubiprostone is capable of stimulating a non-CFTR dependent transepithelial chloride secretion in Calu-3 monolayers, with obvious implications for CF therapy. Cell lines, however, do not always reflect the behaviour of the native tissue with integrity. PMID:17339840

  1. Next Generation Respiratory Viral Vaccine System: Advanced and Emerging Bioengineered Human Lung Epithelia Model (HLEM) Organoid Technology

    NASA Technical Reports Server (NTRS)

    Goodwin, Thomas J.; Schneider, Sandra L.; MacIntosh, Victor; Gibbons, Thomas F.

    2010-01-01

    Acute respiratory infections, including pneumonia and influenza, are the S t" leading cause of United States and worldwide deaths. Newly emerging pathogens signaled the need for an advanced generation of vaccine technology.. Human bronchial-tracheal epithelial tissue was bioengineered to detect, identify, host and study the pathogenesis of acute respiratory viral disease. The 3-dimensional (3D) human lung epithelio-mesechymal tissue-like assemblies (HLEM TLAs) share characteristics with human respiratory epithelium: tight junctions, desmosomes, microvilli, functional markers villin, keratins and production of tissue mucin. Respiratory Syntial Virus (RSV) studies demonstrate viral growth kinetics and membrane bound glycoproteins up to day 20 post infection in the human lung-orgainoid infected cell system. Peak replication of RSV occurred on day 10 at 7 log10 particles forming units per ml/day. HLEM is an advanced virus vaccine model and biosentinel system for emergent viral infectious diseases to support DoD global surveillance and military readiness.

  2. APICAL LOCATION OF FERROPORTIN 1 IN AIRWAY EPITHELIA AND ITS ROLE IN IRON DETOXIFICATION IN THE LUNG

    EPA Science Inventory

    Ferroportin 1 (FPN1; aka MTP1, IREG1, and SLC40A1), which was originally identified as a basolateral iron transporter crucial for nutritional iron absorption in the intestine, is expressed in airway epithelia and upregulated when these cells are exposed to iron. Using immunofluor...

  3. Differential effects of cyclic and constant stress on ATP release and mucociliary transport by human airway epithelia

    PubMed Central

    Button, Brian; Picher, Maryse; Boucher, Richard C

    2007-01-01

    In the lungs, the first line of defence against bacterial infection is the thin layer of airway surface liquid (ASL) lining the airway surface. The superficial airway epithelium exhibits complex regulatory pathways that blend ion transport to adjust ASL volume to maintain proper mucociliary clearance (MCC). We hypothesized that stresses generated by airflow and transmural pressures during breathing govern ASL volume by regulating the rate of epithelial ATP release. Luminal ATP, via interactions with apical membrane P2-purinoceptors, regulates the balance of active ion secretion versus absorption to maintain ASL volume at optimal levels for MCC. In this study we tested the hypothesis that cyclic compressive stress (CCS), mimicking normal tidal breathing, regulates ASL volume in airway epithelia. Polarized tracheobronchial epithelial cultures from normal and cystic fibrosis (CF) subjects responded to a range of CCS by increasing the rate of ATP release. In normal airway epithelia, the CCS-induced increase in ASL ATP concentration was sufficient to induce purinoceptor-mediated increases in ASL height and MCC, via inhibition of epithelial Na+-channel-mediated Na+ absorption and stimulation of Cl− secretion through CFTR and the Ca2+-activated chloride channels. In contrast, static, non-oscillatory stress did not stimulate ATP release, ion transport or MCC, emphasizing the importance of rhythmic mechanical stress for airway defence. In CF airway cultures, which exhibit basal ASL depletion, CCS was partially effective, producing less ASL volume secretion than in normal cultures, but a level sufficient to restore MCC. The present data suggest that CCS may (1) regulate ASL volume in the normal lung and (2) improve clearance in the lungs of CF patients, potentially explaining the beneficial role of exercise in lung defence. PMID:17317749

  4. Topological defects in epithelia govern cell death and extrusion

    NASA Astrophysics Data System (ADS)

    Saw, Thuan Beng; Doostmohammadi, Amin; Nier, Vincent; Kocgozlu, Leyla; Thampi, Sumesh; Toyama, Yusuke; Marcq, Philippe; Lim, Chwee Teck; Yeomans, Julia M.; Ladoux, Benoit

    2017-04-01

    Epithelial tissues (epithelia) remove excess cells through extrusion, preventing the accumulation of unnecessary or pathological cells. The extrusion process can be triggered by apoptotic signalling, oncogenic transformation and overcrowding of cells. Despite the important linkage of cell extrusion to developmental, homeostatic and pathological processes such as cancer metastasis, its underlying mechanism and connections to the intrinsic mechanics of the epithelium are largely unexplored. We approach this problem by modelling the epithelium as an active nematic liquid crystal (that has a long range directional order), and comparing numerical simulations to strain rate and stress measurements within monolayers of MDCK (Madin Darby canine kidney) cells. Here we show that apoptotic cell extrusion is provoked by singularities in cell alignments in the form of comet-shaped topological defects. We find a universal correlation between extrusion sites and positions of nematic defects in the cell orientation field in different epithelium types. The results confirm the active nematic nature of epithelia, and demonstrate that defect-induced isotropic stresses are the primary precursors of mechanotransductive responses in cells, including YAP (Yes-associated protein) transcription factor activity, caspase-3-mediated cell death, and extrusions. Importantly, the defect-driven extrusion mechanism depends on intercellular junctions, because the weakening of cell-cell interactions in an α-catenin knockdown monolayer reduces the defect size and increases both the number of defects and extrusion rates, as is also predicted by our model. We further demonstrate the ability to control extrusion hotspots by geometrically inducing defects through microcontact printing of patterned monolayers. On the basis of these results, we propose a mechanism for apoptotic cell extrusion: spontaneously formed topological defects in epithelia govern cell fate. This will be important in predicting

  5. Advanced technique for long term culture of epithelia in a continuous luminal-basal medium gradient.

    PubMed

    Schumacher, Karl; Strehl, Raimund; de, Vries Uwe; Minuth, Will W

    2002-02-01

    The majority of epithelia in our organism perform barrier functions on being exposed to different fluids at the luminal and basal sides. To simulate this natural situation under in vitro conditions for biomaterial testing and tissue engineering the epithelia have to withstand mechanical and fluid stress over a prolonged period of time. Leakage, edge damage and pressure differences in the culture system have to be avoided so that the epithelial barrier function is maintained. Besides, the environmental influences on important cell biological features such as, sealing or transport functions, have to remain upregulated and a loss of characteristics by dedifferentiation is prevented. Our aim is to expose embryonic renal collecting duct (CD) epithelia as model tissue for 14 days to fluid gradients and to monitor the development of tissue-specific features. For these experiments, cultured embryonic epithelia are placed in tissue carriers and in gradient containers, where different media are superfused at the luminal and basal sides. Epithelia growing on the tissue carriers act as a physiological barrier during the whole culture period. To avoid mechanical damage of the tissue and to suppress fluid pressure differences between the luminal and basal compartments improved transport of the medium and an elimination of unilaterally accumulated gas bubbles in the gradient container compartments by newly developed gas expander modules is introduced. By the application of these tools the yield of embryonic renal collecting duct epithelia with intact barrier function on a fragile natural support material could be increased significantly as compared to earlier experiments. Epithelia treated with a luminal NaCl load ranging from 3 to 24 mmol l were analyzed by immunohistochemical methods to determine the degree of differentiation. The tissue showed an upregulation of individual CD cell features as compared to embryonic epithelia in the neonatal kidney.

  6. Gross and fine dissection of inner ear sensory epithelia in adult zebrafish (Danio rerio).

    PubMed

    Liang, Jin; Burgess, Shawn M

    2009-05-08

    Neurosensory epithelia in the inner ear are the crucial structures for hearing and balance functions. Therefore, it is important to understand the cellular and molecular features of the epithelia, which are mainly composed of two types of cells: hair cells (HCs) and supporting cells (SCs). Here we choose to study the inner ear sensory epithelia in adult zebrafish not only because the epithelial structures are highly conserved in all vertebrates studied, but also because the adult zebrafish is able to regenerate HCs, an ability that mammals lose shortly after birth. We use the inner ear of adult zebrafish as a model system to study the mechanisms of inner ear HC regeneration in adult vertebrates that could be helpful for clinical therapy of hearing/balance deficits in human as a result of HC loss. Here we demonstrate how to do gross and fine dissections of inner ear sensory epithelia in adult zebrafish. The gross dissection removes the tissues surrounding the inner ear and is helpful for preparing tissue sections, which allows us to examine the detailed structure of the sensory epithelia. The fine dissection cleans up the non-sensory-epithelial tissues of each individual epithelium and enables us to examine the heterogeneity of the whole epithelium easily in whole-mount epithelial samples.

  7. Advances in Cell and Gene-based Therapies for Cystic Fibrosis Lung Disease

    PubMed Central

    Oakland, Mayumi; Sinn, Patrick L; McCray Jr, Paul B

    2012-01-01

    Cystic fibrosis (CF) is a disease characterized by airway infection, inflammation, remodeling, and obstruction that gradually destroy the lungs. Direct delivery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene to airway epithelia may offer advantages, as the tissue is accessible for topical delivery of vectors. Yet, physical and host immune barriers in the lung present challenges for successful gene transfer to the respiratory tract. Advances in gene transfer approaches, tissue engineering, and novel animal models are generating excitement within the CF research field. This review discusses current challenges and advancements in viral and nonviral vectors, cell-based therapies, and CF animal models. PMID:22371844

  8. Alveolar Edema Fluid Clearance and Acute Lung Injury

    PubMed Central

    Berthiaume, Yves; Matthay, Michael A.

    2009-01-01

    Although lung-protective ventilation strategies have substantially reduced mortality of acute lung injury patients there is still a need for new therapies that can further decrease mortality in patients with acute lung injury. Studies of epithelial ion and fluid transport across the distal pulmonary epithelia have provided important new concepts regarding potential new therapies for acute lung injury. Overall, there is convincing evidence that the alveolar epithelium is not only a tight epithelial barrier that resists the movement of edema fluid into the alveoli, but it is also actively involved in the transport of ions and solutes, a process that is essential for edema fluid clearance and the resolution of acute lung injury. The objective of this article is to consider some areas of recent progress in the field of alveolar fluid transport under normal and pathologic conditions. Vectorial ion transport across the alveolar and distal airway epithelia is the primary determinant of alveolar fluid clearance. The general paradigm is that active Na+ and Cl− transport drives net alveolar fluid clearance, as demonstrated in several different species, including the human lung. Although these transport processes can be impaired in severe lung injury, multiple experimental studies suggest that upregulation of Na+ and Cl− transport might be an effective therapy in acute lung injury. We will review mechanisms involved in pharmacological modulation of ion transport in lung injury with a special focus on the use of β-adrenergic agonists which has generated considerable interest and is a promising therapy for clinical acute lung injury. PMID:17604701

  9. Characterization of the cell of origin and propagation potential of the fibroblast growth factor 9-induced mouse model of lung adenocarcinoma

    PubMed Central

    Soejima, Kenzo; Kuroda, Aoi; Ishioka, Kota; Yasuda, Hiroyuki; Naoki, Katsuhiko; Shizuko, Kagawa; Hamamoto, Junko; Yin, Yongjun; Ornitz, David M.; Betsuyaku, Tomoko

    2014-01-01

    Fibroblast growth factor (FGF) 9 is essential for lung development and is highly expressed in a subset of human lung adenocarcinomas. We recently described a mouse model in which FGF9 expression in the lung epithelium caused proliferation of the airway epithelium at the terminal bronchioles and led to rapid development of adenocarcinoma. Here, we used this model to characterize the effects of prolonged FGF9 induction on the proximal and distal lung epithelia, and examined the propagation potential of FGF9-induced lung tumors. We show that prolonged FGF9 overexpression in the lung resulted in the development of adenocarcinomas arising from both alveolar type II and airway secretory cells in the lung parenchyma and airways, respectively. We found that tumor cells harbored tumor-propagating cells that were able to form secondary tumors in recipient mice regardless of FGF9 expression. However, the highest degree of tumor propagation was observed when unfractionated tumor cells were coadministered with autologous, tumor-associated mesenchymal cells. Although the initiation of lung adenocarcinomas was dependent on activation of the FGF9/FGF receptor (FGFR) 3 signaling axis, maintenance and propagation of the tumor was independent of this signaling. Activation of an alternative FGF/FGFR and the interaction with tumor stromal cells is likely to be responsible for the development of this independence. This study demonstrates the complex role of FGF/FGFR signaling in the initiation, growth, and propagation of lung cancer. Our findings suggest that analyzing the expressions of FGFs/FGFRs in human lung cancer will be a useful tool for guiding customized therapy. PMID:25413587

  10. Vertex stability and topological transitions in vertex models of foams and epithelia

    NASA Astrophysics Data System (ADS)

    Spencer, Meryl; Jabeen, Zahera; Lubensky, David

    Vertex models are widely used to computationally simulate dry foams and epithelial tissues. This class of models describes the shape and motion of cells as a function of the forces on vertices where 3 or more cells meet. Despite the widespread use of these models, relatively little is known about their basic theoretical properties. One outstanding issue is the stability of fourfold vertices. In real foams, fourfold vertices are always unstable, but it has been unclear whether vertex models necessarily reflect this behavior. In biological tissues, fourfold vertices arise as an intermediate in T1 transitions, which are one of the fundamental processes by which tissues change topology, and stable fourfold vertices have recently been observed in several different epithelia. We show that, when all edges have the same tension, stationary fourfold vertices in vertex models must always break up. However, when tensions depend on edge orientation, as they might in a planar-polarized tissue, fourfold vertices can become stable. These findings pave the way for studies of more biologically realistic models that couple topological transitions to the dynamics of regulatory proteins. NSF Grant No. DMR-1056456 and NSF-GRFP Grant No. DGE-1256260.

  11. Ultramicroscopic examination of the ovine tonsillar epithelia.

    PubMed

    Casteleyn, Christophe; Cornelissen, Maria; Simoens, Paul; Van den Broeck, Wim

    2010-05-01

    As solid morphological knowledge of ovine tonsillar epithelia might contribute to a better understanding of the pathogenesis of several diseases including prion diseases, the epithelia of all tonsils of 7 one-year-old Texel sheep were examined using scanning and transmission electron microscopy. Major parts of the pharyngeal and tubal tonsils were covered by pseudostratified columnar ciliated epithelia that were interrupted by patches of epithelium containing cells with densely packed microfolds or microvilli, and cells with both microvilli and cilia. Smaller parts were covered by either flattened polygonal cells with densely packed microvilli or microfolds, squamous epithelial cells, or patches of reticular epithelium. The palatine and paraepiglottic tonsils were mainly lined by squamous epithelial cells with apical microplicae or short knobs. Additionally, regions of reticular epithelium containing epithelial cells with apical microvilli were seen. The lingual tonsil was uniformly covered by a keratinized squamous epithelium and devoid of microvillous cells and patches of reticular epithelium. The rostral half of the tonsil of the soft palate was lined by a pseudostratified columnar ciliated epithelium with characteristics of the pharyngeal and tubal tonsils. The epithelium of the caudal part resembled the epithelia of the palatine and paraepiglottic tonsils. Putative M cells, mainly characterized by apical microvilli or microfolds and a close association with lymphoid cells, seem manifestly present on the nasopharyngeal tonsils. The reticular epithelium of the palatine and paraepiglottic tonsils also harbor cells with small apical microvilli. The exact nature of these presumptive M cells should, however, be elucidated in functional studies.

  12. Constitutive and inducible expression of SKALP/elafin provides anti-elastase defense in human epithelia.

    PubMed Central

    Pfundt, R; van Ruissen, F; van Vlijmen-Willems, I M; Alkemade, H A; Zeeuwen, P L; Jap, P H; Dijkman, H; Fransen, J; Croes, H; van Erp, P E; Schalkwijk, J

    1996-01-01

    Skin-derived antileukoproteinase (SKALP), also known as elafin, is a serine proteinase inhibitor first discovered in keratinocytes from hyperproliferative human epidermis. In addition to the proteinase inhibiting domain which is directed against polymorphonuclear leukocyte (PMN) derived enzymes such as elastase and proteinase 3, SKALP contains multiple transglutaminase (TGase) substrate domains which enable crosslinking to extracellular and cell envelope proteins. Here we show that SKALP is constitutively expressed in several epithelia that are continuously subjected to inflammatory stimuli, such as the oral cavity and the vagina where it co-localizes with type 1 TGase. All epithelia from sterile body cavities are negative for SKALP. In general, stratified squamous epithelia are positive, whereas pseudostratified epithelia, simple/glandular epithelia and normal epidermis are negative. SKALP was found in fetal tissues of the oral cavity from 17 wk gestation onwards where it continued to be expressed up to adult life. Remarkably, in fetal epidermis SKALP was found from week 28 onwards, but was downregulated to undetectable levels in neonatal skin within three months, suggesting a role during pregnancy in feto-maternal interactions or in the early maturation phase of the epidermis. Immunoelectron microscopy revealed the presence of SKALP in secretory vesicles including the lamellar granules. In culture models for epidermal keratinocytes we found that expression of the endogenous SKALP gene provided protection against cell detachment caused by purified elastase or activated PMNs. Addition of exogenous recombinant SKALP fully protected the keratinocytes against PMN-dependent detachment whereas superoxide dismutase and catalase were only marginally effective. These findings strongly suggest that the constitutive expression of SKALP in squamous epithelia, and the inducible expression in epidermis participate in the control of epithelial integrity, by inhibiting PMN

  13. Structure and functions of keratin proteins in simple, stratified, keratinized and cornified epithelia

    PubMed Central

    Bragulla, Hermann H; Homberger, Dominique G

    2009-01-01

    Historically, the term ‘keratin’ stood for all of the proteins extracted from skin modifications, such as horns, claws and hooves. Subsequently, it was realized that this keratin is actually a mixture of keratins, keratin filament-associated proteins and other proteins, such as enzymes. Keratins were then defined as certain filament-forming proteins with specific physicochemical properties and extracted from the cornified layer of the epidermis, whereas those filament-forming proteins that were extracted from the living layers of the epidermis were grouped as ‘prekeratins’ or ‘cytokeratins’. Currently, the term ‘keratin’ covers all intermediate filament-forming proteins with specific physicochemical properties and produced in any vertebrate epithelia. Similarly, the nomenclature of epithelia as cornified, keratinized or non-keratinized is based historically on the notion that only the epidermis of skin modifications such as horns, claws and hooves is cornified, that the non-modified epidermis is a keratinized stratified epithelium, and that all other stratified and non-stratified epithelia are non-keratinized epithelia. At this point in time, the concepts of keratins and of keratinized or cornified epithelia need clarification and revision concerning the structure and function of keratin and keratin filaments in various epithelia of different species, as well as of keratin genes and their modifications, in view of recent research, such as the sequencing of keratin proteins and their genes, cell culture, transfection of epithelial cells, immunohistochemistry and immunoblotting. Recently, new functions of keratins and keratin filaments in cell signaling and intracellular vesicle transport have been discovered. It is currently understood that all stratified epithelia are keratinized and that some of these keratinized stratified epithelia cornify by forming a Stratum corneum. The processes of keratinization and cornification in skin modifications are

  14. Sensitization to serum albumins in children allergic to cow's milk and epithelia.

    PubMed

    Vicente-Serrano, J; Caballero, M L; Rodríguez-Pérez, R; Carretero, P; Pérez, R; Blanco, J G; Juste, S; Moneo, I

    2007-09-01

    Patients with persistent milk allergy and specific immunoglobulin E (IgE) to bovine serum albumin (BSA) have a greater risk of rhinoconjunctivitis and asthma because of animal dander. To prove the cross-reactivity between serum albumin (SA) of different mammals in milk, meat, and epithelia and determine if heat treatment of meats decrease the allergenicity of albumins. The study was performed using SDS-PAGE and IgE-immunoblotting using sera from eight patients sensitized to milk, BSA, and animal danders. Sera from non-allergic and only animal dander allergic subjects served as a control. With one exception, all patients' sera recognized SA in different meats (beef, lamb, deer, and pork), epithelia (dog, cat, and cow), and cow's milk. Some patients even were only sensitized to SA in meat and epithelia. Danders' allergic only recognized other proteins in epithelia but not SA. No patients reacted to SA from heated meat extracts. Serum albumin is an important allergen involved in milk, meat, and epithelia allergy. The first contact with SA was through cow's milk and patients developed sensitization to epithelia SA even without direct contact with animals. Patients with both BSA and cow's milk allergy must avoid raw meats and furry pets.

  15. Precancerous esophageal epithelia are associated with significantly increased scattering coefficients

    PubMed Central

    Su, Jing-Wei; Lin, Yang-Hsien; Chiang, Chun-Ping; Lee, Jang-Ming; Hsieh, Chao-Mao; Hsieh, Min-Shu; Yang, Pei-Wen; Wang, Chen-Ping; Tseng, Ping-Huei; Lee, Yi-Chia; Sung, Kung-Bin

    2015-01-01

    The progression of epithelial precancers into cancer is accompanied by changes of tissue and cellular structures in the epithelium. Correlations between the structural changes and scattering coefficients of esophageal epithelia were investigated using quantitative phase images and the scattering-phase theorem. An ex vivo study of 14 patients demonstrated that the average scattering coefficient of precancerous epithelia was 37.8% higher than that of normal epithelia from the same patient. The scattering coefficients were highly correlated with morphological features including the cell density and the nuclear-to-cytoplasmic ratio. A high interpatient variability in scattering coefficients was observed and suggests identifying precancerous lesions based on the relative change in scattering coefficients. PMID:26504630

  16. Mucin gene expression is not regulated by estrogen and/or progesterone in the ocular surface epithelia of mice.

    PubMed

    Lange, Christine; Fernandez, Jolene; Shim, David; Spurr-Michaud, Sandra; Tisdale, Ann; Gipson, Ilene K

    2003-07-01

    Dry eye syndrome is prevalent in post-menopausal women, and post-menopausal women secrete less mucus in their reproductive tracts. Using a mouse model, the purpose of this study was to determine if estrogen and/or progesterone regulates Muc4 and Muc5AC gene expression in the ocular surface epithelia, as the hormones do in reproductive tract epithelia. Adult C57BL/6 mice were ovariectomized, and 19 days later, pellets containing estrogen, progesterone, or a combination were inserted subcutaneously. Ocular surface and reproductive tract tissues were harvested following seven days of hormone treatment. A control group consisted of ovariectomized mice that received no hormone treatment. Real-time reverse transcription-polymerase chain reaction was used to determine the tissue expression levels of mucin mRNA of each treatment group relative to the control. Muc4 mRNA expression levels were determined for the reproductive tract, and both Muc4 and Muc5AC expression levels were determined for the ocular surface epithelia. Muc4 and Muc5AC gene expression in ocular surface and Muc4 in reproductive tract epithelia was demonstrated by In Situ hybridization, and Muc4 and Muc5AC protein was demonstrated in the epithelia of animals in the experimental groups. The mRNA expression levels of Muc4 and Muc5AC and the immunofluorescence localization pattern in the ocular surface epithelia were not significantly different in any hormone treatment group when compared to the control ovariectomized group. By comparison, mice that were administered estrogen had a significant increase of Muc4 mRNA in the reproductive tract epithelia, progesterone given in combination with estrogen antagonized the upregulatory effects of estrogen in the reproductive tract, and the amount of Muc4 mRNA in the reproductive tract of progesterone-treated animals was not different from ovariectomized controls. Immunofluorescence localization of Muc4 in the reproductive tract epithelia of the experimental groups

  17. Forensic discrimination of vaginal epithelia by DNA methylation analysis through pyrosequencing.

    PubMed

    Antunes, Joana; Silva, Deborah S B S; Balamurugan, Kuppareddi; Duncan, George; Alho, Clarice S; McCord, Bruce

    2016-10-01

    The accurate identification of body fluids from crime scenes can aid in the discrimination between criminal and innocent intent. This research aimed to determine if the levels of DNA methylation in the locus PFN3A could be used to discriminate vaginal epithelia from other body fluids. In this work we bisulfite-modified and amplified DNA samples from blood, saliva, semen, and vaginal epithelia using primers for PFN3A. Through pyrosequencing we were able to show that vaginal epithelia present distinct methylation levels when compared to other body fluids. Mixtures of different body fluids present methylation values that correlate with single-source body fluid samples and the primers for PFN3A are specific for primates. This report successfully demonstrated that the analysis of methylation in the PFN3A locus can be used for vaginal epithelia discrimination in forensic samples. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Lipotoxin F of Pseudomonas aeruginosa is an AlgU-dependent and alginate-independent outer membrane protein involved in resistance to oxidative stress and adhesion to A549 human lung epithelia.

    PubMed

    Damron, F Heath; Napper, Jennifer; Teter, M Allison; Yu, Hongwei D

    2009-04-01

    Chronic lung infection with P. aeruginosa and excessive neutrophil-associated inflammation are major causes of morbidity and mortality in patients with cystic fibrosis (CF). Overproduction of an exopolysaccharide known as alginate leads to the formation of mucoid biofilms that are resistant to antibiotics and host defences. Alginate overproduction or mucoidy is controlled by a stress-related ECF sigma factor AlgU/T. Mutation in the anti-sigma factor MucA is a known mechanism for conversion to mucoidy. Recently, we showed that inactivation of a kinase (KinB) in nonmucoid strain PAO1 results in overproduction of alginate. Here, we report the initial characterization of lipotoxin F (LptF, PA3692), an OmpA-like outer membrane protein that exhibited increased expression in the mucoid PAO1kinB mutant. The lipotoxin family of proteins has been previously shown to induce inflammation in lung epithelia, which may play a role in CF disease progression. Expression of LptF was observed to be AlgU-dependent and upregulated in CF isolates. Deletion of lptF from the kinB mutant had no effect on alginate production. Deletion of lptF from PAO1 caused a differential susceptibility to oxidants that can be generated by phagocytes. The lptF and algU mutants were more sensitive to hypochlorite than PAO1. However, the lptF mutant displayed increased resistance to hydrogen peroxide. LptF also contributed to adhesion to A549 human lung epithelial cells. Our data suggest that LptF is an outer membrane protein that may be important for P. aeruginosa survival in harsh environments, including lung colonization in CF.

  19. Lipotoxin F of Pseudomonas aeruginosa is an AlgU-dependent and alginate-independent outer membrane protein involved in resistance to oxidative stress and adhesion to A549 human lung epithelia

    PubMed Central

    Damron, F. Heath; Napper, Jennifer; Teter, M. Allison; Yu, Hongwei D.

    2009-01-01

    Chronic lung infection with P. aeruginosa and excessive neutrophil-associated inflammation are major causes of morbidity and mortality in patients with cystic fibrosis (CF). Overproduction of an exopolysaccharide known as alginate leads to the formation of mucoid biofilms that are resistant to antibiotics and host defences. Alginate overproduction or mucoidy is controlled by a stress-related ECF sigma factor AlgU/T. Mutation in the anti-sigma factor MucA is a known mechanism for conversion to mucoidy. Recently, we showed that inactivation of a kinase (KinB) in nonmucoid strain PAO1 results in overproduction of alginate. Here, we report the initial characterization of lipotoxin F (LptF, PA3692), an OmpA-like outer membrane protein that exhibited increased expression in the mucoid PAO1kinB mutant. The lipotoxin family of proteins has been previously shown to induce inflammation in lung epithelia, which may play a role in CF disease progression. Expression of LptF was observed to be AlgU-dependent and upregulated in CF isolates. Deletion of lptF from the kinB mutant had no effect on alginate production. Deletion of lptF from PAO1 caused a differential susceptibility to oxidants that can be generated by phagocytes. The lptF and algU mutants were more sensitive to hypochlorite than PAO1. However, the lptF mutant displayed increased resistance to hydrogen peroxide. LptF also contributed to adhesion to A549 human lung epithelial cells. Our data suggest that LptF is an outer membrane protein that may be important for P. aeruginosa survival in harsh environments, including lung colonization in CF. PMID:19332805

  20. Structural centrosome aberrations sensitize polarized epithelia to basal cell extrusion.

    PubMed

    Ganier, Olivier; Schnerch, Dominik; Nigg, Erich A

    2018-06-01

    Centrosome aberrations disrupt tissue architecture and may confer invasive properties to cancer cells. Here we show that structural centrosome aberrations, induced by overexpression of either Ninein-like protein (NLP) or CEP131/AZI1, sensitize polarized mammalian epithelia to basal cell extrusion. While unperturbed epithelia typically dispose of damaged cells through apical dissemination into luminal cavities, certain oncogenic mutations cause a switch in directionality towards basal cell extrusion, raising the potential for metastatic cell dissemination. Here we report that NLP-induced centrosome aberrations trigger the preferential extrusion of damaged cells towards the basal surface of epithelial monolayers. This switch in directionality from apical to basal dissemination coincides with a profound reorganization of the microtubule cytoskeleton, which in turn prevents the contractile ring repositioning that is required to support extrusion towards the apical surface. While the basal extrusion of cells harbouring NLP-induced centrosome aberrations requires exogenously induced cell damage, structural centrosome aberrations induced by excess CEP131 trigger the spontaneous dissemination of dying cells towards the basal surface from MDCK cysts. Thus, similar to oncogenic mutations, structural centrosome aberrations can favour basal extrusion of damaged cells from polarized epithelia. Assuming that additional mutations may promote cell survival, this process could sensitize epithelia to disseminate potentially metastatic cells. © 2018 The Authors.

  1. [Immunocytochemical study of cholinergic innervation in the neurosensory epithelia of human vestibule].

    PubMed

    Kong, W; Hussl, B; Schrott-Fischer, A

    1998-02-01

    To investigate the cholinergic innervation of the neurosensory epithelia of human vestibule. A modified preembedding immunostaining technique for immunoelectronmicroscopy was applied to this study. A polyclonal antibody to choline acetyltransferase (ChAT) was used as the marker of cholinergic fibers. ChAT-immunoreactive products were restricted to the nerve fibers and terminals which were rich in synaptic vesicles. The ChAT-immunoreactive fibers synaps with afferent chalice as well as with type II sensory hair cells. This study demonstrates that cholinergic fibers innervate the neurosensory epithelia of human vestible. The cholinergic fibers of human vestibular sensory epithelia belong to the vestibular efferent system.

  2. Current Status of Gene Therapy for Inherited Lung Diseases

    PubMed Central

    Driskell, Ryan R.; Engelhardt, John F.

    2007-01-01

    Gene therapy as a treatment modality for pulmonary disorders has attracted significant interest over the past decade. Since the initiation of the first clinical trials for cystic fibrosis lung disease using recombinant adenovirus in the early 1990s, the field has encountered numerous obstacles including vector inflammation, inefficient delivery, and vector production. Despite these obstacles, enthusiasm for lung gene therapy remains high. In part, this enthusiasm is fueled through the diligence of numerous researchers whose studies continue to reveal great potential of new gene transfer vectors that demonstrate increased tropism for airway epithelia. Several newly identified serotypes of adeno-associated virus have demonstrated substantial promise in animal models and will likely surface soon in clinical trials. Furthermore, an increased understanding of vector biology has also led to the development of new technologies to enhance the efficiency and selectivity of gene delivery to the lung. Although the promise of gene therapy to the lung has yet to be realized, the recent concentrated efforts in the field that focus on the basic virology of vector development will undoubtedly reap great rewards over the next decade in treating lung diseases. PMID:12524461

  3. Hypercapnia modulates cAMP signalling and cystic fibrosis transmembrane conductance regulator‐dependent anion and fluid secretion in airway epithelia

    PubMed Central

    Turner, Mark J.; Saint‐Criq, Vinciane; Patel, Waseema; Ibrahim, Salam H.; Verdon, Bernard; Ward, Christopher; Garnett, James P.; Tarran, Robert; Cann, Martin J.

    2015-01-01

    secretion over 24 h, yet had no effect on the HCO3 − content of the secreted fluid. Our data reveal that hypercapnia reduces CFTR‐dependent, electrogenic Cl− and fluid secretion, but not CFTR‐dependent HCO3 − secretion, which highlights a differential sensitivity of Cl− and HCO3 − transporters to raised CO2 in Calu‐3 cells. Hypercapnia also reduced forskolin‐stimulated CFTR‐dependent anion secretion in primary human airway epithelia. Based on current models of airways biology, a reduction in fluid secretion, associated with hypercapnia, would be predicted to have important consequences for airways hydration and the innate defence mechanisms of the lungs. PMID:26574187

  4. Structure and Function of the Mucus Clearance System of the Lung

    PubMed Central

    Button, Brenda M.; Button, Brian

    2013-01-01

    In cystic fibrosis (CF), a defect in ion transport results in thick and dehydrated airway mucus, which is difficult to clear, making such patients prone to chronic inflammation and bacterial infections. Physiotherapy using a variety of airway clearance techniques (ACTs) represents a key treatment regime by helping clear the airways of thickened, adhered, mucus and, thus, reducing the impact of lung infections and improving lung function. This article aims to bridge the gap between our understanding of the physiological effects of mechanical stresses elicited by ACTs on airway epithelia and the reported effectiveness of ACTs in CF patients. In the first part of this review, the effects of mechanical stress on airway epithelia are discussed in relation to changes in ion transport and stimulation in airway surface layer hydration. The second half is devoted to detailing the most commonly used ACTs to stimulate the removal of mucus from the airways of patients with CF. PMID:23751214

  5. Efficient delivery of RNA interference oligonucleotides to polarized airway epithelia in vitro

    PubMed Central

    Ramachandran, Shyam; Krishnamurthy, Sateesh; Jacobi, Ashley M.; Wohlford-Lenane, Christine; Behlke, Mark A.; Davidson, Beverly L.

    2013-01-01

    Polarized and pseudostratified primary airway epithelia present barriers that significantly reduce their transfection efficiency and the efficacy of RNA interference oligonucleotides. This creates an impediment in studies of the airway epithelium, diminishing the utility of loss-of-function as a research tool. Here we outline methods to introduce RNAi oligonucleotides into primary human and porcine airway epithelia grown at an air-liquid interface and difficult-to-transfect transformed epithelial cell lines grown on plastic. At the time of plating, we reverse transfect small-interfering RNA (siRNA), Dicer-substrate siRNA, or microRNA oligonucleotides into cells by use of lipid or peptide transfection reagents. Using this approach we achieve significant knockdown in vitro of hypoxanthine-guanine phosphoribosyltransferase, IL-8, and CFTR expression at the mRNA and protein levels in 1–3 days. We also attain significant reduction of secreted IL-8 in polarized primary pig airway epithelia 3 days posttransfection and inhibition of CFTR-mediated Cl− conductance in polarized air-liquid interface cultures of human airway epithelia 2 wk posttransfection. These results highlight an efficient means to deliver RNA interference reagents to airway epithelial cells and achieve significant knockdown of target gene expression and function. The ability to reliably conduct loss-of-function assays in polarized primary airway epithelia offers benefits to research in studies of epithelial cell homeostasis, candidate gene function, gene-based therapeutics, microRNA biology, and targeting the replication of respiratory viruses. PMID:23624792

  6. Mucin gene expression in human male urogenital tract epithelia

    PubMed Central

    Russo, Cindy Leigh; Spurr-Michaud, Sandra; Tisdale, Ann; Pudney, Jeffrey; Anderson, Deborah; Gipson, Ilene K.

    2010-01-01

    BACKGROUND Mucins are large, hydrophilic glycoproteins that protect wet-surfaced epithelia from pathogen invasion as well as provide lubrication. At least 17 mucin genes have been cloned to date. This study sought to determine the mucin gene expression profile of the human male urogenital tract epithelia, to determine if mucins are present in seminal fluid, and to assess the effect of androgens on mucin expression. METHODS AND RESULTS Testis, epididymis, vas deferens, seminal vesicle, prostate, bladder, urethra and foreskin were assessed for mucin expression by RT-PCR and immunohistochemistry. Epithelia of the vas deferens, prostate and urethra expressed the greatest number of mucins, each expressing 5–8 mucins. Messenger RNA of MUC1 and MUC20, both membrane-associated mucins, were detected in most tissues analyzed. Conversely, MUC6 was predominantly detected in seminal vesicle. MUC1, MUC5B and MUC6 were detected in seminal fluid samples by immunoblot analysis. Androgens had no effect on mucin expression by cultured human prostatic epithelial cells. CONCLUSIONS Each region of urogenital tract epithelium expressed a unique mucin gene repertoire. Secretory mucins are present in seminal fluid, and androgens do not appear to regulate mucin gene expression. PMID:16997931

  7. Identification of Novel Targets for Lung Cancer Therapy Using an Induced Pluripotent Stem Cell Model.

    PubMed

    Shukla, Vivek; Rao, Mahadev; Zhang, Hongen; Beers, Jeanette; Wangsa, Darawalee; Wangsa, Danny; Buishand, Floryne O; Wang, Yonghong; Yu, Zhiya; Stevenson, Holly; Reardon, Emily; McLoughlin, Kaitlin C; Kaufman, Andrew; Payabyab, Eden; Hong, Julie A; Zhang, Mary; Davis, Sean R; Edelman, Daniel C; Chen, Guokai; Miettinen, Markku; Restifo, Nicholas; Ried, Thomas; Meltzer, Paul S; Schrump, David S

    2018-04-01

    Despite extensive studies, the genetic and epigenetic mechanisms that mediate initiation and progression of lung cancers have not been fully elucidated. Previously, we have demonstrated that via complementary mechanisms, including DNA methylation, polycomb repressive complexes, and noncoding RNAs, cigarette smoke induces stem-like phenotypes that coincide with progression to malignancy in normal respiratory epithelia as well as enhanced growth and metastatic potential of lung cancer cells. To further investigate epigenetic mechanisms contributing to stemness/pluripotency in lung cancers and potentially identify novel therapeutic targets in these malignancies, induced pluripotent stem cells were generated from normal human small airway epithelial cells. Lung induced pluripotent stem cells were generated by lentiviral transduction of small airway epithelial cells of OSKM (Yamanaka) factors (octamer-binding transcription factor 4 [Oct4], sex-determining region Y box 2 [SOX2], Kruppel-like factor 4 [KLF4], and MYC proto-oncogene, bHLH transcription factor [MYC]). Western blot, real-time polymerase chain reaction, and chromatin immunoprecipitation sequencing analysis were performed. The lung induced pluripotent stem cells exhibited hallmarks of pluripotency, including morphology, surface antigen and stem cell gene expression, in vitro proliferation, and teratoma formation. In addition, lung induced pluripotent stem cells exhibited no chromosomal aberrations, complete silencing of reprogramming transgenes, genomic hypermethylation, upregulation of genes encoding components of polycomb repressive complex 2, hypermethylation of stem cell polycomb targets, and modulation of more than 15,000 other genes relative to parental small airway epithelial cells. Additional sex combs like-3 (ASXL3), encoding a polycomb repressive complex 2-associated protein not previously described in reprogrammed cells, was markedly upregulated in lung induced pluripotent stem cell as well as human

  8. The thermosensitive TRPV3 channel contributes to rapid wound healing in oral epithelia.

    PubMed

    Aijima, Reona; Wang, Bing; Takao, Tomoka; Mihara, Hiroshi; Kashio, Makiko; Ohsaki, Yasuyoshi; Zhang, Jing-Qi; Mizuno, Atsuko; Suzuki, Makoto; Yamashita, Yoshio; Masuko, Sadahiko; Goto, Masaaki; Tominaga, Makoto; Kido, Mizuho A

    2015-01-01

    The oral cavity provides an entrance to the alimentary tract to serve as a protective barrier against harmful environmental stimuli. The oral mucosa is susceptible to injury because of its location; nonetheless, it has faster wound healing than the skin and less scar formation. However, the molecular pathways regulating this wound healing are unclear. Here, we show that transient receptor potential vanilloid 3 (TRPV3), a thermosensitive Ca(2+)-permeable channel, is more highly expressed in murine oral epithelia than in the skin by quantitative RT-PCR. We found that temperatures above 33°C activated TRPV3 and promoted oral epithelial cell proliferation. The proliferation rate in the oral epithelia of TRPV3 knockout (TRPV3KO) mice was less than that of wild-type (WT) mice. We investigated the contribution of TRPV3 to wound healing using a molar tooth extraction model and found that oral wound closure was delayed in TRPV3KO mice compared with that in WT mice. TRPV3 mRNA was up-regulated in wounded tissues, suggesting that TRPV3 may contribute to oral wound repair. We identified TRPV3 as an essential receptor in heat-induced oral epithelia proliferation and wound healing. Our findings suggest that TRPV3 activation could be a potential therapeutic target for wound healing in skin and oral mucosa. © FASEB.

  9. Lung tumor motion prediction during lung brachytherapy using finite element model

    NASA Astrophysics Data System (ADS)

    Shirzadi, Zahra; Sadeghi Naini, Ali; Samani, Abbas

    2012-02-01

    A biomechanical model is proposed to predict deflated lung tumor motion caused by diaphragm respiratory motion. This model can be very useful for targeting the tumor in tumor ablative procedures such as lung brachytherapy. To minimize motion within the target lung, these procedures are performed while the lung is deflated. However, significant amount of tissue deformation still occurs during respiration due to the diaphragm contact forces. In the absence of effective realtime image guidance, biomechanical models can be used to estimate tumor motion as a function of diaphragm's position. To develop this model, Finite Element Method (FEM) was employed. To demonstrate the concept, we conducted an animal study of an ex-vivo porcine deflated lung with a tumor phantom. The lung was deformed by compressing a diaphragm mimicking cylinder against it. Before compression, 3D-CT image of this lung was acquired, which was segmented and turned into FE mesh. The lung tissue was modeled as hyperelastic material with a contact loading to calculate the lung deformation and tumor motion during respiration. To validate the results from FE model, the motion of a small area on the surface close to the tumor was tracked while the lung was being loaded by the cylinder. Good agreement was demonstrated between the experiment results and simulation results. Furthermore, the impact of tissue hyperelastic parameters uncertainties in the FE model was investigated. For this purpose, we performed in-silico simulations with different hyperelastic parameters. This study demonstrated that the FEM was accurate and robust for tumor motion prediction.

  10. Vasopressin Receptor Signaling and Cycling of Water Channels in Renal Epithelia

    DTIC Science & Technology

    1992-08-22

    as well as renal model epithelia, including amphibian urinary bladder tissue (Bentley, 1958; DiBona , 1981; Hays, 1983; Mia et al., 1987). The increase...propagation of numerous microvilli on the membrane surface (Davis et al., 1974; DiBona , 1981; Mia et al., 1983, 1988; Mills and Malik, 1978; Spinelli et...fusion events are dependent very likely on the presence of cytosolic microtubules and microfilaments (Taylor et al., 1973; Hardy and DiBona , 1982; Hays

  11. HIV Exposure to the Epithelia in Ectocervical and Colon Tissues Induces Inflammatory Cytokines Without Tight Junction Disruption

    PubMed Central

    Sankapal, Soni; Gupta, Phalguni; Ratner, Deena; Ding, Ming; Shen, Chengli; Sanyal, Anwesha; Stolz, Donna; Cu-Uvin, Susan; Ramratnam, Bharat

    2016-01-01

    Abstract Epithelial cells in human cervical and colonic mucosa do not express HIV receptor. However, HIV transmission occurs across the unbreached epithelia by an unknown mechanism. In this study, the effect of HIV exposure on tight junction (TJ) and cytokine production in ectocervical and colon mucosal epithelia in tissue biopsies was investigated in an organ culture model. After HIV exposure, the distribution patterns and quantities of epithelial TJ and adherens proteins were evaluated by immunofluorescence staining followed by confocal microscopy. Cytokine mRNA in the mucosal epithelia was also evaluated by real-time reverse transcription–polymerase chain reaction (RT-PCR). HIV transmission was evaluated by measuring p24 production in culture supernatant. Our results showed there were no significant changes in the distribution and quantities of epithelial TJ/adherens junction (AJ) proteins after exposure to HIV. However, higher levels of CXCL10 and CXCL11 mRNA expression were detected in HIV-exposed ectocervical epithelia. In case of colon mucosa, higher levels of CXCL10 and IL-6 mRNA expression were detected in HIV-exposed colon mucosa. Our study suggests that HIV induces cytokine production in epithelial cells, which may facilitate HIV transmission by recruiting HIV target cells in the submucosal region. Furthermore, HIV transmission may not occur through epithelial TJ/AJ disruption. PMID:27153934

  12. Toxicity of aged gasoline exhaust particles to normal and diseased airway epithelia

    PubMed Central

    Künzi, Lisa; Krapf, Manuel; Daher, Nancy; Dommen, Josef; Jeannet, Natalie; Schneider, Sarah; Platt, Stephen; Slowik, Jay G.; Baumlin, Nathalie; Salathe, Matthias; Prévôt, André S. H.; Kalberer, Markus; Strähl, Christof; Dümbgen, Lutz; Sioutas, Constantinos; Baltensperger, Urs; Geiser, Marianne

    2015-01-01

    Particulate matter (PM) pollution is a leading cause of premature death, particularly in those with pre-existing lung disease. A causative link between particle properties and adverse health effects remains unestablished mainly due to complex and variable physico-chemical PM parameters. Controlled laboratory experiments are required. Generating atmospherically realistic aerosols and performing cell-exposure studies at relevant particle-doses are challenging. Here we examine gasoline-exhaust particle toxicity from a Euro-5 passenger car in a uniquely realistic exposure scenario, combining a smog chamber simulating atmospheric ageing, an aerosol enrichment system varying particle number concentration independent of particle chemistry, and an aerosol deposition chamber physiologically delivering particles on air-liquid interface (ALI) cultures reproducing normal and susceptible health status. Gasoline-exhaust is an important PM source with largely unknown health effects. We investigated acute responses of fully-differentiated normal, distressed (antibiotics-treated) normal, and cystic fibrosis human bronchial epithelia (HBE), and a proliferating, single-cell type bronchial epithelial cell-line (BEAS-2B). We show that a single, short-term exposure to realistic doses of atmospherically-aged gasoline-exhaust particles impairs epithelial key-defence mechanisms, rendering it more vulnerable to subsequent hazards. We establish dose-response curves at realistic particle-concentration levels. Significant differences between cell models suggest the use of fully-differentiated HBE is most appropriate in future toxicity studies. PMID:26119831

  13. Toxicity of aged gasoline exhaust particles to normal and diseased airway epithelia

    NASA Astrophysics Data System (ADS)

    Künzi, Lisa; Krapf, Manuel; Daher, Nancy; Dommen, Josef; Jeannet, Natalie; Schneider, Sarah; Platt, Stephen; Slowik, Jay G.; Baumlin, Nathalie; Salathe, Matthias; Prévôt, André S. H.; Kalberer, Markus; Strähl, Christof; Dümbgen, Lutz; Sioutas, Constantinos; Baltensperger, Urs; Geiser, Marianne

    2015-06-01

    Particulate matter (PM) pollution is a leading cause of premature death, particularly in those with pre-existing lung disease. A causative link between particle properties and adverse health effects remains unestablished mainly due to complex and variable physico-chemical PM parameters. Controlled laboratory experiments are required. Generating atmospherically realistic aerosols and performing cell-exposure studies at relevant particle-doses are challenging. Here we examine gasoline-exhaust particle toxicity from a Euro-5 passenger car in a uniquely realistic exposure scenario, combining a smog chamber simulating atmospheric ageing, an aerosol enrichment system varying particle number concentration independent of particle chemistry, and an aerosol deposition chamber physiologically delivering particles on air-liquid interface (ALI) cultures reproducing normal and susceptible health status. Gasoline-exhaust is an important PM source with largely unknown health effects. We investigated acute responses of fully-differentiated normal, distressed (antibiotics-treated) normal, and cystic fibrosis human bronchial epithelia (HBE), and a proliferating, single-cell type bronchial epithelial cell-line (BEAS-2B). We show that a single, short-term exposure to realistic doses of atmospherically-aged gasoline-exhaust particles impairs epithelial key-defence mechanisms, rendering it more vulnerable to subsequent hazards. We establish dose-response curves at realistic particle-concentration levels. Significant differences between cell models suggest the use of fully-differentiated HBE is most appropriate in future toxicity studies.

  14. Toxicity of aged gasoline exhaust particles to normal and diseased airway epithelia.

    PubMed

    Künzi, Lisa; Krapf, Manuel; Daher, Nancy; Dommen, Josef; Jeannet, Natalie; Schneider, Sarah; Platt, Stephen; Slowik, Jay G; Baumlin, Nathalie; Salathe, Matthias; Prévôt, André S H; Kalberer, Markus; Strähl, Christof; Dümbgen, Lutz; Sioutas, Constantinos; Baltensperger, Urs; Geiser, Marianne

    2015-06-29

    Particulate matter (PM) pollution is a leading cause of premature death, particularly in those with pre-existing lung disease. A causative link between particle properties and adverse health effects remains unestablished mainly due to complex and variable physico-chemical PM parameters. Controlled laboratory experiments are required. Generating atmospherically realistic aerosols and performing cell-exposure studies at relevant particle-doses are challenging. Here we examine gasoline-exhaust particle toxicity from a Euro-5 passenger car in a uniquely realistic exposure scenario, combining a smog chamber simulating atmospheric ageing, an aerosol enrichment system varying particle number concentration independent of particle chemistry, and an aerosol deposition chamber physiologically delivering particles on air-liquid interface (ALI) cultures reproducing normal and susceptible health status. Gasoline-exhaust is an important PM source with largely unknown health effects. We investigated acute responses of fully-differentiated normal, distressed (antibiotics-treated) normal, and cystic fibrosis human bronchial epithelia (HBE), and a proliferating, single-cell type bronchial epithelial cell-line (BEAS-2B). We show that a single, short-term exposure to realistic doses of atmospherically-aged gasoline-exhaust particles impairs epithelial key-defence mechanisms, rendering it more vulnerable to subsequent hazards. We establish dose-response curves at realistic particle-concentration levels. Significant differences between cell models suggest the use of fully-differentiated HBE is most appropriate in future toxicity studies.

  15. Manipulation of Cell Physiology Enables Gene Silencing in Well-differentiated Airway Epithelia

    PubMed Central

    Krishnamurthy, Sateesh; Behlke, Mark A; Ramachandran, Shyam; Salem, Aliasger K; McCray Jr, Paul B; Davidson, Beverly L

    2012-01-01

    The application of RNA interference-based gene silencing to the airway surface epithelium holds great promise to manipulate host and pathogen gene expression for therapeutic purposes. However, well-differentiated airway epithelia display significant barriers to double-stranded small-interfering RNA (siRNA) delivery despite testing varied classes of nonviral reagents. In well-differentiated primary pig airway epithelia (PAE) or human airway epithelia (HAE) grown at the air–liquid interface (ALI), the delivery of a Dicer-substrate small-interfering RNA (DsiRNA) duplex against hypoxanthine–guanine phosphoribosyltransferase (HPRT) with several nonviral reagents showed minimal uptake and no knockdown of the target. In contrast, poorly differentiated cells (2–5-day post-seeding) exhibited significant oligonucleotide internalization and target knockdown. This finding suggested that during differentiation, the barrier properties of the epithelium are modified to an extent that impedes oligonucleotide uptake. We used two methods to overcome this inefficiency. First, we tested the impact of epidermal growth factor (EGF), a known enhancer of macropinocytosis. Treatment of the cells with EGF improved oligonucleotide uptake resulting in significant but modest levels of target knockdown. Secondly, we used the connectivity map (Cmap) database to correlate gene expression changes during small molecule treatments on various cells types with genes that change upon mucociliary differentiation. Several different drug classes were identified from this correlative assessment. Well-differentiated epithelia treated with DsiRNAs and LY294002, a PI3K inhibitor, significantly improved gene silencing and concomitantly reduced target protein levels. These novel findings reveal that well-differentiated airway epithelia, normally resistant to siRNA delivery, can be pretreated with small molecules to improve uptake of synthetic oligonucleotide and RNA interference (RNAi) responses. PMID

  16. An ErbB2-Muc4 complex in rat ocular surface epithelia.

    PubMed

    Swan, Jeremy S; Arango, Maria E; Carothers Carraway, Coralie A; Carraway, Kermit L

    2002-05-01

    To show the presence and localization of type 1 growth factor receptors (ErbB2, ErbB3 and ErbB4) in rat corneal and conjunctival epithelia and investigate the association of ErbB2 with its intramembrane ligand Muc4. Methacarn-fixed, paraffin-embedded sections of corneas and eyelids from female adult rats were immunocytochemically stained using antibodies against the ErbB receptors and Muc4. Sequential immunoprecipitation and immunoblot analyses were performed on epithelial lysates to investigate the presence of a complex of Muc4 and ErbB2 in corneal and conjunctival epithelia. Immunocytochemical staining demonstrated the presence of ErbB2, ErbB3 and ErbB4 growth factor receptors throughout the rat corneal and conjunctival epithelia. Co-immunoprecipitation of the epithelial lysates demonstrated that Muc4 and ErbB2 are present as a complex. The three type 1 growth factor receptors (ErbB2, ErbB3 and ErbB4) are present in the rat corneal and conjunctival epithelia, and ErbB2 is at least partly associated with Muc4. This demonstration of the presence and localization of these three type 1 growth factor receptors may help in understanding how these receptors contribute to ocular epithelial behavior and functions.

  17. Animal Models of Fibrotic Lung Disease

    PubMed Central

    Lawson, William E.; Oury, Tim D.; Sisson, Thomas H.; Raghavendran, Krishnan; Hogaboam, Cory M.

    2013-01-01

    Interstitial lung fibrosis can develop as a consequence of occupational or medical exposure, as a result of genetic defects, and after trauma or acute lung injury leading to fibroproliferative acute respiratory distress syndrome, or it can develop in an idiopathic manner. The pathogenesis of each form of lung fibrosis remains poorly understood. They each result in a progressive loss of lung function with increasing dyspnea, and most forms ultimately result in mortality. To better understand the pathogenesis of lung fibrotic disorders, multiple animal models have been developed. This review summarizes the common and emerging models of lung fibrosis to highlight their usefulness in understanding the cell–cell and soluble mediator interactions that drive fibrotic responses. Recent advances have allowed for the development of models to study targeted injuries of Type II alveolar epithelial cells, fibroblastic autonomous effects, and targeted genetic defects. Repetitive dosing in some models has more closely mimicked the pathology of human fibrotic lung disease. We also have a much better understanding of the fact that the aged lung has increased susceptibility to fibrosis. Each of the models reviewed in this report offers a powerful tool for studying some aspect of fibrotic lung disease. PMID:23526222

  18. Cytoskeleton in motion: the dynamics of keratin intermediate filaments in epithelia.

    PubMed

    Windoffer, Reinhard; Beil, Michael; Magin, Thomas M; Leube, Rudolf E

    2011-09-05

    Epithelia are exposed to multiple forms of stress. Keratin intermediate filaments are abundant in epithelia and form cytoskeletal networks that contribute to cell type-specific functions, such as adhesion, migration, and metabolism. A perpetual keratin filament turnover cycle supports these functions. This multistep process keeps the cytoskeleton in motion, facilitating rapid and protein biosynthesis-independent network remodeling while maintaining an intact network. The current challenge is to unravel the molecular mechanisms underlying the regulation of the keratin cycle in relation to actin and microtubule networks and in the context of epithelial tissue function.

  19. Cytoskeleton in motion: the dynamics of keratin intermediate filaments in epithelia

    PubMed Central

    Windoffer, Reinhard; Beil, Michael; Magin, Thomas M.

    2011-01-01

    Epithelia are exposed to multiple forms of stress. Keratin intermediate filaments are abundant in epithelia and form cytoskeletal networks that contribute to cell type–specific functions, such as adhesion, migration, and metabolism. A perpetual keratin filament turnover cycle supports these functions. This multistep process keeps the cytoskeleton in motion, facilitating rapid and protein biosynthesis–independent network remodeling while maintaining an intact network. The current challenge is to unravel the molecular mechanisms underlying the regulation of the keratin cycle in relation to actin and microtubule networks and in the context of epithelial tissue function. PMID:21893596

  20. Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology.

    PubMed

    Gordon, Sarah; Daneshian, Mardas; Bouwstra, Joke; Caloni, Francesca; Constant, Samuel; Davies, Donna E; Dandekar, Gudrun; Guzman, Carlos A; Fabian, Eric; Haltner, Eleonore; Hartung, Thomas; Hasiwa, Nina; Hayden, Patrick; Kandarova, Helena; Khare, Sangeeta; Krug, Harald F; Kneuer, Carsten; Leist, Marcel; Lian, Guoping; Marx, Uwe; Metzger, Marco; Ott, Katharina; Prieto, Pilar; Roberts, Michael S; Roggen, Erwin L; Tralau, Tewes; van den Braak, Claudia; Walles, Heike; Lehr, Claus-Michael

    2015-01-01

    Models of the outer epithelia of the human body - namely the skin, the intestine and the lung - have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.

  1. Micromechanical model of lung parenchyma hyperelasticity

    NASA Astrophysics Data System (ADS)

    Concha, Felipe; Sarabia-Vallejos, Mauricio; Hurtado, Daniel E.

    2018-03-01

    Mechanics plays a key role in respiratory physiology, as lung tissue cyclically deforms to bring air in and out the lung, a life-long process necessary for respiration. The study of regional mechanisms of deformation in lung parenchyma has received great attention to date due to its clinical relevance, as local overstretching and stress concentration in lung tissue is currently associated to pathological conditions such as lung injury during mechanical ventilation therapy. This mechanical approach to lung physiology has motivated the development of constitutive models to better understand the relation between stress and deformation in the lung. While material models proposed to date have been key in the development of whole-lung simulations, either they do not directly relate microstructural properties of alveolar tissue with coarse-scale behavior, or they require a high computational effort when based on real alveolar geometries. Furthermore, most models proposed to date have not been thoroughly validated for anisotropic deformation states, which are commonly found in normal lungs in-vivo. In this work, we develop a novel micromechanical model of lung parenchyma hyperelasticity using the framework of finite-deformation homogenization. To this end, we consider a tetrakaidecahedron unit cell with incompressible Neo-Hookean structural elements that account for the alveolar wall tissue responsible for the elastic response, and derive expressions for its effective coarse-scale behavior that directly depend on the alveolar wall elasticity, reference porosity, and two other geometrical coefficients. To validate the proposed model, we simulate the non-linear elastic response of twelve representative volume elements (RVEs) of lung parenchyma with micrometric dimensions, whose geometry is obtained from micrometric computed-tomography reconstructions of murine lungs. We show that the proposed micromechanical model accurately captures the RVEs response not only for isotropic

  2. Scribble is required for normal epithelial cell–cell contacts and lumen morphogenesis in the mammalian lung

    PubMed Central

    Yates, Laura L.; Schnatwinkel, Carsten; Hazelwood, Lee; Chessum, Lauren; Paudyal, Anju; Hilton, Helen; Romero, M. Rosario; Wilde, Jonathan; Bogani, Debora; Sanderson, Jeremy; Formstone, Caroline; Murdoch, Jennifer N.; Niswander, Lee A.; Greenfield, Andy; Dean, Charlotte H.

    2013-01-01

    During lung development, proper epithelial cell arrangements are critical for the formation of an arborized network of tubes. Each tube requires a lumen, the diameter of which must be tightly regulated to enable optimal lung function. Lung branching and lumen morphogenesis require close epithelial cell–cell contacts that are maintained as a result of adherens junctions, tight junctions and by intact apical–basal (A/B) polarity. However, the molecular mechanisms that maintain epithelial cohesion and lumen diameter in the mammalian lung are unknown. Here we show that Scribble, a protein implicated in planar cell polarity (PCP) signalling, is necessary for normal lung morphogenesis. Lungs of the Scrib mouse mutant Circletail (Crc) are abnormally shaped with fewer airways, and these airways often lack a visible, ‘open’ lumen. Mechanistically we show that Scrib genetically interacts with the core PCP gene Vangl2 in the developing lung and that the distribution of PCP pathway proteins and Rho mediated cytoskeletal modification is perturbed in ScribCrc/Crc lungs. However A/B polarity, which is disrupted in Drosophila Scrib mutants, is largely unaffected. Notably, we find that Scrib mediates functions not attributed to other PCP proteins in the lung. Specifically, Scrib localises to both adherens and tight junctions of lung epithelia and knockdown of Scrib in lung explants and organotypic cultures leads to reduced cohesion of lung epithelial cells. Live imaging of Scrib knockdown lungs shows that Scrib does not affect bud bifurcation, as previously shown for the PCP protein Celsr1, but is required to maintain epithelial cohesion. To understand the mechanism leading to reduced cell–cell association, we show that Scrib associates with β-catenin in embryonic lung and the sub-cellular distribution of adherens and tight junction proteins is perturbed in mutant lung epithelia. Our data reveal that Scrib is required for normal lung epithelial organisation and lumen

  3. Chloride and potassium channels in cystic fibrosis airway epithelia

    NASA Astrophysics Data System (ADS)

    Welsh, Michael J.; Liedtke, Carole M.

    1986-07-01

    Cystic fibrosis, the most common lethal genetic disease in Caucasians, is characterized by a decreased permeability in sweat gland duct and airway epithelia. In sweat duct epithelium, a decreased Cl- permeability accounts for the abnormally increased salt content of sweat1. In airway epithelia a decreased Cl- permeability, and possibly increased sodium absorption, may account for the abnormal respiratory tract fluid2,3. The Cl- impermeability has been localized to the apical membrane of cystic fibrosis airway epithelial cells4. The finding that hormonally regulated Cl- channels make the apical membrane Cl- permeable in normal airway epithelial cells5 suggested abnormal Cl- channel function in cystic fibrosis. Here we report that excised, cell-free patches of membrane from cystic fibrosis epithelial cells contain Cl- channels that have the same conductive properties as Cl- channels from normal cells. However, Cl- channels from cystic fibrosis cells did not open when they were attached to the cell. These findings suggest defective regulation of Cl- channels in cystic fibrosis epithelia; to begin to address this issue, we performed two studies. First, we found that isoprenaline, which stimulates Cl- secretion, increases cellular levels of cyclic AMP in a similar manner in cystic fibrosis and non-cystic fibrosis epithelial cells. Second, we show that adrenergic agonists open calcium-activated potassium channels, indirectly suggesting that calcium-dependent stimulus-response coupling is intact in cystic fibrosis. These data suggest defective regulation of Cl- channels at a site distal to cAMP accumulation.

  4. On a PCA-based lung motion model

    PubMed Central

    Li, Ruijiang; Lewis, John H; Jia, Xun; Zhao, Tianyu; Liu, Weifeng; Wuenschel, Sara; Lamb, James; Yang, Deshan; Low, Daniel A; Jiang, Steve B

    2014-01-01

    Respiration-induced organ motion is one of the major uncertainties in lung cancer radiotherapy and is crucial to be able to accurately model the lung motion. Most work so far has focused on the study of the motion of a single point (usually the tumor center of mass), and much less work has been done to model the motion of the entire lung. Inspired by the work of Zhang et al (2007 Med. Phys. 34 4772–81), we believe that the spatiotemporal relationship of the entire lung motion can be accurately modeled based on principle component analysis (PCA) and then a sparse subset of the entire lung, such as an implanted marker, can be used to drive the motion of the entire lung (including the tumor). The goal of this work is twofold. First, we aim to understand the underlying reason why PCA is effective for modeling lung motion and find the optimal number of PCA coefficients for accurate lung motion modeling. We attempt to address the above important problems both in a theoretical framework and in the context of real clinical data. Second, we propose a new method to derive the entire lung motion using a single internal marker based on the PCA model. The main results of this work are as follows. We derived an important property which reveals the implicit regularization imposed by the PCA model. We then studied the model using two mathematical respiratory phantoms and 11 clinical 4DCT scans for eight lung cancer patients. For the mathematical phantoms with cosine and an even power (2n) of cosine motion, we proved that 2 and 2n PCA coefficients and eigenvectors will completely represent the lung motion, respectively. Moreover, for the cosine phantom, we derived the equivalence conditions for the PCA motion model and the physiological 5D lung motion model (Low et al 2005 Int. J. Radiat. Oncol. Biol. Phys. 63 921–9). For the clinical 4DCT data, we demonstrated the modeling power and generalization performance of the PCA model. The average 3D modeling error using PCA was within

  5. On a PCA-based lung motion model

    NASA Astrophysics Data System (ADS)

    Li, Ruijiang; Lewis, John H.; Jia, Xun; Zhao, Tianyu; Liu, Weifeng; Wuenschel, Sara; Lamb, James; Yang, Deshan; Low, Daniel A.; Jiang, Steve B.

    2011-09-01

    Respiration-induced organ motion is one of the major uncertainties in lung cancer radiotherapy and is crucial to be able to accurately model the lung motion. Most work so far has focused on the study of the motion of a single point (usually the tumor center of mass), and much less work has been done to model the motion of the entire lung. Inspired by the work of Zhang et al (2007 Med. Phys. 34 4772-81), we believe that the spatiotemporal relationship of the entire lung motion can be accurately modeled based on principle component analysis (PCA) and then a sparse subset of the entire lung, such as an implanted marker, can be used to drive the motion of the entire lung (including the tumor). The goal of this work is twofold. First, we aim to understand the underlying reason why PCA is effective for modeling lung motion and find the optimal number of PCA coefficients for accurate lung motion modeling. We attempt to address the above important problems both in a theoretical framework and in the context of real clinical data. Second, we propose a new method to derive the entire lung motion using a single internal marker based on the PCA model. The main results of this work are as follows. We derived an important property which reveals the implicit regularization imposed by the PCA model. We then studied the model using two mathematical respiratory phantoms and 11 clinical 4DCT scans for eight lung cancer patients. For the mathematical phantoms with cosine and an even power (2n) of cosine motion, we proved that 2 and 2n PCA coefficients and eigenvectors will completely represent the lung motion, respectively. Moreover, for the cosine phantom, we derived the equivalence conditions for the PCA motion model and the physiological 5D lung motion model (Low et al 2005 Int. J. Radiat. Oncol. Biol. Phys. 63 921-9). For the clinical 4DCT data, we demonstrated the modeling power and generalization performance of the PCA model. The average 3D modeling error using PCA was within 1

  6. Pseudomonas aeruginosa biofilm-associated homoserine lactone C12 rapidly activates apoptosis in airway epithelia

    PubMed Central

    Schwarzer, Christian; Fu, Zhu; Patanwala, Maria; Hum, Lauren; Lopez-Guzman, Mirielle; Illek, Beate; Kong, Weidong; Lynch, Susan V.; Machen, Terry E.

    2014-01-01

    Pseudomonas aeruginosa (PA) forms biofilms in lungs of cystic fibrosis CF) patients, a process regulated by quorum sensing molecules including N-(3-oxododecanoyl)-L-homoserine lactone, C12. C12 (10–100 μM) rapidly triggered events commonly associated with the intrinsic apoptotic pathway in JME (CFΔF508CFTR, nasal surface) epithelial cells: depolarization of mitochondrial (mito) membrane potential (Δψmito) and release of cytochrome C (cytoC) from mitos into cytosol and activation of caspases 3/7, 8 and 9. C12 also had novel effects on the endoplasmic reticulum (release of both Ca2+ and ER-targeted GFP and oxidized contents into the cytosol). Effects began within 5 minutes and were complete in 1–2 hrs. C12 caused similar activation of caspases and release of cytoC from mitos in Calu-3 (wtCFTR, bronchial gland) cells, showing that C12-triggered responses occurred similarly in different airway epithelial types. C12 had nearly identical effects on three key aspects of the apoptosis response (caspase 3/7, depolarization of Δψmito and reduction of redox potential in the ER) in JME and CFTR-corrected JME cells (adenoviral expression), showing that CFTR was likely not an important regulator of C12-triggered apoptosis in airway epithelia. Exposure of airway cultures to biofilms from PAO1wt caused depolarization of Δψmito and increases in Cacyto like 10–50 μM C12. In contrast, biofilms from PAO1ΔlasI (C12 deficient) had no effect, suggesting that C12 from P. aeruginosa biofilms may contribute to accumulation of apoptotic cells that cannot be cleared from CF lungs. A model to explain the effects of C12 is proposed. PMID:22233488

  7. Bioelectric Characterization of Epithelia from Neonatal CFTR Knockout Ferrets

    PubMed Central

    Fisher, John T.; Tyler, Scott R.; Zhang, Yulong; Lee, Ben J.; Liu, Xiaoming; Sun, Xingshen; Sui, Hongshu; Liang, Bo; Luo, Meihui; Xie, Weiliang; Yi, Yaling; Zhou, Weihong; Song, Yi; Keiser, Nicholas; Wang, Kai; de Jonge, Hugo R.

    2013-01-01

    Cystic fibrosis (CF) is a life-shortening, recessive, multiorgan genetic disorder caused by the loss of CF transmembrane conductance regulator (CFTR) chloride channel function found in many types of epithelia. Animal models that recapitulate the human disease phenotype are critical to understanding pathophysiology in CF and developing therapies. CFTR knockout ferrets manifest many of the phenotypes observed in the human disease, including lung infections, pancreatic disease and diabetes, liver disease, malnutrition, and meconium ileus. In the present study, we have characterized abnormalities in the bioelectric properties of the trachea, stomach, intestine, and gallbladder of newborn CF ferrets. Short-circuit current (ISC) analysis of CF and wild-type (WT) tracheas revealed the following similarities and differences: (1) amiloride-sensitive sodium currents were similar between genotypes; (2) responses to 4,4′-diisothiocyano-2,2′-stilbene disulphonic acid were 3.3-fold greater in CF animals, suggesting elevated baseline chloride transport through non-CFTR channels in a subset of CF animals; and (3) a lack of 3-isobutyl-1-methylxanthine (IBMX)/forskolin–stimulated and N-(2-Naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene)glycine hydrazide (GlyH-101)–inhibited currents in CF animals due to the lack of CFTR. CFTR mRNA was present throughout all levels of the WT ferret and IBMX/forskolin–inducible ISC was only observed in WT animals. However, despite the lack of CFTR function in the knockout ferret, the luminal pH of the CF ferret gallbladder, stomach, and intestines was not significantly changed relative to WT. The WT stomach and gallbladder exhibited significantly enhanced IBMX/forskolin ISC responses and inhibition by GlyH-101 relative to CF samples. These findings demonstrate that multiple organs affected by disease in the CF ferret have bioelectric abnormalities consistent with the lack of cAMP-mediated chloride transport. PMID:23782101

  8. Bioelectric characterization of epithelia from neonatal CFTR knockout ferrets.

    PubMed

    Fisher, John T; Tyler, Scott R; Zhang, Yulong; Lee, Ben J; Liu, Xiaoming; Sun, Xingshen; Sui, Hongshu; Liang, Bo; Luo, Meihui; Xie, Weiliang; Yi, Yaling; Zhou, Weihong; Song, Yi; Keiser, Nicholas; Wang, Kai; de Jonge, Hugo R; Engelhardt, John F

    2013-11-01

    Cystic fibrosis (CF) is a life-shortening, recessive, multiorgan genetic disorder caused by the loss of CF transmembrane conductance regulator (CFTR) chloride channel function found in many types of epithelia. Animal models that recapitulate the human disease phenotype are critical to understanding pathophysiology in CF and developing therapies. CFTR knockout ferrets manifest many of the phenotypes observed in the human disease, including lung infections, pancreatic disease and diabetes, liver disease, malnutrition, and meconium ileus. In the present study, we have characterized abnormalities in the bioelectric properties of the trachea, stomach, intestine, and gallbladder of newborn CF ferrets. Short-circuit current (ISC) analysis of CF and wild-type (WT) tracheas revealed the following similarities and differences: (1) amiloride-sensitive sodium currents were similar between genotypes; (2) responses to 4,4'-diisothiocyano-2,2'-stilbene disulphonic acid were 3.3-fold greater in CF animals, suggesting elevated baseline chloride transport through non-CFTR channels in a subset of CF animals; and (3) a lack of 3-isobutyl-1-methylxanthine (IBMX)/forskolin-stimulated and N-(2-Naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene)glycine hydrazide (GlyH-101)-inhibited currents in CF animals due to the lack of CFTR. CFTR mRNA was present throughout all levels of the WT ferret and IBMX/forskolin-inducible ISC was only observed in WT animals. However, despite the lack of CFTR function in the knockout ferret, the luminal pH of the CF ferret gallbladder, stomach, and intestines was not significantly changed relative to WT. The WT stomach and gallbladder exhibited significantly enhanced IBMX/forskolin ISC responses and inhibition by GlyH-101 relative to CF samples. These findings demonstrate that multiple organs affected by disease in the CF ferret have bioelectric abnormalities consistent with the lack of cAMP-mediated chloride transport.

  9. [K+ channels and lung epithelial physiology].

    PubMed

    Bardou, Olivier; Trinh, Nguyen Thu Ngan; Brochiero, Emmanuelle

    2009-04-01

    Transcripts of more than 30 different K(+) channels have been detected in the respiratory epithelium lining airways and alveoli. These channels belong to the 3 main classes of K(+) channels, i.e. i) voltage-dependent or calcium-activated, 6 transmembrane segments (TM), ii) 2-pores 4-TM and iii) inward-rectified 2-TM channels. The physiological and functional significance of this high molecular diversity of lung epithelial K(+) channels is not well understood. Surprisingly, relatively few studies are focused on K(+) channel function in lung epithelial physiology. Nevertheless, several studies have shown that KvLQT1, KCa and K(ATP) K(+) channels play a crucial role in ion and fluid transport, contributing to the control of airway and alveolar surface liquid composition and volume. K(+) channels are involved in other key functions, such as O(2) sensing or the capacity of the respiratory epithelia to repair after injury. This mini-review aims to discuss potential functions of lung K(+) channels.

  10. Posterior midgut epithelial cells differ in their organization of the membrane skeleton from other drosophila epithelia.

    PubMed

    Baumann, O

    2001-11-01

    In epithelial cells, the various components of the membrane skeleton are segregated within specialized subregions of the plasma membrane, thus contributing to the development and stabilization of cell surface polarity. It has previously been shown that, in various Drosophila epithelia, the membrane skeleton components ankyrin and alphabeta-spectrin reside at the lateral surface, whereas alphabeta(H)-spectrin is restricted to the apical domain. By use of confocal immunofluorescence microscopy, the present study characterizes the membrane skeleton of epithelial cells in the posterior midgut, leading to a number of unexpected results. First, ankyrin and alphabeta-spectrin are not detected on the entire lateral surface but appear to be restricted to the apicolateral area, codistributing with fasciclin III at smooth septate junctions. The presumptive ankyrin-binding proteins neuroglian and Na(+),K(+)-ATPase, however, do not colocalize with ankyrin. Second, alphabeta(H)-spectrin is enriched at the apical domain but is also present in lower amounts on the entire lateral surface, colocalizing apicolaterally with ankyrin/alphabeta-spectrin. Finally, despite the absence of zonulae adherentes, F-actin, beta(H)-spectrin, and nonmuscle myosin-II are enriched in the midlateral region. Thus, the model established for the organization of the membrane skeleton in Drosophila epithelia does not hold for the posterior midgut, and there is quite some variability between the different epithelia with respect to the organization of the membrane skeleton. Copyright 2001 Academic Press.

  11. Biomechanical interpretation of a free-breathing lung motion model

    NASA Astrophysics Data System (ADS)

    Zhao, Tianyu; White, Benjamin; Moore, Kevin L.; Lamb, James; Yang, Deshan; Lu, Wei; Mutic, Sasa; Low, Daniel A.

    2011-12-01

    The purpose of this paper is to develop a biomechanical model for free-breathing motion and compare it to a published heuristic five-dimensional (5D) free-breathing lung motion model. An ab initio biomechanical model was developed to describe the motion of lung tissue during free breathing by analyzing the stress-strain relationship inside lung tissue. The first-order approximation of the biomechanical model was equivalent to a heuristic 5D free-breathing lung motion model proposed by Low et al in 2005 (Int. J. Radiat. Oncol. Biol. Phys. 63 921-9), in which the motion was broken down to a linear expansion component and a hysteresis component. To test the biomechanical model, parameters that characterize expansion, hysteresis and angles between the two motion components were reported independently and compared between two models. The biomechanical model agreed well with the heuristic model within 5.5% in the left lungs and 1.5% in the right lungs for patients without lung cancer. The biomechanical model predicted that a histogram of angles between the two motion components should have two peaks at 39.8° and 140.2° in the left lungs and 37.1° and 142.9° in the right lungs. The data from the 5D model verified the existence of those peaks at 41.2° and 148.2° in the left lungs and 40.1° and 140° in the right lungs for patients without lung cancer. Similar results were also observed for the patients with lung cancer, but with greater discrepancies. The maximum-likelihood estimation of hysteresis magnitude was reported to be 2.6 mm for the lung cancer patients. The first-order approximation of the biomechanical model fit the heuristic 5D model very well. The biomechanical model provided new insights into breathing motion with specific focus on motion trajectory hysteresis.

  12. Impaired Cell Volume Regulation in Intestinal Crypt Epithelia of Cystic Fibrosis Mice

    NASA Astrophysics Data System (ADS)

    Valverde, M. A.; O'Brien, J. A.; Sepulveda, F. V.; Ratcliff, R. A.; Evans, M. J.; Colledge, W. H.

    1995-09-01

    Cystic fibrosis is a disease characterized by abnormalities in the epithelia of the lungs, intestine, salivary and sweat glands, liver, and reproductive systems, often as a result of inadequate hydration of their secretions. The primary defect in cystic fibrosis is the altered activity of a cAMP-activated Cl^- channel, the cystic fibrosis transmembrane conductance regulator (CFTR) channel. However, it is not clear how a defect in the CFTR Cl^- channel function leads to the observed pathological changes. Although much is known about the structural properties and regulation of the CFTR, little is known of its relationship to cellular functions other than the cAMP-dependent Cl^- secretion. Here we report that cell volume regulation after hypotonic challenge is also defective in intestinal crypt epithelial cells isolated from CFTR -/- mutant mice. Moreover, the impairment of the regulatory volume decrease in CFTR -/- crypts appears to be related to the inability of a K^+ conductance to provide a pathway for the exit of this cation during the volume adjustments. This provides evidence that the lack of CFTR protein may have additional consequences for the cellular function other than the abnormal cAMP-mediated Cl^- secretion.

  13. Functional Roles of Bestrophins in Ocular Epithelia

    PubMed Central

    Marmorstein, Alan D.; Cross, Harold E.; Peachey, Neal S.

    2009-01-01

    There are four members of the bestrophin family of proteins in the human genome, of which two are known to be expressed in the eye. The gene BEST1 (formerly VMD2) which encodes the protein bestrophin-1 (Best1) was first identified in 1998. Mutations in this gene have now been associated with four clinically distinguishable human eye diseases, collectively referred to as “bestrophinopathies”. Over the last decade, laboratories have sought to understand how Best1 mutations could result in eye diseases that range in presentation from macular degeneration to nanophthalmos. The majority of our knowledge comes from studies that have sought to understand how Best1 mutations or dysfunction could induce the classical symptoms of the most common of these diseases: Best vitelliform macular dystrophy (BVMD). BVMD is a dominant trait that is characterized electrophysiologically by a diminished electrooculogram light peak with a normal clinical electroretinogram. This together with the localization of Best1 to the retinal pigment epithelium (RPE) basolateral plasma membrane and data from heterologous expression studies, have led to the proposal that Best1 generates the light peak, and that bestrophins are a family of Ca2+ activated Cl- channels (CaCCs). However, data from Best1 knock-out and knock-in mice, coupled with the recent discovery of a recessive bestrophinopathy suggest that Best1 does not generate the light peak. Recently Best2 was found to be expressed in non-pigmented epithelia in the ciliary body. However, aqueous dynamics in Best2 knock-out mice do not support a role for Best2 as a Cl- channel. Thus, the purported CaCC function of the bestrophins and how loss of this function relates to clinical disease needs to be reassessed. In this article, we examine data obtained from tissue-type and animal models and discuss the current state of bestrophin research, what roles Best1 and Best2 may play in ocular epithelia and ocular electrophysiology, and how perturbation

  14. Pak1 Kinase Maintains Apical Membrane Identity in Epithelia.

    PubMed

    Aguilar-Aragon, Mario; Elbediwy, Ahmed; Foglizzo, Valentina; Fletcher, Georgina C; Li, Vivian S W; Thompson, Barry J

    2018-02-13

    Epithelial cells are polarized along their apical-basal axis by the action of the small GTPase Cdc42, which is known to activate the aPKC kinase at the apical domain. However, loss of aPKC kinase activity was reported to have only mild effects on epithelial cell polarity. Here, we show that Cdc42 also activates a second kinase, Pak1, to specify apical domain identity in Drosophila and mammalian epithelia. aPKC and Pak1 phosphorylate an overlapping set of polarity substrates in kinase assays. Inactivating both aPKC kinase activity and the Pak1 kinase leads to a complete loss of epithelial polarity and morphology, with cells losing markers of apical polarization such as Crumbs, Par3/Bazooka, or ZO-1. This function of Pak1 downstream of Cdc42 is distinct from its role in regulating integrins or E-cadherin. Our results define a conserved dual-kinase mechanism for the control of apical membrane identity in epithelia. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  15. Platelet Activating Factor Receptor Activation Improves siRNA Uptake and RNAi Responses in Well-differentiated Airway Epithelia.

    PubMed

    Krishnamurthy, Sateesh; Behlke, Mark A; Apicella, Michael A; McCray, Paul B; Davidson, Beverly L

    2014-07-15

    Well-differentiated human airway epithelia present formidable barriers to efficient siRNA delivery. We previously reported that treatment of airway epithelia with specific small molecules improves oligonucleotide uptake and facilitates RNAi responses. Here, we exploited the platelet activating factor receptor (PAFR) pathway, utilized by specific bacteria to transcytose into epithelia, as a trigger for internalization of Dicer-substrate siRNAs (DsiRNA). PAFR is a G-protein coupled receptor which can be engaged and activated by phosphorylcholine residues on the lipooligosaccharide (LOS) of nontypeable Haemophilus influenzae and the teichoic acid of Streptococcus pneumoniae as well as by its natural ligand, platelet activating factor (PAF). When well-differentiated airway epithelia were simultaneously treated with either nontypeable Haemophilus influenzae LOS or PAF and transduced with DsiRNA formulated with the peptide transductin, we observed silencing of both endogenous and exogenous targets. PAF receptor antagonists prevented LOS or PAF-assisted DsiRNA silencing, demonstrating that ligand engagement of PAFR is essential for this process. Additionally, PAF-assisted DsiRNA transfection decreased CFTR protein expression and function and reduced exogenous viral protein levels and titer in human airway epithelia. Treatment with spiperone, a small molecule identified using the Connectivity map database to correlate gene expression changes in response to drug treatment with those associated with PAFR stimulation, also induced silencing. These results suggest that the signaling pathway activated by PAFR binding can be manipulated to facilitate siRNA entry and function in difficult to transfect well-differentiated airway epithelial cells.

  16. Plasticity within stem cell hierarchies in mammalian epithelia.

    PubMed

    Tetteh, Paul W; Farin, Henner F; Clevers, Hans

    2015-02-01

    Tissue homeostasis and regeneration are fueled by resident stem cells that have the capacity to self-renew, and to generate all the differentiated cell types that characterize a particular tissue. Classical models of such cellular hierarchies propose that commitment and differentiation occur unidirectionally, with the arrows 'pointing away' from the stem cell. Recent studies, all based on genetic lineage tracing, describe various strategies employed by epithelial stem cell hierarchies to replace damaged or lost cells. While transdifferentiation from one tissue type into another ('metaplasia') appears to be generally forbidden in nonpathological contexts, plasticity within an individual tissue stem cell hierarchy may be much more common than previously appreciated. In this review, we discuss recent examples of such plasticity in selected mammalian epithelia, highlighting the different modes of regeneration and their implications for our understanding of cellular hierarchy and tissue self-renewal. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Practical use of advanced mouse models for lung cancer.

    PubMed

    Safari, Roghaiyeh; Meuwissen, Ralph

    2015-01-01

    To date a variety of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) mouse models have been developed that mimic human lung cancer. Chemically induced or spontaneous lung cancer in susceptible inbred strains has been widely used, but the more recent genetically engineered somatic mouse models recapitulate much better the genotype-phenotype correlations found in human lung cancer. Additionally, improved orthotopic transplantation of primary human cancer tissue fragments or cells into lungs of immune-compromised mice can be valuable tools for preclinical research such as antitumor drug tests. Here we give a short overview of most somatic mouse models for lung cancer that are currently in use. We accompany each different model with a description of its practical use and application for all major lung tumor types, as well as the intratracheal injection or direct injection of fresh or freeze-thawed tumor cells or tumor cell lines into lung parenchyma of recipient mice. All here presented somatic mouse models are based on the ability to (in) activate specific alleles at a time, and in a tissue-specific cell type, of choice. This spatial-temporal controlled induction of genetic lesions allows the selective introduction of main genetic lesions in an adult mouse lung as found in human lung cancer. The resulting conditional somatic mouse models can be used as versatile powerful tools in basic lung cancer research and preclinical translational studies alike. These distinctively advanced lung cancer models permit us to investigate initiation (cell of origin) and progression of lung cancer, along with response and resistance to drug therapy. Cre/lox or FLP/frt recombinase-mediated methods are now well-used techniques to develop tissue-restricted lung cancer in mice with tumor-suppressor gene and/or oncogene (in)activation. Intranasal or intratracheal administration of engineered adenovirus-Cre or lentivirus-Cre has been optimized for introducing Cre

  18. Ablation of Coactivator Med1 Switches the Cell Fate of Dental Epithelia to That Generating Hair

    PubMed Central

    Nguyen, Thai; Sakai, Kiyoshi; He, Bing; Fong, Chak; Oda, Yuko

    2014-01-01

    Cell fates are determined by specific transcriptional programs. Here we provide evidence that the transcriptional coactivator, Mediator 1 (Med1), is essential for the cell fate determination of ectodermal epithelia. Conditional deletion of Med1 in vivo converted dental epithelia into epidermal epithelia, causing defects in enamel organ development while promoting hair formation in the incisors. We identified multiple processes by which hairs are generated in Med1 deficient incisors: 1) dental epithelial stem cells lacking Med 1 fail to commit to the dental lineage, 2) Sox2-expressing stem cells extend into the differentiation zone and remain multi-potent due to reduced Notch1 signaling, and 3) epidermal fate is induced by calcium as demonstrated in dental epithelial cell cultures. These results demonstrate that Med1 is a master regulator in adult stem cells to govern epithelial cell fate. PMID:24949995

  19. Resveratrol inhibits rhinovirus replication and expression of inflammatory mediators in nasal epithelia.

    PubMed

    Mastromarino, Paola; Capobianco, Daniela; Cannata, Federica; Nardis, Chiara; Mattia, Elena; De Leo, Alessandra; Restignoli, Rossella; Francioso, Antonio; Mosca, Luciana

    2015-11-01

    Human rhinoviruses (HRV), the cause of common colds, are the most frequent precipitants of acute exacerbation of asthma and chronic obstructive pulmonary disease, as well as causes of other serious respiratory diseases. No vaccine or antiviral agents are available for the prevention or treatment of HRV infection. Resveratrol exerts antiviral effect against different DNA and RNA viruses. The antiviral effect of a new resveratrol formulation containing carboxymethylated glucan was analyzed in H1HeLa cell monolayers and ex vivo nasal epithelia infected with HRV-16. Virus yield was evaluated by plaque assay and expression of viral capsid proteins by Western blot. IL-10, IFN-β, IL-6, IL-8 and RANTES levels were evaluated by ELISA assay. ICAM-1 was assessed by Western blot and immunofluorescence. Resveratrol exerted a high, dose-dependent, antiviral activity against HRV-16 replication and reduced virus-induced secretion of IL-6, IL-8 and RANTES to levels similar to that of uninfected nasal epithelia. Basal levels of IL-6 and RANTES were also significantly reduced in uninfected epithelia confirming an anti-inflammatory effect of the compound. HRV-induced expression of ICAM-1 was reversed by resveratrol. Resveratrol may be useful for a therapeutic approach to reduce HRV replication and virus-induced cytokine/chemokine production. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Platelet Activating Factor Receptor Activation Improves siRNA Uptake and RNAi Responses in Well-differentiated Airway Epithelia

    PubMed Central

    Krishnamurthy, Sateesh; Behlke, Mark A; Apicella, Michael A; McCray, Paul B; Davidson, Beverly L

    2014-01-01

    Well-differentiated human airway epithelia present formidable barriers to efficient siRNA delivery. We previously reported that treatment of airway epithelia with specific small molecules improves oligonucleotide uptake and facilitates RNAi responses. Here, we exploited the platelet activating factor receptor (PAFR) pathway, utilized by specific bacteria to transcytose into epithelia, as a trigger for internalization of Dicer-substrate siRNAs (DsiRNA). PAFR is a G-protein coupled receptor which can be engaged and activated by phosphorylcholine residues on the lipooligosaccharide (LOS) of nontypeable Haemophilus influenzae and the teichoic acid of Streptococcus pneumoniae as well as by its natural ligand, platelet activating factor (PAF). When well-differentiated airway epithelia were simultaneously treated with either nontypeable Haemophilus influenzae LOS or PAF and transduced with DsiRNA formulated with the peptide transductin, we observed silencing of both endogenous and exogenous targets. PAF receptor antagonists prevented LOS or PAF-assisted DsiRNA silencing, demonstrating that ligand engagement of PAFR is essential for this process. Additionally, PAF-assisted DsiRNA transfection decreased CFTR protein expression and function and reduced exogenous viral protein levels and titer in human airway epithelia. Treatment with spiperone, a small molecule identified using the Connectivity map database to correlate gene expression changes in response to drug treatment with those associated with PAFR stimulation, also induced silencing. These results suggest that the signaling pathway activated by PAFR binding can be manipulated to facilitate siRNA entry and function in difficult to transfect well-differentiated airway epithelial cells. PMID:25025465

  1. Chronic cadmium exposure in vitro induces cancer cell characteristics in human lung cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Person, Rachel J.; Tokar, Erik J.; Xu, Yuanyuan

    Cadmium is a known human lung carcinogen. Here, we attempt to develop an in vitro model of cadmium-induced human lung carcinogenesis by chronically exposing the peripheral lung epithelia cell line, HPL-1D, to a low level of cadmium. Cells were chronically exposed to 5 μM cadmium, a noncytotoxic level, and monitored for acquired cancer characteristics. By 20 weeks of continuous cadmium exposure, these chronic cadmium treated lung (CCT-LC) cells showed marked increases in secreted MMP-2 activity (3.5-fold), invasion (3.4-fold), and colony formation in soft agar (2-fold). CCT-LC cells were hyperproliferative, grew well in serum-free media, and overexpressed cyclin D1. The CCT-LCmore » cells also showed decreased expression of the tumor suppressor genes p16 and SLC38A3 at the protein levels. Also consistent with an acquired cancer cell phenotype, CCT-LC cells showed increased expression of the oncoproteins K-RAS and N-RAS as well as the epithelial-to-mesenchymal transition marker protein Vimentin. Metallothionein (MT) expression is increased by cadmium, and is typically overexpressed in human lung cancers. The major MT isoforms, MT-1A and MT-2A were elevated in CCT-LC cells. Oxidant adaptive response genes HO-1 and HIF-1A were also activated in CCT-LC cells. Expression of the metal transport genes ZNT-1, ZNT-5, and ZIP-8 increased in CCT-LC cells culminating in reduced cadmium accumulation, suggesting adaptation to the metal. Overall, these data suggest that exposure of human lung epithelial cells to cadmium causes acquisition of cancer cell characteristics. Furthermore, transformation occurs despite the cell's ability to adapt to chronic cadmium exposure. - Highlights: • Chronic cadmium exposure induces cancer cell characteristics in human lung cells. • This provides an in vitro model of cadmium-induced human lung cell transformation. • This occurred with general and lung specific changes typical for cancer cells. • These findings add insight to the

  2. Development of inner ear afferent connections: forming primary neurons and connecting them to the developing sensory epithelia

    NASA Technical Reports Server (NTRS)

    Fritzsch, Bernd

    2003-01-01

    The molecular and cellular origin of the primary neurons of the inner ear, the vestibular and spiral neurons, is reviewed including how they connect to the specific sensory epithelia and what the molecular nature of their survival is. Primary neurons of the ear depend on a single basic Helix-Loop-Helix (bHLH) protein for their formation, neurogenin 1 (ngn1). An immediate downstream gene is the bHLH gene neuronal differentiation (NeuroD). Targeted null mutations of ngn1 results in absence of primary neuron formation; targeted null mutation of NeuroD results in loss of almost all spiral and many vestibular neurons. NeuroD and a later expressed gene, Brn3a, play a role in pathfinding to and within sensory epithelia. The molecular nature of this pathfinding property is unknown. Reduction of hair cells in ngn1 null mutations suggests a clonal relationship with primary neurons. This relationship may play some role in specifying the identity of hair cells and the primary neurons that connect with them. Primary neuron neurites growth to sensory epithelia is initially independent of trophic factors released from developing sensory epithelia, but becomes rapidly dependent on those factors. Null mutations of specific neurotrophic factors lose distinct primary neuron populations which undergo rapid embryonic cell death.

  3. Lung Cancer Risk Prediction Model Incorporating Lung Function: Development and Validation in the UK Biobank Prospective Cohort Study.

    PubMed

    Muller, David C; Johansson, Mattias; Brennan, Paul

    2017-03-10

    Purpose Several lung cancer risk prediction models have been developed, but none to date have assessed the predictive ability of lung function in a population-based cohort. We sought to develop and internally validate a model incorporating lung function using data from the UK Biobank prospective cohort study. Methods This analysis included 502,321 participants without a previous diagnosis of lung cancer, predominantly between 40 and 70 years of age. We used flexible parametric survival models to estimate the 2-year probability of lung cancer, accounting for the competing risk of death. Models included predictors previously shown to be associated with lung cancer risk, including sex, variables related to smoking history and nicotine addiction, medical history, family history of lung cancer, and lung function (forced expiratory volume in 1 second [FEV1]). Results During accumulated follow-up of 1,469,518 person-years, there were 738 lung cancer diagnoses. A model incorporating all predictors had excellent discrimination (concordance (c)-statistic [95% CI] = 0.85 [0.82 to 0.87]). Internal validation suggested that the model will discriminate well when applied to new data (optimism-corrected c-statistic = 0.84). The full model, including FEV1, also had modestly superior discriminatory power than one that was designed solely on the basis of questionnaire variables (c-statistic = 0.84 [0.82 to 0.86]; optimism-corrected c-statistic = 0.83; p FEV1 = 3.4 × 10 -13 ). The full model had better discrimination than standard lung cancer screening eligibility criteria (c-statistic = 0.66 [0.64 to 0.69]). Conclusion A risk prediction model that includes lung function has strong predictive ability, which could improve eligibility criteria for lung cancer screening programs.

  4. Measurements of intracellular calcium signals in polarized primary cultures of normal and cystic fibrosis human airway epithelia.

    PubMed

    Ribeiro, Carla M P

    2011-01-01

    The airways are continuously challenged by a variety of stimuli including bacteria, viruses, allergens, and inflammatory factors that act as agonists for G protein-coupled receptors (GPCR). Intracellular calcium (Ca(2+) (i)) mobilization in airway epithelia in response to extracellular stimuli regulates key airway innate defense functions, e.g., Ca(2+)-activated Cl(-) secretion, ciliary beating, mucin secretion, and inflammatory responses. Because Ca(2+) (i) mobilization in response to luminal stimuli is larger in CF vs. normal human airway epithelia, alterations in Ca(2+) (i) signals have been associated with the pathogenesis of CF airway disease. Hence, assessment of Ca(2+) (i) signaling has become an important area of CF research. This chapter will focus on measurements of cytoplasmic and mitochondrial Ca(2+) signals resulting from GPCR activation in polarized primary cultures of normal and CF human bronchial epithelia (HBE).

  5. Mechanisms of Membrane Transport of Folates into Cells and Across Epithelia

    PubMed Central

    Zhao, Rongbao; Diop-Bove, Ndeye; Visentin, Michele; Goldman, I. David

    2013-01-01

    Until recently, the transport of folates into cells and across epithelia has been interpreted primarily within the context of two transporters with high affinity and specificity for folates, the reduced folate carrier and the folate receptors. However, there were discrepancies between the properties of these transporters and characteristics of folate transport in many tissues, most notably the intestinal absorption of folates, in terms of pH dependency and substrate specificity. With the recent cloning of the proton-coupled folate transporter (PCFT) and the demonstration that this transporter is mutated in hereditary folate malabsorption, an autosomal recessive disorder, the molecular basis for this low-pH transport activity is now understood. This review focuses on the properties of PCFT and briefly addresses the two other folate-specific transporters along with other facilitative and ATP-binding cassette (ABC) transporters with folate transport activities. The role of these transporters in the vectorial transport of folates across epithelia is considered. PMID:21568705

  6. Comparison of two Chinese medical herbs, Huangbai and Qianniuzi, on influence of short circuit current across the rat intestinal epithelia.

    PubMed

    Tsai, Jong-Chang; Tsai, Shuli; Chang, Weng-Cheng

    2004-07-01

    Huangbai (Phellodendron spec.) and Qianniuzi (Pharbitis spec.) are two traditional Chinese medical herbs used for anti-diarrheal and laxative agents, respectively. Ethanol and water extracts of these two herbs were prepared and effects of the extracts on ion transport of the rat intestinal epithelia were studied. For measuring changes of the short circuit current across the epithelia, the rat intestinal epithelia were mounted in the Ussing chamber and attached with voltage/current clamp. The intestinal epithelia were firstly activated by serosal administration of 5 microM forskolin. As current raised and being stable, extracts of these herbs were added, respectively, and changes in the short circuit current were recorded. Ethanol extract of Huangbai attenuated the current increment; on the contrary, ethanol extract of Qianniuzi augmented the current increment additionally. Water extracts of the two herbs showed minor effects on the current in comparison to ethanol extracts. The results provide evidences to reveal the pharmacological mechanism of the two Chinese medical herbs on the intestinal tissue.

  7. What we can learn from a tadpole about ciliopathies and airway diseases: Using systems biology in Xenopus to study cilia and mucociliary epithelia.

    PubMed

    Walentek, Peter; Quigley, Ian K

    2017-01-01

    Over the past years, the Xenopus embryo has emerged as an incredibly useful model organism for studying the formation and function of cilia and ciliated epithelia in vivo. This has led to a variety of findings elucidating the molecular mechanisms of ciliated cell specification, basal body biogenesis, cilia assembly, and ciliary motility. These findings also revealed the deep functional conservation of signaling, transcriptional, post-transcriptional, and protein networks employed in the formation and function of vertebrate ciliated cells. Therefore, Xenopus research can contribute crucial insights not only into developmental and cell biology, but also into the molecular mechanisms underlying cilia related diseases (ciliopathies) as well as diseases affecting the ciliated epithelium of the respiratory tract in humans (e.g., chronic lung diseases). Additionally, systems biology approaches including transcriptomics, genomics, and proteomics have been rapidly adapted for use in Xenopus, and broaden the applications for current and future translational biomedical research. This review aims to present the advantages of using Xenopus for cilia research, highlight some of the evolutionarily conserved key concepts and mechanisms of ciliated cell biology that were elucidated using the Xenopus model, and describe the potential for Xenopus research to address unresolved questions regarding the molecular mechanisms of ciliopathies and airway diseases. © 2017 Wiley Periodicals, Inc.

  8. Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop.

    PubMed

    Lama, Vibha N; Belperio, John A; Christie, Jason D; El-Chemaly, Souheil; Fishbein, Michael C; Gelman, Andrew E; Hancock, Wayne W; Keshavjee, Shaf; Kreisel, Daniel; Laubach, Victor E; Looney, Mark R; McDyer, John F; Mohanakumar, Thalachallour; Shilling, Rebecca A; Panoskaltsis-Mortari, Angela; Wilkes, David S; Eu, Jerry P; Nicolls, Mark R

    2017-05-04

    Lung transplantation, a cure for a number of end-stage lung diseases, continues to have the worst long-term outcomes when compared with other solid organ transplants. Preclinical modeling of the most common and serious lung transplantation complications are essential to better understand and mitigate the pathophysiological processes that lead to these complications. Various animal and in vitro models of lung transplant complications now exist and each of these models has unique strengths. However, significant issues, such as the required technical expertise as well as the robustness and clinical usefulness of these models, remain to be overcome or clarified. The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop in March 2016 to review the state of preclinical science addressing the three most important complications of lung transplantation: primary graft dysfunction (PGD), acute rejection (AR), and chronic lung allograft dysfunction (CLAD). In addition, the participants of the workshop were tasked to make consensus recommendations on the best use of these complimentary models to close our knowledge gaps in PGD, AR, and CLAD. Their reviews and recommendations are summarized in this report. Furthermore, the participants outlined opportunities to collaborate and directions to accelerate research using these preclinical models.

  9. Chapter 12: Yale lung cancer model.

    PubMed

    Holford, Theodore R; Ebisu, Keita; McKay, Lisa; Oh, Cheongeun; Zheng, Tongzhang

    2012-07-01

    The age-period-cohort model is known to provide an excellent description of the temporal trends in lung cancer incidence and mortality. This analytic approach is extended to include the contribution of carcinogenesis models for smoking. Usefulness of this strategy is that it offers a way to temporally calibrate a model that is fitted to population data and it can be readily adopted for the consideration of many different models. In addition, it provides diagnostics that can suggest temporal limitations of a particular carcinogenesis model in describing population rates. Alternative carcinogenesis models can be embedded within this framework. The two-stage clonal expansion model is implemented here. The model was used to estimate the impact of tobacco control after dissemination of knowledge of the harmful effects of cigarette smoking by comparing the observed number of lung cancer deaths to those expected if there had been no control compared to an ideal of complete control in 1965. Results indicate that 35.2% and 26.5% of lung cancer deaths that could have been avoided actually were for males and females, respectively. © 2011 Society for Risk Analysis.

  10. EFFECTS OF INGESTED ARSENIC ON DNA AND CHROMOSOME IN HUMAN EXFOLIATED EPITHELIA

    EPA Science Inventory

    Effects of Ingested Arsenic on DNA and Chromosome in Human Exfoliated Epithelia

    Judy L. Mumford, Human Studies Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

    Arsenic...

  11. Inhibitors of ceramide de novo biosynthesis rescue damages induced by cigarette smoke in airways epithelia.

    PubMed

    Zulueta, Aida; Caretti, Anna; Campisi, Giuseppe Matteo; Brizzolari, Andrea; Abad, Jose Luis; Paroni, Rita; Signorelli, Paola; Ghidoni, Riccardo

    2017-07-01

    Exposure to cigarette smoke represents the most important risk factor for the development of chronic obstructive pulmonary disease (COPD). COPD is characterized by chronic inflammation of the airways, imbalance of proteolytic activity resulting in the destruction of lung parenchyma, alveolar hypoxia, oxidative stress, and apoptosis. Sphingolipids are structural membrane components whose metabolism is altered during stress. Known as apoptosis and inflammation inducer, the sphingolipid ceramide was found to accumulate in COPD airways and its plasma concentration increased as well. The present study investigates the role of sphingolipids in the cigarette smoke-induced damage of human airway epithelial cells. Lung epithelial cells were pre-treated with sphingolipid synthesis inhibitors (myriocin or XM462) and then exposed to a mixture of nicotine, acrolein, formaldehyde, and acetaldehyde, the major toxic cigarette smoke components. The inflammatory and proteolytic responses were investigated by analysis of the mRNA expression (RT-PCR) of cytokines IL-1β and IL-8, and matrix metalloproteinase-9 and of the protein expression (ELISA) of IL-8. Ceramide intracellular amounts were measured by LC-MS technique. Ferric-reducing antioxidant power test and superoxide anion radical scavenging activity assay were used to assess the antioxidant power of the inhibitors of ceramide synthesis. We here show that ceramide synthesis is enhanced under treatment with a cigarette smoke mixture correlating with increased expression of inflammatory cytokines and matrix metalloproteinase 9. The use of inhibitors of ceramide synthesis protected from smoke induced damages such as inflammation, oxidative stress, and proteolytic imbalance in airways epithelia.

  12. Analytic Intermodel Consistent Modeling of Volumetric Human Lung Dynamics.

    PubMed

    Ilegbusi, Olusegun; Seyfi, Behnaz; Neylon, John; Santhanam, Anand P

    2015-10-01

    Human lung undergoes breathing-induced deformation in the form of inhalation and exhalation. Modeling the dynamics is numerically complicated by the lack of information on lung elastic behavior and fluid-structure interactions between air and the tissue. A mathematical method is developed to integrate deformation results from a deformable image registration (DIR) and physics-based modeling approaches in order to represent consistent volumetric lung dynamics. The computational fluid dynamics (CFD) simulation assumes the lung is a poro-elastic medium with spatially distributed elastic property. Simulation is performed on a 3D lung geometry reconstructed from four-dimensional computed tomography (4DCT) dataset of a human subject. The heterogeneous Young's modulus (YM) is estimated from a linear elastic deformation model with the same lung geometry and 4D lung DIR. The deformation obtained from the CFD is then coupled with the displacement obtained from the 4D lung DIR by means of the Tikhonov regularization (TR) algorithm. The numerical results include 4DCT registration, CFD, and optimal displacement data which collectively provide consistent estimate of the volumetric lung dynamics. The fusion method is validated by comparing the optimal displacement with the results obtained from the 4DCT registration.

  13. Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

    PubMed Central

    Lama, Vibha N.; Belperio, John A.; Christie, Jason D.; El-Chemaly, Souheil; Fishbein, Michael C.; Gelman, Andrew E.; Hancock, Wayne W.; Keshavjee, Shaf; Kreisel, Daniel; Looney, Mark R.; McDyer, John F.; Shilling, Rebecca A.; Panoskaltsis-Mortari, Angela; Wilkes, David S.; Eu, Jerry P.; Nicolls, Mark R.

    2017-01-01

    Lung transplantation, a cure for a number of end-stage lung diseases, continues to have the worst long-term outcomes when compared with other solid organ transplants. Preclinical modeling of the most common and serious lung transplantation complications are essential to better understand and mitigate the pathophysiological processes that lead to these complications. Various animal and in vitro models of lung transplant complications now exist and each of these models has unique strengths. However, significant issues, such as the required technical expertise as well as the robustness and clinical usefulness of these models, remain to be overcome or clarified. The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop in March 2016 to review the state of preclinical science addressing the three most important complications of lung transplantation: primary graft dysfunction (PGD), acute rejection (AR), and chronic lung allograft dysfunction (CLAD). In addition, the participants of the workshop were tasked to make consensus recommendations on the best use of these complimentary models to close our knowledge gaps in PGD, AR, and CLAD. Their reviews and recommendations are summarized in this report. Furthermore, the participants outlined opportunities to collaborate and directions to accelerate research using these preclinical models. PMID:28469087

  14. Ccdc85C, a causative protein for hydrocephalus and subcortical heterotopia, is expressed in the systemic epithelia with proliferative activity in rats.

    PubMed

    Tanaka, Natsuki; Izawa, Takeshi; Takenaka, Shigeo; Yamate, Jyoji; Kuwamura, Mitsuru

    2015-07-01

    Coiled-coil domain containing 85c (Ccdc85c) is a causative gene for spontaneous mutant mouse with non-obstructive hydrocephalus and subcortical heterotopia. Detailed functions of Ccdc85C protein have not been clarified. To reveal roles of Ccdc85C, we examined the distribution and expression pattern of Ccdc85C in the systemic developing organs in rats. Ccdc85C was expressed in various simple epithelia but not stratified epithelia. In the various epithelia, Ccdc85C was localized at cell-cell junctions and its expression was strong at apical junctions. Furthermore, intense expression was seen at developing period and gradually decreased with advancing development. Distribution of Ccdc85C coincides with that of proliferating epithelial cells. These results suggest that Ccdc85C plays an important role in the proliferative property of simple epithelia.

  15. Computer modeling of lung cancer diagnosis-to-treatment process

    PubMed Central

    Ju, Feng; Lee, Hyo Kyung; Osarogiagbon, Raymond U.; Yu, Xinhua; Faris, Nick

    2015-01-01

    We introduce an example of a rigorous, quantitative method for quality improvement in lung cancer care-delivery. Computer process modeling methods are introduced for lung cancer diagnosis, staging and treatment selection process. Two types of process modeling techniques, discrete event simulation (DES) and analytical models, are briefly reviewed. Recent developments in DES are outlined and the necessary data and procedures to develop a DES model for lung cancer diagnosis, leading up to surgical treatment process are summarized. The analytical models include both Markov chain model and closed formulas. The Markov chain models with its application in healthcare are introduced and the approach to derive a lung cancer diagnosis process model is presented. Similarly, the procedure to derive closed formulas evaluating the diagnosis process performance is outlined. Finally, the pros and cons of these methods are discussed. PMID:26380181

  16. Multi-scale lung modeling.

    PubMed

    Tawhai, Merryn H; Bates, Jason H T

    2011-05-01

    Multi-scale modeling of biological systems has recently become fashionable due to the growing power of digital computers as well as to the growing realization that integrative systems behavior is as important to life as is the genome. While it is true that the behavior of a living organism must ultimately be traceable to all its components and their myriad interactions, attempting to codify this in its entirety in a model misses the insights gained from understanding how collections of system components at one level of scale conspire to produce qualitatively different behavior at higher levels. The essence of multi-scale modeling thus lies not in the inclusion of every conceivable biological detail, but rather in the judicious selection of emergent phenomena appropriate to the level of scale being modeled. These principles are exemplified in recent computational models of the lung. Airways responsiveness, for example, is an organ-level manifestation of events that begin at the molecular level within airway smooth muscle cells, yet it is not necessary to invoke all these molecular events to accurately describe the contraction dynamics of a cell, nor is it necessary to invoke all phenomena observable at the level of the cell to account for the changes in overall lung function that occur following methacholine challenge. Similarly, the regulation of pulmonary vascular tone has complex origins within the individual smooth muscle cells that line the blood vessels but, again, many of the fine details of cell behavior average out at the level of the organ to produce an effect on pulmonary vascular pressure that can be described in much simpler terms. The art of multi-scale lung modeling thus reduces not to being limitlessly inclusive, but rather to knowing what biological details to leave out.

  17. A poroelastic model coupled to a fluid network with applications in lung modelling.

    PubMed

    Berger, Lorenz; Bordas, Rafel; Burrowes, Kelly; Grau, Vicente; Tavener, Simon; Kay, David

    2016-01-01

    We develop a lung ventilation model based on a continuum poroelastic representation of lung parenchyma that is strongly coupled to a pipe network representation of the airway tree. The continuous system of equations is discretized using a low-order stabilised finite element method. The framework is applied to a realistic lung anatomical model derived from computed tomography data and an artificially generated airway tree to model the conducting airway region. Numerical simulations produce physiologically realistic solutions and demonstrate the effect of airway constriction and reduced tissue elasticity on ventilation, tissue stress and alveolar pressure distribution. The key advantage of the model is the ability to provide insight into the mutual dependence between ventilation and deformation. This is essential when studying lung diseases, such as chronic obstructive pulmonary disease and pulmonary fibrosis. Thus the model can be used to form a better understanding of integrated lung mechanics in both the healthy and diseased states. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  18. Comparison of lung protective ventilation strategies in a rabbit model of acute lung injury.

    PubMed

    Rotta, A T; Gunnarsson, B; Fuhrman, B P; Hernan, L J; Steinhorn, D M

    2001-11-01

    To determine the impact of different protective and nonprotective mechanical ventilation strategies on the degree of pulmonary inflammation, oxidative damage, and hemodynamic stability in a saline lavage model of acute lung injury. A prospective, randomized, controlled, in vivo animal laboratory study. Animal research facility of a health sciences university. Forty-six New Zealand White rabbits. Mature rabbits were instrumented with a tracheostomy and vascular catheters. Lavage-injured rabbits were randomized to receive conventional ventilation with either a) low peak end-expiratory pressure (PEEP; tidal volume of 10 mL/kg, PEEP of 2 cm H2O); b) high PEEP (tidal volume of 10 mL/kg, PEEP of 10 cm H2O); c) low tidal volume with PEEP above Pflex (open lung strategy, tidal volume of 6 mL/kg, PEEP set 2 cm H2O > Pflex); or d) high-frequency oscillatory ventilation. Animals were ventilated for 4 hrs. Lung lavage fluid and tissue samples were obtained immediately after animals were killed. Lung lavage fluid was assayed for measurements of total protein, elastase activity, tumor necrosis factor-alpha, and malondialdehyde. Lung tissue homogenates were assayed for measurements of myeloperoxidase activity and malondialdehyde. The need for inotropic support was recorded. Animals that received a lung protective strategy (open lung or high-frequency oscillatory ventilation) exhibited more favorable oxygenation and lung mechanics compared with the low PEEP and high PEEP groups. Animals ventilated by a lung protective strategy also showed attenuation of inflammation (reduced tracheal fluid protein, tracheal fluid elastase, tracheal fluid tumor necrosis factor-alpha, and pulmonary leukostasis). Animals treated with high-frequency oscillatory ventilation had attenuated oxidative injury to the lung and greater hemodynamic stability compared with the other experimental groups. Both lung protective strategies were associated with improved oxygenation, attenuated inflammation, and

  19. Integrated computational model of the bioenergetics of isolated lung mitochondria

    PubMed Central

    Zhang, Xiao; Jacobs, Elizabeth R.; Camara, Amadou K. S.; Clough, Anne V.

    2018-01-01

    Integrated computational modeling provides a mechanistic and quantitative framework for describing lung mitochondrial bioenergetics. Thus, the objective of this study was to develop and validate a thermodynamically-constrained integrated computational model of the bioenergetics of isolated lung mitochondria. The model incorporates the major biochemical reactions and transport processes in lung mitochondria. A general framework was developed to model those biochemical reactions and transport processes. Intrinsic model parameters such as binding constants were estimated using previously published isolated enzymes and transporters kinetic data. Extrinsic model parameters such as maximal reaction and transport velocities were estimated by fitting the integrated bioenergetics model to published and new tricarboxylic acid cycle and respirometry data measured in isolated rat lung mitochondria. The integrated model was then validated by assessing its ability to predict experimental data not used for the estimation of the extrinsic model parameters. For example, the model was able to predict reasonably well the substrate and temperature dependency of mitochondrial oxygen consumption, kinetics of NADH redox status, and the kinetics of mitochondrial accumulation of the cationic dye rhodamine 123, driven by mitochondrial membrane potential, under different respiratory states. The latter required the coupling of the integrated bioenergetics model to a pharmacokinetic model for the mitochondrial uptake of rhodamine 123 from buffer. The integrated bioenergetics model provides a mechanistic and quantitative framework for 1) integrating experimental data from isolated lung mitochondria under diverse experimental conditions, and 2) assessing the impact of a change in one or more mitochondrial processes on overall lung mitochondrial bioenergetics. In addition, the model provides important insights into the bioenergetics and respiration of lung mitochondria and how they differ from

  20. Integrated computational model of the bioenergetics of isolated lung mitochondria.

    PubMed

    Zhang, Xiao; Dash, Ranjan K; Jacobs, Elizabeth R; Camara, Amadou K S; Clough, Anne V; Audi, Said H

    2018-01-01

    Integrated computational modeling provides a mechanistic and quantitative framework for describing lung mitochondrial bioenergetics. Thus, the objective of this study was to develop and validate a thermodynamically-constrained integrated computational model of the bioenergetics of isolated lung mitochondria. The model incorporates the major biochemical reactions and transport processes in lung mitochondria. A general framework was developed to model those biochemical reactions and transport processes. Intrinsic model parameters such as binding constants were estimated using previously published isolated enzymes and transporters kinetic data. Extrinsic model parameters such as maximal reaction and transport velocities were estimated by fitting the integrated bioenergetics model to published and new tricarboxylic acid cycle and respirometry data measured in isolated rat lung mitochondria. The integrated model was then validated by assessing its ability to predict experimental data not used for the estimation of the extrinsic model parameters. For example, the model was able to predict reasonably well the substrate and temperature dependency of mitochondrial oxygen consumption, kinetics of NADH redox status, and the kinetics of mitochondrial accumulation of the cationic dye rhodamine 123, driven by mitochondrial membrane potential, under different respiratory states. The latter required the coupling of the integrated bioenergetics model to a pharmacokinetic model for the mitochondrial uptake of rhodamine 123 from buffer. The integrated bioenergetics model provides a mechanistic and quantitative framework for 1) integrating experimental data from isolated lung mitochondria under diverse experimental conditions, and 2) assessing the impact of a change in one or more mitochondrial processes on overall lung mitochondrial bioenergetics. In addition, the model provides important insights into the bioenergetics and respiration of lung mitochondria and how they differ from

  1. Binding of [35S]saccharin to a protein fraction of rat tongue epithelia.

    PubMed

    Shimazaki, K; Sato, M; Takegami, T

    1981-11-05

    The binding of [35S]saccharin to ammonium sulfate fractions from homogenates of rat tongue epithelia was measured by equilibrium dialysis. The 40--60% saturated ammonium sulfate fraction from the buffer-soluble fraction had the highest saccharin-binding activity. Binding of [35S]saccharin to the 40--60% ammonium sulfate fraction was inhibited by unlabeled saccharin sodium salt. The inhibition increased with increasing unlabeled saccharin concentration and was nearly complete above 10 mM. [35S]Saccharin binding to the 40--60% ammonium sulfate fraction extracted from the tongue epithelia was inhibited by glucose, lactose and sucrose, while binding to similar fractions from tongue muscle was not affected by these sugars. The inhibition of binding of labeled saccharin to the epithelial fraction increased with increasing glucose concentrations. About 35% of the binding was inhibited by 1 M glucose. No significant difference in the amount of inhibition was seen among the three sugars at 0.1 M. The 40--60% ammonium sulfate fraction from tongue epithelium devoid of taste buds bound much less [35S]saccharin than did a similar fraction from epithelium with taste buds. Binding of [35S]saccharin by the preparation from epithelium devoid of taste buds was not inhibited by glucose. The results provide evidence that the 40--60% ammonium sulfate fraction from tongue epithelia with taste buds contains a protein which binds saccharin and sugars. We hypothesize that it is a sweet taste receptor protein.

  2. A comprehensive computational model of sound transmission through the porcine lung

    PubMed Central

    Dai, Zoujun; Peng, Ying; Henry, Brian M.; Mansy, Hansen A.; Sandler, Richard H.; Royston, Thomas J.

    2014-01-01

    A comprehensive computational simulation model of sound transmission through the porcine lung is introduced and experimentally evaluated. This “subject-specific” model utilizes parenchymal and major airway geometry derived from x-ray CT images. The lung parenchyma is modeled as a poroviscoelastic material using Biot theory. A finite element (FE) mesh of the lung that includes airway detail is created and used in comsol FE software to simulate the vibroacoustic response of the lung to sound input at the trachea. The FE simulation model is validated by comparing simulation results to experimental measurements using scanning laser Doppler vibrometry on the surface of an excised, preserved lung. The FE model can also be used to calculate and visualize vibroacoustic pressure and motion inside the lung and its airways caused by the acoustic input. The effect of diffuse lung fibrosis and of a local tumor on the lung acoustic response is simulated and visualized using the FE model. In the future, this type of visualization can be compared and matched with experimentally obtained elastographic images to better quantify regional lung material properties to noninvasively diagnose and stage disease and response to treatment. PMID:25190415

  3. A comprehensive computational model of sound transmission through the porcine lung.

    PubMed

    Dai, Zoujun; Peng, Ying; Henry, Brian M; Mansy, Hansen A; Sandler, Richard H; Royston, Thomas J

    2014-09-01

    A comprehensive computational simulation model of sound transmission through the porcine lung is introduced and experimentally evaluated. This "subject-specific" model utilizes parenchymal and major airway geometry derived from x-ray CT images. The lung parenchyma is modeled as a poroviscoelastic material using Biot theory. A finite element (FE) mesh of the lung that includes airway detail is created and used in comsol FE software to simulate the vibroacoustic response of the lung to sound input at the trachea. The FE simulation model is validated by comparing simulation results to experimental measurements using scanning laser Doppler vibrometry on the surface of an excised, preserved lung. The FE model can also be used to calculate and visualize vibroacoustic pressure and motion inside the lung and its airways caused by the acoustic input. The effect of diffuse lung fibrosis and of a local tumor on the lung acoustic response is simulated and visualized using the FE model. In the future, this type of visualization can be compared and matched with experimentally obtained elastographic images to better quantify regional lung material properties to noninvasively diagnose and stage disease and response to treatment.

  4. Organotypic lung culture: A new model for studying ischemia and ex vivo perfusion in lung transplantation.

    PubMed

    Baste, Jean-Marc; Gay, Arnaud; Smail, Hassiba; Noël, Romain; Bubenheim, Michael; Begueret, Hugues; Morin, Jean-Paul; Litzler, Pierre-Yves

    2015-01-01

    Donors after cardiac death (DCD) in lung transplantation is considered as a solution for organ shortage. However, it is characterized by warm ischemic period, which could be involved in severe Ischemia-Reperfusion lesion (IR) with early graft dysfunction. We describe a new hybrid model combining in vivo ischemia followed by in vitro reoxygenation using organ-specific culture. A hybrid model using in vivo ischemic period followed by in vitro lung slice reoxygenation was set up in rat to mimic DCD in lung transplantation with in vitro perfusion. Different markers (bioenergetics, oxidant stress assays, and histology) were measured to evaluate the viability of lung tissue after different ischemic times (I-0, I-1, I-2, I-4, I-15 hours) and reoxygenation times (R-0, R-1, R-4, R-24 hours). No differences were found in cell viability, ATP concentrations, extracellular LDH assays or histology, demonstrating extensive viability of up to 4 hours in lung tissue warm ischemia. We found oxidative stress mainly during the ischemic period with no burst at reoxygenation. Cytosolic anti-oxidant system was involved first (I-0,I-1,I-2) followed by mitochondrial anti-oxidant system for extensive ischemia (I-4). Histological features showed differences in this model of ischemia-reoxygenation between bronchial epithelium and lung parenchymal cells, with epithelium regeneration after 2 hours of warm ischemia and 24 hours of perfusion. The results of our hybrid model experiment suggest extensive lung viability of up to 4 hours ischemia. Our model could be an interesting tool to evaluate ex vivo reconditioning techniques after different in vivo lung insults.

  5. Hypo-Elastic Model for Lung Parenchyma

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Freed, Alan D.; Einstein, Daniel R.

    2012-03-01

    A simple elastic isotropic constitutive model for the spongy tissue in lung is derived from the theory of hypoelasticity. The model is shown to exhibit a pressure dependent behavior that has been interpreted by some as indicating extensional anisotropy. In contrast, we show that this behavior arises natural from an analysis of isotropic hypoelastic invariants, and is a likely result of non-linearity, not anisotropy. The response of the model is determined analytically for several boundary value problems used for material characterization. These responses give insight into both the material behavior as well as admissible bounds on parameters. The model ismore » characterized against published experimental data for dog lung. Future work includes non-elastic model behavior.« less

  6. Epithelial reticulon 4B (Nogo-B) is an endogenous regulator of Th2-driven lung inflammation

    PubMed Central

    Wright, Paulette L.; Yu, Jun; Di, Y.P. Peter; Homer, Robert J.; Chupp, Geoffrey; Elias, Jack A.; Cohn, Lauren

    2010-01-01

    Nogo-B is a member of the reticulon family of proteins (RTN-4B) that is highly expressed in lung tissue; however, its function remains unknown. We show that mice with Th2-driven lung inflammation results in a loss of Nogo expression in airway epithelium and smooth muscle compared with nonallergic mice, a finding which is replicated in severe human asthma. Mice lacking Nogo-A/B (Nogo-KO) display an exaggerated asthma-like phenotype, and epithelial reconstitution of Nogo-B in transgenic mice blunts Th2-mediated lung inflammation. Microarray analysis of lungs from Nogo-KO mice reveals a marked reduction in palate lung and nasal clone (PLUNC) gene expression, and the levels of PLUNC are enhanced in epithelial Nogo-B transgenic mice. Finally, transgenic expression of PLUNC into Nogo-KO mice rescues the enhanced asthmatic-like responsiveness in these KO mice. These data identify Nogo-B as a novel protective gene expressed in lung epithelia, and its expression regulates the levels of the antibacterial antiinflammatory protein PLUNC. PMID:20975041

  7. A 4DCT imaging-based breathing lung model with relative hysteresis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Miyawaki, Shinjiro; Choi, Sanghun; Hoffman, Eric A.

    To reproduce realistic airway motion and airflow, the authors developed a deforming lung computational fluid dynamics (CFD) model based on four-dimensional (4D, space and time) dynamic computed tomography (CT) images. A total of 13 time points within controlled tidal volume respiration were used to account for realistic and irregular lung motion in human volunteers. Because of the irregular motion of 4DCT-based airways, we identified an optimal interpolation method for airway surface deformation during respiration, and implemented a computational solid mechanics-based moving mesh algorithm to produce smooth deforming airway mesh. In addition, we developed physiologically realistic airflow boundary conditions for bothmore » models based on multiple images and a single image. Furthermore, we examined simplified models based on one or two dynamic or static images. By comparing these simplified models with the model based on 13 dynamic images, we investigated the effects of relative hysteresis of lung structure with respect to lung volume, lung deformation, and imaging methods, i.e., dynamic vs. static scans, on CFD-predicted pressure drop. The effect of imaging method on pressure drop was 24 percentage points due to the differences in airflow distribution and airway geometry. - Highlights: • We developed a breathing human lung CFD model based on 4D-dynamic CT images. • The 4DCT-based breathing lung model is able to capture lung relative hysteresis. • A new boundary condition for lung model based on one static CT image was proposed. • The difference between lung models based on 4D and static CT images was quantified.« less

  8. Development of a Guinea Pig Lung Deposition Model

    DTIC Science & Technology

    2016-01-01

    Development of a Guinea Pig Lung Deposition Model Distribution Statement A. Approved for public release; distribution is unlimited. January...4 Figure 2. Particle deposition in the lung of the guinea pig via endotracheal breathing...Particle deposition in the lungs of guinea pigs via nasal breathing. ......................................... 12 v PREFACE The research work

  9. Animal model of grain worker's lung.

    PubMed Central

    Stepner, N; Broder, I; Baumal, R

    1986-01-01

    We examined the light microscopic changes in the lungs of rabbits exposed to grain dust for variable periods of time, to determine whether an animal model of grain worker's lung could be developed. Experimental animals were exposed to grain dust at a concentration of 20 mg/m3 for 7 hr/day, 5 days/week, for up to 6 months. The lungs of these rabbits demonstrated a granulomatous interstitial pneumonitis associated with exudation of mononuclear cells into the alveoli and conducting airways. These changes appeared within 5 days of the onset of exposure and reached a peak at 3 weeks but were sustained through the longest exposure interval. No abnormalities were observed in the lungs of control rabbits. These results show three points of consistency with those obtained in epidemiologic studies of grain elevator workers. First, the rapid appearance of the experimental changes suggests that the mechanism of tissue injury may not be immunologic. Second, the occurrence of the histopathologic alterations in the interstitium, alveoli, and airways corresponds with the combined restrictive and obstructive ventilatory defect described in the human epidemiologic studies. Third, the absence of lung fibrosis in rabbits exposed to dust for 6 months suggests that the pneumonitis is reversible. Thus this experimental model shows promise of helping to clarify the nature and mechanism of the adverse pulmonary effects of grain dust. Images FIGURE 1. FIGURE 2. PMID:3709485

  10. Predictive Accuracy of the Liverpool Lung Project Risk Model for Stratifying Patients for Computed Tomography Screening for Lung Cancer

    PubMed Central

    Raji, Olaide Y.; Duffy, Stephen W.; Agbaje, Olorunshola F.; Baker, Stuart G.; Christiani, David C.; Cassidy, Adrian; Field, John K.

    2013-01-01

    Background External validation of existing lung cancer risk prediction models is limited. Using such models in clinical practice to guide the referral of patients for computed tomography (CT) screening for lung cancer depends on external validation and evidence of predicted clinical benefit. Objective To evaluate the discrimination of the Liverpool Lung Project (LLP) risk model and demonstrate its predicted benefit for stratifying patients for CT screening by using data from 3 independent studies from Europe and North America. Design Case–control and prospective cohort study. Setting Europe and North America. Patients Participants in the European Early Lung Cancer (EUELC) and Harvard case–control studies and the LLP population-based prospective cohort (LLPC) study. Measurements 5-year absolute risks for lung cancer predicted by the LLP model. Results The LLP risk model had good discrimination in both the Harvard (area under the receiver-operating characteristic curve [AUC], 0.76 [95% CI, 0.75 to 0.78]) and the LLPC (AUC, 0.82 [CI, 0.80 to 0.85]) studies and modest discrimination in the EUELC (AUC, 0.67 [CI, 0.64 to 0.69]) study. The decision utility analysis, which incorporates the harms and benefit of using a risk model to make clinical decisions, indicates that the LLP risk model performed better than smoking duration or family history alone in stratifying high-risk patients for lung cancer CT screening. Limitations The model cannot assess whether including other risk factors, such as lung function or genetic markers, would improve accuracy. Lack of information on asbestos exposure in the LLPC limited the ability to validate the complete LLP risk model. Conclusion Validation of the LLP risk model in 3 independent external data sets demonstrated good discrimination and evidence of predicted benefits for stratifying patients for lung cancer CT screening. Further studies are needed to prospectively evaluate model performance and evaluate the optimal population

  11. Identification of a basic protein of Mr 75,000 as an accessory desmosomal plaque protein in stratified and complex epithelia.

    PubMed

    Kapprell, H P; Owaribe, K; Franke, W W

    1988-05-01

    Desmosomes are intercellular adhering junctions characterized by a special structure and certain obligatory constituent proteins such as the cytoplasmic protein, desmoglein. Desmosomal fractions from bovine muzzle epidermis contain, in addition, a major polypeptide of Mr approximately 75,000 ("band 6 protein") which differs from all other desmosomal proteins so far identified by its positive charge (isoelectric at pH approximately 8.5 in the denatured state) and its avidity to bind certain type I cytokeratins under stringent conditions. We purified this protein from bovine muzzle epidermis and raised antibodies to it. Using affinity-purified antibodies, we identified a protein of identical SDS-PAGE mobility and isoelectric pH in all epithelia of higher complexity, including representatives of stratified, complex (pseudostratified) and transitional epithelia as well as benign and malignant human tumors derived from such epithelia. Immunolocalization studies revealed the location of this protein along cell boundaries in stratified and complex epithelia, often resolved into punctate arrays. In some epithelia it seemed to be restricted to certain cell types and layers; in rat cornea, for example, it was only detected in upper strata. Electron microscopic immunolocalization showed that this protein is a component of the desmosomal plaque. However, it was not found in the desmosomes of all simple epithelia examined, in the tumors and cultured cells derived thereof, in myocardiac and Purkinje fiber cells, in arachnoideal cells and meningiomas, and in dendritic reticulum cells of lymphoid tissue, i.e., all cells containing typical desmosomes. The protein was also absent in all nondesmosomal adhering junctions. From these results we conclude that this basic protein is not an obligatory desmosomal plaque constituent but an accessory component specific to the desmosomes of certain kinds of epithelial cells with stratified tissue architecture. This suggests that the Mr 75

  12. Prolactin and teleost ionocytes: new insights into cellular and molecular targets of prolactin in vertebrate epithelia

    USGS Publications Warehouse

    Breves, Jason P.; McCormick, Stephen D.; Karlstrom, Rolf O.

    2014-01-01

    The peptide hormone prolactin is a functionally versatile hormone produced by the vertebrate pituitary. Comparative studies over the last six decades have revealed that a conserved function for prolactin across vertebrates is the regulation of ion and water transport in a variety of tissues including those responsible for whole-organism ion homeostasis. In teleost fishes, prolactin was identified as the “freshwater-adapting hormone”, promoting ion-conserving and water-secreting processes by acting on the gill, kidney, gut and urinary bladder. In mammals, prolactin is known to regulate renal, intestinal, mammary and amniotic epithelia, with dysfunction linked to hypogonadism, infertility, and metabolic disorders. Until recently, our understanding of the cellular mechanisms of prolactin action in fishes has been hampered by a paucity of molecular tools to define and study ionocytes, specialized cells that control active ion transport across branchial and epidermal epithelia. Here we review work in teleost models indicating that prolactin regulates ion balance through action on ion transporters, tight-junction proteins, and water channels in ionocytes, and discuss recent advances in our understanding of ionocyte function in the genetically and embryonically accessible zebrafish (Danio rerio). Given the high degree of evolutionary conservation in endocrine and osmoregulatory systems, these studies in teleost models are contributing novel mechanistic insight into how prolactin participates in the development, function, and dysfunction of osmoregulatory systems across the vertebrate lineage.

  13. A fully synthetic lung model for wound-ballistic experiments-First results.

    PubMed

    Bolliger, S A; Poschmann, S A; Thali, M J; Eggert, S

    2017-06-01

    Today, synthetic models have all but replaced animal and corpse models in examining damage to soft-tissues and skeletal structures by ballistic trauma. As, however, non-solid organs such as the lungs, have not been able to be replaced by a fully synthetic model we attempted to create such a model. 20% ordnance gelatine was frothed with a household mixer and cooled to stable foam. Several of these foam blocks were then stuck together with liquid gelatine and placed between 10% gelatine blocks. As controls, we embedded pig lungs in gelatine and compared the wound channels seen in computed tomography created upon shooting with 9mm Luger. The fully synthetic models displayed radiological and physical densities comparable to real lungs. The wound profile characteristics of the fully synthetic lung models were very similar to the semisynthetic swine-gelatine models regarding the permanent wound cavity. Furthermore, in both semi- and fully synthetic models we detected a ring surrounding the permanent wound channel, most likely representing the remnants of the temporary wound cavity. Our results indicate that this fully synthetic lung model is a viable substitute for ballistic experiments on lungs. We believe that further research on the temporary wound channel in lungs is possible with this model in order to provide more insight into the effect of ballistic trauma to the lungs not seen otherwise. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Models to teach lung sonopathology and ultrasound-guided thoracentesis.

    PubMed

    Wojtczak, Jacek A

    2014-12-01

    Lung sonography allows rapid diagnosis of lung emergencies such as pulmonary edema, hemothorax or pneumothorax. The ability to timely diagnose an intraoperative pneumothorax is an important skill for the anesthesiologist. However, lung ultrasound exams require an interpretation of not only real images but also complex acoustic artifacts such as A-lines and B-lines. Therefore, appropriate training to gain proficiency is important. Simulated environment using ultrasound phantom models allows controlled, supervised learning. We have developed hybrid models that combine dry or wet polyurethane foams, porcine rib cages and human hand simulating a rib cage. These models simulate fairly accurately pulmonary sonopathology and allow supervised teaching of lung sonography with the immediate feedback. In-vitro models can also facilitate learning of procedural skills, improving transducer and needle positioning and movement, rapid recognition of thoracic anatomy and hand - eye coordination skills. We described a new model to teach an ultrasound guided thoracentesis. This model consists of the experimenter's hand placed on top of the water-filled container with a wet foam. Metacarpal bones of the human hand simulate a rib cage and a wet foam simulates a diseased lung immersed in the pleural fluid. Positive fluid flow offers users feedback when a simulated pleural effusion is accurately assessed.

  15. Effects of vascular flow and PEEP in a multiple hit model of lung injury in isolated perfused rabbit lungs.

    PubMed

    Piacentini, Enrique; López-Aguilar, Josefina; García-Martín, Carolina; Villagrá, Ana; Saenz-Valiente, Alicia; Murias, Gastón; Fernández-Segoviano, Pilar; Hotchkiss, John R; Blanch, Lluis

    2008-07-01

    High vascular flow aggravates lung damage in animal models of ventilator-induced lung injury. Positive end-expiratory pressure (PEEP) can attenuate ventilator-induced lung injury, but its continued effectiveness in the setting of antecedent lung injury is unclear. The objective of the present study was to evaluate whether the application of PEEP diminishes lung injury induced by concurrent high vascular flow and high alveolar pressures in normal lungs and in a preinjury lung model. Two series of experiments were performed. Fifteen sets of isolated rabbit lungs were randomized into three groups (n = 5): low vascular flow/low PEEP; high vascular flow/low PEEP, and high vascular flow/high PEEP. Subsequently, the same protocol was applied in an additional 15 sets of isolated rabbit lungs in which oleic acid was added to the vascular perfusate to produce mild to moderate lung injury. All lungs were ventilated with peak airway pressure of 30 cm H2O for 30 minutes. Outcome measures included frequency of gross structural failure, pulmonary hemorrhage, edema formation, changes in static compliance, pulmonary vascular resistance, and pulmonary ultrafiltration coefficient. In the context of high vascular flow, application of a moderate level of PEEP reduced pulmonary rupture, edema formation, and lung hemorrhage. The protective effects of PEEP were not observed in lungs concurrently injured with oleic acid. Under these experimental conditions, PEEP attenuates lung injury in the setting of high vascular flow. The protective effect of PEEP is lost in a two-hit model of lung injury.

  16. Mineralocorticoid effects in the late gestation ovine fetal lung

    PubMed Central

    McCartney, Jarret; Richards, Elaine M.; Wood, Charles E.; Keller‐Wood, Maureen

    2014-01-01

    Abstract This study was designed to determine the effects of corticosteroids at MR in the late‐gestation fetal lung. Since both the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) are expressed at relatively high levels in the fetal lung, endogenous corticosteroids may act at MR as well as GR in the preterm fetal lung. The GR agonist, betamethasone, the MR agonist, aldosterone, or both were infused intravenously for 48 h in ovine fetuses of approximately 130 days gestation. Effects on airway pressures during stepwise inflation of the in situ lung, expression of ENaC alpha (SCNN1A), ENaC beta (SCNN1B), and Na,K ATPase (ATP1A1), and elastin and collagen content were determined after the infusions. We found that aldosterone significantly reduced the airway pressure measured during the initial step in inflation of the lung, although aldosterone had no overall effect on lung compliance, nor did aldosterone induce expression of ENaCα, ENaCβ or Na,K ATPaseα1. Betamethasone significantly increased expression of the epithelial sodium channel (ENaC) subunit mRNAs, and collagen and elastin content in the lungs, although this dose of betamethasone also had no effect on lung compliance. There was no synergy between effects of the MR and GR agonists. Transcriptomic analysis suggested that although aldosterone did not alter genes in pathways related to epithelial sodium transport, aldosterone did alter genes in pathways involved in cell proliferation in the lungs. The results are consistent with corticosteroid‐induced fluid reabsorption at birth through GR rather than MR, but suggest that MR facilitates lung maturation, and may contribute to inflation with the first breaths via mechanisms distinct from known aldosterone effects in other epithelia. PMID:25347852

  17. IFN-γ-mediated induction of an apical IL-10 receptor on polarized intestinal epithelia.

    PubMed

    Kominsky, Douglas J; Campbell, Eric L; Ehrentraut, Stefan F; Wilson, Kelly E; Kelly, Caleb J; Glover, Louise E; Collins, Colm B; Bayless, Amanda J; Saeedi, Bejan; Dobrinskikh, Evgenia; Bowers, Brittelle E; MacManus, Christopher F; Müller, Werner; Colgan, Sean P; Bruder, Dunja

    2014-02-01

    Cytokines secreted at sites of inflammation impact the onset, progression, and resolution of inflammation. In this article, we investigated potential proresolving mechanisms of IFN-γ in models of inflammatory bowel disease. Guided by initial microarray analysis, in vitro studies revealed that IFN-γ selectively induced the expression of IL-10R1 on intestinal epithelia. Further analysis revealed that IL-10R1 was expressed predominantly on the apical membrane of polarized epithelial cells. Receptor activation functionally induced canonical IL-10 target gene expression in epithelia, concomitant with enhanced barrier restitution. Furthermore, knockdown of IL-10R1 in intestinal epithelial cells results in impaired barrier function in vitro. Colonic tissue isolated from murine colitis revealed that levels of IL-10R1 and suppressor of cytokine signaling 3 were increased in the epithelium and coincided with increased tissue IFN-γ and IL-10 cytokines. In parallel, studies showed that treatment of mice with rIFN-γ was sufficient to drive expression of IL-10R1 in the colonic epithelium. Studies of dextran sodium sulfate colitis in intestinal epithelial-specific IL-10R1-null mice revealed a remarkable increase in disease susceptibility associated with increased intestinal permeability. Together, these results provide novel insight into the crucial and underappreciated role of epithelial IL-10 signaling in the maintenance and restitution of epithelial barrier and of the temporal regulation of these pathways by IFN-γ.

  18. Modeling of the Nitric Oxide Transport in the Human Lungs.

    PubMed

    Karamaoun, Cyril; Van Muylem, Alain; Haut, Benoît

    2016-01-01

    In the human lungs, nitric oxide (NO) acts as a bronchodilatator, by relaxing the bronchial smooth muscles and is closely linked to the inflammatory status of the lungs, owing to its antimicrobial activity. Furthermore, the molar fraction of NO in the exhaled air has been shown to be higher for asthmatic patients than for healthy patients. Multiple models have been developed in order to characterize the NO dynamics in the lungs, owing to their complex structure. Indeed, direct measurements in the lungs are difficult and, therefore, these models are valuable tools to interpret experimental data. In this work, a new model of the NO transport in the human lungs is proposed. It belongs to the family of the morphological models and is based on the morphometric model of Weibel (1963). When compared to models published previously, its main new features are the layered representation of the wall of the airways and the possibility to simulate the influence of bronchoconstriction (BC) and of the presence of mucus on the NO transport in lungs. The model is based on a geometrical description of the lungs, at rest and during a respiratory cycle, coupled with transport equations, written in the layers composing an airway wall and in the lumen of the airways. First, it is checked that the model is able to reproduce experimental information available in the literature. Second, the model is used to discuss some features of the NO transport in healthy and unhealthy lungs. The simulation results are analyzed, especially when BC has occurred in the lungs. For instance, it is shown that BC can have a significant influence on the NO transport in the tissues composing an airway wall. It is also shown that the relation between BC and the molar fraction of NO in the exhaled air is complex. Indeed, BC might lead to an increase or to a decrease of this molar fraction, depending on the extent of the BC and on the possible presence of mucus. This should be confirmed experimentally and might

  19. Chronic cadmium exposure in vitro induces cancer cell characteristics in human lung cells

    PubMed Central

    Person, Rachel J.; Tokar, Erik J.; Xu, Yuanyuan; Orihuela, Ruben; Olive Ngalame, Ntube N.; Waalkes, Michael P.

    2013-01-01

    Cadmium is a known human lung carcinogen. Here, we attempt to develop an in vitro model of cadmium-induced human lung carcinogenesis by chronically exposing the peripheral lung epithelia cell line, HPL-1D, to a low level of cadmium. Cells were chronically exposed to 5 μM cadmium, a noncytotoxic level, and monitored for acquired cancer characteristics. By 20 weeks of continuous cadmium exposure, these chronic cadmium treated lung (CCT-LC) cells showed marked increases in secreted MMP-2 activity (3.5-fold), invasion (3.4-fold), and colony formation in soft agar (2-fold). CCT-LC cells were hyperproliferative, grew well in serum-free media, and overexpressed cyclin D1. The CCT-LC cells also showed decreased expression of the tumor suppressor genes p16 and SLC38A3 at the protein levels. Also consistent with an acquired cancer cell phenotype, CCT-LC cells showed increased expression of the oncoproteins K-RAS and N-RAS as well as the epithelial-to-mesenchymal transition marker protein Vimentin. Metallothionein (MT) expression is increased by cadmium, and is typically overexpressed in human lung cancers. The major MT isoforms, MT-1A and MT-2A were elevated in CCT-LC cells. Oxidant adaptive response genes HO-1 and HIF-1A were also activated in CCT-LC cells. Expression of the metal transport genes ZNT-1, ZNT-5, and ZIP-8 increased in CCT-LC cells culminating in reduced cadmium accumulation, suggesting adaptation to the metal. Overall, these data suggest that exposure of human lung epithelial cells to cadmium causes acquisition of cancer cell characteristics. Furthermore, transformation occurs despite the cell’s ability to adapt to chronic cadmium exposure. PMID:23811327

  20. Statistical modeling of 4D respiratory lung motion using diffeomorphic image registration.

    PubMed

    Ehrhardt, Jan; Werner, René; Schmidt-Richberg, Alexander; Handels, Heinz

    2011-02-01

    Modeling of respiratory motion has become increasingly important in various applications of medical imaging (e.g., radiation therapy of lung cancer). Current modeling approaches are usually confined to intra-patient registration of 3D image data representing the individual patient's anatomy at different breathing phases. We propose an approach to generate a mean motion model of the lung based on thoracic 4D computed tomography (CT) data of different patients to extend the motion modeling capabilities. Our modeling process consists of three steps: an intra-subject registration to generate subject-specific motion models, the generation of an average shape and intensity atlas of the lung as anatomical reference frame, and the registration of the subject-specific motion models to the atlas in order to build a statistical 4D mean motion model (4D-MMM). Furthermore, we present methods to adapt the 4D mean motion model to a patient-specific lung geometry. In all steps, a symmetric diffeomorphic nonlinear intensity-based registration method was employed. The Log-Euclidean framework was used to compute statistics on the diffeomorphic transformations. The presented methods are then used to build a mean motion model of respiratory lung motion using thoracic 4D CT data sets of 17 patients. We evaluate the model by applying it for estimating respiratory motion of ten lung cancer patients. The prediction is evaluated with respect to landmark and tumor motion, and the quantitative analysis results in a mean target registration error (TRE) of 3.3 ±1.6 mm if lung dynamics are not impaired by large lung tumors or other lung disorders (e.g., emphysema). With regard to lung tumor motion, we show that prediction accuracy is independent of tumor size and tumor motion amplitude in the considered data set. However, tumors adhering to non-lung structures degrade local lung dynamics significantly and the model-based prediction accuracy is lower in these cases. The statistical respiratory

  1. Chapter 7: Description of MISCAN-lung, the Erasmus MC Lung Cancer microsimulation model for evaluating cancer control interventions.

    PubMed

    Schultz, F W; Boer, R; de Koning, H J

    2012-07-01

    The MISCAN-lung model was designed to simulate population trends in lung cancer (LC) for comprehensive surveillance of the disease, to relate past exposure to risk factors to (observed) LC incidence and mortality, and to estimate the impact of cancer-control interventions. MISCAN-lung employs the technique of stochastic microsimulation of life histories affected by risk factors. It includes the two-stage clonal expansion model for carcinogenesis and a detailed LC progression model; the latter is specifically intended for the evaluation of screenings. This article elucidates further the principles of MISCAN-lung and describes its application to a comparative study within the CISNET Lung Working Group on the impact of tobacco control on U.S. LC mortality. MISCAN-lung yields an estimate of the number of LC deaths avoided during 1975-2000. The potential number of avoidable LC deaths, had everybody quit smoking in 1965, is 2.2 million; 750,000 deaths (30%) were avoided in the United States due to actual tobacco control interventions. The model fits in the actual tobacco-control scenario, providing credibility to the estimates of other scenarios, although considering survey-reported smoking trends alone has limitations. © 2012 Society for Risk Analysis.

  2. Modeling of weak blast wave propagation in the lung.

    PubMed

    D'yachenko, A I; Manyuhina, O V

    2006-01-01

    Blast injuries of the lung are the most life-threatening after an explosion. The choice of physical parameters responsible for trauma is important to understand its mechanism. We developed a one-dimensional linear model of an elastic wave propagation in foam-like pulmonary parenchyma to identify the possible cause of edema due to the impact load. The model demonstrates different injury localizations for free and rigid boundary conditions. The following parameters were considered: strain, velocity, pressure in the medium and stresses in structural elements, energy dissipation, parameter of viscous criterion. Maximum underpressure is the most suitable wave parameter to be the criterion for edema formation in a rabbit lung. We supposed that observed scattering of experimental data on edema severity is induced by the physiological variety of rabbit lungs. The criterion and the model explain this scattering. The model outlines the demands for experimental data to make an unambiguous choice of physical parameters responsible for lung trauma due to impact load.

  3. THE HUMAN FETAL LUNG XENOGRAFT: VALIDATION AS MODEL OF MICROVASCULAR REMODELING IN THE POSTGLANDULAR LUNG

    PubMed Central

    De Paepe, Monique E.; Chu, Sharon; Hall, Susan; Heger, Nicholas; Thanos, Chris; Mao, Quanfu

    2012-01-01

    Background Coordinated remodeling of epithelium and vasculature is essential for normal postglandular lung development. The value of the human-to-rodent lung xenograft as model of fetal microvascular development remains poorly defined. Aim The aim of this study was to determine the fate of the endogenous (human-derived) microvasculature in fetal lung xenografts. Methods Lung tissues were obtained from spontaneous pregnancy losses (14–22 weeks’ gestation) and implanted in the renal subcapsular or dorsal subcutaneous space of SCID-beige mice (T, B and NK-cell-deficient) and/or nude rats (T-cell-deficient). Informed parental consent was obtained. Lung morphogenesis, microvascular angiogenesis and epithelial differentiation were assessed at two and four weeks post-transplantation by light microscopy, immunohistochemical and gene expression studies. Archival age-matched postmortem lungs served as control. Results The vascular morphology, density and proliferation of renal subcapsular grafts in SCID-beige mice were similar to age-matched control lungs, with preservation of the physiologic association between epithelium and vasculature. The microvasculature of subcutaneous grafts in SCID-beige mice was underdeveloped and dysmorphic, associated with significantly lower VEGF, endoglin, and angiopoietin-2 mRNA expression than renal grafts. Grafts at both sites displayed mild airspace dysplasia. Renal subcapsular grafts in nude rats showed frequent infiltration by host lymphocytes and obliterating bronchiolitis-like changes, associated with markedly decreased endogenous angiogenesis. Conclusion This study demonstrates the critical importance of host and site selection to ensure optimal xenograft development. When transplanted to severely immune suppressed, NK-cell-deficient hosts and engrafted in the renal subcapsular site, the human-to-rodent fetal lung xenograft provides a valid model of postglandular microvascular lung remodeling. PMID:22811288

  4. Lung cancer in never smokers Epidemiology and risk prediction models

    PubMed Central

    McCarthy, William J.; Meza, Rafael; Jeon, Jihyoun; Moolgavkar, Suresh

    2012-01-01

    In this chapter we review the epidemiology of lung cancer incidence and mortality among never smokers/ nonsmokers and describe the never smoker lung cancer risk models used by CISNET modelers. Our review focuses on those influences likely to have measurable population impact on never smoker risk, such as secondhand smoke, even though the individual-level impact may be small. Occupational exposures may also contribute importantly to the population attributable risk of lung cancer. We examine the following risk factors in this chapter: age, environmental tobacco smoke, cooking fumes, ionizing radiation including radon gas, inherited genetic susceptibility, selected occupational exposures, preexisting lung disease, and oncogenic viruses. We also compare the prevalence of never smokers between the three CISNET smoking scenarios and present the corresponding lung cancer mortality estimates among never smokers as predicted by a typical CISNET model. PMID:22882894

  5. Lung Cancer Screening Participation: Developing a Conceptual Model to Guide Research

    PubMed Central

    Carter-Harris, Lisa; Davis, Lorie L.; Rawl, Susan M.

    2017-01-01

    Purpose To describe the development of a conceptual model to guide research focused on lung cancer screening participation from the perspective of the individual in the decision-making process. Methods Based on a comprehensive review of empirical and theoretical literature, a conceptual model was developed linking key psychological variables (stigma, medical mistrust, fatalism, worry, and fear) to the health belief model and precaution adoption process model. Results Proposed model concepts have been examined in prior research of either lung or other cancer screening behavior. To date, a few studies have explored a limited number of variables that influence screening behavior in lung cancer specifically. Therefore, relationships among concepts in the model have been proposed and future research directions presented. Conclusion This proposed model is an initial step to support theoretically based research. As lung cancer screening becomes more widely implemented, it is critical to theoretically guide research to understand variables that may be associated with lung cancer screening participation. Findings from future research guided by the proposed conceptual model can be used to refine the model and inform tailored intervention development. PMID:28304262

  6. Lung Cancer Screening Participation: Developing a Conceptual Model to Guide Research.

    PubMed

    Carter-Harris, Lisa; Davis, Lorie L; Rawl, Susan M

    2016-11-01

    To describe the development of a conceptual model to guide research focused on lung cancer screening participation from the perspective of the individual in the decision-making process. Based on a comprehensive review of empirical and theoretical literature, a conceptual model was developed linking key psychological variables (stigma, medical mistrust, fatalism, worry, and fear) to the health belief model and precaution adoption process model. Proposed model concepts have been examined in prior research of either lung or other cancer screening behavior. To date, a few studies have explored a limited number of variables that influence screening behavior in lung cancer specifically. Therefore, relationships among concepts in the model have been proposed and future research directions presented. This proposed model is an initial step to support theoretically based research. As lung cancer screening becomes more widely implemented, it is critical to theoretically guide research to understand variables that may be associated with lung cancer screening participation. Findings from future research guided by the proposed conceptual model can be used to refine the model and inform tailored intervention development.

  7. Chronic inorganic arsenic exposure in vitro induces a cancer cell phenotype in human peripheral lung epithelial cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Person, Rachel J.; Olive Ngalame, Ntube N.; Makia, Ngome L.

    Inorganic arsenic is a human lung carcinogen. We studied the ability of chronic inorganic arsenic (2 μM; as sodium arsenite) exposure to induce a cancer phenotype in the immortalized, non-tumorigenic human lung peripheral epithelial cell line, HPL-1D. After 38 weeks of continuous arsenic exposure, secreted matrix metalloproteinase-2 (MMP2) activity increased to over 200% of control, levels linked to arsenic-induced cancer phenotypes in other cell lines. The invasive capacity of these chronic arsenic-treated lung epithelial (CATLE) cells increased to 320% of control and colony formation increased to 280% of control. CATLE cells showed enhanced proliferation in serum-free media indicative of autonomousmore » growth. Compared to control cells, CATLE cells showed reduced protein expression of the tumor suppressor gene PTEN (decreased to 26% of control) and the putative tumor suppressor gene SLC38A3 (14% of control). Morphological evidence of epithelial-to-mesenchymal transition (EMT) occurred in CATLE cells together with appropriate changes in expression of the EMT markers vimentin (VIM; increased to 300% of control) and e-cadherin (CDH1; decreased to 16% of control). EMT is common in carcinogenic transformation of epithelial cells. CATLE cells showed increased KRAS (291%), ERK1/2 (274%), phosphorylated ERK (p-ERK; 152%), and phosphorylated AKT1 (p-AKT1; 170%) protein expression. Increased transcript expression of metallothioneins, MT1A and MT2A and the stress response genes HMOX1 (690%) and HIF1A (247%) occurred in CATLE cells possibly in adaptation to chronic arsenic exposure. Thus, arsenic induced multiple cancer cell characteristics in human peripheral lung epithelial cells. This model may be useful to assess mechanisms of arsenic-induced lung cancer. - Highlights: • Chronic arsenic exposure transforms a human peripheral lung epithelia cell line. • Cells acquire characteristics in common with human lung adenocarcinoma cells. • These transformed cells

  8. Lung lobe modeling and segmentation with individualized surface meshes

    NASA Astrophysics Data System (ADS)

    Blaffert, Thomas; Barschdorf, Hans; von Berg, Jens; Dries, Sebastian; Franz, Astrid; Klinder, Tobias; Lorenz, Cristian; Renisch, Steffen; Wiemker, Rafael

    2008-03-01

    An automated segmentation of lung lobes in thoracic CT images is of interest for various diagnostic purposes like the quantification of emphysema or the localization of tumors within the lung. Although the separating lung fissures are visible in modern multi-slice CT-scanners, their contrast in the CT-image often does not separate the lobes completely. This makes it impossible to build a reliable segmentation algorithm without additional information. Our approach uses general anatomical knowledge represented in a geometrical mesh model to construct a robust lobe segmentation, which even gives reasonable estimates of lobe volumes if fissures are not visible at all. The paper describes the generation of the lung model mesh including lobes by an average volume model, its adaptation to individual patient data using a special fissure feature image, and a performance evaluation over a test data set showing an average segmentation accuracy of 1 to 3 mm.

  9. A Lung Segmental Model of Chronic Pseudomonas Infection in Sheep

    PubMed Central

    Collie, David; Govan, John; Wright, Steven; Thornton, Elisabeth; Tennant, Peter; Smith, Sionagh; Doherty, Catherine; McLachlan, Gerry

    2013-01-01

    Background Chronic lung infection with Pseudomonas aeruginosa is a major contributor to morbidity, mortality and premature death in cystic fibrosis. A new paradigm for managing such infections is needed, as are relevant and translatable animal models to identify and test concepts. We sought to improve on limitations associated with existing models of infection in small animals through developing a lung segmental model of chronic Pseudomonas infection in sheep. Methodology/Principal Findings Using local lung instillation of P. aeruginosa suspended in agar beads we were able to demonstrate that such infection led to the development of a suppurative, necrotising and pyogranulomatous pneumonia centred on the instilled beads. No overt evidence of organ or systemic compromise was apparent in any animal during the course of infection. Infection persisted in the lungs of individual animals for as long as 66 days after initial instillation. Quantitative microbiology applied to bronchoalveolar lavage fluid derived from infected segments proved an insensitive index of the presence of significant infection in lung tissue (>104 cfu/g). Conclusions/Significance The agar bead model of chronic P. aeruginosa lung infection in sheep is a relevant platform to investigate both the pathobiology of such infections as well as novel approaches to their diagnosis and therapy. Particular ethical benefits relate to the model in terms of refining existing approaches by compromising a smaller proportion of the lung with infection and facilitating longitudinal assessment by bronchoscopy, and also potentially reducing animal numbers through facilitating within-animal comparisons of differential therapeutic approaches. PMID:23874438

  10. Lung Cancer Risk Prediction Models

    Cancer.gov

    Developing statistical models that estimate the probability of developing lung cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  11. Expression Analysis of the Transmembrane Mucin MUC20 in Human Corneal and Conjunctival Epithelia

    PubMed Central

    Woodward, Ashley M.; Argüeso, Pablo

    2014-01-01

    Purpose. Cell surface mucins are a group of highly O-glycosylated transmembrane glycoproteins responsible for the protection of epithelial cells on mucosal surfaces. The aim of this study was to investigate the localization and regulation of mucin 20 (MUC20) at the ocular surface. Methods. Localization of MUC20 in human corneal and conjunctival epithelia was evaluated by immunofluorescence microscopy. Immortalized corneal (HCLE) and conjunctival (HCjE) cell lines were grown at different stages of differentiation and subjected to quantitative PCR and Western blot analyses. Cell surface proteins on apical cell membranes were biotinylated and isolated by neutravidin chromatography. Results. The MUC20 was detected throughout the entire human ocular surface epithelia, predominantly in cell membranes within intermediate cell layers. In conjunctiva, MUC20 also was observed in the cytoplasm of apical cells within the stratified squamous epithelium, but not in goblet cells. Quantitative PCR and immunoblotting demonstrated expression of MUC20 in HCLE and HCjE cells. Induction of differentiation with serum-containing medium resulted in upregulation of MUC20 mRNA and protein. Biotin labeling of the surface of stratified cultures revealed low levels of MUC20 protein on apical glycocalyces. Further, MUC20 was not detected in the cell culture media or in human tears, suggesting that the extracellular domain of MUC20 is not released from the ocular surface as described previously for other cell surface mucins. Conclusions. Our results indicate that MUC20 is a novel transmembrane mucin expressed by the human corneal and conjunctival epithelia, and suggest that differential expression of MUC20 during differentiation has a role in maintaining ocular surface homeostasis. PMID:25168902

  12. Apical targeting of the formin Diaphanous in Drosophila tubular epithelia

    PubMed Central

    Rousso, Tal; Shewan, Annette M; Mostov, Keith E; Schejter, Eyal D; Shilo, Ben-Zion

    2013-01-01

    Apical secretion from epithelial tubes of the Drosophila embryo is mediated by apical F-actin cables generated by the formin-family protein Diaphanous (Dia). Apical localization and activity of Dia are at the core of restricting F-actin formation to the correct membrane domain. Here we identify the mechanisms that target Dia to the apical surface. PI(4,5)P2 levels at the apical membrane regulate Dia localization in both the MDCK cyst model and in Drosophila tubular epithelia. An N-terminal basic domain of Dia is crucial for apical localization, implying direct binding to PI(4,5)P2. Dia apical targeting also depends on binding to Rho1, which is critical for activation-induced conformational change, as well as physically anchoring Dia to the apical membrane. We demonstrate that binding to Rho1 facilitates interaction with PI(4,5)P2 at the plane of the membrane. Together these cues ensure efficient and distinct restriction of Dia to the apical membrane. DOI: http://dx.doi.org/10.7554/eLife.00666.001 PMID:23853710

  13. Anatomy and bronchoscopy of the porcine lung. A model for translational respiratory medicine.

    PubMed

    Judge, Eoin P; Hughes, J M Lynne; Egan, Jim J; Maguire, Michael; Molloy, Emer L; O'Dea, Shirley

    2014-09-01

    The porcine model has contributed significantly to biomedical research over many decades. The similar size and anatomy of pig and human organs make this model particularly beneficial for translational research in areas such as medical device development, therapeutics and xenotransplantation. In recent years, a major limitation with the porcine model was overcome with the successful generation of gene-targeted pigs and the publication of the pig genome. As a result, the role of this model is likely to become even more important. For the respiratory medicine field, the similarities between pig and human lungs give the porcine model particular potential for advancing translational medicine. An increasing number of lung conditions are being studied and modeled in the pig. Genetically modified porcine models of cystic fibrosis have been generated that, unlike mouse models, develop lung disease similar to human cystic fibrosis. However, the scientific literature relating specifically to porcine lung anatomy and airway histology is limited and is largely restricted to veterinary literature and textbooks. Furthermore, methods for in vivo lung procedures in the pig are rarely described. The aims of this review are to collate the disparate literature on porcine lung anatomy, histology, and microbiology; to provide a comparison with the human lung; and to describe appropriate bronchoscopy procedures for the pig lungs to aid clinical researchers working in the area of translational respiratory medicine using the porcine model.

  14. Sensitivity of tumor motion simulation accuracy to lung biomechanical modeling approaches and parameters.

    PubMed

    Tehrani, Joubin Nasehi; Yang, Yin; Werner, Rene; Lu, Wei; Low, Daniel; Guo, Xiaohu; Wang, Jing

    2015-11-21

    Finite element analysis (FEA)-based biomechanical modeling can be used to predict lung respiratory motion. In this technique, elastic models and biomechanical parameters are two important factors that determine modeling accuracy. We systematically evaluated the effects of lung and lung tumor biomechanical modeling approaches and related parameters to improve the accuracy of motion simulation of lung tumor center of mass (TCM) displacements. Experiments were conducted with four-dimensional computed tomography (4D-CT). A Quasi-Newton FEA was performed to simulate lung and related tumor displacements between end-expiration (phase 50%) and other respiration phases (0%, 10%, 20%, 30%, and 40%). Both linear isotropic and non-linear hyperelastic materials, including the neo-Hookean compressible and uncoupled Mooney-Rivlin models, were used to create a finite element model (FEM) of lung and tumors. Lung surface displacement vector fields (SDVFs) were obtained by registering the 50% phase CT to other respiration phases, using the non-rigid demons registration algorithm. The obtained SDVFs were used as lung surface displacement boundary conditions in FEM. The sensitivity of TCM displacement to lung and tumor biomechanical parameters was assessed in eight patients for all three models. Patient-specific optimal parameters were estimated by minimizing the TCM motion simulation errors between phase 50% and phase 0%. The uncoupled Mooney-Rivlin material model showed the highest TCM motion simulation accuracy. The average TCM motion simulation absolute errors for the Mooney-Rivlin material model along left-right, anterior-posterior, and superior-inferior directions were 0.80 mm, 0.86 mm, and 1.51 mm, respectively. The proposed strategy provides a reliable method to estimate patient-specific biomechanical parameters in FEM for lung tumor motion simulation.

  15. Ion Transport by Pulmonary Epithelia

    PubMed Central

    Hollenhorst, Monika I.; Richter, Katrin; Fronius, Martin

    2011-01-01

    The lung surface of air-breathing vertebrates is formed by a continuous epithelium that is covered by a fluid layer. In the airways, this epithelium is largely pseudostratified consisting of diverse cell types such as ciliated cells, goblet cells, and undifferentiated basal cells, whereas the alveolar epithelium consists of alveolar type I and alveolar type II cells. Regulation and maintenance of the volume and viscosity of the fluid layer covering the epithelium is one of the most important functions of the epithelial barrier that forms the outer surface area of the lungs. Therefore, the epithelial cells are equipped with a wide variety of ion transport proteins, among which Na+, Cl−, and K+ channels have been identified to play a role in the regulation of the fluid layer. Malfunctions of pulmonary epithelial ion transport processes and, thus, impairment of the liquid balance in our lungs is associated with severe diseases, such as cystic fibrosis and pulmonary oedema. Due to the important role of pulmonary epithelial ion transport processes for proper lung function, the present paper summarizes the recent findings about composition, function, and ion transport properties of the airway epithelium as well as of the alveolar epithelium. PMID:22131798

  16. Automated Image Analysis of Lung Branching Morphogenesis from Microscopic Images of Fetal Rat Explants

    PubMed Central

    Rodrigues, Pedro L.; Rodrigues, Nuno F.; Duque, Duarte; Granja, Sara; Correia-Pinto, Jorge; Vilaça, João L.

    2014-01-01

    Background. Regulating mechanisms of branching morphogenesis of fetal lung rat explants have been an essential tool for molecular research. This work presents a new methodology to accurately quantify the epithelial, outer contour, and peripheral airway buds of lung explants during cellular development from microscopic images. Methods. The outer contour was defined using an adaptive and multiscale threshold algorithm whose level was automatically calculated based on an entropy maximization criterion. The inner lung epithelium was defined by a clustering procedure that groups small image regions according to the minimum description length principle and local statistical properties. Finally, the number of peripheral buds was counted as the skeleton branched ends from a skeletonized image of the lung inner epithelia. Results. The time for lung branching morphometric analysis was reduced in 98% in contrast to the manual method. Best results were obtained in the first two days of cellular development, with lesser standard deviations. Nonsignificant differences were found between the automatic and manual results in all culture days. Conclusions. The proposed method introduces a series of advantages related to its intuitive use and accuracy, making the technique suitable to images with different lighting characteristics and allowing a reliable comparison between different researchers. PMID:25250057

  17. Ruminal and Abomasal Starch Hydrolysate Infusions Selectively Decrease the Expression of Cationic Amino Acid Transporter mRNA by Small Intestinal Epithelia of Forage-fed Beef Steers

    USDA-ARS?s Scientific Manuscript database

    Although cationic amino acids (CAA) are consid-ered essential to maximize optimal growth of cattle, transporters responsible for CAA absorption by bovine small intestinal epithelia have not been described. This study was conducted to test 2 hypotheses: 1) the duo¬denal, jejunal, and ileal epithelia ...

  18. Characterizing human vestibular sensory epithelia for experimental studies: new hair bundles on old tissue and implications for therapeutic interventions in ageing

    PubMed Central

    Taylor, Ruth R.; Jagger, Daniel J.; Saeed, Shakeel R.; Axon, Patrick; Donnelly, Neil; Tysome, James; Moffatt, David; Irving, Richard; Monksfield, Peter; Coulson, Chris; Freeman, Simon R.; Lloyd, Simon K.; Forge, Andrew

    2015-01-01

    Balance disequilibrium is a significant contributor to falls in the elderly. The most common cause of balance dysfunction is loss of sensory cells from the vestibular sensory epithelia of the inner ear. However, inaccessibility of inner ear tissue in humans severely restricts possibilities for experimental manipulation to develop therapies to ameliorate this loss. We provide a structural and functional analysis of human vestibular sensory epithelia harvested at trans-labyrinthine surgery. We demonstrate the viability of the tissue and labeling with specific markers of hair cell function and of ion homeostasis in the epithelium. Samples obtained from the oldest patients revealed a significant loss of hair cells across the tissue surface, but we found immature hair bundles present in epithelia harvested from patients >60 years of age. These results suggest that the environment of the human vestibular sensory epithelium could be responsive to stimulation of developmental pathways to enhance hair cell regeneration, as has been demonstrated successfully in the vestibular organs of adult mice. PMID:25818177

  19. Sensitivity of Tumor Motion Simulation Accuracy to Lung Biomechanical Modeling Approaches and Parameters

    PubMed Central

    Tehrani, Joubin Nasehi; Yang, Yin; Werner, Rene; Lu, Wei; Low, Daniel; Guo, Xiaohu

    2015-01-01

    Finite element analysis (FEA)-based biomechanical modeling can be used to predict lung respiratory motion. In this technique, elastic models and biomechanical parameters are two important factors that determine modeling accuracy. We systematically evaluated the effects of lung and lung tumor biomechanical modeling approaches and related parameters to improve the accuracy of motion simulation of lung tumor center of mass (TCM) displacements. Experiments were conducted with four-dimensional computed tomography (4D-CT). A Quasi-Newton FEA was performed to simulate lung and related tumor displacements between end-expiration (phase 50%) and other respiration phases (0%, 10%, 20%, 30%, and 40%). Both linear isotropic and non-linear hyperelastic materials, including the Neo-Hookean compressible and uncoupled Mooney-Rivlin models, were used to create a finite element model (FEM) of lung and tumors. Lung surface displacement vector fields (SDVFs) were obtained by registering the 50% phase CT to other respiration phases, using the non-rigid demons registration algorithm. The obtained SDVFs were used as lung surface displacement boundary conditions in FEM. The sensitivity of TCM displacement to lung and tumor biomechanical parameters was assessed in eight patients for all three models. Patient-specific optimal parameters were estimated by minimizing the TCM motion simulation errors between phase 50% and phase 0%. The uncoupled Mooney-Rivlin material model showed the highest TCM motion simulation accuracy. The average TCM motion simulation absolute errors for the Mooney-Rivlin material model along left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions were 0.80 mm, 0.86 mm, and 1.51 mm, respectively. The proposed strategy provides a reliable method to estimate patient-specific biomechanical parameters in FEM for lung tumor motion simulation. PMID:26531324

  20. Animal Models in Carotenoids Research and Lung Cancer Prevention1

    PubMed Central

    Kim, Jina; Kim, Yuri

    2011-01-01

    Numerous epidemiological studies have consistently demonstrated that individuals who eat more fruits and vegetables (which are rich in carotenoids) and who have higher serum β-carotene levels have a lower risk of cancer, especially lung cancer. However, two human intervention trials conducted in Finland and in the United States have reported contrasting results with high doses of β-carotene supplementation increasing the risk of lung cancer among smokers. The failure of these trials to demonstrate actual efficacy has resulted in the initiation of animal studies to reproduce the findings of these two studies and to elucidate the mechanisms responsible for the harmful or protective effects of carotenoids in lung carcinogenesis. Although these studies have been limited by a lack of animal models that appropriately represent human lung cancer induced by cigarette smoke, ferrets and A/J mice are currently the most widely used models for these types of studies. There are several proposed mechanisms for the protective effects of carotenoids on cigarette smoke-induced lung carcinogenesis, and these include antioxidant/prooxidant effects, modulation of retinoic acid signaling pathway and metabolism, induction of cytochrome P450, and molecular signaling involved in cell proliferation and/or apoptosis. The technical challenges associated with animal models include strain-specific and diet-specific effects, differences in the absorption and distribution of carotenoids, and differences in the interactions of carotenoids with other antioxidants. Despite the problems associated with extrapolating from animal models to humans, the understanding and development of various animal models may provide useful information regarding the protective effects of carotenoids against lung carcinogenesis. PMID:21966544

  1. Interleukin-8 responses of multi-layer gingival epithelia to subgingival biofilms: role of the "red complex" species.

    PubMed

    Belibasakis, Georgios N; Thurnheer, Thomas; Bostanci, Nagihan

    2013-01-01

    Periodontitis is an infectious inflammatory disease that results in the destruction of the tooth-supporting (periodontal) tissues. The Gram-negative anaerobic species Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola, (also known as the "red complex" species) are highly associated with subgingival biofilms at periodontitis-affected sites. A major chemokine produced by the gingival epithelium in response to biofilm challenge, is interleukin (IL)-8. The aim of this in vitro study was to investigate the relative effect of the "red complex" species as constituents of subgingival biofilms, on the regulation of IL-8 by gingival epithelia. Multi-layered organotypic human gingival epithelial cultures were challenged with a 10-species in vitro subgingival biofilm model, or its 7-species variant, excluding the "red complex". IL-8 gene expression and secretion analyses were performed by qPCR and ELISA, respectively. After 3 h, both biofilms up-regulated IL-8 gene expression, but the presence of the "red complex" resulted in 3-fold greater response. IL-8 secretion was also up-regulated by both biofilms, with no differences between them. After 24 h, the 10-species biofilm reduced IL-8 secretion to 50% of the control, but this was not affected when the "red complex" was absent. In conclusion, as part of biofilms, "red complex" species differentially regulate IL-8 in gingival epithelia, potentially affecting the chemotactic responses of the tissue.

  2. Towards a virtual lung: multi-scale, multi-physics modelling of the pulmonary system.

    PubMed

    Burrowes, K S; Swan, A J; Warren, N J; Tawhai, M H

    2008-09-28

    The essential function of the lung, gas exchange, is dependent on adequate matching of ventilation and perfusion, where air and blood are delivered through complex branching systems exposed to regionally varying transpulmonary and transmural pressures. Structure and function in the lung are intimately related, yet computational models in pulmonary physiology usually simplify or neglect structure. The geometries of the airway and vascular systems and their interaction with parenchymal tissue have an important bearing on regional distributions of air and blood, and therefore on whole lung gas exchange, but this has not yet been addressed by modelling studies. Models for gas exchange have typically incorporated considerable detail at the level of chemical reactions, with little thought for the influence of structure. To date, relatively little attention has been paid to modelling at the cellular or subcellular level in the lung, or to linking information from the protein structure/interaction and cellular levels to the operation of the whole lung. We review previous work in developing anatomically based models of the lung, airways, parenchyma and pulmonary vasculature, and some functional studies in which these models have been used. Models for gas exchange at several spatial scales are briefly reviewed, and the challenges and benefits from modelling cellular function in the lung are discussed.

  3. Expression profile of undifferentiated cell transcription factor 1 in normal and cancerous human epithelia.

    PubMed

    Mouallif, Mustapha; Albert, Adelin; Zeddou, Mustapha; Ennaji, My Mustapha; Delvenne, Philippe; Guenin, Samuel

    2014-08-01

    Undifferentiated cell Transcription Factor 1 (UTF1) is a chromatin-bound protein involved in stem cell differentiation. It was initially reported to be restricted to stem cells or germinal tissues. However, recent work suggests that UTF1 is also expressed in somatic cells and that its expression may increase during carcinogenesis. To further clarify the expression profile of UTF1, we evaluated UTF1 expression levels immunohistochemically in eight normal human epithelia (from breast, prostate, endometrium, bladder, colon, oesophagus, lung and kidney) and their corresponding tumours as well as in several epithelial cell lines. We showed UTF1 staining in normal and tumour epithelial tissues, but with varying intensities according to the tissue location. In vitro analyses also revealed that UTF1 is expressed in somatic epithelial cell lines even in the absence of Oct4A and Sox2, its two main known regulators. The comparison of UTF1 levels in normal and tumoral tissues revealed significant overexpression in endometrial and prostatic adenocarcinomas, whereas lower intensity of the staining was observed in renal and colic tumours, suggesting a potential tissue-specific function of UTF1. Altogether, these results highlight a potential dual role for UTF1, acting either as an oncogene or as a tumour suppressor depending on the tissue. These findings also question its role as a specific marker for stem cells. © 2014 The Authors. International Journal of Experimental Pathology © 2014 International Journal of Experimental Pathology.

  4. Optimal flow conditions of a tracheobronchial model to reengineer lung structures

    NASA Astrophysics Data System (ADS)

    Casarin, Stefano; Aletti, Federico; Baselli, Giuseppe; Garbey, Marc

    2017-04-01

    The high demand for lung transplants cannot be matched by an adequate number of lungs from donors. Since fully ex-novo lungs are far from being feasible, tissue engineering is actively considering implantation of engineered lungs where the devitalized structure of a donor is used as scaffold to be repopulated by stem cells of the receiving patient. A decellularized donated lung is treated inside a bioreactor where transport through the tracheobronchial tree (TBT) will allow for both deposition of stem cells and nourishment for their subsequent growth, thus developing new lung tissue. The key concern is to set optimally the boundary conditions to utilize in the bioreactor. We propose a predictive model of slow liquid ventilation, which combines a one-dimensional (1-D) mathematical model of the TBT and a solute deposition model strongly dependent on fluid velocity across the tree. With it, we were able to track and drive the concentration of a generic solute across the airways, looking for its optimal distribution. This was given by properly adjusting the pumps' regime serving the bioreactor. A feedback system, created by coupling the two models, allowed us to derive the optimal pattern. The TBT model can be easily invertible, thus yielding a straightforward flow/pressure law at the inlet to optimize the efficiency of the bioreactor.

  5. A 4DCT imaging-based breathing lung model with relative hysteresis

    NASA Astrophysics Data System (ADS)

    Miyawaki, Shinjiro; Choi, Sanghun; Hoffman, Eric A.; Lin, Ching-Long

    2016-12-01

    To reproduce realistic airway motion and airflow, the authors developed a deforming lung computational fluid dynamics (CFD) model based on four-dimensional (4D, space and time) dynamic computed tomography (CT) images. A total of 13 time points within controlled tidal volume respiration were used to account for realistic and irregular lung motion in human volunteers. Because of the irregular motion of 4DCT-based airways, we identified an optimal interpolation method for airway surface deformation during respiration, and implemented a computational solid mechanics-based moving mesh algorithm to produce smooth deforming airway mesh. In addition, we developed physiologically realistic airflow boundary conditions for both models based on multiple images and a single image. Furthermore, we examined simplified models based on one or two dynamic or static images. By comparing these simplified models with the model based on 13 dynamic images, we investigated the effects of relative hysteresis of lung structure with respect to lung volume, lung deformation, and imaging methods, i.e., dynamic vs. static scans, on CFD-predicted pressure drop. The effect of imaging method on pressure drop was 24 percentage points due to the differences in airflow distribution and airway geometry.

  6. A 4DCT imaging-based breathing lung model with relative hysteresis

    PubMed Central

    Miyawaki, Shinjiro; Choi, Sanghun; Hoffman, Eric A.; Lin, Ching-Long

    2016-01-01

    To reproduce realistic airway motion and airflow, the authors developed a deforming lung computational fluid dynamics (CFD) model based on four-dimensional (4D, space and time) dynamic computed tomography (CT) images. A total of 13 time points within controlled tidal volume respiration were used to account for realistic and irregular lung motion in human volunteers. Because of the irregular motion of 4DCT-based airways, we identified an optimal interpolation method for airway surface deformation during respiration, and implemented a computational solid mechanics-based moving mesh algorithm to produce smooth deforming airway mesh. In addition, we developed physiologically realistic airflow boundary conditions for both models based on multiple images and a single image. Furthermore, we examined simplified models based on one or two dynamic or static images. By comparing these simplified models with the model based on 13 dynamic images, we investigated the effects of relative hysteresis of lung structure with respect to lung volume, lung deformation, and imaging methods, i.e., dynamic vs. static scans, on CFD-predicted pressure drop. The effect of imaging method on pressure drop was 24 percentage points due to the differences in airflow distribution and airway geometry. PMID:28260811

  7. Pseudotyped adeno-associated virus 2/9-delivered CCL11 shRNA alleviates lung inflammation in an allergen-sensitized mouse model.

    PubMed

    Wu, Chia-Jen; Huang, Wen-Chung; Chen, Li-Chen; Shen, Chia-Rui; Kuo, Ming-Ling

    2012-11-01

    Airway infiltration by eosinophils is a major characteristic of chronic asthma. CCL11 (eotaxin-1) is secreted by lung epithelial cells and functions as the major chemokine for eosinophil recruitment. Pseudotyped adeno-associated virus (AAV) 2/9, composed by the AAV2 rep and AAV9 cap genes, can efficiently target lung epithelial cells and might carry gene sequences with therapeutic potential for asthma. This study aimed to determine whether pseudotyped AAV2/9 virus carrying the small hairpin RNA targeting CCL11 and expressed by CMV/U6 promoter could reduce eosinophilia and asthmatic responses in mite allergen-sensitized mice. Mice were sensitized by intraperitoneal and challenged by intratracheal injection with recombinant Dermatophagoides pteronyssinus group 2 allergen (rDp2). AAV2/9 viral vectors were intratracheally injected three days before the first challenge. AAV2/9 sh47 virus significantly reduced airway hyperresponsiveness, airway resistance, CCL11 levels, and eosinophilia in the lungs of sensitized mice. Th2 cytokines, including interleukins (IL)-4, IL-5, and IL-10, were also significantly reduced in the bronchoalveolar lavage fluid of AAV2/9 sh47 virus-treated mice. Th2 cytokine levels were also reduced in rDp2-stimulated mediastinal lymphocytes in treated mice. However, serum levels of rDp2-specific IgG1 and IgE, as well as Th2 cytokine levels in rDp2-stimulated splenocyte culture supernatants, were comparable to the sensitized control group. The results suggest that AAV2/9 sh47 virus relieved local instead of systemic inflammatory responses. Therefore, the CMV/U6 promoter with AAV2/9 viral vector, which is preferable to target lung epithelia cells, might be applied as a novel therapeutic approach for asthma.

  8. Pseudotyped Adeno-Associated Virus 2/9-Delivered CCL11 shRNA Alleviates Lung Inflammation in an Allergen-Sensitized Mouse Model

    PubMed Central

    Wu, Chia-Jen; Huang, Wen-Chung; Chen, Li-Chen; Shen, Chia-Rui

    2012-01-01

    Abstract Airway infiltration by eosinophils is a major characteristic of chronic asthma. CCL11 (eotaxin-1) is secreted by lung epithelial cells and functions as the major chemokine for eosinophil recruitment. Pseudotyped adeno-associated virus (AAV) 2/9, composed by the AAV2 rep and AAV9 cap genes, can efficiently target lung epithelial cells and might carry gene sequences with therapeutic potential for asthma. This study aimed to determine whether pseudotyped AAV2/9 virus carrying the small hairpin RNA targeting CCL11 and expressed by CMV/U6 promoter could reduce eosinophilia and asthmatic responses in mite allergen-sensitized mice. Mice were sensitized by intraperitoneal and challenged by intratracheal injection with recombinant Dermatophagoides pteronyssinus group 2 allergen (rDp2). AAV2/9 viral vectors were intratracheally injected three days before the first challenge. AAV2/9 sh47 virus significantly reduced airway hyperresponsiveness, airway resistance, CCL11 levels, and eosinophilia in the lungs of sensitized mice. Th2 cytokines, including interleukins (IL)-4, IL-5, and IL-10, were also significantly reduced in the bronchoalveolar lavage fluid of AAV2/9 sh47 virus-treated mice. Th2 cytokine levels were also reduced in rDp2-stimulated mediastinal lymphocytes in treated mice. However, serum levels of rDp2-specific IgG1 and IgE, as well as Th2 cytokine levels in rDp2-stimulated splenocyte culture supernatants, were comparable to the sensitized control group. The results suggest that AAV2/9 sh47 virus relieved local instead of systemic inflammatory responses. Therefore, the CMV/U6 promoter with AAV2/9 viral vector, which is preferable to target lung epithelia cells, might be applied as a novel therapeutic approach for asthma. PMID:22913580

  9. Clearance of Apoptotic Cells by Tissue Epithelia: A Putative Role for Hepatocytes in Liver Efferocytosis

    PubMed Central

    Davies, Scott P.; Reynolds, Gary M.; Stamataki, Zania

    2018-01-01

    Toxic substances and microbial or food-derived antigens continuously challenge the liver, which is tasked with their safe neutralization. This vital organ is also important for the removal of apoptotic immune cells during inflammation and has been previously described as a “graveyard” for dying lymphocytes. The clearance of apoptotic and necrotic cells is known as efferocytosis and is a critical liver function to maintain tissue homeostasis. Much of the research into this form of immunological control has focused on Kupffer cells, the liver-resident macrophages. However, hepatocytes (and other liver resident cells) are competent efferocytes and comprise 80% of the liver mass. Little is known regarding the mechanisms of apoptotic and necrotic cell capture by epithelia, which lack key receptors that mediate phagocytosis in macrophages. Herein, we discuss recent developments that increased our understanding of efferocytosis in tissues, with a special focus on the liver parenchyma. We discuss the impact of efferocytosis in health and in inflammation, highlighting the role of phagocytic epithelia. PMID:29422896

  10. CD4+ T Cell Help Guides Formation of CD103+ Lung-Resident Memory CD8+ T Cells during Influenza Viral Infection

    PubMed Central

    Laidlaw, Brian J.; Zhang, Nianzhi; Marshall, Heather D.; Staron, Mathew M.; Guan, Tianxia; Hu, Yinghong; Cauley, Linda S.; Craft, Joe; Kaech, Susan M.

    2014-01-01

    SUMMARY Tissue-resident memory T (Trm) cells provide enhanced protection against infection at mucosal sites. Here we found that CD4+ T cells are important for the formation of functional lung-resident CD8+ T cells after influenza virus infection. In the absence of CD4+ T cells, CD8+ T cells displayed reduced expression of CD103 (Itgae), were mislocalized away from airway epithelia, and demonstrated an impaired ability to recruit CD8+ T cells to the lung air-ways upon heterosubtypic challenge. CD4+ T cell-derived interferon-γ was necessary for generating lung-resident CD103+ CD8+ Trm CD8 T cells. Furthermore, expression of the transcription factor T-bet was increased in “unhelped” lung Trm cells, and a reduction in T-bet rescued CD103 expression in the absence of CD4+ T cell help. Thus, CD4+ T cell-dependent signals are important to limit expression of T-bet and allow for the development of CD103+ CD8+ Trm cells in the lung airways following respiratory infection. PMID:25308332

  11. Proteomic analysis of rainbow trout (Oncorhynchus mykiss) intestinal epithelia: physiological acclimation to short-term starvation.

    PubMed

    Baumgarner, Bradley L; Bharadwaj, Anant S; Inerowicz, Dorota; Goodman, Angela S; Brown, Paul B

    2013-03-01

    The intestinal epithelia form the first line of defense against harmful agents in the gut lumen of most monogastric vertebrates, including teleost fishes. Previous investigations into the effect of starvation on the intestinal epithelia of teleost fishes have focused primarily on changes in morphological characteristics and targeted molecular analysis of specific enzymes. The goal of this study was to use a comprehensive approach to help reveal how the intestinal epithelia of carnivorous teleost fishes acclimate to short-term nutrient deprivation. We utilized two-dimensional gel electrophoresis (2-DE) to conduct the proteomic analysis of the mucosal and epithelial layer of the anterior gut intestinal tract (GIT) from satiation fed vs. 4 week starved rainbow trout (Oncorhynchus mykiss). A total of 40 proteins were determined to be differentially expressed and were subsequently picked for in-gel trypsin digestion. Peptide mass fingerprint analysis was conducted using matrix assisted laser desorption time-of-flight/time-of-flight. Nine of the 11 positively identified proteins were directly related to innate immunity. The expression of α-1 proteinase inhibitor decreased in starved vs. fed fish. Also, the concentration of one leukocyte elastase inhibitor (LEI) isomer decreased in starved fish, though the concentration of another LEI isomer increased in due to starvation. In addition, starvation promoted an increased concentration of the important xenobiotic-transporter p-glycoprotein. Finally, starvation resulted in a significant increase in type II keratin E2. Overall, our results indicate that starvation promoted a reduced capacity to inhibit enzymatic stress but increased xenobiotic resistance and paracellular permeability of epithelial cells in the anterior intestine of rainbow trout. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. RECONSTRUCTION OF A HUMAN LUNG MORPHOLOGY MODEL FROM MAGNETIC RESONANCE IMAGES

    EPA Science Inventory

    RATIONALE A description of lung morphological structure is necessary for modeling the deposition and fate of inhaled therapeutic aerosols. A morphological model of the lung boundary was generated from magnetic resonance (MR) images with the goal of creating a framework for anato...

  13. Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice.

    PubMed

    Li, Kun; Wohlford-Lenane, Christine L; Channappanavar, Rudragouda; Park, Jung-Eun; Earnest, James T; Bair, Thomas B; Bates, Amber M; Brogden, Kim A; Flaherty, Heather A; Gallagher, Tom; Meyerholz, David K; Perlman, Stanley; McCray, Paul B

    2017-04-11

    The Middle East respiratory syndrome (MERS) emerged in Saudi Arabia in 2012, caused by a zoonotically transmitted coronavirus (CoV). Over 1,900 cases have been reported to date, with ∼36% fatality rate. Lack of autopsies from MERS cases has hindered understanding of MERS-CoV pathogenesis. A small animal model that develops progressive pulmonary manifestations when infected with MERS-CoV would advance the field. As mice are restricted to infection at the level of DPP4, the MERS-CoV receptor, we generated mice with humanized exons 10-12 of the mouse Dpp4 locus. Upon inoculation with MERS-CoV, human DPP4 knockin (KI) mice supported virus replication in the lungs, but developed no illness. After 30 serial passages through the lungs of KI mice, a mouse-adapted virus emerged (MERS MA ) that grew in lungs to over 100 times higher titers than the starting virus. A plaque-purified MERS MA clone caused weight loss and fatal infection. Virus antigen was observed in airway epithelia, pneumocytes, and macrophages. Pathologic findings included diffuse alveolar damage with pulmonary edema and hyaline membrane formation associated with accumulation of activated inflammatory monocyte-macrophages and neutrophils in the lungs. Relative to the parental MERS-CoV, MERS MA viruses contained 13-22 mutations, including several within the spike (S) glycoprotein gene. S-protein mutations sensitized viruses to entry-activating serine proteases and conferred more rapid entry kinetics. Recombinant MERS MA bearing mutant S proteins were more virulent than the parental virus in hDPP4 KI mice. The hDPP4 KI mouse and the MERS MA provide tools to investigate disease causes and develop new therapies.

  14. A human lung xenograft mouse model of Nipah virus infection.

    PubMed

    Valbuena, Gustavo; Halliday, Hailey; Borisevich, Viktoriya; Goez, Yenny; Rockx, Barry

    2014-04-01

    Nipah virus (NiV) is a member of the genus Henipavirus (family Paramyxoviridae) that causes severe and often lethal respiratory illness and encephalitis in humans with high mortality rates (up to 92%). NiV can cause Acute Lung Injury (ALI) in humans, and human-to-human transmission has been observed in recent outbreaks of NiV. While the exact route of transmission to humans is not known, we have previously shown that NiV can efficiently infect human respiratory epithelial cells. The molecular mechanisms of NiV-associated ALI in the human respiratory tract are unknown. Thus, there is an urgent need for models of henipavirus infection of the human respiratory tract to study the pathogenesis and understand the host responses. Here, we describe a novel human lung xenograft model in mice to study the pathogenesis of NiV. Following transplantation, human fetal lung xenografts rapidly graft and develop mature structures of adult lungs including cartilage, vascular vessels, ciliated pseudostratified columnar epithelium, and primitive "air" spaces filled with mucus and lined by cuboidal to flat epithelium. Following infection, NiV grows to high titers (10(7) TCID50/gram lung tissue) as early as 3 days post infection (pi). NiV targets both the endothelium as well as respiratory epithelium in the human lung tissues, and results in syncytia formation. NiV infection in the human lung results in the production of several cytokines and chemokines including IL-6, IP-10, eotaxin, G-CSF and GM-CSF on days 5 and 7 pi. In conclusion, this study demonstrates that NiV can replicate to high titers in a novel in vivo model of the human respiratory tract, resulting in a robust inflammatory response, which is known to be associated with ALI. This model will facilitate progress in the fundamental understanding of henipavirus pathogenesis and virus-host interactions; it will also provide biologically relevant models for other respiratory viruses.

  15. Characterizing the lung tissue mechanical properties using a micromechanical model of alveolar sac

    NASA Astrophysics Data System (ADS)

    Karami, Elham; Seify, Behzad; Moghadas, Hadi; Sabsalinejad, Masoomeh; Lee, Ting-Yim; Samani, Abbas

    2017-03-01

    According to statistics, lung disease is among the leading causes of death worldwide. As such, many research groups are developing powerful tools for understanding, diagnosis and treatment of various lung diseases. Recently, biomechanical modeling has emerged as an effective tool for better understanding of human physiology, disease diagnosis and computer assisted medical intervention. Mechanical properties of lung tissue are important requirements for methods developed for lung disease diagnosis and medical intervention. As such, the main objective of this study is to develop an effective tool for estimating the mechanical properties of normal and pathological lung parenchyma tissue based on its microstructure. For this purpose, a micromechanical model of the lung tissue was developed using finite element (FE) method, and the model was demonstrated to have application in estimating the mechanical properties of lung alveolar wall. The proposed model was developed by assembling truncated octahedron tissue units resembling the alveoli. A compression test was simulated using finite element method on the created geometry and the hyper-elastic parameters of the alveoli wall were calculated using reported alveolar wall stress-strain data and an inverse optimization framework. Preliminary results indicate that the proposed model can be potentially used to reconstruct microstructural images of lung tissue using macro-scale tissue response for normal and different pathological conditions. Such images can be used for effective diagnosis of lung diseases such as Chronic Obstructive Pulmonary Disease (COPD).

  16. Characterizing human vestibular sensory epithelia for experimental studies: new hair bundles on old tissue and implications for therapeutic interventions in ageing.

    PubMed

    Taylor, Ruth R; Jagger, Daniel J; Saeed, Shakeel R; Axon, Patrick; Donnelly, Neil; Tysome, James; Moffatt, David; Irving, Richard; Monksfield, Peter; Coulson, Chris; Freeman, Simon R; Lloyd, Simon K; Forge, Andrew

    2015-06-01

    Balance disequilibrium is a significant contributor to falls in the elderly. The most common cause of balance dysfunction is loss of sensory cells from the vestibular sensory epithelia of the inner ear. However, inaccessibility of inner ear tissue in humans severely restricts possibilities for experimental manipulation to develop therapies to ameliorate this loss. We provide a structural and functional analysis of human vestibular sensory epithelia harvested at trans-labyrinthine surgery. We demonstrate the viability of the tissue and labeling with specific markers of hair cell function and of ion homeostasis in the epithelium. Samples obtained from the oldest patients revealed a significant loss of hair cells across the tissue surface, but we found immature hair bundles present in epithelia harvested from patients >60 years of age. These results suggest that the environment of the human vestibular sensory epithelium could be responsive to stimulation of developmental pathways to enhance hair cell regeneration, as has been demonstrated successfully in the vestibular organs of adult mice. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  17. A tree-parenchyma coupled model for lung ventilation simulation.

    PubMed

    Pozin, Nicolas; Montesantos, Spyridon; Katz, Ira; Pichelin, Marine; Vignon-Clementel, Irene; Grandmont, Céline

    2017-11-01

    In this article, we develop a lung ventilation model. The parenchyma is described as an elastic homogenized media. It is irrigated by a space-filling dyadic resistive pipe network, which represents the tracheobronchial tree. In this model, the tree and the parenchyma are strongly coupled. The tree induces an extra viscous term in the system constitutive relation, which leads, in the finite element framework, to a full matrix. We consider an efficient algorithm that takes advantage of the tree structure to enable a fast matrix-vector product computation. This framework can be used to model both free and mechanically induced respiration, in health and disease. Patient-specific lung geometries acquired from computed tomography scans are considered. Realistic Dirichlet boundary conditions can be deduced from surface registration on computed tomography images. The model is compared to a more classical exit compartment approach. Results illustrate the coupling between the tree and the parenchyma, at global and regional levels, and how conditions for the purely 0D model can be inferred. Different types of boundary conditions are tested, including a nonlinear Robin model of the surrounding lung structures. Copyright © 2017 John Wiley & Sons, Ltd.

  18. Targeted aerosolized delivery of ascorbate in the lungs of chlorine-exposed rats.

    PubMed

    Bracher, Andreas; Doran, Stephen F; Squadrito, Giuseppe L; Postlethwait, Edward M; Bowen, Larry; Matalon, Sadis

    2012-12-01

    Chlorine (Cl(2))-induced lung injury is a serious public health threat that may result from industrial and household accidents. Post-Cl(2) administration of aerosolized ascorbate in rodents decreased lung injury and mortality. However, the extent to which aerosolized ascorbate augments depleted ascorbate stores in distal lung compartments has not been assessed. We exposed rats to Cl(2) (300 ppm for 30 min) and returned them to room air. Within 15-30 min postexposure, rats breathed aerosolized ascorbate and desferal or vehicle (mean particle size 3.3 μm) through a nose-only exposure system for 60 min and were euthanized. We measured the concentrations of reduced ascorbate in the bronchoalveolar lavage (BAL), plasma, and lung tissues with high-pressure liquid chromatography, protein plasma concentration in the BAL, and the volume of the epithelia lining fluid (ELF). Cl(2)-exposed rats that breathed aerosolized vehicle had lower values of ascorbate in their BAL, ELF, and lung tissues compared to air-breathing rats. Delivery of aerosolized ascorbate increased reduced ascorbate in BAL, ELF, lung tissues, and plasma of both Cl(2) and air-exposed rats without causing lung injury. Based on mean diameter of aerosolized particles and airway sizes we calculated that approximately 5% and 1% of inhaled ascorbate was deposited in distal lung regions of air and Cl(2)-exposed rats, respectively. Significantly higher ascorbate levels were present in the BAL of Cl(2)-exposed rats when aerosol delivery was initiated 1 h post-Cl(2). Aerosol administration is an effective, safe, and noninvasive method for the delivery of low molecular weight antioxidants to the lungs of Cl(2)-exposed individuals for the purpose of decreasing morbidity and mortality. Delivery is most effective when initiated 1 h postexposure when the effects of Cl(2) on minute ventilation subside.

  19. Modeling small cell lung cancer (SCLC) biology through deterministic and stochastic mathematical models.

    PubMed

    Salgia, Ravi; Mambetsariev, Isa; Hewelt, Blake; Achuthan, Srisairam; Li, Haiqing; Poroyko, Valeriy; Wang, Yingyu; Sattler, Martin

    2018-05-25

    Mathematical cancer models are immensely powerful tools that are based in part on the fractal nature of biological structures, such as the geometry of the lung. Cancers of the lung provide an opportune model to develop and apply algorithms that capture changes and disease phenotypes. We reviewed mathematical models that have been developed for biological sciences and applied them in the context of small cell lung cancer (SCLC) growth, mutational heterogeneity, and mechanisms of metastasis. The ultimate goal is to develop the stochastic and deterministic nature of this disease, to link this comprehensive set of tools back to its fractalness and to provide a platform for accurate biomarker development. These techniques may be particularly useful in the context of drug development research, such as combination with existing omics approaches. The integration of these tools will be important to further understand the biology of SCLC and ultimately develop novel therapeutics.

  20. Development and validation of risk models to select ever-smokers for CT lung-cancer screening

    PubMed Central

    Katki, Hormuzd A.; Kovalchik, Stephanie A.; Berg, Christine D.; Cheung, Li C.; Chaturvedi, Anil K.

    2016-01-01

    Importance The US Preventive Services Task Force (USPSTF) recommends computed-tomography (CT) lung-cancer screening for ever-smokers ages 55-80 years who smoked at least 30 pack-years with no more than 15 years since quitting. However, selecting ever-smokers for screening using individualized lung-cancer risk calculations may be more effective and efficient than current USPSTF recommendations. Objective Comparison of modeled outcomes from risk-based CT lung-screening strategies versus USPSTF recommendations. Design/Setting/Participants Empirical risk models for lung-cancer incidence and death in the absence of CT screening using data on ever-smokers from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO; 1993-2009) control group. Covariates included age, education, sex, race, smoking intensity/duration/quit-years, Body Mass Index, family history of lung-cancer, and self-reported emphysema. Model validation in the chest radiography groups of the PLCO and the National Lung Screening Trial (NLST; 2002-2009), with additional validation of the death model in the National Health Interview Survey (NHIS; 1997-2001), a representative sample of the US. Models applied to US ever-smokers ages 50-80 (NHIS 2010-2012) to estimate outcomes of risk-based selection for CT lung-screening, assuming screening for all ever-smokers yields the percent changes in lung-cancer detection and death observed in the NLST. Exposure Annual CT lung-screening for 3 years. Main Outcomes and Measures Model validity: calibration (number of model-predicted cases divided by number of observed cases (Estimated/Observed)) and discrimination (Area-Under-Curve (AUC)). Modeled screening outcomes: estimated number of screen-avertable lung-cancer deaths, estimated screening effectiveness (number needed to screen (NNS) to prevent 1 lung-cancer death). Results Lung-cancer incidence and death risk models were well-calibrated in PLCO and NLST. The lung-cancer death model calibrated and

  1. Development and Validation of Risk Models to Select Ever-Smokers for CT Lung Cancer Screening.

    PubMed

    Katki, Hormuzd A; Kovalchik, Stephanie A; Berg, Christine D; Cheung, Li C; Chaturvedi, Anil K

    2016-06-07

    The US Preventive Services Task Force (USPSTF) recommends computed tomography (CT) lung cancer screening for ever-smokers aged 55 to 80 years who have smoked at least 30 pack-years with no more than 15 years since quitting. However, selecting ever-smokers for screening using individualized lung cancer risk calculations may be more effective and efficient than current USPSTF recommendations. Comparison of modeled outcomes from risk-based CT lung-screening strategies vs USPSTF recommendations. Empirical risk models for lung cancer incidence and death in the absence of CT screening using data on ever-smokers from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO; 1993-2009) control group. Covariates included age; education; sex; race; smoking intensity, duration, and quit-years; body mass index; family history of lung cancer; and self-reported emphysema. Model validation in the chest radiography groups of the PLCO and the National Lung Screening Trial (NLST; 2002-2009), with additional validation of the death model in the National Health Interview Survey (NHIS; 1997-2001), a representative sample of the United States. Models were applied to US ever-smokers aged 50 to 80 years (NHIS 2010-2012) to estimate outcomes of risk-based selection for CT lung screening, assuming screening for all ever-smokers, yield the percent changes in lung cancer detection and death observed in the NLST. Annual CT lung screening for 3 years beginning at age 50 years. For model validity: calibration (number of model-predicted cases divided by number of observed cases [estimated/observed]) and discrimination (area under curve [AUC]). For modeled screening outcomes: estimated number of screen-avertable lung cancer deaths and estimated screening effectiveness (number needed to screen [NNS] to prevent 1 lung cancer death). Lung cancer incidence and death risk models were well calibrated in PLCO and NLST. The lung cancer death model calibrated and discriminated well for US

  2. Bayesian modelling of lung function data from multiple-breath washout tests.

    PubMed

    Mahar, Robert K; Carlin, John B; Ranganathan, Sarath; Ponsonby, Anne-Louise; Vuillermin, Peter; Vukcevic, Damjan

    2018-05-30

    Paediatric respiratory researchers have widely adopted the multiple-breath washout (MBW) test because it allows assessment of lung function in unsedated infants and is well suited to longitudinal studies of lung development and disease. However, a substantial proportion of MBW tests in infants fail current acceptability criteria. We hypothesised that a model-based approach to analysing the data, in place of traditional simple empirical summaries, would enable more efficient use of these tests. We therefore developed a novel statistical model for infant MBW data and applied it to 1197 tests from 432 individuals from a large birth cohort study. We focus on Bayesian estimation of the lung clearance index, the most commonly used summary of lung function from MBW tests. Our results show that the model provides an excellent fit to the data and shed further light on statistical properties of the standard empirical approach. Furthermore, the modelling approach enables the lung clearance index to be estimated by using tests with different degrees of completeness, something not possible with the standard approach. Our model therefore allows previously unused data to be used rather than discarded, as well as routine use of shorter tests without significant loss of precision. Beyond our specific application, our work illustrates a number of important aspects of Bayesian modelling in practice, such as the importance of hierarchical specifications to account for repeated measurements and the value of model checking via posterior predictive distributions. Copyright © 2018 John Wiley & Sons, Ltd.

  3. Percutaneous radiofrequency ablation of lung tumors in a large animal model.

    PubMed

    Ahrar, Kamran; Price, Roger E; Wallace, Michael J; Madoff, David C; Gupta, Sanjay; Morello, Frank A; Wright, Kenneth C

    2003-08-01

    Percutaneous radiofrequency ablation (RFA) is accepted therapy for liver tumors in the appropriate clinical setting, but its use in lung neoplasms remains investigational. We undertook this study to evaluate the feasibility and immediate effectiveness of RFA for treatment of both solitary pulmonary nodules and clusters of lung tumors in a large animal model. Percutaneous RFA of 14 lung tumors in five dogs was performed under CT guidance. Animals were euthanatized 8-48 hours after the procedure. The lungs and adjacent structures were harvested for gross and histopathologic evaluation. Five solitary pulmonary nodules (range, 17-26 mm) and three clusters of three nodules each (range, 7-17 mm per nodule) were treated with RFA. All ablations were technically successful. Perilesional ground-glass opacity and small asymptomatic pneumothoraces (n = 4) were visualized during the RFA sessions. One dog developed a large pneumothorax treated with tube thoracostomy but was euthanatized 8 hours post-RFA for persistent pneumothorax and continued breathing difficulty. Follow-up CT 48 hours post-RFA revealed opacification of the whole lung segment. Gross and histopathologic evaluation showed complete thermal coagulation necrosis of all treated lesions without evidence of any viable tumor. The region of thermal coagulation necrosis typically extended to the lung surface. Small regions of pulmonary hemorrhage and congestion often surrounded the areas of coagulation necrosis. RFA can be used to treat both solitary pulmonary nodules and clusters of tumor nodules in the canine lung tumor model. This model may be useful for development of specific RFA protocols for human lung tumors.

  4. Computational models for the study of heart-lung interactions in mammals.

    PubMed

    Ben-Tal, Alona

    2012-01-01

    The operation and regulation of the lungs and the heart are closely related. This is evident when examining the anatomy within the thorax cavity, in the brainstem and in the aortic and carotid arteries where chemoreceptors and baroreceptors, which provide feedback affecting the regulation of both organs, are concentrated. This is also evident in phenomena such as respiratory sinus arrhythmia where the heart rate increases during inspiration and decreases during expiration, in other types of synchronization between the heart and the lungs known as cardioventilatory coupling and in the association between heart failure and sleep apnea where breathing is interrupted periodically by periods of no-breathing. The full implication and physiological significance of the cardiorespiratory coupling under normal, pathological, or extreme physiological conditions are still unknown and are subject to ongoing investigation both experimentally and theoretically using mathematical models. This article reviews mathematical models that take heart-lung interactions into account. The main ideas behind low dimensional, phenomenological models for the study of the heart-lung synchronization and sleep apnea are described first. Higher dimensions, physiology-based models are described next. These models can vary widely in detail and scope and are characterized by the way the heart-lung interaction is taken into account: via gas exchange, via the central nervous system, via the mechanical interactions, and via time delays. The article emphasizes the need for the integration of the different sources of heart-lung coupling as well as the different mathematical approaches. Copyright © 2011 Wiley Periodicals, Inc.

  5. Computational modeling of the obstructive lung diseases asthma and COPD

    PubMed Central

    2014-01-01

    Asthma and chronic obstructive pulmonary disease (COPD) are characterized by airway obstruction and airflow limitation and pose a huge burden to society. These obstructive lung diseases impact the lung physiology across multiple biological scales. Environmental stimuli are introduced via inhalation at the organ scale, and consequently impact upon the tissue, cellular and sub-cellular scale by triggering signaling pathways. These changes are propagated upwards to the organ level again and vice versa. In order to understand the pathophysiology behind these diseases we need to integrate and understand changes occurring across these scales and this is the driving force for multiscale computational modeling. There is an urgent need for improved diagnosis and assessment of obstructive lung diseases. Standard clinical measures are based on global function tests which ignore the highly heterogeneous regional changes that are characteristic of obstructive lung disease pathophysiology. Advances in scanning technology such as hyperpolarized gas MRI has led to new regional measurements of ventilation, perfusion and gas diffusion in the lungs, while new image processing techniques allow these measures to be combined with information from structural imaging such as Computed Tomography (CT). However, it is not yet known how to derive clinical measures for obstructive diseases from this wealth of new data. Computational modeling offers a powerful approach for investigating this relationship between imaging measurements and disease severity, and understanding the effects of different disease subtypes, which is key to developing improved diagnostic methods. Gaining an understanding of a system as complex as the respiratory system is difficult if not impossible via experimental methods alone. Computational models offer a complementary method to unravel the structure-function relationships occurring within a multiscale, multiphysics system such as this. Here we review the current

  6. Role of Aquaporin-4 in Airspace-to-Capillary Water Permeability in Intact Mouse Lung Measured by a Novel Gravimetric Method

    PubMed Central

    Song, Yuanlin; Ma, Tonghui; Matthay, Michael A.; Verkman, A.S.

    2000-01-01

    The mammalian peripheral lung contains at least three aquaporin (AQP) water channels: AQP1 in microvascular endothelia, AQP4 in airway epithelia, and AQP5 in alveolar epithelia. In this study, we determined the role of AQP4 in airspace-to-capillary water transport by comparing water permeability in wild-type mice and transgenic null mice lacking AQP1, AQP4, or AQP1/AQP4 together. An apparatus was constructed to measure lung weight continuously during pulmonary artery perfusion of isolated mouse lungs. Osmotically induced water flux (Jv) between the airspace and capillary compartments was measured from the kinetics of lung weight change in saline-filled lungs in response to changes in perfusate osmolality. Jv in wild-type mice varied linearly with osmotic gradient size (4.4 × 10−5 cm3 s−1 mOsm−1) and was symmetric, independent of perfusate osmolyte size, weakly temperature dependent, and decreased 11-fold by AQP1 deletion. Transcapillary osmotic water permeability was greatly reduced by AQP1 deletion, as measured by the same method except that the airspace saline was replaced by an inert perfluorocarbon. Hydrostatically induced lung edema was characterized by lung weight changes in response to changes in pulmonary arterial inflow or pulmonary venous outflow pressure. At 5 cm H2O outflow pressure, the filtration coefficient was 4.7 cm3 s−1 mOsm−1 and reduced 1.4-fold by AQP1 deletion. To study the role of AQP4 in lung water transport, AQP1/AQP4 double knockout mice were generated by crossbreeding of AQP1 and AQP4 null mice. Jv were (cm3 s−1 mOsm−1 × 10−5, SEM, n = 7–12 mice): 3.8 ± 0.4 (wild type), 0.35 ± 0.02 (AQP1 null), 3.7 ± 0.4 (AQP4 null), and 0.25 ± 0.01 (AQP1/AQP4 null). The significant reduction in P f in AQP1 vs. AQP1/AQP4 null mice was confirmed by an independent pleural surface fluorescence method showing a 1.6 ± 0.2-fold (SEM, five mice) reduced P f in the AQP1/AQP4 double knockout mice vs. AQP1 null mice. These results establish

  7. Expression pattern of adhesion molecules in junctional epithelium differs from that in other gingival epithelia.

    PubMed

    Hatakeyama, S; Yaegashi, T; Oikawa, Y; Fujiwara, H; Mikami, T; Takeda, Y; Satoh, M

    2006-08-01

    The gingival epithelium is the physiologically important interface between the bacterially colonized gingival sulcus and periodontal soft and mineralized connective tissues, requiring protection from exposure to bacteria and their products. However, of the three epithelia comprising the gingival epithelium, the junctional epithelium has much wider intercellular spaces than the sulcular epithelium and oral gingival epithelium. Hence, the aim of the present study was to characterize the cell adhesion structure in the junctional epithelium compared with the other two epithelia. Gingival epithelia excised at therapeutic flap surgery from patients with periodontitis were examined for expression of adhesion molecules by immunofluorescence. In the oral gingival epithelium and sulcular epithelium, but not in the junctional epithelium, desmoglein 1 and 2 in cell-cell contact sites were more abundant in the upper than the suprabasal layers. E-cadherin, the main transmembranous molecule of adherens junctions, was present in spinous layers of the oral gingival epithelium and sulcular epithelium, but was scarce in the junctional epithelium. In contrast, desmoglein 3 and P-cadherin were present in all layers of the junctional epithelium as well as the oral gingival epithelium and sulcular epithelium. Connexin 43 was clearly localized to spinous layers of the oral gingival epithelium, sulcular epithelium and parts of the junctional epithelium. Claudin-1 and occludin were expressed in the cell membranes of a few superficial layers of the oral gingival epithelium. These findings indicated that the junctional epithelium contains only a few desmosomes, composed of only desmoglein 3; adherens junctions are probably absent because of defective E-cadherin. Thus, the anchoring junctions connecting junctional epithelium cells are lax, causing widened intercellular spaces. In contrast, the oral gingival epithelium, which has a few tight junctions, functions as a barrier.

  8. Increased apical Na+ permeability in cystic fibrosis is supported by a quantitative model of epithelial ion transport

    PubMed Central

    O’Donoghue, Donal L; Dua, Vivek; Moss, Guy W J; Vergani, Paola

    2013-01-01

    Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes an anion channel. In the human lung CFTR loss causes abnormal ion transport across airway epithelial cells. As a result CF individuals produce thick mucus, suffer persistent bacterial infections and have a much reduced life expectancy. Trans-epithelial potential difference (Vt) measurements are routinely carried out on nasal epithelia of CF patients in the clinic. CF epithelia exhibit a hyperpolarised basal Vt and a larger Vt change in response to amiloride (a blocker of the epithelial Na+ channel, ENaC). Are these altered bioelectric properties solely a result of electrical coupling between the ENaC and CFTR currents, or are they due to an increased ENaC permeability associated with CFTR loss? To examine these issues we have developed a quantitative mathematical model of human nasal epithelial ion transport. We find that while the loss of CFTR permeability hyperpolarises Vt and also increases amiloride-sensitive Vt, these effects are too small to account for the magnitude of change observed in CF epithelia. Instead, a parallel increase in ENaC permeability is required to adequately fit observed experimental data. Our study provides quantitative predictions for the complex relationships between ionic permeabilities and nasal Vt, giving insights into the physiology of CF disease that have important implications for CF therapy. PMID:23732645

  9. Applying Risk Prediction Models to Optimize Lung Cancer Screening: Current Knowledge, Challenges, and Future Directions.

    PubMed

    Sakoda, Lori C; Henderson, Louise M; Caverly, Tanner J; Wernli, Karen J; Katki, Hormuzd A

    2017-12-01

    Risk prediction models may be useful for facilitating effective and high-quality decision-making at critical steps in the lung cancer screening process. This review provides a current overview of published lung cancer risk prediction models and their applications to lung cancer screening and highlights both challenges and strategies for improving their predictive performance and use in clinical practice. Since the 2011 publication of the National Lung Screening Trial results, numerous prediction models have been proposed to estimate the probability of developing or dying from lung cancer or the probability that a pulmonary nodule is malignant. Respective models appear to exhibit high discriminatory accuracy in identifying individuals at highest risk of lung cancer or differentiating malignant from benign pulmonary nodules. However, validation and critical comparison of the performance of these models in independent populations are limited. Little is also known about the extent to which risk prediction models are being applied in clinical practice and influencing decision-making processes and outcomes related to lung cancer screening. Current evidence is insufficient to determine which lung cancer risk prediction models are most clinically useful and how to best implement their use to optimize screening effectiveness and quality. To address these knowledge gaps, future research should be directed toward validating and enhancing existing risk prediction models for lung cancer and evaluating the application of model-based risk calculators and its corresponding impact on screening processes and outcomes.

  10. [Expression and clinical significance of Xiap and Caspase-3 protien in primary epithelia ovarian cancer].

    PubMed

    Chen, Wei; Peng, Ping

    2010-07-01

    To study the expression and clinical significance of Xiap, Caspase-3 protein in primary epithelia ovarian cancer. The Xiap and Caspase-3 were detected by immunohistochemical in 40 cases of epithelial ovarian cancer 20 cases of borderline ovarian tumor, 15 cases of benign ovarian tumor, and 15 normal ovarian tissues. There were significantly different between the expression of Xiap in epithelial ovarian cancer, borderline ovarian tumor, benign ovarian tumor and normal ovarian tissues. The expression of Caspase-3 in epithelial ovarian cancer and borderline ovarian tumor was significantly lower than that in benign ovarian tumor and normal ovarian tissue (P<0.01). The expression of Xiap in epithelial ovarian cancer was related to clinc stage, pathological grade and living. The expression of caspase-3 in epithelial ovarian cancer was related to clinc stage and living (P<0.01). The expressions of Xiap and Caspase-3 may be important roles for the formation and development of epithelia ovarian cancer. The expressions of Xiap and Caspase-3 are the poor prognostic factors in epithelial ovarian carcinomas.

  11. Application of a neutral community model to assess structuring of the human lung microbiome.

    PubMed

    Venkataraman, Arvind; Bassis, Christine M; Beck, James M; Young, Vincent B; Curtis, Jeffrey L; Huffnagle, Gary B; Schmidt, Thomas M

    2015-01-20

    DNA from phylogenetically diverse microbes is routinely recovered from healthy human lungs and used to define the lung microbiome. The proportion of this DNA originating from microbes adapted to the lungs, as opposed to microbes dispersing to the lungs from other body sites and the atmosphere, is not known. We use a neutral model of community ecology to distinguish members of the lung microbiome whose presence is consistent with dispersal from other body sites and those that deviate from the model, suggesting a competitive advantage to these microbes in the lungs. We find that the composition of the healthy lung microbiome is consistent with predictions of the neutral model, reflecting the overriding role of dispersal of microbes from the oral cavity in shaping the microbial community in healthy lungs. In contrast, the microbiome of diseased lungs was readily distinguished as being under active selection. We also assessed the viability of microbes from lung samples by cultivation with a variety of media and incubation conditions. Bacteria recovered by cultivation from healthy lungs represented species that comprised 61% of the 16S rRNA-encoding gene sequences derived from bronchoalveolar lavage samples. Neutral distribution of microbes is a distinguishing feature of the microbiome in healthy lungs, wherein constant dispersal of bacteria from the oral cavity overrides differential growth of bacteria. No bacterial species consistently deviated from the model predictions in healthy lungs, although representatives of many of the dispersed species were readily cultivated. In contrast, bacterial populations in diseased lungs were identified as being under active selection. Quantification of the relative importance of selection and neutral processes such as dispersal in shaping the healthy lung microbiome is a first step toward understanding its impacts on host health. Copyright © 2015 Venkataraman et al.

  12. Risk prediction models for selection of lung cancer screening candidates: A retrospective validation study

    PubMed Central

    ten Haaf, Kevin; Tammemägi, Martin C.; Han, Summer S.; Kong, Chung Yin; Plevritis, Sylvia K.; de Koning, Harry J.; Steyerberg, Ewout W.

    2017-01-01

    Background Selection of candidates for lung cancer screening based on individual risk has been proposed as an alternative to criteria based on age and cumulative smoking exposure (pack-years). Nine previously established risk models were assessed for their ability to identify those most likely to develop or die from lung cancer. All models considered age and various aspects of smoking exposure (smoking status, smoking duration, cigarettes per day, pack-years smoked, time since smoking cessation) as risk predictors. In addition, some models considered factors such as gender, race, ethnicity, education, body mass index, chronic obstructive pulmonary disease, emphysema, personal history of cancer, personal history of pneumonia, and family history of lung cancer. Methods and findings Retrospective analyses were performed on 53,452 National Lung Screening Trial (NLST) participants (1,925 lung cancer cases and 884 lung cancer deaths) and 80,672 Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) ever-smoking participants (1,463 lung cancer cases and 915 lung cancer deaths). Six-year lung cancer incidence and mortality risk predictions were assessed for (1) calibration (graphically) by comparing the agreement between the predicted and the observed risks, (2) discrimination (area under the receiver operating characteristic curve [AUC]) between individuals with and without lung cancer (death), and (3) clinical usefulness (net benefit in decision curve analysis) by identifying risk thresholds at which applying risk-based eligibility would improve lung cancer screening efficacy. To further assess performance, risk model sensitivities and specificities in the PLCO were compared to those based on the NLST eligibility criteria. Calibration was satisfactory, but discrimination ranged widely (AUCs from 0.61 to 0.81). The models outperformed the NLST eligibility criteria over a substantial range of risk thresholds in decision curve analysis, with a higher

  13. A multiscale MDCT image-based breathing lung model with time-varying regional ventilation

    PubMed Central

    Yin, Youbing; Choi, Jiwoong; Hoffman, Eric A.; Tawhai, Merryn H.; Lin, Ching-Long

    2012-01-01

    A novel algorithm is presented that links local structural variables (regional ventilation and deforming central airways) to global function (total lung volume) in the lung over three imaged lung volumes, to derive a breathing lung model for computational fluid dynamics simulation. The algorithm constitutes the core of an integrative, image-based computational framework for subject-specific simulation of the breathing lung. For the first time, the algorithm is applied to three multi-detector row computed tomography (MDCT) volumetric lung images of the same individual. A key technique in linking global and local variables over multiple images is an in-house mass-preserving image registration method. Throughout breathing cycles, cubic interpolation is employed to ensure C1 continuity in constructing time-varying regional ventilation at the whole lung level, flow rate fractions exiting the terminal airways, and airway deformation. The imaged exit airway flow rate fractions are derived from regional ventilation with the aid of a three-dimensional (3D) and one-dimensional (1D) coupled airway tree that connects the airways to the alveolar tissue. An in-house parallel large-eddy simulation (LES) technique is adopted to capture turbulent-transitional-laminar flows in both normal and deep breathing conditions. The results obtained by the proposed algorithm when using three lung volume images are compared with those using only one or two volume images. The three-volume-based lung model produces physiologically-consistent time-varying pressure and ventilation distribution. The one-volume-based lung model under-predicts pressure drop and yields un-physiological lobar ventilation. The two-volume-based model can account for airway deformation and non-uniform regional ventilation to some extent, but does not capture the non-linear features of the lung. PMID:23794749

  14. Organization of tubules in the human caput epididymidis and the ultrastructure of their epithelia.

    PubMed

    Yeung, C H; Cooper, T G; Bergmann, M; Schulze, H

    1991-07-01

    The structure of the human caput epididymidis was examined by gross morphological and light and electron microscopic techniques. There were at least seven types of tubules, each characterized by a different epithelium. These tubules were connected with one another by at least eight types of junctions to form a network. Most of the caput epididymidis was composed of efferent ducts. Within these, five types of tubules, each with a different ciliated epithelium, were found in different regions; and four types of junctions between the efferent ducts and the epididymal tubule were observed. The efferent ducts left the testis, initially as parallel straight tubules containing both ciliated and non-ciliated cells in an epithelium of irregular height. Each efferent duct then coiled tortuously into lobules that folded over one another. These efferent ducts then branched out as thin tubules to join a network of dark tubules which were lined by a regular epithelium containing prominently vacuolated, non-ciliated cells. These tubules anastomosed via common cavities characterized by a ciliated cuboidal epithelium and sometimes joined tubules exhibiting a non-vacuolated ciliated epithelium. The latter, as well as typical efferent ducts, made connection with the epididymis proper in both end-to-end and end-to-side junctions. In the more distal junctions with the epididymis, the efferent ducts joined to a transitional epididymal ductule before joining to the side of the epididymis proper. Post-junctional epithelia in the beginning of the epididymis occasionally contained patches of cells characteristic of efferent ducts. Tall cells with long stereocilia constituted a discontinuous "initial segment"-like region of the epididymis. This is the most detailed study so far of the epithelia and the tubule organization in the caput epididymidis of any species, and most of the results are reported for the first time for the human. Although the pattern of the tubule network resembles that

  15. The porcine lung as a potential model for cystic fibrosis

    PubMed Central

    Rogers, Christopher S.; Abraham, William M.; Brogden, Kim A.; Engelhardt, John F.; Fisher, John T.; McCray, Paul B.; McLennan, Geoffrey; Meyerholz, David K.; Namati, Eman; Ostedgaard, Lynda S.; Prather, Randall S.; Sabater, Juan R.; Stoltz, David Anthony; Zabner, Joseph; Welsh, Michael J.

    2008-01-01

    Airway disease currently causes most of the morbidity and mortality in patients with cystic fibrosis (CF). However, understanding the pathogenesis of CF lung disease and developing novel therapeutic strategies have been hampered by the limitations of current models. Although the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) has been targeted in mice, CF mice fail to develop lung or pancreatic disease like that in humans. In many respects, the anatomy, biochemistry, physiology, size, and genetics of pigs resemble those of humans. Thus pigs with a targeted CFTR gene might provide a good model for CF. Here, we review aspects of porcine airways and lung that are relevant to CF. PMID:18487356

  16. The Audible Human Project: Modeling Sound Transmission in the Lungs and Torso

    NASA Astrophysics Data System (ADS)

    Dai, Zoujun

    Auscultation has been used qualitatively by physicians for hundreds of years to aid in the monitoring and diagnosis of pulmonary diseases. Alterations in the structure and function of the pulmonary system that occur in disease or injury often give rise to measurable changes in lung sound production and transmission. Numerous acoustic measurements have revealed the differences of breath sounds and transmitted sounds in the lung under normal and pathological conditions. Compared to the extensive cataloging of lung sound measurements, the mechanism of sound transmission in the pulmonary system and how it changes with alterations of lung structural and material properties has received less attention. A better understanding of sound transmission and how it is altered by injury and disease might improve interpretation of lung sound measurements, including new lung imaging modalities that are based on an array measurement of the acoustic field on the torso surface via contact sensors or are based on a 3-dimensional measurement of the acoustic field throughout the lungs and torso using magnetic resonance elastography. A long-term goal of the Audible Human Project (AHP ) is to develop a computational acoustic model that would accurately simulate generation, transmission and noninvasive measurement of sound and vibration within the pulmonary system and torso caused by both internal (e.g. respiratory function) and external (e.g. palpation) sources. The goals of this dissertation research, fitting within the scope of the AHP, are to develop specific improved theoretical understandings, computational algorithms and experimental methods aimed at transmission and measurement. The research objectives undertaken in this dissertation are as follows. (1) Improve theoretical modeling and experimental identification of viscoelasticity in soft biological tissues. (2) Develop a poroviscoelastic model for lung tissue vibroacoustics. (3) Improve lung airway acoustics modeling and its

  17. Tracking boundary movement and exterior shape modelling in lung EIT imaging.

    PubMed

    Biguri, A; Grychtol, B; Adler, A; Soleimani, M

    2015-06-01

    Electrical impedance tomography (EIT) has shown significant promise for lung imaging. One key challenge for EIT in this application is the movement of electrodes during breathing, which introduces artefacts in reconstructed images. Various approaches have been proposed to compensate for electrode movement, but no comparison of these approaches is available. This paper analyses boundary model mismatch and electrode movement in lung EIT. The aim is to evaluate the extent to which various algorithms tolerate movement, and to determine if a patient specific model is required for EIT lung imaging. Movement data are simulated from a CT-based model, and image analysis is performed using quantitative figures of merit. The electrode movement is modelled based on expected values of chest movement and an extended Jacobian method is proposed to make use of exterior boundary tracking. Results show that a dynamical boundary tracking is the most robust method against any movement, but is computationally more expensive. Simultaneous electrode movement and conductivity reconstruction algorithms show increased robustness compared to only conductivity reconstruction. The results of this comparative study can help develop a better understanding of the impact of shape model mismatch and electrode movement in lung EIT.

  18. Turing mechanism underlying a branching model for lung morphogenesis.

    PubMed

    Xu, Hui; Sun, Mingzhu; Zhao, Xin

    2017-01-01

    The mammalian lung develops through branching morphogenesis. Two primary forms of branching, which occur in order, in the lung have been identified: tip bifurcation and side branching. However, the mechanisms of lung branching morphogenesis remain to be explored. In our previous study, a biological mechanism was presented for lung branching pattern formation through a branching model. Here, we provide a mathematical mechanism underlying the branching patterns. By decoupling the branching model, we demonstrated the existence of Turing instability. We performed Turing instability analysis to reveal the mathematical mechanism of the branching patterns. Our simulation results show that the Turing patterns underlying the branching patterns are spot patterns that exhibit high local morphogen concentration. The high local morphogen concentration induces the growth of branching. Furthermore, we found that the sparse spot patterns underlie the tip bifurcation patterns, while the dense spot patterns underlies the side branching patterns. The dispersion relation analysis shows that the Turing wavelength affects the branching structure. As the wavelength decreases, the spot patterns change from sparse to dense, the rate of tip bifurcation decreases and side branching eventually occurs instead. In the process of transformation, there may exists hybrid branching that mixes tip bifurcation and side branching. Since experimental studies have reported that branching mode switching from side branching to tip bifurcation in the lung is under genetic control, our simulation results suggest that genes control the switch of the branching mode by regulating the Turing wavelength. Our results provide a novel insight into and understanding of the formation of branching patterns in the lung and other biological systems.

  19. Effects of sevoflurane on ventilator induced lung injury in a healthy lung experimental model.

    PubMed

    Romero, A; Moreno, A; García, J; Sánchez, C; Santos, M; García, J

    2016-01-01

    Ventilator-induced lung injury (VILI) causes a systemic inflammatory response in tissues, with an increase in IL-1, IL-6 and TNF-α in blood and tissues. Cytoprotective effects of sevoflurane in different experimental models are well known, and this protective effect can also be observed in VILI. The objective of this study was to assess the effects of sevoflurane in VILI. A prospective, randomized, controlled study was designed. Twenty female rats were studied. The animals were mechanically ventilated, without sevoflurane in the control group and sevoflurane 3% in the treated group (SEV group). VILI was induced applying a maximal inspiratory pressure of 35 cmH2O for 20 min without any positive end-expiratory pressure for 20 min (INJURY time). The animals were then ventilated 30 min with a maximal inspiratory pressure of 12 cmH2O and 3 cmH2O positive end-expiratory pressure (time 30 min POST-INJURY), at which time the animals were euthanized and pathological and biomarkers studies were performed. Heart rate, invasive blood pressure, pH, PaO2, and PaCO2 were recorded. The lung wet-to-dry weight ratio was used as an index of lung edema. No differences were found in the blood gas analysis parameters or heart rate between the 2 groups. Blood pressure was statistically higher in the control group, but still within the normal clinical range. The percentage of pulmonary edema and concentrations of TNF-α and IL-6 in lung tissue in the SEV group were lower than in the control group. Sevoflurane attenuates VILI in a previous healthy lung in an experimental subclinical model in rats. Copyright © 2015 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

  20. Electroporation-mediated Delivery of Genes in Rodent Models of Lung Contusion

    PubMed Central

    Machado-Aranda, David; Raghavendran, Krishnan

    2015-01-01

    Several of the biological processes involved in the pathogenesis of acute lung injury and acute respiratory distress syndrome after lung contusion are regulated at a genetic and epigenetic level. Thus, strategies to manipulate gene expression in this context are highly desirable not only to elucidate the mechanisms involved but also to look for potential therapies. In the present chapter, we describe mouse and rat models of inducing blunt thoracic injury followed by electroporation-mediated gene delivery to the lung. Electroporation is a highly efficient and easily reproducible technique that allows circumvention of several of lung gene delivery challenges and safety issues present with other forms of lung gene therapy. PMID:24510825

  1. A fluorescence model of the murine lung for optical detection of pathogenic bacteria

    NASA Astrophysics Data System (ADS)

    Durkee, Madeleine S.; Cirillo, Jeffrey D.; Maitland, Kristen C.

    2017-07-01

    We present a computer model of intravital excitation and external fluorescence detection in the murine lungs validated with a three-dimensional lung tissue phantom. The model is applied to optical detection of pulmonary tuberculosis infection.

  2. In vivo retroviral gene transfer into human bronchial epithelia of xenografts.

    PubMed

    Engelhardt, J F; Yankaskas, J R; Wilson, J M

    1992-12-01

    Cystic fibrosis (CF) is the most common lethal inherited disease in the Caucasian population with an incidence of approximately 1 in 2,500 live births. Pulmonary complications of CF, which are the most morbid aspects of the disease, are caused by primary abnormalities in epithelial cells that lead to impaired mucociliary clearance. One potential therapeutic strategy is to reconstitute expression of the CF gene in airway epithelia by somatic gene transfer. To this end, we have developed an animal model of the human airway using bronchial xenografts and have tested the efficiency of in vivo retroviral gene transfer. Using the LacZ reporter gene, we find the efficiency of in vivo retroviral gene transfer to be dramatically dependent on the regenerative and mitotic state of the epithelium. Within an undifferentiated regenerating epithelium in which 40% of nuclei labeled with BrdU, 5-10% retroviral gene transfer was obtained. In contrast, no gene transfer was noted in a fully differentiated epithelium in which 1% of nuclei labeled with BrdU. These findings suggest that retroviral mediated gene transfer to the airway in vivo may be feasible if the proper regenerative state can be induced.

  3. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

    NASA Astrophysics Data System (ADS)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B.; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

  4. Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology

    PubMed Central

    Mairpady Shambat, Srikanth; Chen, Puran; Nguyen Hoang, Anh Thu; Bergsten, Helena; Vandenesch, Francois; Siemens, Nikolai; Lina, Gerard; Monk, Ian R.; Foster, Timothy J.; Arakere, Gayathri; Svensson, Mattias; Norrby-Teglund, Anna

    2015-01-01

    ABSTRACT Staphylococcus aureus necrotizing pneumonia is recognized as a toxin-mediated disease, yet the tissue-destructive events remain elusive, partly as a result of lack of mechanistic studies in human lung tissue. In this study, a three-dimensional (3D) tissue model composed of human lung epithelial cells and fibroblasts was used to delineate the role of specific staphylococcal exotoxins in tissue pathology associated with severe pneumonia. To this end, the models were exposed to the mixture of exotoxins produced by S. aureus strains isolated from patients with varying severity of lung infection, namely necrotizing pneumonia or lung empyema, or to purified toxins. The necrotizing pneumonia strains secreted high levels of α-toxin and Panton-Valentine leukocidin (PVL), and triggered high cytotoxicity, inflammation, necrosis and loss of E-cadherin from the lung epithelium. In contrast, the lung empyema strain produced moderate levels of PVL, but negligible amounts of α-toxin, and triggered limited tissue damage. α-toxin had a direct damaging effect on the epithelium, as verified using toxin-deficient mutants and pure α-toxin. Moreover, PVL contributed to pathology through the lysis of neutrophils. A combination of α-toxin and PVL resulted in the most severe epithelial injury. In addition, toxin-induced release of pro-inflammatory mediators from lung tissue models resulted in enhanced neutrophil migration. Using a collection of 31 strains from patients with staphylococcal pneumonia revealed that strains producing high levels of α-toxin and PVL were cytotoxic and associated with fatal outcome. Also, the strains that produced the highest toxin levels induced significantly greater epithelial disruption. Of importance, toxin-mediated lung epithelium destruction could be inhibited by polyspecific intravenous immunoglobulin containing antibodies against α-toxin and PVL. This study introduces a novel model system for study of staphylococcal pneumonia in a human

  5. Targeted deletion of Atg5 reveals differential roles of autophagy in keratin K5-expressing epithelia

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sukseree, Supawadee; Department of Biochemistry, Faculty of Medicine, Srinakharinwirot University, Bangkok; Rossiter, Heidemarie

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer We generated mice lacking Atg5 and autophagy in keratin K5-positive epithelia. Black-Right-Pointing-Pointer Suppression of autophagy in thymic epithelium was not associated with signs of autoimmunity. Black-Right-Pointing-Pointer Autophagy was required for normal terminal differentiation of preputial gland cells. Black-Right-Pointing-Pointer Autophagy-deficient cells of the preputial glands degraded nuclear DNA prematurely. -- Abstract: Autophagy contributes to the homeostasis of many tissues, yet its role in epithelia is incompletely understood. A recent report proposed that Atg5-dependent autophagy in thymic epithelial cells is essential for their function in the negative selection of self-reactive T-cells and, thus, for the suppression of tissue inflammation. Heremore » we crossed mice carrying floxed alleles of the Atg5 gene with mice expressing the Cre recombinase under the control of the keratin K5 promoter to suppress autophagy in all K5-positive epithelia. The efficiency of autophagy abrogation was confirmed by immunoanalyses of LC3, which was converted to the autophagy-associated LC3-II form in normal but not Atg5-deficient cells, and of p62, which accumulated in Atg5-deficient cells. Mice carrying the epithelium-specific deletion of Atg5 showed normal weight gain, absence of tissue inflammation, and a normal morphology of the thymic epithelium. By contrast, autophagy-deficient epithelial cells of the preputial gland showed aberrant eosinophilic staining in histology and premature degradation of nuclear DNA during terminal differentiation. Taken together, the results of this study suggest that autophagy is dispensable for the suppression of autoimmunity by thymic epithelial cells but essential for normal differentiation of the preputial gland in mice.« less

  6. Gene Expression Analysis to Assess the Relevance of Rodent Models to Human Lung Injury.

    PubMed

    Sweeney, Timothy E; Lofgren, Shane; Khatri, Purvesh; Rogers, Angela J

    2017-08-01

    The relevance of animal models to human diseases is an area of intense scientific debate. The degree to which mouse models of lung injury recapitulate human lung injury has never been assessed. Integrating data from both human and animal expression studies allows for increased statistical power and identification of conserved differential gene expression across organisms and conditions. We sought comprehensive integration of gene expression data in experimental acute lung injury (ALI) in rodents compared with humans. We performed two separate gene expression multicohort analyses to determine differential gene expression in experimental animal and human lung injury. We used correlational and pathway analyses combined with external in vitro gene expression data to identify both potential drivers of underlying inflammation and therapeutic drug candidates. We identified 21 animal lung tissue datasets and three human lung injury bronchoalveolar lavage datasets. We show that the metasignatures of animal and human experimental ALI are significantly correlated despite these widely varying experimental conditions. The gene expression changes among mice and rats across diverse injury models (ozone, ventilator-induced lung injury, LPS) are significantly correlated with human models of lung injury (Pearson r = 0.33-0.45, P < 1E -16 ). Neutrophil signatures are enriched in both animal and human lung injury. Predicted therapeutic targets, peptide ligand signatures, and pathway analyses are also all highly overlapping. Gene expression changes are similar in animal and human experimental ALI, and provide several physiologic and therapeutic insights to the disease.

  7. The small intestinal epithelia of beef steers differentially express sugar transporter messenger ribonucleic acid in response to abomasal versus ruminal infusion of starch hydrolysate.

    PubMed

    Liao, S F; Harmon, D L; Vanzant, E S; McLeod, K R; Boling, J A; Matthews, J C

    2010-01-01

    In mammals, the absorption of monosaccharides from small intestinal lumen involves at least 3 sugar transporters (SugT): sodium-dependent glucose transporter 1 (SGLT1; gene SLC5A1) transports glucose and galactose, whereas glucose transporter (GLUT) 5 (GLUT5; gene SLC2A5) transports fructose, across the apical membrane of enterocytes. In contrast, GLUT2 (gene SLC2A2) transports all of these sugars across basolateral and apical membranes. To compare the distribution patterns and sensitivity with nutritional regulation of these 3 SugT mRNA in beef cattle small intestinal tissue, 18 ruminally and abomasally catheterized Angus steers (BW approximately 260 kg) were assigned to water (control), ruminal cornstarch (partially hydrolyzed by alpha-amylase; SH), or abomasal SH infusion treatments (n = 6) and fed an alfalfa-cube-based diet at 1.3 x NE(m) requirement. The SH infusions amounted to 20% of ME intake. After 14- or 16-d of infusion, steers were killed; duodenal, jejunal, and ileal epithelia harvested; and total RNA extracted. The relative amount of SugT mRNA in epithelia was determined using real-time reverse transcription-PCR quantification methods. Basal expression of GLUT2 and SGLT1 mRNA was greater (P < 0.09) by jejunal than by duodenal or ileal epithelia, whereas basal content of GLUT5 mRNA was greater (P < or = 0.02) by jejunal and duodenal than by ileal epithelia. The content of GLUT5 mRNA in small intestinal epithelia was not affected (P > or = 0.16) by either SH infusion treatment. In contrast, GLUT2 and SGLT1 mRNA content in the ileal epithelium was increased (P < or = 0.05) by 6.5- and 1.3-fold, respectively, after abomasal SH infusion. Duodenal SGLT1 mRNA content also was increased (P = 0.07) by 64% after ruminal SH infusion. These results demonstrate that the ileum of beef cattle small intestine adapts to an increased luminal supply of glucose by increasing SGLT1 and GLUT2 mRNA content, whereas increased ruminal SH supply results in duodenal

  8. Effects of budesonide on the lung functions, inflammation and apoptosis in a saline-lavage model of acute lung injury.

    PubMed

    Mokra, D; Kosutova, P; Balentova, S; Adamkov, M; Mikolka, P; Mokry, J; Antosova, M; Calkovska, A

    2016-12-01

    improved lung functions in a lavage model of ALI. These findings suggest a potential of therapy with inhaled budesonide also for patients with ARDS.

  9. Near infrared photoimmunotherapy prevents lung cancer metastases in a murine model

    PubMed Central

    Sato, Kazuhide; Nagaya, Tadanobu; Nakamura, Yuko; Harada, Toshiko; Choyke, Peter L.; Kobayashi, Hisataka

    2015-01-01

    Near infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that combines the specificity of intravenously injected antibodies with the acute toxicity induced by photosensitizers after exposure to NIR-light. Herein, we evaluate the efficacy of NIR-PIT in preventing lung metastases in a mouse model. Lung is one of the most common sites for developing metastases, but it also has the deepest tissue light penetration. Thus, lung is the ideal site for treating early metastases by using a light-based strategy. In vitro NIR-PIT cytotoxicity was assessed with dead cell staining, luciferase activity, and a decrease in cytoplasmic GFP fluorescence in 3T3/HER2-luc-GFP cells incubated with an anti-HER2 antibody photosensitizer conjugate. Cell-specific killing was demonstrated in mixed 2D/3D cell cultures of 3T3/HER2-luc-GFP (target) and 3T3-RFP (non-target) cells. In vivo NIR-PIT was performed in the left lung in a mouse model of lung metastases, and the number of metastasis nodules, tumor fluorescence, and luciferase activity were all evaluated. All three evaluations demonstrated that the NIR-PIT-treated lung had significant reductions in metastatic disease (*p < 0.0001, Mann-Whitney U-test) and that NIR-PIT did not damage non-target tumors or normal lung tissue. Thus, NIR-PIT can specifically prevent early metastases and is a promising anti-metastatic therapy. PMID:25992770

  10. NTCP modelling of lung toxicity after SBRT comparing the universal survival curve and the linear quadratic model for fractionation correction.

    PubMed

    Wennberg, Berit M; Baumann, Pia; Gagliardi, Giovanna; Nyman, Jan; Drugge, Ninni; Hoyer, Morten; Traberg, Anders; Nilsson, Kristina; Morhed, Elisabeth; Ekberg, Lars; Wittgren, Lena; Lund, Jo-Åsmund; Levin, Nina; Sederholm, Christer; Lewensohn, Rolf; Lax, Ingmar

    2011-05-01

    In SBRT of lung tumours no established relationship between dose-volume parameters and the incidence of lung toxicity is found. The aim of this study is to compare the LQ model and the universal survival curve (USC) to calculate biologically equivalent doses in SBRT to see if this will improve knowledge on this relationship. Toxicity data on radiation pneumonitis grade 2 or more (RP2+) from 57 patients were used, 10.5% were diagnosed with RP2+. The lung DVHs were corrected for fractionation (LQ and USC) and analysed with the Lyman- Kutcher-Burman (LKB) model. In the LQ-correction α/β = 3 Gy was used and the USC parameters used were: α/β = 3 Gy, D(0) = 1.0 Gy, [Formula: see text] = 10, α = 0.206 Gy(-1) and d(T) = 5.8 Gy. In order to understand the relative contribution of different dose levels to the calculated NTCP the concept of fractional NTCP was used. This might give an insight to the questions of whether "high doses to small volumes" or "low doses to large volumes" are most important for lung toxicity. NTCP analysis with the LKB-model using parameters m = 0.4, D(50) = 30 Gy resulted for the volume dependence parameter (n) with LQ correction n = 0.87 and with USC correction n = 0.71. Using parameters m = 0.3, D(50) = 20 Gy n = 0.93 with LQ correction and n = 0.83 with USC correction. In SBRT of lung tumours, NTCP modelling of lung toxicity comparing models (LQ,USC) for fractionation correction, shows that low dose contribute less and high dose more to the NTCP when using the USC-model. Comparing NTCP modelling of SBRT data and data from breast cancer, lung cancer and whole lung irradiation implies that the response of the lung is treatment specific. More data are however needed in order to have a more reliable modelling.

  11. Risk Estimation for Lung Cancer in Libya: Analysis Based on Standardized Morbidity Ratio, Poisson-Gamma Model, BYM Model and Mixture Model

    PubMed Central

    Alhdiri, Maryam Ahmed; Samat, Nor Azah; Mohamed, Zulkifley

    2017-01-01

    Cancer is the most rapidly spreading disease in the world, especially in developing countries, including Libya. Cancer represents a significant burden on patients, families, and their societies. This disease can be controlled if detected early. Therefore, disease mapping has recently become an important method in the fields of public health research and disease epidemiology. The correct choice of statistical model is a very important step to producing a good map of a disease. Libya was selected to perform this work and to examine its geographical variation in the incidence of lung cancer. The objective of this paper is to estimate the relative risk for lung cancer. Four statistical models to estimate the relative risk for lung cancer and population censuses of the study area for the time period 2006 to 2011 were used in this work. They are initially known as Standardized Morbidity Ratio, which is the most popular statistic, which used in the field of disease mapping, Poisson-gamma model, which is one of the earliest applications of Bayesian methodology, Besag, York and Mollie (BYM) model and Mixture model. As an initial step, this study begins by providing a review of all proposed models, which we then apply to lung cancer data in Libya. Maps, tables and graph, goodness-of-fit (GOF) were used to compare and present the preliminary results. This GOF is common in statistical modelling to compare fitted models. The main general results presented in this study show that the Poisson-gamma model, BYM model, and Mixture model can overcome the problem of the first model (SMR) when there is no observed lung cancer case in certain districts. Results show that the Mixture model is most robust and provides better relative risk estimates across a range of models. PMID:28440974

  12. Risk Estimation for Lung Cancer in Libya: Analysis Based on Standardized Morbidity Ratio, Poisson-Gamma Model, BYM Model and Mixture Model

    PubMed

    Alhdiri, Maryam Ahmed; Samat, Nor Azah; Mohamed, Zulkifley

    2017-03-01

    Cancer is the most rapidly spreading disease in the world, especially in developing countries, including Libya. Cancer represents a significant burden on patients, families, and their societies. This disease can be controlled if detected early. Therefore, disease mapping has recently become an important method in the fields of public health research and disease epidemiology. The correct choice of statistical model is a very important step to producing a good map of a disease. Libya was selected to perform this work and to examine its geographical variation in the incidence of lung cancer. The objective of this paper is to estimate the relative risk for lung cancer. Four statistical models to estimate the relative risk for lung cancer and population censuses of the study area for the time period 2006 to 2011 were used in this work. They are initially known as Standardized Morbidity Ratio, which is the most popular statistic, which used in the field of disease mapping, Poisson-gamma model, which is one of the earliest applications of Bayesian methodology, Besag, York and Mollie (BYM) model and Mixture model. As an initial step, this study begins by providing a review of all proposed models, which we then apply to lung cancer data in Libya. Maps, tables and graph, goodness-of-fit (GOF) were used to compare and present the preliminary results. This GOF is common in statistical modelling to compare fitted models. The main general results presented in this study show that the Poisson-gamma model, BYM model, and Mixture model can overcome the problem of the first model (SMR) when there is no observed lung cancer case in certain districts. Results show that the Mixture model is most robust and provides better relative risk estimates across a range of models. Creative Commons Attribution License

  13. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments.

    PubMed

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk. Copyright © 2016 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.

  14. CD44s and CD44v6 Expression in Head and Neck Epithelia

    PubMed Central

    Mack, Brigitte; Gires, Olivier

    2008-01-01

    Background CD44 splice variants are long-known as being associated with cell transformation. Recently, the standard form of CD44 (CD44s) was shown to be part of the signature of cancer stem cells (CSCs) in colon, breast, and in head and neck squamous cell carcinomas (HNSCC). This is somewhat in contradiction to previous reports on the expression of CD44s in HNSCC. The aim of the present study was to clarify the actual pattern of CD44 expression in head and neck epithelia. Methods Expression of CD44s and CD44v6 was analysed by immunohistochemistry with specific antibodies in primary head and neck tissues. Scoring of all specimens followed a two-parameters system, which implemented percentages of positive cells and staining intensities from − to +++ (score = %×intensity; resulting max. score 300). In addition, cell surface expression of CD44s and CD44v6 was assessed in lymphocytes and HNSCC. Results In normal epithelia CD44s and CD44v6 were expressed in 60–95% and 50–80% of cells and yielded mean scores with a standard error of a mean (SEM) of 249.5±14.5 and 198±11.13, respectively. In oral leukoplakia and in moderately differentiated carcinomas CD44s and CD44v6 levels were slightly increased (278.9±7.16 and 242±11.7; 291.8±5.88 and 287.3±6.88). Carcinomas in situ displayed unchanged levels of both proteins whereas poorly differentiated carcinomas consistently expressed diminished CD44s and CD44v6 levels. Lymphocytes and HNSCC lines strongly expressed CD44s but not CD44v6. Conclusion CD44s and CD44v6 expression does not distinguish normal from benign or malignant epithelia of the head and neck. CD44s and CD44v6 were abundantly present in the great majority of cells in head and neck tissues, including carcinomas. Hence, the value of CD44s as a marker for the definition of a small subset of cells (i.e. less than 10%) representing head and neck cancer stem cells may need revision. PMID:18852874

  15. COMPUTER RECONSTRUCTION OF A HUMAN LUNG MORPHOLOGY MODEL FROM MAGNETIC RESONANCE (MR) IMAGES

    EPA Science Inventory


    A mathematical description of the morphological structure of the lung is necessary for modeling and analysis of the deposition of inhaled aerosols. A morphological model of the lung boundary was generated from magnetic resonance (MR) images, with the goal of creating a frame...

  16. Intersections of lung progenitor cells, lung disease and lung cancer.

    PubMed

    Kim, Carla F

    2017-06-30

    The use of stem cell biology approaches to study adult lung progenitor cells and lung cancer has brought a variety of new techniques to the field of lung biology and has elucidated new pathways that may be therapeutic targets in lung cancer. Recent results have begun to identify the ways in which different cell populations interact to regulate progenitor activity, and this has implications for the interventions that are possible in cancer and in a variety of lung diseases. Today's better understanding of the mechanisms that regulate lung progenitor cell self-renewal and differentiation, including understanding how multiple epigenetic factors affect lung injury repair, holds the promise for future better treatments for lung cancer and for optimising the response to therapy in lung cancer. Working between platforms in sophisticated organoid culture techniques, genetically engineered mouse models of injury and cancer, and human cell lines and specimens, lung progenitor cell studies can begin with basic biology, progress to translational research and finally lead to the beginnings of clinical trials. Copyright ©ERS 2017.

  17. Chimeric Antigen Receptor-Redirected Regulatory T Cells Suppress Experimental Allergic Airway Inflammation, a Model of Asthma.

    PubMed

    Skuljec, Jelena; Chmielewski, Markus; Happle, Christine; Habener, Anika; Busse, Mandy; Abken, Hinrich; Hansen, Gesine

    2017-01-01

    Cellular therapy with chimeric antigen receptor (CAR)-redirected cytotoxic T cells has shown impressive efficacy in the treatment of hematologic malignancies. We explored a regulatory T cell (Treg)-based therapy in the treatment of allergic airway inflammation, a model for asthma, which is characterized by an airway hyper-reactivity (AHR) and a chronic, T helper-2 (Th2) cell-dominated immune response to allergen. To restore the immune balance in the lung, we redirected Tregs by a CAR toward lung epithelia in mice upon experimentally induced allergic asthma, closely mimicking the clinical situation. Adoptively transferred CAR Tregs accumulated in the lung and in tracheobronchial lymph nodes, reduced AHR and diminished eosinophilic airway inflammation, indicated by lower cell numbers in the bronchoalveolar lavage fluid and decreased cell infiltrates in the lung. CAR Treg cells furthermore prevented excessive pulmonary mucus production as well as increase in allergen-specific IgE and Th2 cytokine levels in exposed animals. CAR Tregs were more efficient in controlling asthma than non-modified Tregs, indicating the pivotal role of specific Treg cell activation in the affected organ. Data demonstrate that lung targeting CAR Treg cells ameliorate key features of experimental airway inflammation, paving the way for cell therapy of severe allergic asthma.

  18. Lung and Intestine: A Specific Link in an Ulcerative Colitis Rat Model

    PubMed Central

    Liu, Yuan; Wang, Xin-Yue; Yang, Xue; Jing, Shan; Zhu, Li; Gao, Si-Hua

    2013-01-01

    Background. To investigate the link and mechanisms between intestine and lung in the ulcerative colitis (UC) rat model. Materials and Methods. We used the UC rat model by immunological sensitization combined with local 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) in 50% ethanol enema, observed dynamically animal general state and body weight, examined the histological and functional changes in the colon, lung, liver, and kidney tissues, and detected microvascular endothelium response towards inflammation characterized with the expression of iNOS, TXB2, P-selectin, ICAM-1, and vascular endothelial growth factor A (VEGF-A) in the colon and lung tissue. Results. Pulmonary function results suggested ventilator disorder, and pathological findings showed interstitial pneumonia. There were no significant changes in the liver and kidney function and histopathology. The colon and lung tissue iNOS, TXB2, P-selectin, ICAM-1, and VEGF-A expression of the model rats was significantly higher than the normal rats at both time points. Conclusions. Our study is the first to demonstrate the close association between the large intestine and lung in the immune-TNBS-ethanol-induced UC rat model. Different organs and tissues with the same embryonic origin may share the same pathological specificities in a disease. The present study provided a new way of thinking for pathological changes in clinical complex diseases manifested with multiorgan damage. PMID:23606829

  19. Single-cell RNA-Seq reveals cell heterogeneity and hierarchy within mouse mammary epithelia.

    PubMed

    Sun, Heng; Miao, Zhengqiang; Zhang, Xin; Chan, Un In; Su, Sek Man; Guo, Sen; Wong, Chris Koon Ho; Xu, Xiaoling; Deng, Chu-Xia

    2018-06-01

    The mammary gland is very intricately and well organized into distinct tissues, including epithelia, endothelia, adipocytes, and stromal and immune cells. Many mammary gland diseases, such as breast cancer, arise from abnormalities in the mammary epithelium, which is mainly composed of two distinct lineages, the basal and luminal cells. Because of the limitation of traditional transcriptome analysis of bulk mammary cells, the hierarchy and heterogeneity of mammary cells within these two lineages remain unclear. To this end, using single-cell RNA-Seq coupled with FACS analysis and principal component analysis, we determined gene expression profiles of mammary epithelial cells of virgin and pregnant mice. These analyses revealed a much higher heterogeneity among the mammary cells than has been previously reported and enabled cell classification into distinct subgroups according to signature gene markers present in each group. We also identified and verified a rare CDH5 + cell subpopulation within a basal cell lineage as quiescent mammary stem cells (MaSCs). Moreover, using pseudo-temporal analysis, we reconstructed the developmental trajectory of mammary epithelia and uncovered distinct changes in gene expression and in biological functions of mammary cells along the developmental process. In conclusion, our work greatly refines the resolution of the cellular hierarchy in developing mammary tissues. The discovery of CDH5 + cells as MaSCs in these tissues may have implications for our understanding of the initiation, development, and pathogenesis of mammary tumors. © 2018 Sun et al.

  20. A computer simulation model of the cost-effectiveness of routine Staphylococcus aureus screening and decolonization among lung and heart-lung transplant recipients.

    PubMed

    Clancy, C J; Bartsch, S M; Nguyen, M H; Stuckey, D R; Shields, R K; Lee, B Y

    2014-06-01

    Our objective was to model the cost-effectiveness and economic value of routine peri-operative Staphylococcus aureus screening and decolonization of lung and heart-lung transplant recipients from hospital and third-party payer perspectives. We used clinical data from 596 lung and heart-lung transplant recipients to develop a model in TreeAge Pro 2009 (Williamsport, MA, USA). Sensitivity analyses varied S. aureus colonization rate (5-15 %), probability of infection if colonized (10-30 %), and decolonization efficacy (25-90 %). Data were collected from the Cardiothoracic Transplant Program at the University of Pittsburgh Medical Center. Consecutive lung and heart-lung transplant recipients from January 2006 to December 2010 were enrolled retrospectively. Baseline rates of S. aureus colonization, infection and decolonization efficacy were 9.6 %, 36.7 %, and 31.9 %, respectively. Screening and decolonization was economically dominant for all scenarios tested, providing more cost savings and health benefits than no screening. Savings per case averted (2012 $US) ranged from $73,567 to $133,157 (hospital perspective) and $10,748 to $16,723 (third party payer perspective), varying with the probability of colonization, infection, and decolonization efficacy. Using our clinical data, screening and decolonization led to cost savings per case averted of $240,602 (hospital perspective) and averted 6.7 S. aureus infections (4.3 MRSA and 2.4 MSSA); 89 patients needed to be screened to prevent one S. aureus infection. Our data support routine S. aureus screening and decolonization of lung and heart-lung transplant patients. The economic value of screening and decolonization was greater than in previous models of other surgical populations.

  1. Desmoplakin II expression is not restricted to stratified epithelia.

    PubMed

    Angst, B D; Nilles, L A; Green, K J

    1990-10-01

    Desmosomes are major intercellular junctions found in association with intermediate filaments in epithelial, cardiac and arachnoidal tissue. Desmoplakins I and II (DPI and II) are highly related proteins localized in the innermost part of the desmosomal plaque and are candidates for linking intermediate filaments (IF) to the desmosomal complex. While investigators agree that DPI is present in all epithelia, they disagree on the distribution of DPII. Some have reported DPII to be restricted to stratified tissue and have furthermore suggested that the expression of DPII may be linked to stratification. We have compared the expression of DPI and II at the mRNA and protein levels in cell lines derived from simple, transitional and stratified epithelia. Northern blot analysis revealed DPI and II mRNA to be present in all cell lines as well as simple and stratified epithelial tissues. However, DPII mRNA could not be detected in cardiac muscle tissue. Immunoblotting and immunoprecipitation demonstrated the presence of DPI and II in all cell lines at the whole-cell protein level as well as in association with cytoskeletal fractions. Immunofluorescence staining was used to correlate the biochemical findings with the localization of DPI and II. While most cell lines exhibited typical intercellular and in many cases cytoplasmic DP staining, T24 cells exhibited predominantly diffuse and dotty cytoplasmic staining. In addition, we investigated whether changes in DPI and II expression occurred following calcium-induced cell contact formation and stratification in the human pharyngeal cell line, FaDu. No significant changes in mRNA or whole-cell protein levels were observed during a period of 5 days following the calcium switch. However, immunoblotting revealed a significant increase in DPI and II levels in the insoluble protein pool during desmosome formation. These observations indicated a possible recruitment of soluble DPI/II into an insoluble pool after induction of

  2. Glycine ameliorates lung reperfusion injury after cold preservation in an ex vivo rat lung model.

    PubMed

    Omasa, Mitsugu; Fukuse, Tatsuo; Toyokuni, Shinya; Mizutani, Yoichi; Yoshida, Hiroshi; Ikeyama, Kazuyuki; Hasegawa, Seiki; Wada, Hiromi

    2003-03-15

    The role of glycine has not been investigated in lung ischemia-reperfusion injury after cold preservation. Furthermore, the role of apoptosis after reperfusion following cold preservation has not been fully understood. Lewis rats were divided into three groups (n=6 each). In the GLY(-) and GLY(+) groups, isolated lungs were preserved for 15 hr at 4 degrees C after a pulmonary artery (PA) flush using our previously developed preservation solution (ET-K; extracellular-type trehalose containing Kyoto), with or without the addition of glycine (5 mM). In the Fresh group, isolated lungs were reperfused immediately after a PA flush with ET-K. They were reperfused for 60 min with an ex vivo perfusion model. Pulmonary function, oxidative stress, apoptosis, and tumor necrosis factor (TNF)-alpha expression were assessed after reperfusion. Shunt fraction and peak inspiratory pressure after reperfusion in the GLY(-) group were significantly higher than those in the GLY(+) and Fresh groups. Oxidative damage and apoptosis in the alveolar epithelial cells of the GLY(-) group, assessed by immunohistochemical staining and quantification of 8-hydroxy-2'-deoxyguanosine and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling method, were significantly higher than those of the GLY(+) and Fresh groups. There were correlations among shunt fraction, oxidative damage, and apoptosis. There was no expression of TNF-alpha messenger RNA in all groups evaluated by the reverse transcription-polymerase chain reaction. Glycine attenuates ischemia/reperfusion injury after cold preservation by reducing oxidative damage and suppressing apoptosis independent of TNF-alpha in this model. The suppression of apoptosis might ameliorate lung function after reperfusion.

  3. Lung regeneration by fetal lung tissue implantation in a mouse pulmonary emphysema model.

    PubMed

    Uyama, Koh; Sakiyama, Shoji; Yoshida, Mitsuteru; Kenzaki, Koichiro; Toba, Hiroaki; Kawakami, Yukikiyo; Okumura, Kazumasa; Takizawa, Hiromitsu; Kondo, Kazuya; Tangoku, Akira

    2016-01-01

    The mortality and morbidity of chronic obstructive pulmonary disease are high. However, no radical therapy has been developed to date. The purpose of this study was to evaluate whether fetal mouse lung tissue can grow and differentiate in the emphysematous lung. Fetal lung tissue from green fluorescent protein C57BL/6 mice at 16 days' gestation was used as donor material. Twelve-month-old pallid mice were used as recipients. Donor lungs were cut into small pieces and implanted into the recipient left lung by performing thoracotomy under anesthesia. The recipient mice were sacrificed at day 7, 14, and 28 after implantation and used for histological examination. Well-developed spontaneous pulmonary emphysema was seen in 12-month-old pallid mice. Smooth and continuous connection between implanted fetal lung tissue and recipient lung was recognized. Air space expansion and donor tissue differentiation were observed over time. We could clearly distinguish the border zones between injected tissue and native tissue by the green fluorescence of grafts. Fetal mouse lung fragments survived and differentiated in the emphysematous lung of pallid mice. Implantation of fetal lung tissue in pallid mice might lead to further lung regeneration research from the perspective of respiratory and exercise function. J. Med. Invest. 63: 182-186, August, 2016.

  4. Distinct Roles of Cervical Epithelia and Stroma in Pregnancy and Parturition.

    PubMed

    Nallasamy, Shanmugasundaram; Mahendroo, Mala

    2017-03-01

    Through pregnancy the cervix must simultaneously remain competent for pregnancy maintenance and yet become progressively compliant to ensure on time parturition. Cervical changes precede not only term but also preterm birth. Thus, an understanding of the molecular mechanisms by which the cervix maintains the delicate balance between competence and compliance is required to prevent the potential for lifelong health complications that can result from a premature birth. Recent advances and accumulating evidence support distinct roles for the cervical epithelia and stroma in sustaining competence. Concurrently, structural reorganization of the stromal extracellular matrix allows for the gradual decline in tissue compliance. In recent years, advances in our understanding of the cervical remodeling process has resulted from the collective insights derived from biological, genomics, engineering, and mathematical modeling studies on clinical samples and animal models. This review will highlight recent literature that advances understanding of (1) the importance of barrier function in the lower female reproductive tract in protection against ascending infection, (2) cellular and extracellular matrix changes in the cervical stroma that influence the mechanical function of the cervix, (3) the potential translation of biological insights into clinical tools that impact preterm birth, and (4) the distinction between term and specific pathways of preterm birth. Finally, we present a discussion of future areas of investigation that are likely to advance understanding and lead to the development of clinical tools for accurate detection and prevention of premature birth. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  5. Computational Modeling of Airway and Pulmonary Vascular Structure and Function: Development of a “Lung Physiome”

    PubMed Central

    Tawhai, M. H.; Clark, A. R.; Donovan, G. M.; Burrowes, K. S.

    2011-01-01

    Computational models of lung structure and function necessarily span multiple spatial and temporal scales, i.e., dynamic molecular interactions give rise to whole organ function, and the link between these scales cannot be fully understood if only molecular or organ-level function is considered. Here, we review progress in constructing multiscale finite element models of lung structure and function that are aimed at providing a computational framework for bridging the spatial scales from molecular to whole organ. These include structural models of the intact lung, embedded models of the pulmonary airways that couple to model lung tissue, and models of the pulmonary vasculature that account for distinct structural differences at the extra- and intra-acinar levels. Biophysically based functional models for tissue deformation, pulmonary blood flow, and airway bronchoconstriction are also described. The development of these advanced multiscale models has led to a better understanding of complex physiological mechanisms that govern regional lung perfusion and emergent heterogeneity during bronchoconstriction. PMID:22011236

  6. Ferret lung transplant: an orthotopic model of obliterative bronchiolitis.

    PubMed

    Sui, H; Olivier, A K; Klesney-Tait, J A; Brooks, L; Tyler, S R; Sun, X; Skopec, A; Kline, J; Sanchez, P G; Meyerholz, D K; Zavazava, N; Iannettoni, M; Engelhardt, J F; Parekh, K R

    2013-02-01

    Obliterative bronchiolitis (OB) is the primary cause of late morbidity and mortality following lung transplantation. Current animal models do not reliably develop OB pathology. Given the similarities between ferret and human lung biology, we hypothesized an orthotopic ferret lung allograft would develop OB. Orthotopic left lower lobe transplants were successfully performed in 22 outbred domestic ferrets in the absence of immunosuppression (IS; n = 5) and presence of varying IS protocols (n = 17). CT scans were performed to evaluate the allografts. At intervals between 3-6 months the allografts were examined histologically for evidence of acute/chronic rejection. IS protects allografts from acute rejection and early graft loss. Reduction of IS dosage by 50% allowed development of controlled rejection. Allografts developed infiltrates on CT and classic histologic acute rejection and lymphocytic bronchiolitis. Cycling of IS, to induce repeated episodes of controlled rejection, promoted classic histologic hallmarks of OB including fibrosis-associated occlusion of the bronchiolar airways in all allografts of long-term survivors. In conclusion, we have developed an orthotopic lung transplant model in the ferret with documented long-term functional allograft survival. Allografts develop acute rejection and lymphocytic bronchiolitis, similar to humans. Long-term survivors develop histologic changes in the allografts that are hallmarks of OB. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

  7. Participant selection for lung cancer screening by risk modelling (the Pan-Canadian Early Detection of Lung Cancer [PanCan] study): a single-arm, prospective study.

    PubMed

    Tammemagi, Martin C; Schmidt, Heidi; Martel, Simon; McWilliams, Annette; Goffin, John R; Johnston, Michael R; Nicholas, Garth; Tremblay, Alain; Bhatia, Rick; Liu, Geoffrey; Soghrati, Kam; Yasufuku, Kazuhiro; Hwang, David M; Laberge, Francis; Gingras, Michel; Pasian, Sergio; Couture, Christian; Mayo, John R; Nasute Fauerbach, Paola V; Atkar-Khattra, Sukhinder; Peacock, Stuart J; Cressman, Sonya; Ionescu, Diana; English, John C; Finley, Richard J; Yee, John; Puksa, Serge; Stewart, Lori; Tsai, Scott; Haider, Ehsan; Boylan, Colm; Cutz, Jean-Claude; Manos, Daria; Xu, Zhaolin; Goss, Glenwood D; Seely, Jean M; Amjadi, Kayvan; Sekhon, Harmanjatinder S; Burrowes, Paul; MacEachern, Paul; Urbanski, Stefan; Sin, Don D; Tan, Wan C; Leighl, Natasha B; Shepherd, Frances A; Evans, William K; Tsao, Ming-Sound; Lam, Stephen

    2017-11-01

    Results from retrospective studies indicate that selecting individuals for low-dose CT lung cancer screening on the basis of a highly predictive risk model is superior to using criteria similar to those used in the National Lung Screening Trial (NLST; age, pack-year, and smoking quit-time). We designed the Pan-Canadian Early Detection of Lung Cancer (PanCan) study to assess the efficacy of a risk prediction model to select candidates for lung cancer screening, with the aim of determining whether this approach could better detect patients with early, potentially curable, lung cancer. We did this single-arm, prospective study in eight centres across Canada. We recruited participants aged 50-75 years, who had smoked at some point in their life (ever-smokers), and who did not have a self-reported history of lung cancer. Participants had at least a 2% 6-year risk of lung cancer as estimated by the PanCan model, a precursor to the validated PLCOm2012 model. Risk variables in the model were age, smoking duration, pack-years, family history of lung cancer, education level, body-mass index, chest x-ray in the past 3 years, and history of chronic obstructive pulmonary disease. Individuals were screened with low-dose CT at baseline (T0), and at 1 (T1) and 4 (T4) years post-baseline. The primary outcome of the study was incidence of lung cancer. This study is registered with ClinicalTrials.gov, number NCT00751660. 7059 queries came into the study coordinating centre and were screened for PanCan risk. 15 were duplicates, so 7044 participants were considered for enrolment. Between Sept 24, 2008, and Dec 17, 2010, we recruited and enrolled 2537 eligible ever-smokers. After a median follow-up of 5·5 years (IQR 3·2-6·1), 172 lung cancers were diagnosed in 164 individuals (cumulative incidence 0·065 [95% CI 0·055-0·075], incidence rate 138·1 per 10 000 person-years [117·8-160·9]). There were ten interval lung cancers (6% of lung cancers and 6% of individuals with cancer

  8. Acoustically detectable cellular-level lung injury induced by fluid mechanical stresses in microfluidic airway systems.

    PubMed

    Huh, Dongeun; Fujioka, Hideki; Tung, Yi-Chung; Futai, Nobuyuki; Paine, Robert; Grotberg, James B; Takayama, Shuichi

    2007-11-27

    We describe a microfabricated airway system integrated with computerized air-liquid two-phase microfluidics that enables on-chip engineering of human airway epithelia and precise reproduction of physiologic or pathologic liquid plug flows found in the respiratory system. Using this device, we demonstrate cellular-level lung injury under flow conditions that cause symptoms characteristic of a wide range of pulmonary diseases. Specifically, propagation and rupture of liquid plugs that simulate surfactant-deficient reopening of closed airways lead to significant injury of small airway epithelial cells by generating deleterious fluid mechanical stresses. We also show that the explosive pressure waves produced by plug rupture enable detection of the mechanical cellular injury as crackling sounds.

  9. SPECT/CT of lung nodules using 111In-DOTA-c(RGDfK) in a mouse lung carcinogenesis model.

    PubMed

    Hayakawa, Takuya; Mutoh, Michihiro; Imai, Toshio; Tsuta, Koji; Yanaka, Akinori; Fujii, Hirofumi; Yoshimoto, Mitsuyoshi

    2013-08-01

    Lung cancer is one of the leading causes of cancer-related deaths worldwide, including Japan. Although computed tomography (CT) can detect small lung lesions such as those appearing as ground glass opacity, it cannot differentiate between malignant and non-malignant lesions. Previously, we have shown that single photon emission computed tomography (SPECT) imaging using (111)In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-cyclo-(Arg-Gly-Asp-D-Phe-Lys) (DOTA-c(RGDfK)), an imaging probe of αvβ3 integrin, is useful for the early detection of pancreatic cancer in a hamster pancreatic carcinogenesis model. In this study, we aimed to assess the usefulness of SPECT/CT with (111)In-DOTA-c(RGDfK) for the evaluation of the malignancy of lung cancer. Lung tumors were induced by a single intraperitoneal injection (250 mg/kg) of urethane in male A/J mice. Twenty-six weeks after the urethane treatment, SPECT was performed an hour after injection of (111)In-DOTA-c(RGDfK). Following this, the radioactivity ratios of tumor to normal lung tissue were measured by autoradiography (ARG) in the excised lung samples. We also examined the expression of αvβ3 integrin in mouse and human lung samples. Urethane treatment induced 5 hyperplasias, 41 adenomas and 12 adenocarcinomas in the lungs of 8 A/J mice. SPECT with (111)In-DOTA-c(RGDfK) could clearly visualize lung nodules, though we failed to detect small lung nodules like adenoma and hyperplasias (adenocarcinoma: 66.7%, adenoma: 33.6%, hyperplasia: 0.0%). ARG analysis revealed significant uptake of (111)In-DOTA-c(RGDfK) in all the lesions. Moreover, tumor to normal lung tissue ratios increased along with the progression of carcinogenesis. Histopathological examination using human lung tissue samples revealed clear up-regulation of αvβ3 integrin in well-differentiated adenocarcinoma (Noguchi type B and C) rather than atypical adenomatous hyperplasia. Although there are some limitations in evaluating the malignancy of

  10. Neurogenin 1 Null Mutant Ears Develop Fewer, Morphologically Normal Hair Cells in Smaller Sensory Epithelia Devoid of Innervation

    PubMed Central

    Ma, Qiufu; Anderson, David J.

    2000-01-01

    The proneuronal gene neurogenin 1 (ngn1) is essential for development of the inner-ear sensory neurons that are completely absent in ngn1 null mutants. Neither afferent, efferent, nor autonomic nerve fibers were detected in the ears of ngn1 null mutants. We suggest that efferent and autonomic fibers are lost secondarily to the absence of afferents. In this article we show that ngn1 null mutants develop smaller sensory epithelia with morphologically normal hair cells. In particular, the saccule is reduced dramatically and forms only a small recess with few hair cells along a duct connecting the utricle with the cochlea. Hair cells of newborn ngn1 null mutants show no structural abnormalities, suggesting that embryonic development of hair cells is independent of innervation. However, the less regular pattern of dispersal within sensory epithelia may be caused by some effects of afferents or to the stunted growth of the sensory epithelia. Tracing of facial and stato-acoustic nerves in control and ngn1 null mutants showed that only the distal, epibranchial, placode-derived sensory neurons of the geniculate ganglion exist in mutants. Tracing further showed that these geniculate ganglion neurons project exclusively to the solitary tract. In addition to the normal complement of facial branchial and visceral motoneurons, ngn1 null mutants have some trigeminal motoneurons and contralateral inner-ear efferents projecting, at least temporarily, through the facial nerve. These data suggest that some neurons in the brainstem (e.g., inner-ear efferents, trigeminal motoneurons) require afferents to grow along and redirect to ectopic cranial nerve roots in the absence of their corresponding sensory roots. PMID:11545141

  11. Nicotine does not enhance tumorigenesis in mutant K-ras-driven mouse models of lung cancer.

    PubMed

    Maier, Colleen R; Hollander, M Christine; Hobbs, Evthokia A; Dogan, Irem; Linnoila, R Ilona; Dennis, Phillip A

    2011-11-01

    Smoking is the leading cause of preventable cancer deaths in the United States. Nicotine replacement therapies (NRT) have been developed to aid in smoking cessation, which decreases lung cancer incidence. However, the safety of NRT is controversial because numerous preclinical studies have shown that nicotine enhances tumor cell growth in vitro and in vivo. We modeled NRT in mice to determine the effects of physiologic levels of nicotine on lung tumor formation, tumor growth, or metastasis. Nicotine administered in drinking water did not enhance lung tumorigenesis after treatment with the tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Tumors that develop in this model have mutations in K-ras, which is commonly observed in smoking-related, human lung adenocarcinomas. In a transgenic model of mutant K-ras-driven lung cancer, nicotine did not increase tumor number or size and did not affect overall survival. Likewise, in a syngeneic model using lung cancer cell lines derived from NNK-treated mice, oral nicotine did not enhance tumor growth or metastasis. These data show that nicotine does not enhance lung tumorigenesis when given to achieve levels comparable with those of NRT, suggesting that nicotine has a dose threshold, below which it has no appreciable effect. These studies are consistent with epidemiologic data showing that NRT does not enhance lung cancer risk in former smokers.

  12. [Economic impact of lung cancer screening in France: A modeling study].

    PubMed

    Gendarme, S; Perrot, É; Reskot, F; Bhoowabul, V; Fourre, G; Souquet, P-J; Milleron, B; Couraud, S

    2017-09-01

    The National Lung Screening Trial found that, in a selected population with a high risk of lung cancer, an annual low-dose CT-scan decreased lung cancer mortality by 20% and overall mortality by 7% compared to annual chest X-Ray. In France, a work group stated that individual screening should be considered in this setting. However, the economic impact of an organized and generalized (to all eligible individuals) screening in France was never reported. This is a modeling study using French population demographic data and published data from randomized screening trials. We used the same selection criteria as NLST: 55-74-year-old smokers for at least 30 pack-years, current smoker or quit less than 15 years. We computed a second model including also 50-54-year-old individuals. Then, we used different participation rates: 65%, 45%, and 32%. According to the considered model, there would be 1,650,588 to 2,283,993 subjects eligible to screening in France. According to the model and participation rate, lung cancer screening would diagnose 3600 to 10,118 stages 1/2 lung cancer each year. There would be 5991 to 16,839 false-positives, of whom 1416 to 3981 would undergo unnecessary surgery. Screening policy would cost 105 to 215 € million per year. However, increasing the price of a cigarette pack by 0.05 to 0.10 € would fully cover the screening costs. Participation rate is a key point for screening impact. Screening could be easily funded by a small increase in cigarette prices. Copyright © 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.

  13. Combined gene expression analysis of whole-tissue and microdissected pancreatic ductal adenocarcinoma identifies genes specifically overexpressed in tumor epithelia.

    PubMed

    Badea, Liviu; Herlea, Vlad; Dima, Simona Olimpia; Dumitrascu, Traian; Popescu, Irinel

    2008-01-01

    The precise details of pancreatic ductal adenocarcinoma (PDAC) pathogenesis are still insufficiently known, requiring the use of high-throughput methods. However, PDAC is especially difficult to study using microarrays due to its strong desmoplastic reaction, which involves a hyperproliferating stroma that effectively "masks" the contribution of the minoritary neoplastic epithelial cells. Thus it is not clear which of the genes that have been found differentially expressed between normal and whole tumor tissues are due to the tumor epithelia and which simply reflect the differences in cellular composition. To address this problem, laser microdissection studies have been performed, but these have to deal with much smaller tissue sample quantities and therefore have significantly higher experimental noise. In this paper we combine our own large sample whole-tissue study with a previously published smaller sample microdissection study by Grützmann et al. to identify the genes that are specifically overexpressed in PDAC tumor epithelia. The overlap of this list of genes with other microarray studies of pancreatic cancer as well as with the published literature is impressive. Moreover, we find a number of genes whose over-expression appears to be inversely correlated with patient survival: keratin 7, laminin gamma 2, stratifin, platelet phosphofructokinase, annexin A2, MAP4K4 and OACT2 (MBOAT2), which are all specifically upregulated in the neoplastic epithelia, rather than the tumor stroma. We improve on other microarray studies of PDAC by putting together the higher statistical power due to a larger number of samples with information about cell-type specific expression and patient survival.

  14. Regeneration of the lung: Lung stem cells and the development of lung mimicking devices.

    PubMed

    Schilders, Kim A A; Eenjes, Evelien; van Riet, Sander; Poot, André A; Stamatialis, Dimitrios; Truckenmüller, Roman; Hiemstra, Pieter S; Rottier, Robbert J

    2016-04-23

    Inspired by the increasing burden of lung associated diseases in society and an growing demand to accommodate patients, great efforts by the scientific community produce an increasing stream of data that are focused on delineating the basic principles of lung development and growth, as well as understanding the biomechanical properties to build artificial lung devices. In addition, the continuing efforts to better define the disease origin, progression and pathology by basic scientists and clinicians contributes to insights in the basic principles of lung biology. However, the use of different model systems, experimental approaches and readout systems may generate somewhat conflicting or contradictory results. In an effort to summarize the latest developments in the lung epithelial stem cell biology, we provide an overview of the current status of the field. We first describe the different stem cells, or progenitor cells, residing in the homeostatic lung. Next, we focus on the plasticity of the different cell types upon several injury-induced activation or repair models, and highlight the regenerative capacity of lung cells. Lastly, we summarize the generation of lung mimics, such as air-liquid interface cultures, organoids and lung on a chip, that are required to test emerging hypotheses. Moreover, the increasing collaboration between distinct specializations will contribute to the eventual development of an artificial lung device capable of assisting reduced lung function and capacity in human patients.

  15. Which risk models perform best in selecting ever-smokers for lung cancer screening?

    Cancer.gov

    A new analysis by scientists at NCI evaluates nine different individualized lung cancer risk prediction models based on their selections of ever-smokers for computed tomography (CT) lung cancer screening.

  16. Role of inflammatory cells and adenosine in lung ischemia reoxygenation injury using a model of lung donation after cardiac death.

    PubMed

    Smail, Hassiba; Baste, Jean-Marc; Gay, Arnaud; Begueret, Hugues; Noël, Romain; Morin, Jean-Paul; Litzler, Pierre-Yves

    2016-04-01

    The objective of this study is to analyze the role of inflammation in the lung ischemia reperfusion (IR) injury and determine the protective role of adenosine in an in vitro lung transplantation model. We used a hybrid model of lung donor after cardiac death, with warm ischemia in corpo of varying duration (2 h, 4 h) followed by in vitro lung slices culture for reoxygenation (1 h, 4 h and 24 h), in the presence or not of lymphocytes and of adenosine. To quantify the inflammatory lesions, we performed TNFα, IL2 assays, and histological analysis. In this model of a nonblood perfused system, the addition of lymphocytes during reoxygenation lead to higher rates of TNFα and IL2 after 4 h than after 2 h of warm ischemia (P < .05). These levels increased with the duration of reoxygenation and were maximum at 24 h (P < .05). In the presence of adenosine TNFα and IL2 decreased. After 2 h of warm ischemia, we observed a significant inflammatory infiltration, alveolar thickening and a necrosis of the bronchiolar cells. After 4 h of warm ischemia, alveolar cells necrosis was associated. This model showed that lymphocytes increased the inflammatory response and the histological lesions after 4 h of warm ischemia and that adenosine could have an anti-inflammatory role with potential reconditioning action when used in the pneumoplegia solution.

  17. Membrane Lipid Microenvironment Modulates Thermodynamic Properties of the Na+-K+-ATPase in Branchial and Intestinal Epithelia in Euryhaline Fish In vivo

    PubMed Central

    Díaz, Mario; Dópido, Rosa; Gómez, Tomás; Rodríguez, Covadonga

    2016-01-01

    We have analyzed the effects of different native membrane lipid composition on the thermodynamic properties of the Na+-K+-ATPase in different epithelia from the gilthead seabream Sparus aurata. Thermodynamic parameters of activation for the Na+-K+-ATPase, as well as contents of lipid classes and fatty acids from polar lipids were determined for gill epithelia and enterocytes isolated from pyloric caeca, anterior intestine and posterior intestine. Arrhenius analyses of control animals revealed differences in thermal discontinuity values (Td) and activation energies determined at both sides of Td between intestinal and gill epithelia. Eyring plots disclosed important differences in enthalpy of activation (ΔH‡) and entropy of activation (ΔS‡) between enterocytes and branchial cells. Induction of n-3 LCPUFA deficiency dramatically altered membrane lipid composition in enterocytes, being the most dramatic changes the increase in 18:1n-9 (oleic acid) and the reduction of n-3 LCPUFA (mainly DHA, docosahexaenoic acid). Strikingly, branchial cells were much more resistant to diet-induced lipid alterations than enterocytes, indicating the existence of potent lipostatic mechanisms preserving membrane lipid matrix in gill epithelia. Paralleling lipid alterations, values of Ea1, ΔH‡ and ΔS‡ for the Na+-K+-ATPase were all increased, while Td values vanished, in LCPUFA deficient enterocytes. In turn, Differences in thermodynamic parameters were highly correlated with specific changes in fatty acids, but not with individual lipid classes including cholesterol in vivo. Thus, Td was positively related to 18:1n-9 and negatively to DHA. Td, Ea1 and ΔH‡ were exponentially related to DHA/18:1n-9 ratio. The exponential nature of these relationships highlights the strong impact of subtle changes in the contents of oleic acid and DHA in setting the thermodynamic properties of epithelial Na+-K+-ATPase in vivo. The effects are consistent with physical effects on the lipid

  18. Simvastatin attenuates neutrophil recruitment in one-lung ventilation model in rats.

    PubMed

    Leite, Camila Ferreira; Marangoni, Fábio André; Camargo, Enilton Aparecido; Braga, Angélica de Fátima de Assunção; Toro, Ivan Felizardo Contrera; Antunes, Edson; Landucci, Elen Cristina Tiezem; Mussi, Ricardo Kalaf

    2013-04-01

    To investigate the anti-inflammatory effects of simvastatin in rats undergoing one-lung ventilation (OLV) followed by lung re-expansion. Male Wistar rats (n=30) were submitted to 1-h OLV followed by 1-h lung re-expansion. Treated group received simvastatin (40 mg/kg for 21 days) previous to OLV protocol. Control group received no treatment or surgical/ventilation interventions. Measurements of pulmonary myeloperoxidase (MPO) activity, pulmonary protein extravasation, and serum levels of cytokines and C-reactive protein (CRP) were performed. OLV significantly increased the MPO activity in the collapsed and continuously ventilated lungs (31% and 52% increase, respectively) compared with control (p<0.05). Treatment with simvastatin significantly reduced the MPO activity in the continuously ventilated lung but had no effect on lung edema after OLV. The serum IL-6 and CRP levels were markedly higher in OLV group, but simvastatin treatment failed to affect the production of these inflammatory markers. Serum levels of IL-1β, TNF-α and IL-10 remained below the detection limit in all groups. In an experimental one-lung ventilation model pre-operative treatment with simvastatin reduces remote neutrophil infiltration in the continuously ventilated lung. Our findings suggest that simvastatin may be of therapeutic value in OLV-induced pulmonary inflammation deserving clinical investigations.

  19. An integrated physiology model to study regional lung damage effects and the physiologic response

    PubMed Central

    2014-01-01

    Background This work expands upon a previously developed exercise dynamic physiology model (DPM) with the addition of an anatomic pulmonary system in order to quantify the impact of lung damage on oxygen transport and physical performance decrement. Methods A pulmonary model is derived with an anatomic structure based on morphometric measurements, accounting for heterogeneous ventilation and perfusion observed experimentally. The model is incorporated into an existing exercise physiology model; the combined system is validated using human exercise data. Pulmonary damage from blast, blunt trauma, and chemical injury is quantified in the model based on lung fluid infiltration (edema) which reduces oxygen delivery to the blood. The pulmonary damage component is derived and calibrated based on published animal experiments; scaling laws are used to predict the human response to lung injury in terms of physical performance decrement. Results The augmented dynamic physiology model (DPM) accurately predicted the human response to hypoxia, altitude, and exercise observed experimentally. The pulmonary damage parameters (shunt and diffusing capacity reduction) were fit to experimental animal data obtained in blast, blunt trauma, and chemical damage studies which link lung damage to lung weight change; the model is able to predict the reduced oxygen delivery in damage conditions. The model accurately estimates physical performance reduction with pulmonary damage. Conclusions We have developed a physiologically-based mathematical model to predict performance decrement endpoints in the presence of thoracic damage; simulations can be extended to estimate human performance and escape in extreme situations. PMID:25044032

  20. A three-dimensional model of human lung development and disease from pluripotent stem cells.

    PubMed

    Chen, Ya-Wen; Huang, Sarah Xuelian; de Carvalho, Ana Luisa Rodrigues Toste; Ho, Siu-Hong; Islam, Mohammad Naimul; Volpi, Stefano; Notarangelo, Luigi D; Ciancanelli, Michael; Casanova, Jean-Laurent; Bhattacharya, Jahar; Liang, Alice F; Palermo, Laura M; Porotto, Matteo; Moscona, Anne; Snoeck, Hans-Willem

    2017-05-01

    Recapitulation of lung development from human pluripotent stem cells (hPSCs) in three dimensions (3D) would allow deeper insight into human development, as well as the development of innovative strategies for disease modelling, drug discovery and regenerative medicine. We report here the generation from hPSCs of lung bud organoids (LBOs) that contain mesoderm and pulmonary endoderm and develop into branching airway and early alveolar structures after xenotransplantation and in Matrigel 3D culture. Expression analysis and structural features indicated that the branching structures reached the second trimester of human gestation. Infection in vitro with respiratory syncytial virus, which causes small airway obstruction and bronchiolitis in infants, led to swelling, detachment and shedding of infected cells into the organoid lumens, similar to what has been observed in human lungs. Introduction of mutation in HPS1, which causes an early-onset form of intractable pulmonary fibrosis, led to accumulation of extracellular matrix and mesenchymal cells, suggesting the potential use of this model to recapitulate fibrotic lung disease in vitro. LBOs therefore recapitulate lung development and may provide a useful tool to model lung disease.

  1. A three-dimensional model of human lung development and disease from pluripotent stem cells

    PubMed Central

    Chen, Ya-Wen; Huang, Sarah Xuelian; de Carvalho, Ana Luisa Rodrigues Toste; Ho, Siu-Hong; Islam, Mohammad Naimul; Volpi, Stefano; Notarangelo, Luigi D; Ciancanelli, Michael; Casanova, Jean-Laurent; Bhattacharya, Jahar; Liang, Alice F.; Palermo, Laura M; Porotto, Matteo; Moscona, Anne; Snoeck, Hans-Willem

    2017-01-01

    Recapitulation of lung development from human pluripotent stem cells (hPSCs) in three dimensions (3D) would allow deeper insight into human development, as well as the development of innovative strategies for disease modeling, drug discovery and regenerative medicine1. We report here the generation from hPSCs of lung bud organoids (LBOs) that contain mesoderm and pulmonary endoderm and develop into branching airway and early alveolar structures after xenotransplantation and in Matrigel 3D culture. Expression analysis and structural features indicated that the branching structures reached the second trimester of human gestation. Infection in vitro with respiratory syncytial virus, which causes small airway obstruction and bronchiolitis in infants2, led to swelling, detachment and shedding of infected cells into the organoid lumens, similar to what has been observed in human lungs3. Introduction of mutation in HPS1, which causes an early-onset form of intractable pulmonary fibrosis4,5, led to accumulation of extracellular matrix and mesenchymal cells, suggesting the potential use of this model to recapitulate fibrotic lung disease in vitro. LBOs therefore recapitulate lung development and may provide a useful tool to model lung disease. PMID:28436965

  2. Oxidative stress and lung injury induced by short-term exposure to wood smoke in guinea pigs.

    PubMed

    Ramos, Carlos; Pedraza-Chaverri, José; Becerril, C; Cisneros, J; González-Ávila, G; Rivera-Rosales, R; Sommer, B; Medina-Campos, O N; Montaño, M

    2013-11-01

    Oxidative stress and lung injury induced by short-term exposure to wood smoke were evaluated in guinea pigs through cell profile, bronchoalveolar lavage (BAL), conventional histology and immunohistochemistry (4-hydroxynonenal, 3-nitrotyrosine, Mn-superoxide dismutase, heme oxygenase-1); malondialdehyde and 4-hydroxynonenal concentration, Mn-superoxide dismutase, glutathione reductase, glutathione peroxidase, and catalase activities in plasma, lung and BAL. Total cells increased in BAL, and the percentage of macrophages, neutrophils and lymphocytes augmented (72-96 h). Histopathological examination of lung tissues showed mild thickening of membranous bronchiole walls, infiltration of foamy macrophages and polymorphonuclear leukocytes in bronchial, bronchiolar and intraalveolar spaces. Goblet cell hyperplasia was also observed in bronchial and bronchiolar epithelia. Plasma malondialdehyde concentration was increased at all times, while 4-hydroxynonenal was increased only in plasma and BAL after 24 h. Plasma glutathione reductase activity increased at 24 and 72 h, BAL glutathione peroxidase activity decreased at 72 and 96 h, whereas catalase activity increased in plasma at 72 h, and decreased in BAL at 24 h. Immunostaining intensity to 4-hydroxynonenal, 3-nitrotyrosine, Mn-superoxide dismutase and heme oxygenase-1 was enhanced mainly in macrophages, bronchial/bronchiolar epithelial cells and type II pneumocytes after 72-96 h of wood smoke exposure. Overall, short-term exposure to wood smoke induces alterations in oxidative/antioxidant state in lung and airway injury, similar to those observed in humans with domestic exposure.

  3. Lung flooding enables efficient lung sonography and tumour imaging in human ex vivo and porcine in vivo lung cancer model

    PubMed Central

    2013-01-01

    Background Sonography has become the imaging technique of choice for guiding intraoperative interventions in abdominal surgery. Due to artefacts from residual air content, however, videothoracoscopic and open intraoperative ultrasound-guided thermoablation of lung malignancies are impossible. Lung flooding is a new method that allows complete ultrasound imaging of lungs and their tumours. Methods Fourteen resected tumourous human lung lobes were examined transpleurally with B-mode ultrasound before (in atelectasis) and after lung flooding with isotonic saline solution. In two swine, the left lung was filled with 15 ml/kg isotonic saline solution through the left side of a double-lumen tube. Lung tumours were simulated by transthoracic ultrasound-guided injection of 5 ml of purified bovine serum albumin in glutaraldehyde, centrally into the left lower lung lobe. The rate of tumour detection, the severity of disability caused by residual gas, and sonomorphology of the lungs and tumours were assessed. Results The ex vivo tumour detection rate was 100% in flooded human lung lobes and 43% (6/14) in atelectatic lungs. In all cases of atelectasis, sonographic tumour imaging was impaired by residual gas. Tumours and atelectatic tissue were isoechoic. In 28% of flooded lungs, a little residual gas was observed that did not impair sonographic tumour imaging. In contrast to tumours, flooded lung tissue was hyperechoic, homogeneous, and of fine-grained structure. Because of the bronchial wall three-laminar structure, sonographic differentiation of vessels and bronchi was possible. In all cases, malignant tumours in the flooded lung appeared well-demarcated from the lung parenchyma. Adenocarcinoma, squamous, and large cell carcinomas were hypoechoic. Bronchioloalveolar cell carcinoma was slightly hyperechoic. Transpleural sonography identifies endobronchial tumour growth and bronchial wall destruction. With transthoracic sonography, the flooded animal lung can be completely

  4. COMPUTER SIMULATIONS OF LUNG AIRWAY STRUCTURES USING DATA-DRIVEN SURFACE MODELING TECHNIQUES

    EPA Science Inventory

    ABSTRACT

    Knowledge of human lung morphology is a subject critical to many areas of medicine. The visualization of lung structures naturally lends itself to computer graphics modeling due to the large number of airways involved and the complexities of the branching systems...

  5. Three-dimensional pulmonary model using rapid-prototyping in patient with lung cancer requiring segmentectomy.

    PubMed

    Akiba, Tadashi; Nakada, Takeo; Inagaki, Takuya

    2014-01-01

    Thoracoscopic pulmonary segmentectomy of the lung is sometime adopted for the lung cancer, but a problem with segmentectomy is variable anatomy. Recently, we are exploring the impact of three-dimensional models using rapid-prototyping technique. It is useful for decision making, surgical planning, and intraoperative orientation for surgical treatment in patient with lung cancer who underwent pulmonary segmentectomy. These newly created models allow us to clearly identify the surgical margin and the intersegmental plane, vessels, and bronchi related to the cancer in the posterior segment. To the best of our knowledge, there are few reports describing a pulmonary model so far.

  6. Genetically manipulated mouse models of lung disease: potential and pitfalls

    PubMed Central

    Choi, Alexander J. S.; Owen, Caroline A.; Choi, Augustine M. K.

    2012-01-01

    Gene targeting in mice (transgenic and knockout) has provided investigators with an unparalleled armamentarium in recent decades to dissect the cellular and molecular basis of critical pathophysiological states. Fruitful information has been derived from studies using these genetically engineered mice with significant impact on our understanding, not only of specific biological processes spanning cell proliferation to cell death, but also of critical molecular events involved in the pathogenesis of human disease. This review will focus on the use of gene-targeted mice to study various models of lung disease including airways diseases such as asthma and chronic obstructive pulmonary disease, and parenchymal lung diseases including idiopathic pulmonary fibrosis, pulmonary hypertension, pneumonia, and acute lung injury. We will attempt to review the current technological approaches of generating gene-targeted mice and the enormous dataset derived from these studies, providing a template for lung investigators. PMID:22198907

  7. Ultrasound-induced cavitation damage to external epithelia of fish skin.

    PubMed

    Frenkel, V; Kimmel, E; Iger, Y

    1999-10-01

    Transmission electron microscopy was used to show the effects of therapeutic ultrasound (< or = 1.0 W/cm2, 1 MHz) on the external epithelia of fish skin. Exposures of up to 90 s produced damage to 5 to 6 of the outermost layers. Negligible temperature elevations and lack of damage observed when using degassed water indicated that the effects were due to cavitation. The minimal intensity was determined for inducing cellular damage, where the extent and depth of damage to the tissues was correlated to the exposure duration. The results may be interpreted as a damage front, advancing slowly from the outer cells inward, presumably in association with the slow replacement of the perforated cell contents with the surrounding water. This study illustrates that a controlled level of microdamage may be induced to the outer layers of the tissues.

  8. Anterograde Trafficking of KCa3.1 in Polarized Epithelia Is Rab1- and Rab8-Dependent and Recycling Endosome-Independent

    PubMed Central

    Bertuccio, Claudia A.; Lee, Shih-Liang; Wu, Guangyu; Butterworth, Michael B.; Hamilton, Kirk L.; Devor, Daniel C.

    2014-01-01

    The intermediate conductance, Ca2+-activated K+ channel (KCa3.1) targets to the basolateral (BL) membrane in polarized epithelia where it plays a key role in transepithelial ion transport. However, there are no studies defining the anterograde and retrograde trafficking of KCa3.1 in polarized epithelia. Herein, we utilize Biotin Ligase Acceptor Peptide (BLAP)-tagged KCa3.1 to address these trafficking steps in polarized epithelia, using MDCK, Caco-2 and FRT cells. We demonstrate that KCa3.1 is exclusively targeted to the BL membrane in these cells when grown on filter supports. Following endocytosis, KCa3.1 degradation is prevented by inhibition of lysosomal/proteosomal pathways. Further, the ubiquitylation of KCa3.1 is increased following endocytosis from the BL membrane and PR-619, a deubiquitylase inhibitor, prevents degradation, indicating KCa3.1 is targeted for degradation by ubiquitylation. We demonstrate that KCa3.1 is targeted to the BL membrane in polarized LLC-PK1 cells which lack the μ1B subunit of the AP-1 complex, indicating BL targeting of KCa3.1 is independent of μ1B. As Rabs 1, 2, 6 and 8 play roles in ER/Golgi exit and trafficking of proteins to the BL membrane, we evaluated the role of these Rabs in the trafficking of KCa3.1. In the presence of dominant negative Rab1 or Rab8, KCa3.1 cell surface expression was significantly reduced, whereas Rabs 2 and 6 had no effect. We also co-immunoprecipitated KCa3.1 with both Rab1 and Rab8. These results suggest these Rabs are necessary for the anterograde trafficking of KCa3.1. Finally, we determined whether KCa3.1 traffics directly to the BL membrane or through recycling endosomes in MDCK cells. For these studies, we used either recycling endosome ablation or dominant negative RME-1 constructs and determined that KCa3.1 is trafficked directly to the BL membrane rather than via recycling endosomes. These results are the first to describe the anterograde and retrograde trafficking of KCa3.1 in polarized

  9. Extracellular ATP mediates the late phase of neutrophil recruitment to the lung in murine models of acute lung injury.

    PubMed

    Shah, Dilip; Romero, Freddy; Stafstrom, William; Duong, Michelle; Summer, Ross

    2014-01-01

    Acute lung injury (ALI) is a severe inflammatory condition whose pathogenesis is irrevocably linked to neutrophil emigration to the lung. Activation and recruitment of neutrophils to the lung is mostly attributable to local production of the chemokines. However, much of our understanding of neutrophil recruitment to the lung is based on studies focusing on early time points after initiation of injury. In this study, we sought to evaluate the extended temporal relationship between neutrophil chemotactic factor expression and influx of neutrophils into the lung after intratracheal administration of either LPS or bleomycin. In both models, results demonstrated two phases of neutrophil chemotactic factor expression; first, an early phase characterized by high levels of CXCL1/keratinocyte-derived chemokine, CXCL2/monocyte-inhibitory protein-2, and CXCL5/LPS-induced chemokine expression, and second, a late phase distinguished by increases in extracellular ATP. Furthermore, we show that strategies aimed at either enhancing ATP catabolism (ip ecto-5'-nucleotidase administration) or inhibiting glycolytic ATP production (ip 2-deoxy-d-glucose treatment) reduce extracellular ATP accumulation, limit vascular leakage, and effectively block the late, but not the early, stages of neutrophil recruitment to the lung after LPS instillation. In conclusion, this study illustrates that neutrophil recruitment to the lung is mediated by the time-dependent expression of chemotactic factors and suggests that novel strategies, which reduce extracellular ATP accumulation, may attenuate late neutrophil recruitment and limit lung injury during ALI.

  10. Extracellular ATP mediates the late phase of neutrophil recruitment to the lung in murine models of acute lung injury

    PubMed Central

    Shah, Dilip; Romero, Freddy; Stafstrom, William; Duong, Michelle

    2013-01-01

    Acute lung injury (ALI) is a severe inflammatory condition whose pathogenesis is irrevocably linked to neutrophil emigration to the lung. Activation and recruitment of neutrophils to the lung is mostly attributable to local production of the chemokines. However, much of our understanding of neutrophil recruitment to the lung is based on studies focusing on early time points after initiation of injury. In this study, we sought to evaluate the extended temporal relationship between neutrophil chemotactic factor expression and influx of neutrophils into the lung after intratracheal administration of either LPS or bleomycin. In both models, results demonstrated two phases of neutrophil chemotactic factor expression; first, an early phase characterized by high levels of CXCL1/keratinocyte-derived chemokine, CXCL2/monocyte-inhibitory protein-2, and CXCL5/LPS-induced chemokine expression, and second, a late phase distinguished by increases in extracellular ATP. Furthermore, we show that strategies aimed at either enhancing ATP catabolism (ip ecto-5′-nucleotidase administration) or inhibiting glycolytic ATP production (ip 2-deoxy-d-glucose treatment) reduce extracellular ATP accumulation, limit vascular leakage, and effectively block the late, but not the early, stages of neutrophil recruitment to the lung after LPS instillation. In conclusion, this study illustrates that neutrophil recruitment to the lung is mediated by the time-dependent expression of chemotactic factors and suggests that novel strategies, which reduce extracellular ATP accumulation, may attenuate late neutrophil recruitment and limit lung injury during ALI. PMID:24285266

  11. Internal Motion Estimation by Internal-external Motion Modeling for Lung Cancer Radiotherapy.

    PubMed

    Chen, Haibin; Zhong, Zichun; Yang, Yiwei; Chen, Jiawei; Zhou, Linghong; Zhen, Xin; Gu, Xuejun

    2018-02-27

    The aim of this study is to develop an internal-external correlation model for internal motion estimation for lung cancer radiotherapy. Deformation vector fields that characterize the internal-external motion are obtained by respectively registering the internal organ meshes and external surface meshes from the 4DCT images via a recently developed local topology preserved non-rigid point matching algorithm. A composite matrix is constructed by combing the estimated internal phasic DVFs with external phasic and directional DVFs. Principle component analysis is then applied to the composite matrix to extract principal motion characteristics, and generate model parameters to correlate the internal-external motion. The proposed model is evaluated on a 4D NURBS-based cardiac-torso (NCAT) synthetic phantom and 4DCT images from five lung cancer patients. For tumor tracking, the center of mass errors of the tracked tumor are 0.8(±0.5)mm/0.8(±0.4)mm for synthetic data, and 1.3(±1.0)mm/1.2(±1.2)mm for patient data in the intra-fraction/inter-fraction tracking, respectively. For lung tracking, the percent errors of the tracked contours are 0.06(±0.02)/0.07(±0.03) for synthetic data, and 0.06(±0.02)/0.06(±0.02) for patient data in the intra-fraction/inter-fraction tracking, respectively. The extensive validations have demonstrated the effectiveness and reliability of the proposed model in motion tracking for both the tumor and the lung in lung cancer radiotherapy.

  12. HOSVD-Based 3D Active Appearance Model: Segmentation of Lung Fields in CT Images.

    PubMed

    Wang, Qingzhu; Kang, Wanjun; Hu, Haihui; Wang, Bin

    2016-07-01

    An Active Appearance Model (AAM) is a computer vision model which can be used to effectively segment lung fields in CT images. However, the fitting result is often inadequate when the lungs are affected by high-density pathologies. To overcome this problem, we propose a Higher-order Singular Value Decomposition (HOSVD)-based Three-dimensional (3D) AAM. An evaluation was performed on 310 diseased lungs form the Lung Image Database Consortium Image Collection. Other contemporary AAMs operate directly on patterns represented by vectors, i.e., before applying the AAM to a 3D lung volume,it has to be vectorized first into a vector pattern by some technique like concatenation. However, some implicit structural or local contextual information may be lost in this transformation. According to the nature of the 3D lung volume, HOSVD is introduced to represent and process the lung in tensor space. Our method can not only directly operate on the original 3D tensor patterns, but also efficiently reduce the computer memory usage. The evaluation resulted in an average Dice coefficient of 97.0 % ± 0.59 %, a mean absolute surface distance error of 1.0403 ± 0.5716 mm, a mean border positioning errors of 0.9187 ± 0.5381 pixel, and a Hausdorff Distance of 20.4064 ± 4.3855, respectively. Experimental results showed that our methods delivered significant and better segmentation results, compared with the three other model-based lung segmentation approaches, namely 3D Snake, 3D ASM and 3D AAM.

  13. A Novel Model for Squamous Cell Carcinoma of the Lung | Center for Cancer Research

    Cancer.gov

    In the U.S. lung cancer remains the most deadly cancer type with less than one in five patients alive five years after diagnosis. The majority of lung cancer deaths are due to tobacco smoke, and the squamous cell carcinoma (SCC) subtype of lung cancer is strongly associated with smoking. Researchers have identified a number of mutations in lung SCC tumors but have failed to generate an animal model of lung SCC, which is critical for understanding the biology of the disease and for identifying novel therapeutic targets.

  14. Cell density and N-cadherin interactions regulate cell proliferation in the sensory epithelia of the inner ear.

    PubMed

    Warchol, Mark E

    2002-04-01

    Sensory hair cells in the inner ears of nonmammalian vertebrates can regenerate after injury. In many species, replacement hair cells are produced by the proliferation of epithelial supporting cells. Thus, the ability of supporting cells to undergo renewed proliferation is a key determinant of regenerative ability. The present study used cultures of isolated inner ear sensory epithelia to identify cellular signals that regulate supporting cell proliferation. Small pieces of sensory epithelia from the chicken utricle were cultured in glass microwells. Under those conditions, cell proliferation was inversely related to local cell density. The signaling molecules N-cadherin, beta-catenin, and focal adhesion kinase were immunolocalized in the cultured epithelial cells, and high levels of phosphotyrosine immunoreactivity were present at cell-cell junctions and focal contacts of proliferating cells. Binding of microbeads coated with a function-blocking antibody to N-cadherin inhibited ongoing proliferation. The growth of epithelial cells was also affected by the density of extracellular matrix molecules. The results suggest that cell density, cell-cell contact, and the composition of the extracellular matrix may be critical influences on the regulation of sensory regeneration in the inner ear.

  15. Multiscale image-based modeling and simulation of gas flow and particle transport in the human lungs

    PubMed Central

    Tawhai, Merryn H; Hoffman, Eric A

    2013-01-01

    Improved understanding of structure and function relationships in the human lungs in individuals and sub-populations is fundamentally important to the future of pulmonary medicine. Image-based measures of the lungs can provide sensitive indicators of localized features, however to provide a better prediction of lung response to disease, treatment and environment, it is desirable to integrate quantifiable regional features from imaging with associated value-added high-level modeling. With this objective in mind, recent advances in computational fluid dynamics (CFD) of the bronchial airways - from a single bifurcation symmetric model to a multiscale image-based subject-specific lung model - will be reviewed. The interaction of CFD models with local parenchymal tissue expansion - assessed by image registration - allows new understanding of the interplay between environment, hot spots where inhaled aerosols could accumulate, and inflammation. To bridge ventilation function with image-derived central airway structure in CFD, an airway geometrical modeling method that spans from the model ‘entrance’ to the terminal bronchioles will be introduced. Finally, the effects of turbulent flows and CFD turbulence models on aerosol transport and deposition will be discussed. CFD simulation of airflow and particle transport in the human lung has been pursued by a number of research groups, whose interest has been in studying flow physics and airways resistance, improving drug delivery, or investigating which populations are most susceptible to inhaled pollutants. The three most important factors that need to be considered in airway CFD studies are lung structure, regional lung function, and flow characteristics. Their correct treatment is important because the transport of therapeutic or pollutant particles is dependent on the characteristics of the flow by which they are transported; and the airflow in the lungs is dependent on the geometry of the airways and how ventilation

  16. Integrin Beta 1 Suppresses Multilayering of a Simple Epithelium

    PubMed Central

    Chen, Jichao; Krasnow, Mark A.

    2012-01-01

    Epithelia are classified as either simple, a single cell layer thick, or stratified (multilayered). Stratified epithelia arise from simple epithelia during development, and transcription factor p63 functions as a key positive regulator of epidermal stratification. Here we show that deletion of integrin beta 1 (Itgb1) in the developing mouse airway epithelium abrogates airway branching and converts this monolayer epithelium into a multilayer epithelium with more than 10 extra layers. Mutant lung epithelial cells change mitotic spindle orientation to seed outer layers, and cells in different layers become molecularly and functionally distinct, hallmarks of normal stratification. However, mutant lung epithelial cells do not activate p63 and do not switch to the stratified keratin profile of epidermal cells. These data, together with previous data implicating Itgb1 in regulation of epidermal stratification, suggest that the simple-versus-stratified developmental decision may involve not only stratification inducers like p63 but suppressors like Itgb1 that prevent simple epithelia from inappropriately activating key steps in the stratification program. PMID:23285215

  17. A GPU-based framework for modeling real-time 3D lung tumor conformal dosimetry with subject-specific lung tumor motion.

    PubMed

    Min, Yugang; Santhanam, Anand; Neelakkantan, Harini; Ruddy, Bari H; Meeks, Sanford L; Kupelian, Patrick A

    2010-09-07

    In this paper, we present a graphics processing unit (GPU)-based simulation framework to calculate the delivered dose to a 3D moving lung tumor and its surrounding normal tissues, which are undergoing subject-specific lung deformations. The GPU-based simulation framework models the motion of the 3D volumetric lung tumor and its surrounding tissues, simulates the dose delivery using the dose extracted from a treatment plan using Pinnacle Treatment Planning System, Phillips, for one of the 3DCTs of the 4DCT and predicts the amount and location of radiation doses deposited inside the lung. The 4DCT lung datasets were registered with each other using a modified optical flow algorithm. The motion of the tumor and the motion of the surrounding tissues were simulated by measuring the changes in lung volume during the radiotherapy treatment using spirometry. The real-time dose delivered to the tumor for each beam is generated by summing the dose delivered to the target volume at each increase in lung volume during the beam delivery time period. The simulation results showed the real-time capability of the framework at 20 discrete tumor motion steps per breath, which is higher than the number of 4DCT steps (approximately 12) reconstructed during multiple breathing cycles.

  18. The protective effect of dexmedetomidine in a rat ex vivo lung model of ischemia-reperfusion injury.

    PubMed

    Zhou, Yan; Zhou, Xinqiao; Zhou, Wenjuan; Pang, Qingfeng; Wang, Zhiping

    2018-01-01

    To investigate the effect of dexmedetomidine (Dex) in a rat ex vivo lung model of ischemia-reperfusion injury. An IL-2 ex vivo lung perfusion system was used to establish a rat ex vivo lung model of ischemia-reperfusion injury. Drugs were added to the perfusion solution for reperfusion. Lung injury was assessed by histopathological changes, airway pressure (Res), lung compliance (Compl), perfusion flow (Flow), pulmonary venous oxygen partial pressure (PaO2), and lung wet/dry (W/D) weight ratio. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), 78 kDa glucose-regulated protein (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) were measured, respectively. The introduction of Dex attenuated the post-ischemia-reperfusion lung damage and MDA level, improved lung histology, W/D ratio, lung injury scores and SOD activity. Decreased mRNA and protein levels of GRP78 and CHOP compared with the IR group were observed after Dex treatment. The effect of Dex was dosage-dependence and a high dose of Dex (10 nM) was shown to confer the strongest protective effect against lung damage (P<0.05). Yohimbine, an α2 receptor antagonist, significantly reversed the protective effect of Dex in lung tissues (P<0.05). Dex reduced ischemia-reperfusion injury in rat ex vivo lungs.

  19. Animal Models, Learning Lessons to Prevent and Treat Neonatal Chronic Lung Disease

    PubMed Central

    Jobe, Alan H.

    2015-01-01

    Bronchopulmonary dysplasia (BPD) is a unique injury syndrome caused by prolonged injury and repair imposed on an immature and developing lung. The decreased septation and decreased microvascular development phenotype of BPD can be reproduced in newborn rodents with increased chronic oxygen exposure and in premature primates and sheep with oxygen and/or mechanical ventilation. The inflammation caused by oxidants, inflammatory agonists, and/or stretch injury from mechanical ventilation seems to promote the anatomic abnormalities. Multiple interventions targeted to specific inflammatory cells or pathways or targeted to decreasing ventilation-mediated injury can substantially prevent the anatomic changes associated with BPD in term rodents and in preterm sheep or primate models. Most of the anti-inflammatory therapies with benefit in animal models have not been tested clinically. None of the interventions that have been tested clinically are as effective as anticipated from the animal models. These inconsistencies in responses likely are explained by the antenatal differences in lung exposures of the developing animals relative to very preterm humans. The animals generally have normal lungs while the lungs of preterm infants are exposed variably to intrauterine inflammation, growth abnormalities, antenatal corticosteroids, and poorly understood effects from the causes of preterm delivery. The animal models have been essential for the definition of the mediators that can cause a BPD phenotype. These models will be necessary to develop and test future-targeted interventions to prevent and treat BPD. PMID:26301222

  20. Ex vivo administration of trimetazidine improves post-transplant lung function in pig model.

    PubMed

    Cosgun, Tugba; Iskender, Ilker; Yamada, Yoshito; Arni, Stephan; Lipiski, Miriam; van Tilburg, Koen; Weder, Walter; Inci, Ilhan

    2017-07-01

    Ex vivo lung perfusion (EVLP) is not only used to assess marginal donor lungs but is also used as a platform to deliver therapeutic agents outside the body. We previously showed the beneficial effects of trimetazidine (TMZ) on ischaemia reperfusion (IR) injury in a rat model. This study evaluated the effects of TMZ in a pig EVLP transplant model. Pig lungs were retrieved and stored for 24 h at 4°C, followed by 4 h of EVLP. Allografts were randomly allocated to 2 groups ( n  = 5 each). TMZ (5 mg/kg) was added to the prime solution prior to EVLP. After EVLP, left lungs were transplanted and recipients were observed for 4 h. Allograft gas exchange function and lung mechanics were recorded hourly throughout reperfusion. Microscopic lung injury and inflammatory and biochemical parameters were assessed. There was a trend towards better oxygenation during EVLP in the TMZ group ( P  = 0.06). After transplantation, pulmonary gas exchange was significantly better during the 4-h reperfusion period and after isolation of the allografts for 10 min ( P  < 0.05). Tissue thiobarbituric acid levels, myeloperoxidase activity and protein concentrations in bronchoalveolar lavage samples were significantly lower in the TMZ group at the end of EVLP ( P  < 0.05). Ex vivo treatment of donor lungs with TMZ significantly improved immediate post-transplant lung function. Further studies are warranted to understand the effect of this strategy on long-term lung function. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

  1. Surfactant Protein–C Chromatin-Bound Green Fluorescence Protein Reporter Mice Reveal Heterogeneity of Surfactant Protein C–Expressing Lung Cells

    PubMed Central

    Lee, Joo-Hyeon; Kim, Jonghwan; Gludish, David; Roach, Rebecca R.; Saunders, Arven H.; Barrios, Juliana; Woo, Andrew Jonghan; Chen, Huaiyong; Conner, David A.; Fujiwara, Yuko; Stripp, Barry R.

    2013-01-01

    The regeneration of alveolar epithelial cells is a critical aspect of alveolar reorganization after lung injury. Although alveolar Type II (AT2) cells have been described as progenitor cells for alveolar epithelia, more remains to be understood about how their progenitor cell properties are regulated. A nuclear, chromatin-bound green fluorescence protein reporter (H2B-GFP) was driven from the murine surfactant protein–C (SPC) promoter to generate SPC H2B-GFP transgenic mice. The SPC H2B-GFP allele allowed the FACS-based enrichment and gene expression profiling of AT2 cells. Approximately 97% of AT2 cells were GFP-labeled on Postnatal Day 1, and the percentage of GFP-labeled AT2 cells decreased to approximately 63% at Postnatal Week 8. Isolated young adult SPC H2B-GFP+ cells displayed proliferation, differentiation, and self-renewal capacity in the presence of lung fibroblasts in a Matrigel-based three-dimensional culture system. Heterogeneity within the GFP+ population was revealed, because cells with distinct alveolar and bronchiolar gene expression arose in three-dimensional cultures. CD74, a surface marker highly enriched on GFP+ cells, was identified as a positive selection marker, providing 3-fold enrichment for AT2 cells. In vivo, GFP expression was induced within other epithelial cell types during maturation of the distal lung. The utility of the SPC H2B-GFP murine model for the identification of AT2 cells was greatest in early postnatal lungs and more limited with age, when some discordance between SPC and GFP expression was observed. In adult mice, this allele may allow for the enrichment and future characterization of other SPC-expressing alveolar and bronchiolar cells, including putative stem/progenitor cell populations. PMID:23204392

  2. Space radiation-associated lung injury in a murine model.

    PubMed

    Christofidou-Solomidou, Melpo; Pietrofesa, Ralph A; Arguiri, Evguenia; Schweitzer, Kelly S; Berdyshev, Evgeny V; McCarthy, Maureen; Corbitt, Astrid; Alwood, Joshua S; Yu, Yongjia; Globus, Ruth K; Solomides, Charalambos C; Ullrich, Robert L; Petrache, Irina

    2015-03-01

    Despite considerable progress in identifying health risks to crewmembers related to exposure to galactic/cosmic rays and solar particle events (SPE) during space travel, its long-term effects on the pulmonary system are unknown. We used a murine risk projection model to investigate the impact of exposure to space-relevant radiation (SR) on the lung. C3H mice were exposed to (137)Cs gamma rays, protons (acute, low-dose exposure mimicking the 1972 SPE), 600 MeV/u (56)Fe ions, or 350 MeV/u (28)Si ions at the NASA Space Radiation Laboratory at Brookhaven National Laboratory. Animals were irradiated at the age of 2.5 mo and evaluated 23.5 mo postirradiation, at 26 mo of age. Compared with age-matched nonirradiated mice, SR exposures led to significant air space enlargement and dose-dependent decreased systemic oxygenation levels. These were associated with late mild lung inflammation and prominent cellular injury, with significant oxidative stress and apoptosis (caspase-3 activation) in the lung parenchyma. SR, especially high-energy (56)Fe or (28)Si ions markedly decreased sphingosine-1-phosphate levels and Akt- and p38 MAPK phosphorylation, depleted anti-senescence sirtuin-1 and increased biochemical markers of autophagy. Exposure to SR caused dose-dependent, pronounced late lung pathological sequelae consistent with alveolar simplification and cellular signaling of increased injury and decreased repair. The associated systemic hypoxemia suggested that this previously uncharacterized space radiation-associated lung injury was functionally significant, indicating that further studies are needed to define the risk and to develop appropriate lung-protective countermeasures for manned deep space missions. Copyright © 2015 the American Physiological Society.

  3. Decreased lung compliance increases preload dynamic tests in a pediatric acute lung injury model.

    PubMed

    Erranz, Benjamín; Díaz, Franco; Donoso, Alejandro; Salomón, Tatiana; Carvajal, Cristóbal; Torres, María Fernanda; Cruces, Pablo

    2015-01-01

    Preload dynamic tests, pulse pressure variation (PPV) and stroke volume variation (SVV) have emerged as powerful tools to predict response to fluid administration. The influence of factors other than preload in dynamic preload test is currently poorly understood in pediatrics. The aim of our study was to assess the effect of tidal volume (VT) on PPV and SVV in the context of normal and reduced lung compliance in a piglet model. Twenty large-white piglets (5.2±0.4kg) were anesthetized, paralyzed and monitored with pulse contour analysis. PPV and SVV were recorded during mechanical ventilation with a VT of 6 and 12mL/kg (low and high VT, respectively), both before and after tracheal instillation of polysorbate 20. Before acute lung injury (ALI) induction, modifications of VT did not significantly change PPV and SVV readings. After ALI, PPV and SVV were significantly greater during ventilation with a high VT compared to a low VT (PPV increased from 8.9±1.2 to 12.4±1.1%, and SVV from 8.5±1.0 to 12.7±1.2%, both P<0.01). This study found that a high VT and reduced lung compliance due to ALI increase preload dynamic tests, with a greater influence of the latter. In subjects with ALI, lung compliance should be considered when interpreting the preload dynamic tests. Copyright © 2015 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  4. Mesenchymal Stem Cell Attenuates Neutrophil-predominant Inflammation and Acute Lung Injury in an In Vivo Rat Model of Ventilator-induced Lung Injury

    PubMed Central

    Lai, Tian-Shun; Wang, Zhi-Hong; Cai, Shao-Xi

    2015-01-01

    Background: Subsequent neutrophil (polymorphonuclear neutrophil [PMN])-predominant inflammatory response is a predominant feature of ventilator-induced lung injury (VILI), and mesenchymal stem cell (MSC) can improve mice survival model of endotoxin-induced acute lung injury, reduce lung impairs, and enhance the repair of VILI. However, whether MSC could attenuate PMN-predominant inflammatory in the VILI is still unknown. This study aimed to test whether MSC intervention could attenuate the PMN-predominate inflammatory in the mechanical VILI. Methods: Sprague-Dawley rats were ventilated for 2 hours with large tidal volume (20 mL/kg). MSCs were given before or after ventilation. The inflammatory chemokines and gas exchange were observed and compared dynamically until 4 hours after ventilation, and pulmonary pathological change and activation of PMN were observed and compared 4 hours after ventilation. Results: Mechanical ventilation (MV) caused significant lung injury reflected by increasing in PMN pulmonary sequestration, inflammatory chemokines (tumor necrosis factor-alpha, interleukin-6 and macrophage inflammatory protein 2) in the bronchoalveolar lavage fluid, and injury score of the lung tissue. These changes were accompanied with excessive PMN activation which reflected by increases in PMN elastase activity, production of radical oxygen series. MSC intervention especially pretreatment attenuated subsequent lung injury, systemic inflammation response and PMN pulmonary sequestration and excessive PMN activation initiated by injurious ventilation. Conclusions: MV causes profound lung injury and PMN-predominate inflammatory responses. The protection effect of MSC in the VILI rat model is related to the suppression of the PMN activation. PMID:25635432

  5. Animals devoid of pulmonary system as infection models in the study of lung bacterial pathogens

    PubMed Central

    López Hernández, Yamilé; Yero, Daniel; Pinos-Rodríguez, Juan M.; Gibert, Isidre

    2015-01-01

    Biological disease models can be difficult and costly to develop and use on a routine basis. Particularly, in vivo lung infection models performed to study lung pathologies use to be laborious, demand a great time and commonly are associated with ethical issues. When infections in experimental animals are used, they need to be refined, defined, and validated for their intended purpose. Therefore, alternative and easy to handle models of experimental infections are still needed to test the virulence of bacterial lung pathogens. Because non-mammalian models have less ethical and cost constraints as a subjects for experimentation, in some cases would be appropriated to include these models as valuable tools to explore host–pathogen interactions. Numerous scientific data have been argued to the more extensive use of several kinds of alternative models, such as, the vertebrate zebrafish (Danio rerio), and non-vertebrate insects and nematodes (e.g., Caenorhabditis elegans) in the study of diverse infectious agents that affect humans. Here, we review the use of these vertebrate and non-vertebrate models in the study of bacterial agents, which are considered the principal causes of lung injury. Curiously none of these animals have a respiratory system as in air-breathing vertebrates, where respiration takes place in lungs. Despite this fact, with the present review we sought to provide elements in favor of the use of these alternative animal models of infection to reveal the molecular signatures of host–pathogen interactions. PMID:25699030

  6. Health effects of sulfur-related environmental air pollution. V. Lung structure.

    PubMed

    Takenaka, S; Godleski, J J; Heini, A; Karg, E; Kreyling, W G; Ritter, B; Schulz, H; Ziesenis, A; Heyder, J

    1999-05-01

    The lungs of 8 male beagle dogs were examined morphologically and morphometrically after exposure for 13 mo to a respirable sulfur(IV) aerosol at a mass concentration of 1.53 mg m(-3) (16.5 h/day), and to an acidic sulfate aerosol carrying 15.2 micromol m(-3) hydrogen ions into the lungs (6 h/day). An additional eight dogs served as unexposed controls. Standard morphometric analyses of both the surface epithelia of the conducting airways and the alveolar region were performed. These analyses showed no difference between the exposure group and control group. However, there was a tendency to an increase in the volume density of bronchial glands in the exposure group. Five of eight exposed animals showed thickened ridges (knob-like structures) at the entrance to alveoli in the alveolar duct and alveolar sac. Transmission electron microscopy revealed that the thickening was mainly due to type II cell proliferation. As the previous experiment using sulfite aerosol only showed no alterations in the proximal alveolar regions, the changes observed may be considered as effects of acidic sulfate aerosol alone or in combination with sulfite. These findings suggest that sulfur aerosols have the potential to induce epithelial alterations in the proximal alveolar region, which is a primary target for air pollutants.

  7. Directional Multi-scale Modeling of High-Resolution Computed Tomography (HRCT) Lung Images for Diffuse Lung Disease Classification

    NASA Astrophysics Data System (ADS)

    Vo, Kiet T.; Sowmya, Arcot

    A directional multi-scale modeling scheme based on wavelet and contourlet transforms is employed to describe HRCT lung image textures for classifying four diffuse lung disease patterns: normal, emphysema, ground glass opacity (GGO) and honey-combing. Generalized Gaussian density parameters are used to represent the detail sub-band features obtained by wavelet and contourlet transforms. In addition, support vector machines (SVMs) with excellent performance in a variety of pattern classification problems are used as classifier. The method is tested on a collection of 89 slices from 38 patients, each slice of size 512x512, 16 bits/pixel in DICOM format. The dataset contains 70,000 ROIs of those slices marked by experienced radiologists. We employ this technique at different wavelet and contourlet transform scales for diffuse lung disease classification. The technique presented here has best overall sensitivity 93.40% and specificity 98.40%.

  8. Lung cancer risk prediction to select smokers for screening CT--a model based on the Italian COSMOS trial.

    PubMed

    Maisonneuve, Patrick; Bagnardi, Vincenzo; Bellomi, Massimo; Spaggiari, Lorenzo; Pelosi, Giuseppe; Rampinelli, Cristiano; Bertolotti, Raffaella; Rotmensz, Nicole; Field, John K; Decensi, Andrea; Veronesi, Giulia

    2011-11-01

    Screening with low-dose helical computed tomography (CT) has been shown to significantly reduce lung cancer mortality but the optimal target population and time interval to subsequent screening are yet to be defined. We developed two models to stratify individual smokers according to risk of developing lung cancer. We first used the number of lung cancers detected at baseline screening CT in the 5,203 asymptomatic participants of the COSMOS trial to recalibrate the Bach model, which we propose using to select smokers for screening. Next, we incorporated lung nodule characteristics and presence of emphysema identified at baseline CT into the Bach model and proposed the resulting multivariable model to predict lung cancer risk in screened smokers after baseline CT. Age and smoking exposure were the main determinants of lung cancer risk. The recalibrated Bach model accurately predicted lung cancers detected during the first year of screening. Presence of nonsolid nodules (RR = 10.1, 95% CI = 5.57-18.5), nodule size more than 8 mm (RR = 9.89, 95% CI = 5.84-16.8), and emphysema (RR = 2.36, 95% CI = 1.59-3.49) at baseline CT were all significant predictors of subsequent lung cancers. Incorporation of these variables into the Bach model increased the predictive value of the multivariable model (c-index = 0.759, internal validation). The recalibrated Bach model seems suitable for selecting the higher risk population for recruitment for large-scale CT screening. The Bach model incorporating CT findings at baseline screening could help defining the time interval to subsequent screening in individual participants. Further studies are necessary to validate these models.

  9. Meta-markers for the differential diagnosis of lung cancer and lung disease.

    PubMed

    Kim, Yong-In; Ahn, Jung-Mo; Sung, Hye-Jin; Na, Sang-Su; Hwang, Jaesung; Kim, Yongdai; Cho, Je-Yoel

    2016-10-04

    Misdiagnosis of lung cancer remains a serious problem due to the difficulty of distinguishing lung cancer from other respiratory lung diseases. As a result, the development of serum-based differential diagnostic biomarkers is in high demand. In this study, 198 clinical serum samples from non-cancer lung disease and lung cancer patients were analyzed using nLC-MRM-MS for the levels of seven lung cancer biomarker candidates. When the candidates were assessed individually, only SERPINEA4 showed statistically significant changes in the serum levels. The MRM results and clinical information were analyzed using a logistic regression analysis to select model for the best 'meta-marker', or combination of biomarkers for differential diagnosis. Also, under consideration of statistical interaction, variables having low significance as a single factor but statistically influencing on meta-marker model were selected. Using this probabilistic classification, the best meta-marker was determined to be made up of two proteins SERPINA4 and PON1 with age factor. This meta-marker showed an enhanced differential diagnostic capability (AUC=0.915) for distinguishing the two patient groups. Our results suggest that a statistical model can determine optimal meta-markers, which may have better specificity and sensitivity than a single biomarker and thus improve the differential diagnosis of lung cancer and lung disease patients. Diagnosing lung cancer commonly involves the use of radiographic methods. However, an imaging-based diagnosis may fail to differentiate lung cancer from non-cancerous lung disease. In this study, we examined several serum proteins in the sera of 198 lung cancer and non-cancerous lung disease patients by multiple-reaction monitoring. We then used a combination of variables to generate a meta-marker model that is useful as a differential diagnostic biomarker. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  10. Neonatal lungs--can absolute lung resistivity be determined non-invasively?

    PubMed

    Brown, B H; Primhak, R A; Smallwood, R H; Milnes, P; Narracott, A J; Jackson, M J

    2002-07-01

    The electrical resistivity of lung tissue can be related to the structure and composition of the tissue and also to the air content. Conditions such as pulmonary oedema and emphysema have been shown to change lung resistivity. However, direct access to the lungs to enable resistivity to be measured is very difficult. We have developed a new method of using electrical impedance tomographic (EIT) measurements on a group of 142 normal neonates to determine the absolute resistivity of lung tissue. The methodology involves comparing the measured EIT data with that from a finite difference model of the thorax in which lung tissue resistivity can be changed. A mean value of 5.7 +/- 1.7 omega(m) was found over the frequency range 4 kHz to 813 kHz. This value is lower than that usually given for adult lung tissue but consistent with the literature on the composition of the neonatal lung and with structural modelling.

  11. Predicting Survival within the Lung Cancer Histopathological Hierarchy Using a Multi-Scale Genomic Model of Development

    PubMed Central

    Liu, Hongye; Kho, Alvin T; Kohane, Isaac S; Sun, Yao

    2006-01-01

    Background The histopathologic heterogeneity of lung cancer remains a significant confounding factor in its diagnosis and prognosis—spurring numerous recent efforts to find a molecular classification of the disease that has clinical relevance. Methods and Findings Molecular profiles of tumors from 186 patients representing four different lung cancer subtypes (and 17 normal lung tissue samples) were compared with a mouse lung development model using principal component analysis in both temporal and genomic domains. An algorithm for the classification of lung cancers using a multi-scale developmental framework was developed. Kaplan–Meier survival analysis was conducted for lung adenocarcinoma patient subgroups identified via their developmental association. We found multi-scale genomic similarities between four human lung cancer subtypes and the developing mouse lung that are prognostically meaningful. Significant association was observed between the localization of human lung cancer cases along the principal mouse lung development trajectory and the corresponding patient survival rate at three distinct levels of classical histopathologic resolution: among different lung cancer subtypes, among patients within the adenocarcinoma subtype, and within the stage I adenocarcinoma subclass. The earlier the genomic association between a human tumor profile and the mouse lung development sequence, the poorer the patient's prognosis. Furthermore, decomposing this principal lung development trajectory identified a gene set that was significantly enriched for pyrimidine metabolism and cell-adhesion functions specific to lung development and oncogenesis. Conclusions From a multi-scale disease modeling perspective, the molecular dynamics of murine lung development provide an effective framework that is not only data driven but also informed by the biology of development for elucidating the mechanisms of human lung cancer biology and its clinical outcome. PMID:16800721

  12. Lung ultrasound accurately detects pneumothorax in a preterm newborn lamb model.

    PubMed

    Blank, Douglas A; Hooper, Stuart B; Binder-Heschl, Corinna; Kluckow, Martin; Gill, Andrew W; LaRosa, Domenic A; Inocencio, Ishmael M; Moxham, Alison; Rodgers, Karyn; Zahra, Valerie A; Davis, Peter G; Polglase, Graeme R

    2016-06-01

    Pneumothorax is a common emergency affecting extremely preterm. In adult studies, lung ultrasound has performed better than chest x-ray in the diagnosis of pneumothorax. The purpose of this study was to determine the efficacy of lung ultrasound (LUS) examination to detect pneumothorax using a preterm animal model. This was a prospective, observational study using newborn Border-Leicester lambs at gestational age = 126 days (equivalent to gestational age = 26 weeks in humans) receiving mechanical ventilation from birth to 2 h of life. At the conclusion of the experiment, LUS was performed, the lambs were then euthanised and a post-mortem exam was immediately performed. We used previously published ultrasound techniques to identify pneumothorax. Test characteristics of LUS to detect pneumothorax were calculated, using the post-mortem exam as the 'gold standard' test. Nine lambs (18 lungs) were examined. Four lambs had a unilateral pneumothorax, all of which were identified by LUS with no false positives. This was the first study to use post-mortem findings to test the efficacy of LUS to detect pneumothorax in a newborn animal model. Lung ultrasound accurately detected pneumothorax, verified by post-mortem exam, in premature, newborn lambs. © 2016 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

  13. A model for morbidity after lung resection in octogenarians.

    PubMed

    Berry, Mark F; Onaitis, Mark W; Tong, Betty C; Harpole, David H; D'Amico, Thomas A

    2011-06-01

    Age is an important risk factor for morbidity after lung resection. This study was performed to identify specific risk factors for complications after lung resection in octogenarians. A prospective database containing patients aged 80 years or older, who underwent lung resection at a single institution between January 2000 and June 2009, was reviewed. Preoperative, histopathologic, perioperative, and outcome variables were assessed. Morbidity was measured as a patient having any perioperative event as defined by the Society of Thoracic Surgeons General Thoracic Surgery Database. A multivariable risk model for morbidity was developed using a panel of established preoperative and operative variables. Survival was calculated using the Kaplan-Meier method. During the study period, 193 patients aged 80 years or older (median age 82 years) underwent lung resection: wedge resection in 77, segmentectomy in 13, lobectomy in 96, bilobectomy in four, and pneumonectomy in three. Resection was accomplished via thoracoscopy in 149 patients (77%). Operative mortality was 3.6% (seven patients) and morbidity was 46% (89 patients). A total of 181 (94%) patients were discharged directly home. Postoperative events included atrial arrhythmia in 38 patients (20%), prolonged air leak in 24 patients (12%), postoperative transfusion in 22 patients (11%), delirium in 16 patients (8%), need for bronchoscopy in 14 patients (7%), and pneumonia in 10 patients (5%). Significant predictors of morbidity by multivariable analysis included resection greater than wedge (odds ratio 2.98, p=0.006), thoracotomy as operative approach (odds ratio 2.6, p=0.03), and % predicted forced expiratory volume in 1s (odds ratio 1.28 for each 10% decrement, p=0.01). Octogenarians can undergo lung resection with low mortality. Extent of resection, use of a thoracotomy, and impaired lung function increase the risk of complications. Careful evaluation is necessary to select the most appropriate approach in

  14. IMPACT OF VENTILATION FREQUENCY AND PARENCHYMAL STIFFNESS ON FLOW AND PRESSURE DISTRIBUTION IN A CANINE LUNG MODEL

    PubMed Central

    Amini, Reza; Kaczka, David W.

    2013-01-01

    To determine the impact of ventilation frequency, lung volume, and parenchymal stiffness on ventilation distribution, we developed an anatomically-based computational model of the canine lung. Each lobe of the model consists of an asymmetric branching airway network subtended by terminal, viscoelastic acinar units. The model allows for empiric dependencies of airway segment dimensions and parenchymal stiffness on transpulmonary pressure. We simulated the effects of lung volume and parenchymal recoil on global lung impedance and ventilation distribution from 0.1 to 100 Hz, with mean transpulmonary pressures from 5 to 25 cmH2O. With increasing lung volume, the distribution of acinar flows narrowed and became more synchronous for frequencies below resonance. At higher frequencies, large variations in acinar flow were observed. Maximum acinar flow occurred at first antiresonance frequency, where lung impedance achieved a local maximum. The distribution of acinar pressures became very heterogeneous and amplified relative to tracheal pressure at the resonant frequency. These data demonstrate the important interaction between frequency and lung tissue stiffness on the distribution of acinar flows and pressures. These simulations provide useful information for the optimization of frequency, lung volume, and mean airway pressure during conventional ventilation or high frequency oscillation (HFOV). Moreover our model indicates that an optimal HFOV bandwidth exists between the resonant and antiresonant frequencies, for which interregional gas mixing is maximized. PMID:23872936

  15. Angiotensin II stimulates calcineurin activity in proximal tubule epithelia through AT-1 receptor-mediated tyrosine phosphorylation of the PLC-gamma1 isoform.

    PubMed

    Lea, Janice P; Jin, Shao G; Roberts, Brian R; Shuler, Michael S; Marrero, Mario B; Tumlin, James A

    2002-07-01

    Angiotensin II (AngII) contributes to the maintenance of extracellular fluid volume by regulating sodium transport in the nephron. In nonepithelial cells, activation of phospholipase C (PLC) by AT-1 receptors stimulates the generation of 1,4,5-trisphosphate (IP(3)) and the release of intracellular calcium. Calcineurin, a serine-threonine phosphatase, is activated by calcium and calmodulin, and both PLC and calcineurin have been linked to sodium transport in the proximal tubule. An examination of whether AngII activates calcineurin in a model of proximal tubule epithelia (LLC-PK1 cells) was performed; AngII increased calcineurin activity within 30 s. An examination of whether AngII activates PLC in proximal tubule epithelia was also performed after first showing that all three families of PLC isoforms are present in LLC-PK1 cells. Application of AngII increased IP(3) generation by 60% within 15 s, which coincided with AngII-induced tyrosine phosphorylation of the PLC-gamma1 isoform also observed at 15 s. AngII-induced tyrosine phosphorylation was blocked by the AT-1 receptor antagonist, Losartan. Subsequently, an inhibitor of tyrosine phosphorylation blocked the AngII-induced activation of calcineurin, as did coincubation with an inhibitor of PLC activity and with an antagonist of the AT-1 receptor. It is therefore concluded that AngII stimulates calcineurin phosphatase activity in proximal tubule epithelial cells through a mechanism involving AT-1 receptor-mediated tyrosine phosphorylation of the PLC isoform.

  16. Implications of Nine Risk Prediction Models for Selecting Ever-Smokers for Computed Tomography Lung Cancer Screening.

    PubMed

    Katki, Hormuzd A; Kovalchik, Stephanie A; Petito, Lucia C; Cheung, Li C; Jacobs, Eric; Jemal, Ahmedin; Berg, Christine D; Chaturvedi, Anil K

    2018-05-15

    Lung cancer screening guidelines recommend using individualized risk models to refer ever-smokers for screening. However, different models select different screening populations. The performance of each model in selecting ever-smokers for screening is unknown. To compare the U.S. screening populations selected by 9 lung cancer risk models (the Bach model; the Spitz model; the Liverpool Lung Project [LLP] model; the LLP Incidence Risk Model [LLPi]; the Hoggart model; the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Model 2012 [PLCOM2012]; the Pittsburgh Predictor; the Lung Cancer Risk Assessment Tool [LCRAT]; and the Lung Cancer Death Risk Assessment Tool [LCDRAT]) and to examine their predictive performance in 2 cohorts. Population-based prospective studies. United States. Models selected U.S. screening populations by using data from the National Health Interview Survey from 2010 to 2012. Model performance was evaluated using data from 337 388 ever-smokers in the National Institutes of Health-AARP Diet and Health Study and 72 338 ever-smokers in the CPS-II (Cancer Prevention Study II) Nutrition Survey cohort. Model calibration (ratio of model-predicted to observed cases [expected-observed ratio]) and discrimination (area under the curve [AUC]). At a 5-year risk threshold of 2.0%, the models chose U.S. screening populations ranging from 7.6 million to 26 million ever-smokers. These disagreements occurred because, in both validation cohorts, 4 models (the Bach model, PLCOM2012, LCRAT, and LCDRAT) were well-calibrated (expected-observed ratio range, 0.92 to 1.12) and had higher AUCs (range, 0.75 to 0.79) than 5 models that generally overestimated risk (expected-observed ratio range, 0.83 to 3.69) and had lower AUCs (range, 0.62 to 0.75). The 4 best-performing models also had the highest sensitivity at a fixed specificity (and vice versa) and similar discrimination at a fixed risk threshold. These models showed better agreement on size of the

  17. [Computer aided diagnosis model for lung tumor based on ensemble convolutional neural network].

    PubMed

    Wang, Yuanyuan; Zhou, Tao; Lu, Huiling; Wu, Cuiying; Yang, Pengfei

    2017-08-01

    The convolutional neural network (CNN) could be used on computer-aided diagnosis of lung tumor with positron emission tomography (PET)/computed tomography (CT), which can provide accurate quantitative analysis to compensate for visual inertia and defects in gray-scale sensitivity, and help doctors diagnose accurately. Firstly, parameter migration method is used to build three CNNs (CT-CNN, PET-CNN, and PET/CT-CNN) for lung tumor recognition in CT, PET, and PET/CT image, respectively. Then, we aimed at CT-CNN to obtain the appropriate model parameters for CNN training through analysis the influence of model parameters such as epochs, batchsize and image scale on recognition rate and training time. Finally, three single CNNs are used to construct ensemble CNN, and then lung tumor PET/CT recognition was completed through relative majority vote method and the performance between ensemble CNN and single CNN was compared. The experiment results show that the ensemble CNN is better than single CNN on computer-aided diagnosis of lung tumor.

  18. Irreversible Electroporation in a Swine Lung Model

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dupuy, Damian E., E-mail: ddupuy@lifespan.org; Aswad, Bassam, E-mail: baswad@lifespan.org; Ng, Thomas, E-mail: tng@usasurg.org

    2011-04-15

    Purpose: This study was designed to evaluate the safety and tissue effects of IRE in a swine lung model. Methods: This study was approved by the institutional animal care committee. Nine anesthetized domestic swine underwent 15 percutaneous irreversible electroporation (IRE) lesion creations (6 with bipolar and 3 with 3-4 monopolar electrodes) under fluoroscopic guidance and with pancuronium neuromuscular blockade and EKG gating. IRE electrodes were placed into the central and middle third of the right mid and lower lobes in all animals. Postprocedure PA and lateral chest radiographs were obtained to evaluate for pneumothorax. Three animals were sacrificed at 2more » weeks and six at 4 weeks. Animals underwent high-resolution CT scanning and PA and lateral radiographs 1 h before sacrifice. The treated lungs were removed en bloc, perfused with formalin, and sectioned. Gross pathologic and microscopic changes after standard hematoxylin and eosin staining were analyzed within the areas of IRE lesion creation. Results: No significant adverse events were identified. CT showed focal areas of spiculated high density ranging in greatest diameter from 1.1-2.2 cm. On gross inspection of the sectioned lung, focal areas of tan discoloration and increased density were palpated in the areas of IRE. Histological analysis revealed focal areas of diffuse alveolar damage with fibrosis and inflammatory infiltration that respected the boundaries of the interlobular septae. No pathological difference could be discerned between the 2- and 4-week time points. The bronchioles and blood vessels within the areas of IRE were intact and did not show signs of tissue injury. Conclusion: IRE creates focal areas of diffuse alveolar damage without creating damage to the bronchioles or blood vessels. Short-term safety in a swine model appears to be satisfactory.« less

  19. Internal epithelia in Drosophila display rudimentary competence to form cytoplasmic networks of transgenic human vimentin.

    PubMed

    Gullmets, Josef; Torvaldson, Elin; Lindqvist, Julia; Imanishi, Susumu Y; Taimen, Pekka; Meinander, Annika; Eriksson, John E

    2017-12-01

    Cytoplasmic intermediate filaments (cIFs) are found in all eumetazoans, except arthropods. To investigate the compatibility of cIFs in arthropods, we expressed human vimentin (hVim), a cIF with filament-forming capacity in vertebrate cells and tissues, transgenically in Drosophila Transgenic hVim could be recovered from whole-fly lysates by using a standard procedure for intermediate filament (IF) extraction. When this procedure was used to test for the possible presence of IF-like proteins in flies, only lamins and tropomyosin were observed in IF-enriched extracts, thereby providing biochemical reinforcement to the paradigm that arthropods lack cIFs. In Drosophila , transgenic hVim was unable to form filament networks in S2 cells and mesenchymal tissues; however, cage-like vimentin structures could be observed around the nuclei in internal epithelia, which suggests that Drosophila retains selective competence for filament formation. Taken together, our results imply that although the filament network formation competence is partially lost in Drosophila , a rudimentary filament network formation ability remains in epithelial cells. As a result of the observed selective competence for cIF assembly in Drosophila , we hypothesize that internal epithelial cIFs were the last cIFs to disappear from arthropods.-Gullmets, J., Torvaldson, E., Lindqvist, J., Imanishi, S. Y., Taimen, P., Meinander, A., Eriksson, J. E. Internal epithelia in Drosophila display rudimentary competence to form cytoplasmic networks of transgenic human vimentin. © FASEB.

  20. Florida Red Tides, Manatee Brevetoxicosis, and Lung Models

    PubMed Central

    Kirkpatrick, Barbara; Colbert, Debborah E.; Dalpra, Dana; Newton, Elizabeth A. C.; Gaspard, Joseph; Littlefield, Brandi; Manire, Charles

    2010-01-01

    In 1996, 149 Florida manatees, Trichechus manatus latirostris, died along the southwest coast of Florida. Necropsy pathology results of these animals indicated that brevetoxin from the Florida red tide, Karenia brevis, caused their death. A red tide bloom had been previously documented in the area where these animals stranded. The necropsy data suggested the mortality occurred from chronic inhalation and/or ingestion. Inhalation theories include high doses of brevetoxin deposited/stored in the manatee lung or significant manatee sensitivity to the brevetoxin. Laboratory models of the manatee lungs can be constructed from casts of necropsied animals for further studies; however, it is necessary to define the breathing pattern in the manatee, specifically the volumes and flow rates per breath to estimate toxin deposition in the lung. To obtain this information, two captive-born Florida manatees, previously trained for husbandry and research behaviors, were trained to breathe into a plastic mask placed over their nares. The mask was connected to a spirometer that measured volumes and flows in situ. Results reveal high volumes, short inspiratory and expiratory times and high flow rates, all consistent with observed breathing patterns. PMID:26448968

  1. Patterns of lung cancer mortality in 23 countries: application of the age-period-cohort model.

    PubMed

    Liaw, Yung-Po; Huang, Yi-Chia; Lien, Guang-Wen

    2005-03-05

    Smoking habits do not seem to be the main explanation of the epidemiological characteristics of female lung cancer mortality in Asian countries. However, Asian countries are often excluded from studies of geographical differences in trends for lung cancer mortality. We thus examined lung cancer trends from 1971 to 1995 among men and women for 23 countries, including four in Asia. International and national data were used to analyze lung cancer mortality from 1971 to 1995 in both sexes. Age-standardized mortality rates (ASMR) were analyzed in five consecutive five-year periods and for each five-year age group in the age range 30 to 79. The age-period-cohort (APC) model was used to estimate the period effect (adjusted for age and cohort effects) for mortality from lung cancer. The sex ratio of the ASMR for lung cancer was lower in Asian countries, while the sex ratio of smoking prevalence was higher in Asian countries. The mean values of the sex ratio of the ASMR from lung cancer in Taiwan, Hong Kong, Singapore, and Japan for the five 5-year period were 2.10, 2.39, 3.07, and 3.55, respectively. These values not only remained quite constant over each five-year period, but were also lower than seen in the western countries. The period effect, for lung cancer mortality as derived for the 23 countries from the APC model, could be classified into seven patterns. Period effects for both men and women in 23 countries, as derived using the APC model, could be classified into seven patterns. Four Asian countries have a relatively low sex ratio in lung cancer mortality and a relatively high sex ratio in smoking prevalence. Factors other than smoking might be important, especially for women in Asian countries.

  2. Patterns of lung cancer mortality in 23 countries: Application of the Age-Period-Cohort model

    PubMed Central

    Liaw, Yung-Po; Huang, Yi-Chia; Lien, Guang-Wen

    2005-01-01

    Background Smoking habits do not seem to be the main explanation of the epidemiological characteristics of female lung cancer mortality in Asian countries. However, Asian countries are often excluded from studies of geographical differences in trends for lung cancer mortality. We thus examined lung cancer trends from 1971 to 1995 among men and women for 23 countries, including four in Asia. Methods International and national data were used to analyze lung cancer mortality from 1971 to 1995 in both sexes. Age-standardized mortality rates (ASMR) were analyzed in five consecutive five-year periods and for each five-year age group in the age range 30 to 79. The age-period-cohort (APC) model was used to estimate the period effect (adjusted for age and cohort effects) for mortality from lung cancer. Results The sex ratio of the ASMR for lung cancer was lower in Asian countries, while the sex ratio of smoking prevalence was higher in Asian countries. The mean values of the sex ratio of the ASMR from lung cancer in Taiwan, Hong Kong, Singapore, and Japan for the five 5-year period were 2.10, 2.39, 3.07, and 3.55, respectively. These values not only remained quite constant over each five-year period, but were also lower than seen in the western countries. The period effect, for lung cancer mortality as derived for the 23 countries from the APC model, could be classified into seven patterns. Conclusion Period effects for both men and women in 23 countries, as derived using the APC model, could be classified into seven patterns. Four Asian countries have a relatively low sex ratio in lung cancer mortality and a relatively high sex ratio in smoking prevalence. Factors other than smoking might be important, especially for women in Asian countries. PMID:15748289

  3. Multiscale Airflow Model and Aerosol Deposition in Healthy and Emphysematous Rat Lungs

    NASA Astrophysics Data System (ADS)

    Oakes, Jessica; Marsden, Alison; Grandmont, Celine; Darquenne, Chantal; Vignon-Clementel, Irene

    2012-11-01

    The fate of aerosol particles in healthy and emphysematic lungs is needed to determine the toxic or therapeutic effects of inhalable particles. In this study we used a multiscale numerical model that couples a 0D resistance and capacitance model to 3D airways generated from MR images. Airflow simulations were performed using an in-house 3D finite element solver (SimVascular, simtk.org). Seven simulations were performed; 1 healthy, 1 uniform emphysema and 5 different cases of heterogeneous emphysema. In the heterogeneous emphysema cases the disease was confined to a single lobe. As a post processing step, 1 micron diameter particles were tracked in the flow field using Lagrangian particle tracking. The simulation results showed that the inhaled flow distribution was equal for the healthy and uniform emphysema cases. However, in the heterogeneous emphysema cases the delivery of inhaled air was larger in the diseased lobe. Additionally, there was an increase in delivery of aerosol particles to the diseased lobe. This suggests that as the therapeutic particles would reach the diseased areas of the lung, while toxic particles would increasingly harm the lung. The 3D-0D model described here is the first of its kind to be used to study healthy and emphysematic lungs. NSF Graduate Fellowship (Oakes), Burroughs Wellcome Fund (Marsden, Oakes) 1R21HL087805-02 from NHLBI at NIH, INRIA Team Grant.

  4. Coupling of EIT with computational lung modeling for predicting patient-specific ventilatory responses.

    PubMed

    Roth, Christian J; Becher, Tobias; Frerichs, Inéz; Weiler, Norbert; Wall, Wolfgang A

    2017-04-01

    Providing optimal personalized mechanical ventilation for patients with acute or chronic respiratory failure is still a challenge within a clinical setting for each case anew. In this article, we integrate electrical impedance tomography (EIT) monitoring into a powerful patient-specific computational lung model to create an approach for personalizing protective ventilatory treatment. The underlying computational lung model is based on a single computed tomography scan and able to predict global airflow quantities, as well as local tissue aeration and strains for any ventilation maneuver. For validation, a novel "virtual EIT" module is added to our computational lung model, allowing to simulate EIT images based on the patient's thorax geometry and the results of our numerically predicted tissue aeration. Clinically measured EIT images are not used to calibrate the computational model. Thus they provide an independent method to validate the computational predictions at high temporal resolution. The performance of this coupling approach has been tested in an example patient with acute respiratory distress syndrome. The method shows good agreement between computationally predicted and clinically measured airflow data and EIT images. These results imply that the proposed framework can be used for numerical prediction of patient-specific responses to certain therapeutic measures before applying them to an actual patient. In the long run, definition of patient-specific optimal ventilation protocols might be assisted by computational modeling. NEW & NOTEWORTHY In this work, we present a patient-specific computational lung model that is able to predict global and local ventilatory quantities for a given patient and any selected ventilation protocol. For the first time, such a predictive lung model is equipped with a virtual electrical impedance tomography module allowing real-time validation of the computed results with the patient measurements. First promising results

  5. Hierarchical Bayesian modeling of spatio-temporal patterns of lung cancer incidence risk in Georgia, USA: 2000-2007

    NASA Astrophysics Data System (ADS)

    Yin, Ping; Mu, Lan; Madden, Marguerite; Vena, John E.

    2014-10-01

    Lung cancer is the second most commonly diagnosed cancer in both men and women in Georgia, USA. However, the spatio-temporal patterns of lung cancer risk in Georgia have not been fully studied. Hierarchical Bayesian models are used here to explore the spatio-temporal patterns of lung cancer incidence risk by race and gender in Georgia for the period of 2000-2007. With the census tract level as the spatial scale and the 2-year period aggregation as the temporal scale, we compare a total of seven Bayesian spatio-temporal models including two under a separate modeling framework and five under a joint modeling framework. One joint model outperforms others based on the deviance information criterion. Results show that the northwest region of Georgia has consistently high lung cancer incidence risk for all population groups during the study period. In addition, there are inverse relationships between the socioeconomic status and the lung cancer incidence risk among all Georgian population groups, and the relationships in males are stronger than those in females. By mapping more reliable variations in lung cancer incidence risk at a relatively fine spatio-temporal scale for different Georgian population groups, our study aims to better support healthcare performance assessment, etiological hypothesis generation, and health policy making.

  6. Scenarios of future lung cancer incidence by educational level: Modelling study in Denmark.

    PubMed

    Menvielle, Gwenn; Soerjomataram, Isabelle; de Vries, Esther; Engholm, Gerda; Barendregt, Jan J; Coebergh, Jan Willem; Kunst, Anton E

    2010-09-01

    To model future trends in lung cancer incidence in Denmark by education under different scenarios for cigarette smoking. Lung cancer incidence until 2050 was modelled using Prevent software. We estimated lung cancer incidence under a baseline scenario and under four alternative scenarios for smoking reduction: decreasing initiation rates among the young, increasing cessation rates among smokers, a scenario combining both changes and a levelling-up scenario in which people with low and medium levels of education acquired the smoking prevalence of the highly educated. Danish National Health Interview Surveys (1987-2005) and cancer registry data combined with individual education status from Statistics Denmark were used for empirical input. Under the baseline scenario, lung cancer rates are expected to decrease for most educational groups during the next few decades, but educational inequalities will increase further. Under the alternative scenarios, an additional decrease in lung cancer rates will be observed from 2030 onwards, but only from 2050 onwards it will be observed under the initiation scenario. The cessation and the combined scenarios show the largest decrease in lung cancer rates for all educational groups. However, in none of these scenarios would the relative differences between educational groups be reduced. A modest decrease in these inequalities will be observed under the levelling-up scenario. Our analyses show that relative inequalities in lung cancer incidence rates will tend to increase. They may be reduced to a small extent if the smoking prevalence of people with a low level of education was to converge towards those more highly educated people. An important decrease in lung cancer rates will be observed in all educational groups, however, especially when focusing on both initiation and cessation strategies. Copyright © 2010 Elsevier Ltd. All rights reserved.

  7. Amniotic fluid derived mesenchymal stromal cells augment fetal lung growth in a nitrofen explant model.

    PubMed

    Di Bernardo, Julie; Maiden, Michael M; Hershenson, Marc B; Kunisaki, Shaun M

    2014-06-01

    Recent experimental work suggests the therapeutic role of mesenchymal stromal cells (MSCs) during lung morphogenesis. The purpose of this study was to investigate the potential paracrine effects of amniotic fluid-derived MSCs (AF-MSCs) on fetal lung growth in a nitrofen explant model. Pregnant Sprague-Dawley dams were gavage fed nitrofen on gestational day 9.5 (E9.5). E14.5 lung explants were subsequently harvested and cultured ex vivo for three days on filter membranes in conditioned media from rat AF-MSCs isolated from control (AF-Ctr) or nitrofen-exposed (AF-Nitro) dams. The lungs were analyzed morphometrically and by quantitative gene expression. Although there were no significant differences in total lung surface area among hypoplastic lungs, there were significant increases in terminal budding among E14.5+3 nitrofen explants exposed to AF-Ctr compared to explants exposed to medium alone (58.8±8.4 vs. 39.0±10.0 terminal buds, respectively; p<0.05). In contrast, lungs cultured in AF-Nitro medium failed to augment terminal budding. Nitrofen explants exposed to AF-Ctr showed significant upregulation of surfactant protein C to levels observed in normal fetal lungs. AF-MSCs can augment branching morphogenesis and lung epithelial maturation in a fetal explant model of pulmonary hypoplasia. Cell therapy using donor-derived AF-MSCs may represent a novel strategy for the treatment of fetal congenital diaphragmatic hernia. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Establishment of an orthotopic lung cancer model in nude mice and its evaluation by spiral CT.

    PubMed

    Liu, Xiang; Liu, Jun; Guan, Yubao; Li, Huiling; Huang, Liyan; Tang, Hailing; He, Jianxing

    2012-04-01

    To establish a simple and highly efficient orthotopic animal model of lung cancer cell line A549 and evaluate the growth pattern of intrathoracic tumors by spiral CT. A549 cells (5×10(6) mL(-1)) were suspended and inoculated into the right lung of BALB/c nude mice via intrathoracic injection. Nude mice were scanned three times each week by spiral CT after inoculation of lung cancer cell line A549. The survival time and body weight of nude mice as well as tumor invasion and metastasis were examined. Tissue was collected for subsequent histological assay after autopsia of mice. The tumor-forming rate of the orthotopic lung cancer model was 90%. The median survival time was 30.7 (range, 20-41) days. The incidence of tumor metastasis was 100%. The mean tumor diameter and the average CT value gradually increased in a time-dependent manner. The method of establishing the orthotopic lung cancer model through transplanting A549 cells into the lung of nude mice is simple and highly successful. Spiral CT can be used to evaluate intrathoracic tumor growth in nude mice vividly and dynamically.

  9. Establishment of an orthotopic lung cancer model in nude mice and its evaluation by spiral CT

    PubMed Central

    Liu, Xiang; Liu, Jun; Guan, Yubao; Li, Huiling; Huang, Liyan; Tang, Hailing

    2012-01-01

    Objective To establish a simple and highly efficient orthotopic animal model of lung cancer cell line A549 and evaluate the growth pattern of intrathoracic tumors by spiral CT. Methods A549 cells (5×106 mL-1) were suspended and inoculated into the right lung of BALB/c nude mice via intrathoracic injection. Nude mice were scanned three times each week by spiral CT after inoculation of lung cancer cell line A549. The survival time and body weight of nude mice as well as tumor invasion and metastasis were examined. Tissue was collected for subsequent histological assay after autopsia of mice. Results The tumor-forming rate of the orthotopic lung cancer model was 90%. The median survival time was 30.7 (range, 20-41) days. The incidence of tumor metastasis was 100%. The mean tumor diameter and the average CT value gradually increased in a time-dependent manner. Conclusions The method of establishing the orthotopic lung cancer model through transplanting A549 cells into the lung of nude mice is simple and highly successful. Spiral CT can be used to evaluate intrathoracic tumor growth in nude mice vividly and dynamically. PMID:22833819

  10. Gene expression analysis in hypoplastic lungs in the nitrofen model of congenital diaphragmatic hernia.

    PubMed

    Burgos, Carmen Mesas; Uggla, Andreas Ringman; Fagerström-Billai, Fredrik; Eklöf, Ann-Christine; Frenckner, Björn; Nord, Magnus

    2010-07-01

    Pulmonary hypoplasia and persistent pulmonary hypertension are the main causes of mortality and morbidity in newborns with congenital diaphragmatic hernia (CDH). Nitrofen is well known to induce CDH and lung hypoplasia in a rat model, but the mechanism remains unknown. To increase the understanding of the underlying pathogenesis of CDH, we performed a global gene expression analysis using microarray technology. Pregnant rats were given 100 mg nitrofen on gestational day 9.5 to create CDH. On day 21, fetuses after nitrofen administration and control fetuses were removed; and lungs were harvested. Global gene expression analysis was performed using Affymetrix Platform and the RAE 230 set arrays. For validation of microarray data, we performed real-time polymerase chain reaction and Western blot analysis. Significantly decreased genes after nitrofen administration included several growth factors and growth factors receptors involved in lung development, transcription factors, water and ion channels, and genes involved in angiogenesis and extracellular matrix. These results could be confirmed with real-time polymerase chain reaction and protein expression studies. The pathogenesis of lung hypoplasia and CDH in the nitrofen model includes alteration at a molecular level of several pathways involved in lung development. The complexity of the nitrofen mechanism of action reminds of human CDH; and the picture is consistent with lung hypoplasia and vascular disease, both important contributors to the high mortality and morbidity in CDH. Increased understanding of the molecular mechanisms that control lung growth may be the key to develop novel therapeutic techniques to stimulate pre- and postnatal lung growth. Copyright 2010 Elsevier Inc. All rights reserved.

  11. Expression and Activity of Breast Cancer Resistance Protein (BCRP/ABCG2) in Human Distal Lung Epithelial Cells In Vitro.

    PubMed

    Nickel, Sabrina; Selo, Mohammed Ali; Fallack, Juliane; Clerkin, Caoimhe G; Huwer, Hanno; Schneider-Daum, Nicole; Lehr, Claus-Michael; Ehrhardt, Carsten

    2017-12-01

    Breast cancer resistance protein (BCRP/ABCG2) has previously been identified with high expression levels in human lung. The subcellular localisation and functional activity of the transporter in lung epithelia, however, remains poorly investigated. The aim of this project was to study BCRP expression and activity in freshly isolated human alveolar epithelial type 2 (AT2) and type 1-like (AT1-like) cells in primary culture, and to compare these findings with data obtained from the NCI-H441 cell line. BCRP expression levels in AT2 and AT1-like cells and in different passages of NCI-H441 cells were determined using q-PCR and immunoblot. Transporter localisation was confirmed by confocal laser scanning microscopy. Efflux and transport studies using the BCRP substrate BODIPY FL prazosin and the inhibitor Ko143 were carried out to assess BCRP activity in the different cell models. BCRP expression decreased during transdifferentiation from AT2 to AT1-like phenotype. Culturing NCI-H441 cells at an air-liquid interface or submersed did not change BCRP abundance, however, BCRP levels increased with passage number. BCRP was localised to the apical membrane and cytosol in NCI-H441 cells. In primary cells, the protein was found predominantly in the nucleus. Functional studies were consistent with expression data. BCRP is differently expressed in AT2 and AT1-like cells with lower abundance and activity in the latter ones. Nuclear BCRP might play a transcriptional role in distal lung epithelium. In NCI-H441 cells, BCRP is expressed in apical cell membranes and its activity is consistent with the localisation pattern.

  12. G protein-coupled estrogen receptor inhibits the P2Y receptor-mediated Ca(2+) signaling pathway in human airway epithelia.

    PubMed

    Hao, Yuan; Chow, Alison W; Yip, Wallace C; Li, Chi H; Wan, Tai F; Tong, Benjamin C; Cheung, King H; Chan, Wood Y; Chen, Yangchao; Cheng, Christopher H; Ko, Wing H

    2016-08-01

    P2Y receptor activation causes the release of inflammatory cytokines in the bronchial epithelium, whereas G protein-coupled estrogen receptor (GPER), a novel estrogen (E2) receptor, may play an anti-inflammatory role in this process. We investigated the cellular mechanisms underlying the inhibitory effect of GPER activation on the P2Y receptor-mediated Ca(2+) signaling pathway and cytokine production in airway epithelia. Expression of GPER in primary human bronchial epithelial (HBE) or 16HBE14o- cells was confirmed on both the mRNA and protein levels. Stimulation of HBE or 16HBE14o- cells with E2 or G1, a specific agonist of GPER, attenuated the nucleotide-evoked increases in [Ca(2+)]i, whereas this effect was reversed by G15, a GPER-specific antagonist. G1 inhibited the secretion of two proinflammatory cytokines, interleukin (IL)-6 and IL-8, in cells stimulated by adenosine 5'-(γ-thio)triphosphate (ATPγS). G1 stimulated a real-time increase in cAMP levels in 16HBE14o- cells, which could be inhibited by adenylyl cyclase inhibitors. The inhibitory effects of E2 or G1 on P2Y receptor-induced increases in Ca(2+) were reversed by treating the cells with a protein kinase A (PKA) inhibitor. These results demonstrated that the inhibitory effects of G1 or E2 on P2Y receptor-mediated Ca(2+) mobilization and cytokine secretion were due to GPER-mediated activation of a cAMP-dependent PKA pathway. This study has reported, for the first time, the expression and function of GPER as an anti-inflammatory component in human bronchial epithelia, which may mediate through its opposing effects on the pro-inflammatory pathway activated by the P2Y receptors in inflamed airway epithelia.

  13. Modeling pressure relationships of inspired air into the human lung bifurcations through simulations

    NASA Astrophysics Data System (ADS)

    Aghasafari, Parya; Ibrahim, Israr B. M.; Pidaparti, Ramana

    2018-03-01

    Applied pressure on human lung wall has great importance on setting up protective ventilatory strategies, therefore, estimating pressure relationships in terms of specific parameters would provide invaluable information specifically during mechanical ventilation (MV). A three-dimensional model from a healthy human lung MRI is analyzed by computational fluid dynamic (CFD), and results for pressure are curve fitted to estimate relationships that associate pressure to breathing time, cross section and generation numbers of intended locations. Among all possible functions, it is observed that exponential and polynomial pressure functions present most accurate results for normal breathing (NB) and MV, respectively. For validation, pressure-location curves from CFD and results from this study are compared and good correlations are found. Also, estimated pressure values are used to calculate pressure drop and airway resistance to the induced air into the lung bifurcations. It is concluded that maximum pressure drop appeared in generation number 2 and medium sized airways show higher resistance to air flow and that resistance decreased as cross sectional area increased through the model. Results from this study are in good agreement with previous studies and provide potentials for further studies on influence of air pressure on human lung tissue and reducing lung injuries during MV.

  14. Establishment and quantitative imaging of a 3D lung organotypic model of mammary tumor outgrowth.

    PubMed

    Martin, Michelle D; Fingleton, Barbara; Lynch, Conor C; Wells, Sam; McIntyre, J Oliver; Piston, David W; Matrisian, Lynn M

    2008-01-01

    The lung is the second most common site of metastatic spread in breast cancer and experimental evidence has been provided in many systems for the importance of an organ-specific microenvironment in the development of metastasis. To better understand the interaction between tumor and host cells in this important secondary site, we have developed a 3D in vitro organotypic model of breast tumor metastatic growth in the lung. In our model, cells isolated from mouse lungs are placed in a collagen sponge to serve as a scaffold and co-cultured with a green fluorescent protein-labeled polyoma virus middle T antigen (PyVT) mammary tumor cell line. Analysis of the co-culture system was performed using flow cytometry to determine the relative constitution of the co-cultures over time. This analysis determined that the cultures consisted of viable lung and breast cancer cells over a 5-day period. Confocal microscopy was then used to perform live cell imaging of the co-cultures over time. Our studies determined that host lung cells influence the ability of tumor cells to grow, as the presence of lung parenchyma positively affected the proliferation of the mammary tumor cells in culture. In summary, we have developed a novel in vitro model of breast tumor cells in a common metastatic site that can be used to study tumor/host interactions in an important microenvironment.

  15. Unique spatial and cellular expression patterns of Hoxa5, Hoxb4 and Hoxb6 proteins in normal developing murine lung are modified in pulmonary hypoplasia

    PubMed Central

    Volpe, MaryAnn Vitoria; Wang, Karen Ting Wai; Nielsen, Heber Carl; Chinoy, Mala Romeshchandra

    2009-01-01

    Background Hox transcription factors modulate signaling pathways controlling organ morphogenesis and maintain cell fate and differentiation in adults. Retinoid signaling, key in regulating Hox expression, is altered in pulmonary hypoplasia. Information on pattern-specific expression of Hox proteins in normal lung development and in pulmonary hypoplasia is minimal. Our objective was to determine how pulmonary hypoplasia alters temporal, spatial and cellular expression of Hoxa5, Hoxb4 and Hoxb6 proteins compared to normal lung development. Methods Temporal, spatial and cellular Hoxa5, Hoxb4 and Hoxb6 expression was studied in normal (untreated) and nitrofen-induced hypoplastic (NT-PH) lungs from gestational day 13.5, 16, 19 fetuses and neonates using western blot and immunohistochemistry. Results Modification of protein levels and spatial and cellular Hox expression patterns in NT-PH lungs was consistent with delayed lung development. Distinct protein isoforms were detected for each Hox protein. Expression levels of the Hoxa5 and Hoxb6 isoforms changed with development and further in NT-PH lungs. Compared to normal lungs, Gd19 and neonatal NT-PH lungs had decreased Hoxb6 and increased Hoxa5 and Hoxb4. Hoxa5 cellular localization changed from mesenchyme to epithelia earlier in normal lungs. Hoxb4 was expressed in mesenchyme and epithelial cells throughout development. Hoxb6 remained mainly in mesenchymal cells around distal airways. Conclusions Unique spatial and cellular expression of Hoxa5, Hoxb4 and Hoxb6 participates in branching morphogenesis and terminal sac formation. Altered Hox protein temporal and cellular balance of expression either contributes to pulmonary hypoplasia or functions as a compensatory mechanism attempting to correct abnormal lung development and maturation in this condition. PMID:18553509

  16. Epidemiology of Lung Cancer.

    PubMed

    Schwartz, Ann G; Cote, Michele L

    2016-01-01

    Lung cancer continues to be one of the most common causes of cancer death despite understanding the major cause of the disease: cigarette smoking. Smoking increases lung cancer risk 5- to 10-fold with a clear dose-response relationship. Exposure to environmental tobacco smoke among nonsmokers increases lung cancer risk about 20%. Risks for marijuana and hookah use, and the new e-cigarettes, are yet to be consistently defined and will be important areas for continued research as use of these products increases. Other known environmental risk factors include exposures to radon, asbestos, diesel, and ionizing radiation. Host factors have also been associated with lung cancer risk, including family history of lung cancer, history of chronic obstructive pulmonary disease and infections. Studies to identify genes associated with lung cancer susceptibility have consistently identified chromosomal regions on 15q25, 6p21 and 5p15 associated with lung cancer risk. Risk prediction models for lung cancer typically include age, sex, cigarette smoking intensity and/or duration, medical history, and occupational exposures, however there is not yet a risk prediction model currently recommended for general use. As lung cancer screening becomes more widespread, a validated model will be needed to better define risk groups to inform screening guidelines.

  17. Gastrointestinal cell lines form polarized epithelia with an adherent mucus layer when cultured in semi-wet interfaces with mechanical stimulation.

    PubMed

    Navabi, Nazanin; McGuckin, Michael A; Lindén, Sara K

    2013-01-01

    Mucin glycoproteins are secreted in large quantities by mucosal epithelia and cell surface mucins are a prominent feature of the glycocalyx of all mucosal epithelia. Currently, studies investigating the gastrointestinal mucosal barrier use either animal experiments or non-in vivo like cell cultures. Many pathogens cause different pathology in mice compared to humans and the in vitro cell cultures used are suboptimal because they are very different from an in vivo mucosal surface, are often not polarized, lack important components of the glycocalyx, and often lack the mucus layer. Although gastrointestinal cell lines exist that produce mucins or polarize, human cell line models that reproducibly create the combination of a polarized epithelial cell layer, functional tight junctions and an adherent mucus layer have been missing until now. We trialed a range of treatments to induce polarization, 3D-organization, tight junctions, mucin production, mucus secretion, and formation of an adherent mucus layer that can be carried out using standard equipment. These treatments were tested on cell lines of intestinal (Caco-2, LS513, HT29, T84, LS174T, HT29 MTX-P8 and HT29 MTX-E12) and gastric (MKN7, MKN45, AGS, NCI-N87 and its hTERT Clone5 and Clone6) origins using Ussing chamber methodology and (immuno)histology. Semi-wet interface culture in combination with mechanical stimulation and DAPT caused HT29 MTX-P8, HT29 MTX-E12 and LS513 cells to polarize, form functional tight junctions, a three-dimensional architecture resembling colonic crypts, and produce an adherent mucus layer. Caco-2 and T84 cells also polarized, formed functional tight junctions and produced a thin adherent mucus layer after this treatment, but with less consistency. In conclusion, culture methods affect cell lines differently, and testing a matrix of methods vs. cell lines may be important to develop better in vitro models. The methods developed herein create in vitro mucosal surfaces suitable for studies

  18. Gastrointestinal Cell Lines Form Polarized Epithelia with an Adherent Mucus Layer when Cultured in Semi-Wet Interfaces with Mechanical Stimulation

    PubMed Central

    Navabi, Nazanin; McGuckin, Michael A.; Lindén, Sara K.

    2013-01-01

    Mucin glycoproteins are secreted in large quantities by mucosal epithelia and cell surface mucins are a prominent feature of the glycocalyx of all mucosal epithelia. Currently, studies investigating the gastrointestinal mucosal barrier use either animal experiments or non-in vivo like cell cultures. Many pathogens cause different pathology in mice compared to humans and the in vitro cell cultures used are suboptimal because they are very different from an in vivo mucosal surface, are often not polarized, lack important components of the glycocalyx, and often lack the mucus layer. Although gastrointestinal cell lines exist that produce mucins or polarize, human cell line models that reproducibly create the combination of a polarized epithelial cell layer, functional tight junctions and an adherent mucus layer have been missing until now. We trialed a range of treatments to induce polarization, 3D-organization, tight junctions, mucin production, mucus secretion, and formation of an adherent mucus layer that can be carried out using standard equipment. These treatments were tested on cell lines of intestinal (Caco-2, LS513, HT29, T84, LS174T, HT29 MTX-P8 and HT29 MTX-E12) and gastric (MKN7, MKN45, AGS, NCI-N87 and its hTERT Clone5 and Clone6) origins using Ussing chamber methodology and (immuno)histology. Semi-wet interface culture in combination with mechanical stimulation and DAPT caused HT29 MTX-P8, HT29 MTX-E12 and LS513 cells to polarize, form functional tight junctions, a three-dimensional architecture resembling colonic crypts, and produce an adherent mucus layer. Caco-2 and T84 cells also polarized, formed functional tight junctions and produced a thin adherent mucus layer after this treatment, but with less consistency. In conclusion, culture methods affect cell lines differently, and testing a matrix of methods vs. cell lines may be important to develop better in vitro models. The methods developed herein create in vitro mucosal surfaces suitable for studies

  19. Propofol attenuates oxidant-induced acute lung injury in an isolated perfused rabbit-lung model.

    PubMed

    Yumoto, Masato; Nishida, Osamu; Nakamura, Fujio; Katsuya, Hirotada

    2005-01-01

    Reactive oxygen species have been strongly implicated in the pathogenesis of acute lung injury (ALI). Some animal studies suggest that free radical scavengers inhibit the onset of oxidant-induced ALI. Propofol (2,6-diisopropylphenol) is chemically similar to phenol-based free radical scavengers such as the endogenous antioxidant vitamin E. Both in vivo and in vitro studies have suggested that propofol has antioxidant potential. We hypothesized that propofol may attenuate ALI by acting as a free-radical scavenger. We investigated the effects of propofol on oxidant-induced ALI induced by purine and xanthine oxidase (XO), in isolated perfused rabbit lung, in two series of experiments. In series 1, we examined the relationship between the severity of ALI and the presence of hydrogen peroxide (H2O2). In series 2, we evaluated the effects of propofol on attenuating ALI and the dose dependence of these effects. The lungs were perfused for 90 min, and we evaluated the effects on the severity of ALI by monitoring the pulmonary capillary filtration coefficient (Kfc), pulmonary arterial pressure (Ppa), and the pulmonary capillary hydrostatic pressure (Ppc). In series 1, treatment with catalase (an H2O2 scavenger) prior to the addition of purine and XO resulted in complete prevention of ALI, suggesting that H2O2 may be involved closely in the pathogenesis of ALI. In series 2, pretreatment with propofol at concentrations in excess of 0.5 mM significantly inhibited the increases in the Kfc values, and that in excess of 0.75 mM significantly inhibited the increase in the Ppa values. Propofol attenuates oxidant-induced ALI in an isolated perfused rabbit lung model, probably due to its antioxidant action.

  20. Survival Benefit of Lung Transplantation in the Modern Era of Lung Allocation.

    PubMed

    Vock, David M; Durheim, Michael T; Tsuang, Wayne M; Finlen Copeland, C Ashley; Tsiatis, Anastasios A; Davidian, Marie; Neely, Megan L; Lederer, David J; Palmer, Scott M

    2017-02-01

    Lung transplantation is an accepted and increasingly employed treatment for advanced lung diseases, but the anticipated survival benefit of lung transplantation is poorly understood. To determine whether and for which patients lung transplantation confers a survival benefit in the modern era of U.S. lung allocation. Data on 13,040 adults listed for lung transplantation between May 2005 and September 2011 were obtained from the United Network for Organ Sharing. A structural nested accelerated failure time model was used to model the survival benefit of lung transplantation over time. The effects of patient, donor, and transplant center characteristics on the relative survival benefit of transplantation were examined. Overall, 73.8% of transplant recipients were predicted to achieve a 2-year survival benefit with lung transplantation. The survival benefit of transplantation varied by native disease group (P = 0.062), with 2-year expected benefit in 39.2 and 98.9% of transplants occurring in those with obstructive lung disease and cystic fibrosis, respectively, and by lung allocation score at the time of transplantation (P < 0.001), with net 2-year benefit in only 6.8% of transplants occurring for lung allocation score less than 32.5 and in 99.9% of transplants for lung allocation score exceeding 40. A majority of adults undergoing transplantation experience a survival benefit, with the greatest potential benefit in those with higher lung allocation scores or restrictive native lung disease or cystic fibrosis. These results provide novel information to assess the expected benefit of lung transplantation at an individual level and to enhance lung allocation policy.

  1. A novel method for right one-lung ventilation modeling in rabbits.

    PubMed

    Xu, Ze-Ping; Gu, Lian-Bing; Bian, Qing-Ming; Li, Peng-Yi; Wang, Li-Jun; Chen, Xiao-Xiang; Zhang, Jing-Yuan

    2016-08-01

    There is no standard method by which to establish a right one-lung ventilation (OLV) model in rabbits. In the present study, a novel method is proposed to compare with two other methods. After 0.5 h of baseline two-lung ventilation (TLV), 40 rabbits were randomly divided into sham group (TLV for 3 h as a contrast) and three right-OLV groups (right OLV for 3 h with different methods): Deep intubation group, clamp group and blocker group (deeply intubate the self-made bronchial blocker into the left main bronchus, the novel method). These three methods were compared using a number of variables: Circulation by heart rate (HR), mean arterial pressure (MAP); oxygenation by arterial blood gas analysis; airway pressure; lung injury by histopathology; and time, blood loss, success rate of modeling. Following OLV, compared with the sham group, arterial partial pressure of oxygen and arterial hemoglobin oxygen saturation decreased, peak pressure increased and lung injury scores were higher in three OLV groups at 3 h of OLV. All these indexes showed no differences between the three OLV groups. During right-OLV modeling, less time was spent in the blocker group (6±2 min), compared with the other two OLV groups (13±4 min in deep intubation group, P<0.05; 33±9 min in clamp group, P<0.001); more blood loss was observed in clamp group (11.7±2.8 ml), compared with the other two OLV groups (2.3±0.5 ml in deep intubation group, P<0.001; 2.1±0.6 ml in blocker group, P<0.001). The first-time and final success rate of modeling showed no differences among the three OLV groups. Deep intubation of the self-made bronchial blocker into the left main bronchus is an easy, effective and reliable method to establish a right-OLV model in rabbits.

  2. A novel method for right one-lung ventilation modeling in rabbits

    PubMed Central

    Xu, Ze-Ping; Gu, Lian-Bing; Bian, Qing-Ming; Li, Peng-Yi; Wang, Li-Jun; Chen, Xiao-Xiang; Zhang, Jing-Yuan

    2016-01-01

    There is no standard method by which to establish a right one-lung ventilation (OLV) model in rabbits. In the present study, a novel method is proposed to compare with two other methods. After 0.5 h of baseline two-lung ventilation (TLV), 40 rabbits were randomly divided into sham group (TLV for 3 h as a contrast) and three right-OLV groups (right OLV for 3 h with different methods): Deep intubation group, clamp group and blocker group (deeply intubate the self-made bronchial blocker into the left main bronchus, the novel method). These three methods were compared using a number of variables: Circulation by heart rate (HR), mean arterial pressure (MAP); oxygenation by arterial blood gas analysis; airway pressure; lung injury by histopathology; and time, blood loss, success rate of modeling. Following OLV, compared with the sham group, arterial partial pressure of oxygen and arterial hemoglobin oxygen saturation decreased, peak pressure increased and lung injury scores were higher in three OLV groups at 3 h of OLV. All these indexes showed no differences between the three OLV groups. During right-OLV modeling, less time was spent in the blocker group (6±2 min), compared with the other two OLV groups (13±4 min in deep intubation group, P<0.05; 33±9 min in clamp group, P<0.001); more blood loss was observed in clamp group (11.7±2.8 ml), compared with the other two OLV groups (2.3±0.5 ml in deep intubation group, P<0.001; 2.1±0.6 ml in blocker group, P<0.001). The first-time and final success rate of modeling showed no differences among the three OLV groups. Deep intubation of the self-made bronchial blocker into the left main bronchus is an easy, effective and reliable method to establish a right-OLV model in rabbits. PMID:27446346

  3. Early Impairment of Lung Mechanics in a Murine Model of Marfan Syndrome

    PubMed Central

    Uriarte, Juan J.; Meirelles, Thayna; Gorbenko del Blanco, Darya; Nonaka, Paula N.; Campillo, Noelia; Sarri, Elisabet; Navajas, Daniel; Egea, Gustavo; Farré, Ramon

    2016-01-01

    Early morbidity and mortality in patients with Marfan syndrome (MFS) -a connective tissue disease caused by mutations in fibrillin-1 gene- are mainly caused by aorta aneurysm and rupture. However, the increase in the life expectancy of MFS patients recently achieved by reparatory surgery promotes clinical manifestations in other organs. Although some studies have reported respiratory alterations in MFS, our knowledge of how this connective tissue disease modifies lung mechanics is scarce. Hence, we assessed whether the stiffness of the whole lung and of its extracellular matrix (ECM) is affected in a well-characterized MFS mouse model (FBN1C1039G/+). The stiffness of the whole lung and of its ECM were measured by conventional mechanical ventilation and atomic force microscopy, respectively. We studied 5-week and 9-month old mice, whose ages are representative of early and late stages of the disease. At both ages, the lungs of MFS mice were significantly more compliant than in wild type (WT) mice. By contrast, no significant differences were found in local lung ECM stiffness. Moreover, histopathological lung evaluation showed a clear emphysematous-like pattern in MFS mice since alveolar space enlargement was significantly increased compared with WT mice. These data suggest that the mechanism explaining the increased lung compliance in MFS is not a direct consequence of reduced ECM stiffness, but an emphysema-like alteration in the 3D structural organization of the lung. Since lung alterations in MFS are almost fully manifested at an early age, it is suggested that respiratory monitoring could provide early biomarkers for diagnosis and/or follow-up of patients with the Marfan syndrome. PMID:27003297

  4. Modeling of lung cancer risk due to radon exhalation of granite stone in dwelling houses.

    PubMed

    Abbasi, Akbar

    2017-01-01

    Due to increasing occurrences of lung cancer, radon exhalation rates, radon concentrations, and lung cancer risks in several types of commonly used granite stone, samples used for flooring in buildings, have been investigated. We measured the radon exhalation rates due to granite stones by means of an AlphaGUARD Model PQ2000 in a cube container with changeable floor by various granite stones. The lung cancer risk and percentage of lung cancer deaths (LCRn) due to those conditions were calculated using Darby's model. The radon exhalation rates ranged from 1.59 ± 0.41 to 9.43 ± 0.74 Bq/m 2/h. The radon concentrations in the standard room with poor and normal ventilation were calculated 20.10-71.09 Bq/m 3 and 16.12-47.01 Bq/m 3, respectively. The estimated numbers of lung cancer deaths attributable to indoor radon due to granite stones in 2013 were 145 (3.33%) and 103 (2.37%) for poor and normal ventilation systems, respectively. According to our estimations, the values of 3.33% and 2.37% of lung cancer deaths in 2013 are attributed to radon exhalation of granite stones with poor and normal ventilation systems, respectively.

  5. Segmentation of lung fields using Chan-Vese active contour model in chest radiographs

    NASA Astrophysics Data System (ADS)

    Sohn, Kiwon

    2011-03-01

    A CAD tool for chest radiographs consists of several procedures and the very first step is segmentation of lung fields. We develop a novel methodology for segmentation of lung fields in chest radiographs that can satisfy the following two requirements. First, we aim to develop a segmentation method that does not need a training stage with manual estimation of anatomical features in a large training dataset of images. Secondly, for the ease of implementation, it is desirable to apply a well established model that is widely used for various image-partitioning practices. The Chan-Vese active contour model, which is based on Mumford-Shah functional in the level set framework, is applied for segmentation of lung fields. With the use of this model, segmentation of lung fields can be carried out without detailed prior knowledge on the radiographic anatomy of the chest, yet in some chest radiographs, the trachea regions are unfavorably segmented out in addition to the lung field contours. To eliminate artifacts from the trachea, we locate the upper end of the trachea, find a vertical center line of the trachea and delineate it, and then brighten the trachea region to make it less distinctive. The segmentation process is finalized by subsequent morphological operations. We randomly select 30 images from the Japanese Society of Radiological Technology image database to test the proposed methodology and the results are shown. We hope our segmentation technique can help to promote of CAD tools, especially for emerging chest radiographic imaging techniques such as dual energy radiography and chest tomosynthesis.

  6. Examples of Mesh and NURBS modelling for in vivo lung counting studies.

    PubMed

    Farah, Jad; Broggio, David; Franck, Didier

    2011-03-01

    Realistic calibration coefficients for in vivo counting installations are assessed using voxel phantoms and Monte Carlo calculations. However, voxel phantoms construction is time consuming and their flexibility extremely limited. This paper involves Mesh and non-uniform rational B-splines graphical formats, of greater flexibility, to optimise the calibration of in vivo counting installations. Two studies validating the use of such phantoms and involving geometry deformation and modelling were carried out to study the morphologic effect on lung counting efficiency. The created 3D models fitted with the reference ones, with volumetric differences of <5 %. Moreover, it was found that counting efficiency varies with the inverse of lungs' volume and that the latter primes when compared with chest wall thickness. Finally, a series of different thoracic female phantoms of various cup sizes, chest girths and internal organs' volumes were created starting from the International Commission on Radiological Protection (ICRP) adult female reference computational phantom to give correction factors for the lung monitoring of female workers.

  7. Modeling tuberculosis pathogenesis through ex vivo lung tissue infection.

    PubMed

    Carranza-Rosales, Pilar; Carranza-Torres, Irma Edith; Guzmán-Delgado, Nancy Elena; Lozano-Garza, Gerardo; Villarreal-Treviño, Licet; Molina-Torres, Carmen; Villarreal, Javier Vargas; Vera-Cabrera, Lucio; Castro-Garza, Jorge

    2017-12-01

    Tuberculosis (TB) is one of the top 10 causes of death worldwide. Several in vitro and in vivo experimental models have been used to study TB pathogenesis and induction of immune response during Mycobacterium tuberculosis infection. Precision cut lung tissue slices (PCLTS) is an experimental model, in which all the usual cell types of the organ are found, the tissue architecture and the interactions amongst the different cells are maintained. PCLTS in good physiological conditions, monitored by MTT assay and histology, were infected with either virulent Mycobacterium tuberculosis strain H37Rv or the TB vaccine strain Mycobacterium bovis BCG. Histological analysis showed that bacilli infecting lung tissue slices were observed in the alveolar septa, alveolar light spaces, near to type II pneumocytes, and inside macrophages. Mycobacterial infection of PCLTS induced TNF-α production, which is consistent with previous M. tuberculosis in vitro and in vivo studies. This is the first report of using PCLTS as a system to study M. tuberculosis infection. The PCLTS model provides a useful tool to evaluate the innate immune responses and other aspects during the early stages of mycobacterial infection. Copyright © 2017. Published by Elsevier Ltd.

  8. Effects of Hydrostatic Pressure on Carcinogenic Properties of Epithelia.

    PubMed

    Tokuda, Shinsaku; Kim, Young Hak; Matsumoto, Hisako; Muro, Shigeo; Hirai, Toyohiro; Mishima, Michiaki; Furuse, Mikio

    2015-01-01

    The relationship between chronic inflammation and cancer is well known. The inflammation increases the permeability of blood vessels and consequently elevates pressure in the interstitial tissues. However, there have been only a few reports on the effects of hydrostatic pressure on cultured cells, and the relationship between elevated hydrostatic pressure and cell properties related to malignant tumors is less well understood. Therefore, we investigated the effects of hydrostatic pressure on the cultured epithelial cells seeded on permeable filters. Surprisingly, hydrostatic pressure from basal to apical side induced epithelial stratification in Madin-Darby canine kidney (MDCK) I and Caco-2 cells, and cavities with microvilli and tight junctions around their surfaces were formed within the multi-layered epithelia. The hydrostatic pressure gradient also promoted cell proliferation, suppressed cell apoptosis, and increased transepithelial ion permeability. The inhibition of protein kinase A (PKA) promoted epithelial stratification by the hydrostatic pressure whereas the activation of PKA led to suppressed epithelial stratification. These results indicate the role of the hydrostatic pressure gradient in the regulation of various epithelial cell functions. The findings in this study may provide clues for the development of a novel strategy for the treatment of the carcinoma.

  9. Effects of Hydrostatic Pressure on Carcinogenic Properties of Epithelia

    PubMed Central

    Tokuda, Shinsaku; Kim, Young Hak; Matsumoto, Hisako; Muro, Shigeo; Hirai, Toyohiro; Mishima, Michiaki; Furuse, Mikio

    2015-01-01

    The relationship between chronic inflammation and cancer is well known. The inflammation increases the permeability of blood vessels and consequently elevates pressure in the interstitial tissues. However, there have been only a few reports on the effects of hydrostatic pressure on cultured cells, and the relationship between elevated hydrostatic pressure and cell properties related to malignant tumors is less well understood. Therefore, we investigated the effects of hydrostatic pressure on the cultured epithelial cells seeded on permeable filters. Surprisingly, hydrostatic pressure from basal to apical side induced epithelial stratification in Madin-Darby canine kidney (MDCK) I and Caco-2 cells, and cavities with microvilli and tight junctions around their surfaces were formed within the multi-layered epithelia. The hydrostatic pressure gradient also promoted cell proliferation, suppressed cell apoptosis, and increased transepithelial ion permeability. The inhibition of protein kinase A (PKA) promoted epithelial stratification by the hydrostatic pressure whereas the activation of PKA led to suppressed epithelial stratification. These results indicate the role of the hydrostatic pressure gradient in the regulation of various epithelial cell functions. The findings in this study may provide clues for the development of a novel strategy for the treatment of the carcinoma. PMID:26716691

  10. Sirt1 restrains lung inflammasome activation in a murine model of sepsis.

    PubMed

    Gao, Rong; Ma, Zhongsen; Hu, Yuxin; Chen, Jiao; Shetty, Sreerama; Fu, Jian

    2015-04-15

    Excessive inflammation is a major cause of organ damage during sepsis. The elderly are highly susceptible to sepsis-induced organ injury. Sirt1 expression is reduced during aging. In the present study, we investigated the role of Sirt1, a histone deacetylase, in controlling inflammatory responses in a murine sepsis model induced by cecal ligation and puncture (CLP). We examined lung inflammatory signaling in inducible Sirt1 knockout (Sirt1(-/-)) mice and wild-type littermates (Sirt1(+/+)) after CLP. Our results demonstrated that Sirt1 deficiency led to severe lung inflammatory injury. To further investigate molecular mechanisms of Sirt1 regulation of lung inflammatory responses in sepsis, we conducted a series of experiments to assess lung inflammasome activation after CLP. We detected increased lung inflammatory signaling including NF-κB, signal transducer and activator of transcription 3, and ERK1/2 activation in Sirt1(-/-) mice after CLP. Furthermore, inflammasome activity was increased in Sirt1(-/-) mice after CLP, as demonstrated by increased IL-1β and caspase-7 cleavage and activation. Aggravated inflammasome activation in Sirt1(-/-) mice was associated with the increased production of lung proinflammatory mediators, including ICAM-1 and high-mobility group box 1, and further disruption of tight junctions and adherens junctions, as demonstrated by dramatic reduction of lung claudin-1 and vascular endothelial-cadherin expression, which was associated with the upregulation of matrix metallopeptidase 9 expression. In summary, our results suggest that Sirt1 suppresses acute lung inflammation during sepsis by controlling inflammasome activation pathway. Copyright © 2015 the American Physiological Society.

  11. Adenovirus Entry From the Apical Surface of Polarized Epithelia Is Facilitated by the Host Innate Immune Response

    PubMed Central

    Kotha, Poornima L. N.; Sharma, Priyanka; Kolawole, Abimbola O.; Yan, Ran; Alghamri, Mahmoud S.; Brockman, Trisha L.; Gomez-Cambronero, Julian; Excoffon, Katherine J. D. A.

    2015-01-01

    Prevention of viral-induced respiratory disease begins with an understanding of the factors that increase or decrease susceptibility to viral infection. The primary receptor for most adenoviruses is the coxsackievirus and adenovirus receptor (CAR), a cell-cell adhesion protein normally localized at the basolateral surface of polarized epithelia and involved in neutrophil transepithelial migration. Recently, an alternate isoform of CAR, CAREx8, has been identified at the apical surface of polarized airway epithelia and is implicated in viral infection from the apical surface. We hypothesized that the endogenous role of CAREx8 may be to facilitate host innate immunity. We show that IL-8, a proinflammatory cytokine and a neutrophil chemoattractant, stimulates the protein expression and apical localization of CAREx8 via activation of AKT/S6K and inhibition of GSK3β. Apical CAREx8 tethers infiltrating neutrophils at the apical surface of a polarized epithelium. Moreover, neutrophils present on the apical-epithelial surface enhance adenovirus entry into the epithelium. These findings suggest that adenovirus evolved to co-opt an innate immune response pathway that stimulates the expression of its primary receptor, apical CAREx8, to allow the initial infection the intact epithelium. In addition, CAREx8 is a new target for the development of novel therapeutics for both respiratory inflammatory disease and adenoviral infection. PMID:25768646

  12. Acute lung injury and persistent small airway disease in a rabbit model of chlorine inhalation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Musah, Sadiatu; Schlueter, Connie F.; Humphrey, Da

    Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbitsmore » were extubated and were allowed to survive for up to 24 h after exposure to 800 ppm chlorine for 4 min to study acute effects or up to 7 days after exposure to 400 ppm for 8 min to study longer term effects. Acute effects observed 6 or 24 h after inhalation of 800 ppm chlorine for 4 min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400 ppm chlorine for 8 min, rabbits exhibited mild hypoxemia, increased area of pressure–volume loops, and airway hyperreactivity. Lung histology 7 days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury. - Highlights: • A novel rabbit model of chlorine-induced lung disease was

  13. A 3D Human Lung Tissue Model for Functional Studies on Mycobacterium tuberculosis Infection.

    PubMed

    Braian, Clara; Svensson, Mattias; Brighenti, Susanna; Lerm, Maria; Parasa, Venkata R

    2015-10-05

    Tuberculosis (TB) still holds a major threat to the health of people worldwide, and there is a need for cost-efficient but reliable models to help us understand the disease mechanisms and advance the discoveries of new treatment options. In vitro cell cultures of monolayers or co-cultures lack the three-dimensional (3D) environment and tissue responses. Herein, we describe an innovative in vitro model of a human lung tissue, which holds promise to be an effective tool for studying the complex events that occur during infection with Mycobacterium tuberculosis (M. tuberculosis). The 3D tissue model consists of tissue-specific epithelial cells and fibroblasts, which are cultured in a matrix of collagen on top of a porous membrane. Upon air exposure, the epithelial cells stratify and secrete mucus at the apical side. By introducing human primary macrophages infected with M. tuberculosis to the tissue model, we have shown that immune cells migrate into the infected-tissue and form early stages of TB granuloma. These structures recapitulate the distinct feature of human TB, the granuloma, which is fundamentally different or not commonly observed in widely used experimental animal models. This organotypic culture method enables the 3D visualization and robust quantitative analysis that provides pivotal information on spatial and temporal features of host cell-pathogen interactions. Taken together, the lung tissue model provides a physiologically relevant tissue micro-environment for studies on TB. Thus, the lung tissue model has potential implications for both basic mechanistic and applied studies. Importantly, the model allows addition or manipulation of individual cell types, which thereby widens its use for modelling a variety of infectious diseases that affect the lungs.

  14. Stereotactic Body Radiation Therapy Delivery in a Genetically Engineered Mouse Model of Lung Cancer.

    PubMed

    Du, Shisuo; Lockamy, Virginia; Zhou, Lin; Xue, Christine; LeBlanc, Justin; Glenn, Shonna; Shukla, Gaurav; Yu, Yan; Dicker, Adam P; Leeper, Dennis B; Lu, You; Lu, Bo

    2016-11-01

    To implement clinical stereotactic body radiation therapy (SBRT) using a small animal radiation research platform (SARRP) in a genetically engineered mouse model of lung cancer. A murine model of multinodular Kras-driven spontaneous lung tumors was used for this study. High-resolution cone beam computed tomography (CBCT) imaging was used to identify and target peripheral tumor nodules, whereas off-target lung nodules in the contralateral lung were used as a nonirradiated control. CBCT imaging helps localize tumors, facilitate high-precision irradiation, and monitor tumor growth. SBRT planning, prescription dose, and dose limits to normal tissue followed the guidelines set by RTOG protocols. Pathologic changes in the irradiated tumors were investigated using immunohistochemistry. The image guided radiation delivery using the SARRP system effectively localized and treated lung cancer with precision in a genetically engineered mouse model of lung cancer. Immunohistochemical data confirmed the precise delivery of SBRT to the targeted lung nodules. The 60 Gy delivered in 3 weekly fractions markedly reduced the proliferation index, Ki-67, and increased apoptosis per staining for cleaved caspase-3 in irradiated lung nodules. It is feasible to use the SARRP platform to perform dosimetric planning and delivery of SBRT in mice with lung cancer. This allows for preclinical studies that provide a rationale for clinical trials involving SBRT, especially when combined with immunotherapeutics. Copyright © 2016. Published by Elsevier Inc.

  15. Multi-Modal Imaging in a Mouse Model of Orthotopic Lung Cancer.

    PubMed

    Patel, Priya; Kato, Tatsuya; Ujiie, Hideki; Wada, Hironobu; Lee, Daiyoon; Hu, Hsin-Pei; Hirohashi, Kentaro; Ahn, Jin Young; Zheng, Jinzi; Yasufuku, Kazuhiro

    2016-01-01

    Investigation of CF800, a novel PEGylated nano-liposomal imaging agent containing indocyanine green (ICG) and iohexol, for real-time near infrared (NIR) fluorescence and computed tomography (CT) image-guided surgery in an orthotopic lung cancer model in nude mice. CF800 was intravenously administered into 13 mice bearing the H460 orthotopic human lung cancer. At 48 h post-injection (peak imaging agent accumulation time point), ex vivo NIR and CT imaging was performed. A clinical NIR imaging system (SPY®, Novadaq) was used to measure fluorescence intensity of tumor and lung. Tumor-to-background-ratios (TBR) were calculated in inflated and deflated states. The mean Hounsfield unit (HU) of lung tumor was quantified using the CT data set and a semi-automated threshold-based method. Histological evaluation using H&E, the macrophage marker F4/80 and the endothelial cell marker CD31, was performed, and compared to the liposomal fluorescence signal obtained from adjacent tissue sections. The fluorescence TBR measured when the lung is in the inflated state (2.0 ± 0.58) was significantly greater than in the deflated state (1.42 ± 0.380 (n = 7, p<0.003). Mean fluorescent signal in tumor was highly variable across samples, (49.0 ± 18.8 AU). CT image analysis revealed greater contrast enhancement in lung tumors (a mean increase of 110 ± 57 HU) when CF800 is administered compared to the no contrast enhanced tumors (p = 0.0002). Preliminary data suggests that the high fluorescence TBR and CT tumor contrast enhancement provided by CF800 may have clinical utility in localization of lung cancer during CT and NIR image-guided surgery.

  16. WE-H-BRA-02: Radiobiological Modeling of Tumor Control Probability (TCP) and Radiation-Induced Pneumonitis (RP) for Lung Cancer Patients Treated with Monte Carlo-Based Lung SBRT

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Pokhrel, D; Sood, S; Shen, X

    2016-06-15

    Purpose: To present radiobiological modeling of TCP using tumor size-adjusted BED(s-BED)and PTV(D99) to lung SBRT patients treated with X-ray Voxel Monte Carlo(XVMC) algorithm, apply parameterized Lyman-NTCP model to predict grade-2 RP and subsequently, compare with clinical outcomes/observations. Methods: Dosimetric parameters and clinical follow-up for XVMC-based lung-SBRT patients were retrospectively evaluated. Patients were treated at Novalis-TX with hybrid(2 non-coplanar partial-arcs plus 3–6 static-beams)plan using HD-MLC/6MV-SRS-beam.For TCP,s-BED modelling was utilized: TCP=EXP[sBED-TCD50]/k/(1.0+EXP[sBED-TCD50]/k), where k=31Gy corresponding to TCD50=0Gy and s-BED was defined as BED10 minus 10 times the tumor diameter(in centimeters)by Ohri et al.(IJROBP,2012). For 2-yr local-control, we used more-realistic MC-computed PTVD99 as amore » predictive parameter, s-BED(D99).Due to relatively shorter median follow-up interval(12-months),Kaplan-Meier curves were generated to estimate 2-yr observed local-control and compared to predicted-rate by TCP modeling. For NTCP, we employed parameterized Lyman-NTCP model utilizing normal-lung DVH and α/β=3Gy fitted to predict grade-2 RP after lung-SBRT. Results: Total 108 patients (137 tumors) treated for 35–70Gy in 3–5 fractions, either primary-lung(n=74)or metastatic-lung(n=53)tumors were included.F or the given prescription dose with MC-computed MUs, 2-yr local-control rates with s-BED(D99) was 87±8%. Kaplan-Meier generated observed local-control rate at 2-yr was 87.5%,suggesting that PTV(D99) could be a potential predictor (p-value=0.38). Observed vs predicted TCP for primary-lung tumors and metastatic tumors were 97% vs 88±7% and 94% vs 86±9%.NTCP model predicted well for symptomatic-RP with predicted vs observed (3±5% vs 2%). Radiographic and clinically significant RP was observed in 13% and 2% of patients. Higher rates of radiographic change were observed in patients who received >50Gy compared to

  17. Validating Lung Models Using the ASL 5000 Breathing Simulator.

    PubMed

    Dexter, Amanda; McNinch, Neil; Kaznoch, Destiny; Volsko, Teresa A

    2018-04-01

    This study sought to validate pediatric models with normal and altered pulmonary mechanics. PubMed and CINAHL databases were searched for studies directly measuring pulmonary mechanics of healthy infants and children, infants with severe bronchopulmonary dysplasia and neuromuscular disease. The ASL 5000 was used to construct models using tidal volume (VT), inspiratory time (TI), respiratory rate, resistance, compliance, and esophageal pressure gleaned from literature. Data were collected for a 1-minute period and repeated three times for each model. t tests compared modeled data with data abstracted from the literature. Repeated measures analyses evaluated model performance over multiple iterations. Statistical significance was established at a P value of less than 0.05. Maximum differences of means (experimental iteration mean - clinical standard mean) for TI and VT are the following: term infant without lung disease (TI = 0.09 s, VT = 0.29 mL), severe bronchopulmonary dysplasia (TI = 0.08 s, VT = 0.17 mL), child without lung disease (TI = 0.10 s, VT = 0.17 mL), and child with neuromuscular disease (TI = 0.09 s, VT = 0.57 mL). One-sample testing demonstrated statistically significant differences between clinical controls and VT and TI values produced by the ASL 5000 for each iteration and model (P < 0.01). The greatest magnitude of differences was negligible (VT < 1.6%, TI = 18%) and not clinically relevant. Inconsistencies occurred with the models constructed on the ASL 5000. It was deemed accurate for the study purposes. It is therefore essential to test models and evaluate magnitude of differences before use.

  18. Survival Benefit of Lung Transplantation in the Modern Era of Lung Allocation

    PubMed Central

    Tsuang, Wayne M.; Copeland, C. Ashley Finlen; Tsiatis, Anastasios A.; Davidian, Marie; Neely, Megan L.; Lederer, David J.; Palmer, Scott M.

    2017-01-01

    Rationale: Lung transplantation is an accepted and increasingly employed treatment for advanced lung diseases, but the anticipated survival benefit of lung transplantation is poorly understood. Objectives: To determine whether and for which patients lung transplantation confers a survival benefit in the modern era of U.S. lung allocation. Methods: Data on 13,040 adults listed for lung transplantation between May 2005 and September 2011 were obtained from the United Network for Organ Sharing. A structural nested accelerated failure time model was used to model the survival benefit of lung transplantation over time. The effects of patient, donor, and transplant center characteristics on the relative survival benefit of transplantation were examined. Measurements and Main Results: Overall, 73.8% of transplant recipients were predicted to achieve a 2-year survival benefit with lung transplantation. The survival benefit of transplantation varied by native disease group (P = 0.062), with 2-year expected benefit in 39.2 and 98.9% of transplants occurring in those with obstructive lung disease and cystic fibrosis, respectively, and by lung allocation score at the time of transplantation (P < 0.001), with net 2-year benefit in only 6.8% of transplants occurring for lung allocation score less than 32.5 and in 99.9% of transplants for lung allocation score exceeding 40. Conclusions: A majority of adults undergoing transplantation experience a survival benefit, with the greatest potential benefit in those with higher lung allocation scores or restrictive native lung disease or cystic fibrosis. These results provide novel information to assess the expected benefit of lung transplantation at an individual level and to enhance lung allocation policy. PMID:27779905

  19. Interleukin-6 Contributes to Inflammation and Remodeling in a Model of Adenosine Mediated Lung Injury

    PubMed Central

    Pedroza, Mesias; Schneider, Daniel J.; Karmouty-Quintana, Harry; Coote, Julie; Shaw, Stevan; Corrigan, Rebecca; Molina, Jose G.; Alcorn, Joseph L.; Galas, David; Gelinas, Richard; Blackburn, Michael R.

    2011-01-01

    Background Chronic lung diseases are the third leading cause of death in the United States due in part to an incomplete understanding of pathways that govern the progressive tissue remodeling that occurs in these disorders. Adenosine is elevated in the lungs of animal models and humans with chronic lung disease where it promotes air-space destruction and fibrosis. Adenosine signaling increases the production of the pro-fibrotic cytokine interleukin-6 (IL-6). Based on these observations, we hypothesized that IL-6 signaling contributes to tissue destruction and remodeling in a model of chronic lung disease where adenosine levels are elevated. Methodology/Principal Findings We tested this hypothesis by neutralizing or genetically removing IL-6 in adenosine deaminase (ADA)-deficient mice that develop adenosine dependent pulmonary inflammation and remodeling. Results demonstrated that both pharmacologic blockade and genetic removal of IL-6 attenuated pulmonary inflammation, remodeling and fibrosis in this model. The pursuit of mechanisms involved revealed adenosine and IL-6 dependent activation of STAT-3 in airway epithelial cells. Conclusions/Significance These findings demonstrate that adenosine enhances IL-6 signaling pathways to promote aspects of chronic lung disease. This suggests that blocking IL-6 signaling during chronic stages of disease may provide benefit in halting remodeling processes such as fibrosis and air-space destruction. PMID:21799929

  20. Local tumor control probability modeling of primary and secondary lung tumors in stereotactic body radiotherapy.

    PubMed

    Guckenberger, Matthias; Klement, Rainer J; Allgäuer, Michael; Andratschke, Nicolaus; Blanck, Oliver; Boda-Heggemann, Judit; Dieckmann, Karin; Duma, Marciana; Ernst, Iris; Ganswindt, Ute; Hass, Peter; Henkenberens, Christoph; Holy, Richard; Imhoff, Detlef; Kahl, Henning K; Krempien, Robert; Lohaus, Fabian; Nestle, Ursula; Nevinny-Stickel, Meinhard; Petersen, Cordula; Semrau, Sabine; Streblow, Jan; Wendt, Thomas G; Wittig, Andrea; Flentje, Michael; Sterzing, Florian

    2016-03-01

    To evaluate whether local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) varies between lung metastases of different primary cancer sites and between primary non-small cell lung cancer (NSCLC) and secondary lung tumors. A retrospective multi-institutional (n=22) database of 399 patients with stage I NSCLC and 397 patients with 525 lung metastases was analyzed. Irradiation doses were converted to biologically effective doses (BED). Logistic regression was used for local tumor control probability (TCP) modeling and the second-order bias corrected Akaike Information Criterion was used for model comparison. After median follow-up of 19 months and 16 months (n.s.), local tumor control was observed in 87.7% and 86.7% of the primary and secondary lung tumors (n.s.), respectively. A strong dose-response relationship was observed in the primary NSCLC and metastatic cohort but dose-response relationships were not significantly different: the TCD90 (dose to achieve 90% TCP; BED of maximum planning target volume dose) estimates were 176 Gy (151-223) and 160 Gy (123-237) (n.s.), respectively. The dose-response relationship was not influenced by the primary cancer site within the metastatic cohort. Dose-response relationships for local tumor control in SBRT were not different between lung metastases of various primary cancer sites and between primary NSCLC and lung metastases. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  1. Ex Vivo Lung Perfusion Rehabilitates Sepsis-Induced Lung Injury

    PubMed Central

    Mehaffey, J. Hunter; Charles, Eric J.; Sharma, Ashish K.; Salmon, Morgan; Money, Dustin; Schubert, Sarah; Stoler, Mark H; Tribble, Curtis G.; Laubach, Victor E.; Roeser, Mark E.; Kron, Irving L.

    2017-01-01

    Objective Sepsis is the number one cause of lung injury in adults. Ex vivo lung perfusion (EVLP) is gaining clinical acceptance for donor lung evaluation and rehabilitation, and may expand the use of marginal organs for transplantation. We hypothesized that four hours of normothermic EVLP would improve compliance and oxygenation in a porcine model of sepsis-induced lung injury. Methods We utilized a porcine lung injury model using intravenous lipopolysaccharide (LPS) to induce a systemic inflammatory response. Two groups (n=4 animals/group) received a 2-hour infusion of LPS via the external jugular vein. Serial blood gases were performed every 30 min until the PO2/FiO2 ratio dropped below 150 on two consecutive readings. Lungs were then randomized to treatment with 4 hours of normothermic EVLP with Steen solution or 4 additional hours of in vivo perfusion (Control). Airway pressures and blood gases were recorded for calculation of dynamic lung compliance and PO2/FiO2 ratios. EVLP was performed according to the NOVEL trial protocol with hourly recruitment maneuvers and oxygen challenge. Results All animals reached a PO2/FiO2 ratio < 150 mmHg within 3 hours after start of LPS infusion. Animals in the Control group had continued decline of oxygenation and compliance during the 4-hour in vivo perfusion period with three of the four animals dying within 4 hours due to severe hypoxia. The EVLP group demonstrated significant improvements in oxygenation and dynamic compliance from hour 1 to hour 4 (365.8±53.0 vs 584.4±21.0 mmHg, p=0.02; 9.0±2.8 vs 15.0±3.6, p=0.02 mL/cmH2O). Conclusions EVLP can successfully rehabilitate LPS-induced lung injury in this preclinical porcine model. Thus EVLP may provide a means to rehabilitate many types of acute lung injury. PMID:28434548

  2. Multiplicity of Mathematical Modeling Strategies to Search for Molecular and Cellular Insights into Bacteria Lung Infection

    PubMed Central

    Cantone, Martina; Santos, Guido; Wentker, Pia; Lai, Xin; Vera, Julio

    2017-01-01

    Even today two bacterial lung infections, namely pneumonia and tuberculosis, are among the 10 most frequent causes of death worldwide. These infections still lack effective treatments in many developing countries and in immunocompromised populations like infants, elderly people and transplanted patients. The interaction between bacteria and the host is a complex system of interlinked intercellular and the intracellular processes, enriched in regulatory structures like positive and negative feedback loops. Severe pathological condition can emerge when the immune system of the host fails to neutralize the infection. This failure can result in systemic spreading of pathogens or overwhelming immune response followed by a systemic inflammatory response. Mathematical modeling is a promising tool to dissect the complexity underlying pathogenesis of bacterial lung infection at the molecular, cellular and tissue levels, and also at the interfaces among levels. In this article, we introduce mathematical and computational modeling frameworks that can be used for investigating molecular and cellular mechanisms underlying bacterial lung infection. Then, we compile and discuss published results on the modeling of regulatory pathways and cell populations relevant for lung infection and inflammation. Finally, we discuss how to make use of this multiplicity of modeling approaches to open new avenues in the search of the molecular and cellular mechanisms underlying bacterial infection in the lung. PMID:28912729

  3. Multiplicity of Mathematical Modeling Strategies to Search for Molecular and Cellular Insights into Bacteria Lung Infection.

    PubMed

    Cantone, Martina; Santos, Guido; Wentker, Pia; Lai, Xin; Vera, Julio

    2017-01-01

    Even today two bacterial lung infections, namely pneumonia and tuberculosis, are among the 10 most frequent causes of death worldwide. These infections still lack effective treatments in many developing countries and in immunocompromised populations like infants, elderly people and transplanted patients. The interaction between bacteria and the host is a complex system of interlinked intercellular and the intracellular processes, enriched in regulatory structures like positive and negative feedback loops. Severe pathological condition can emerge when the immune system of the host fails to neutralize the infection. This failure can result in systemic spreading of pathogens or overwhelming immune response followed by a systemic inflammatory response. Mathematical modeling is a promising tool to dissect the complexity underlying pathogenesis of bacterial lung infection at the molecular, cellular and tissue levels, and also at the interfaces among levels. In this article, we introduce mathematical and computational modeling frameworks that can be used for investigating molecular and cellular mechanisms underlying bacterial lung infection. Then, we compile and discuss published results on the modeling of regulatory pathways and cell populations relevant for lung infection and inflammation. Finally, we discuss how to make use of this multiplicity of modeling approaches to open new avenues in the search of the molecular and cellular mechanisms underlying bacterial infection in the lung.

  4. Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid

    PubMed Central

    Rizk, Matthew L.; Lala, Mallika; Chavez‐Eng, Cynthia; Visser, Sandra A. G.; Kerbusch, Thomas; Danhof, Meindert; Rao, Gauri; van der Graaf, Piet H.

    2016-01-01

    Aims Several clinical trials have confirmed the therapeutic benefit of imipenem for treatment of lung infections. There is however no knowledge of the penetration of imipenem into the lung epithelial lining fluid (ELF), the site of action relevant for lung infections. Furthermore, although the plasma pharmacokinetics (PK) of imipenem has been widely studied, most studies have been based on selected patient groups. The aim of this analysis was to characterize imipenem plasma PK across populations and to quantify imipenem ELF penetration. Methods A population model for imipenem plasma PK was developed using data obtained from healthy volunteers, elderly subjects and subjects with renal impairment, in order to identify predictors for inter‐individual variability (IIV) of imipenem PK. Subsequently, a clinical study which measured plasma and ELF concentrations of imipenem was included in order to quantify lung penetration. Results A two compartmental model best described the plasma PK of imipenem. Creatinine clearance and body weight were included as subject characteristics predictive for IIV on clearance. Typical estimates for clearance, central and peripheral volume, and inter‐compartmental clearance were 11.5 l h–1, 9.37 l, 6.41 l, 13.7 l h–1, respectively (relative standard error (RSE) <8%). The distribution of imipenem into ELF was described using a time‐independent penetration coefficient of 0.44 (RSE 14%). Conclusion The identified lung penetration coefficient confirms the clinical relevance of imipenem for treatment of lung infections, while the population PK model provided insights into predictors of IIV for imipenem PK and may be of relevance to support dose optimization in various subject groups. PMID:26852277

  5. Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid.

    PubMed

    van Hasselt, J G Coen; Rizk, Matthew L; Lala, Mallika; Chavez-Eng, Cynthia; Visser, Sandra A G; Kerbusch, Thomas; Danhof, Meindert; Rao, Gauri; van der Graaf, Piet H

    2016-06-01

    Several clinical trials have confirmed the therapeutic benefit of imipenem for treatment of lung infections. There is however no knowledge of the penetration of imipenem into the lung epithelial lining fluid (ELF), the site of action relevant for lung infections. Furthermore, although the plasma pharmacokinetics (PK) of imipenem has been widely studied, most studies have been based on selected patient groups. The aim of this analysis was to characterize imipenem plasma PK across populations and to quantify imipenem ELF penetration. A population model for imipenem plasma PK was developed using data obtained from healthy volunteers, elderly subjects and subjects with renal impairment, in order to identify predictors for inter-individual variability (IIV) of imipenem PK. Subsequently, a clinical study which measured plasma and ELF concentrations of imipenem was included in order to quantify lung penetration. A two compartmental model best described the plasma PK of imipenem. Creatinine clearance and body weight were included as subject characteristics predictive for IIV on clearance. Typical estimates for clearance, central and peripheral volume, and inter-compartmental clearance were 11.5 l h(-1) , 9.37 l, 6.41 l, 13.7 l h(-1) , respectively (relative standard error (RSE) <8%). The distribution of imipenem into ELF was described using a time-independent penetration coefficient of 0.44 (RSE 14%). The identified lung penetration coefficient confirms the clinical relevance of imipenem for treatment of lung infections, while the population PK model provided insights into predictors of IIV for imipenem PK and may be of relevance to support dose optimization in various subject groups. © 2016 The British Pharmacological Society.

  6. Crossroads of integrins and cadherins in epithelia and stroma remodeling

    PubMed Central

    Epifano, Carolina; Perez-Moreno, Mirna

    2012-01-01

    Adhesion events mediated by cadherin and integrin adhesion receptors have fundamental roles in the maintenance of the physiological balance of epithelial tissues, and it is well established that perturbations in their normal functional activity and/or changes in their expression are associated with tumorigenesis. Over the last decades, increasing evidence of a dynamic collaborative interaction between these complexes through their shared interactions with cytoskeletal proteins and common signaling pathways has emerged not only as an important regulator of several aspects of epithelial cell behavior, but also as a coordinated adhesion module that senses and transmits signals from and to the epithelia surrounding microenvironment. The tight regulation of their crosstalk is particularly important during epithelial remodeling events that normally take place during morphogenesis and tissue repair, and when defective it leads to cell transformation and aggravated responses of the tumor microenvironment that contribute to tumorigenesis. In this review we highlight some of the interactions that regulate their crosstalk and how this could be implicated in regulating signals across epithelial tissues to sustain homeostasis. PMID:22568988

  7. Off-the-job training for VATS employing anatomically correct lung models.

    PubMed

    Obuchi, Toshiro; Imakiire, Takayuki; Miyahara, Sou; Nakashima, Hiroyasu; Hamanaka, Wakako; Yanagisawa, Jun; Hamatake, Daisuke; Shiraishi, Takeshi; Moriyama, Shigeharu; Iwasaki, Akinori

    2012-02-01

    We evaluated our simulated major lung resection employing anatomically correct lung models as "off-the-job training" for video-assisted thoracic surgery trainees. A total of 76 surgeons voluntarily participated in our study. They performed video-assisted thoracic surgical lobectomy employing anatomically correct lung models, which are made of sponges so that vessels and bronchi can be cut using usual surgical techniques with typical forceps. After the simulation surgery, participants answered questionnaires on a visual analogue scale, in terms of their level of interest and the reality of our training method as off-the-job training for trainees. We considered that the closer a score was to 10, the more useful our method would be for training new surgeons. Regarding the appeal or level of interest in this simulation surgery, the mean score was 8.3 of 10, and regarding reality, it was 7.0. The participants could feel some of the real sensations of the surgery and seemed to be satisfied to perform the simulation lobectomy. Our training method is considered to be suitable as an appropriate type of surgical off-the-job training.

  8. Volume Oscillations Delivered to a Lung Model Using 4 Different Bubble CPAP Systems.

    PubMed

    Poli, Jonathan A; Richardson, C Peter; DiBlasi, Robert M

    2015-03-01

    High-frequency pressure oscillations created by gas bubbling through an underwater seal during bubble CPAP may enhance ventilation and aid in lung recruitment in premature infants. We hypothesized that there are no differences in the magnitude of oscillations in lung volume (ΔV) in a preterm neonatal lung model when different bubble CPAP systems are used. An anatomically realistic replica of an infant nasal airway model was attached to a Silastic test lung sealed within a calibrated plethysmograph. Nasal prongs were affixed to the simulated neonate and supported using bubble CPAP systems set at 6 cm H2O. ΔV was calculated using pressure measurements obtained from the plethysmograph. The Fisher & Paykel Healthcare bubble CPAP system provided greater ΔV than any of the other devices at all of the respective bias flows (P < .05). The Fisher & Paykel Healthcare and Babi.Plus systems generally provided ΔV at lower frequencies than the other bubble CPAP systems. The magnitude of ΔV increased at bias flows of > 4 L/min in the Fisher & Paykel Healthcare, Airways Development, and homemade systems, but appeared to decrease as bias flow increased with the Babi.Plus system. The major finding of this study is that bubble CPAP can provide measureable ventilation effects in an infant lung model. We speculate that the differences noted in ΔV between the different devices are a combination of the circuit/nasal prong configuration, bubbler configuration, and frequency of oscillations. Additional testing is needed in spontaneously breathing infants to determine whether a physiologic benefit exists when using the different bubble CPAP systems. Copyright © 2015 by Daedalus Enterprises.

  9. Quantifying lung morphology with respiratory-gated micro-CT in a murine model of emphysema

    NASA Astrophysics Data System (ADS)

    Ford, N. L.; Martin, E. L.; Lewis, J. F.; Veldhuizen, R. A. W.; Holdsworth, D. W.; Drangova, M.

    2009-04-01

    Non-invasive micro-CT imaging techniques have been developed to investigate lung structure in free-breathing rodents. In this study, we investigate the utility of retrospectively respiratory-gated micro-CT imaging in an emphysema model to determine if anatomical changes could be observed in the image-derived quantitative analysis at two respiratory phases. The emphysema model chosen was a well-characterized, genetically altered model (TIMP-3 knockout mice) that exhibits a homogeneous phenotype. Micro-CT scans of the free-breathing, anaesthetized mice were obtained in 50 s and retrospectively respiratory sorted and reconstructed, providing 3D images representing peak inspiration and end expiration with 0.15 mm isotropic voxel spacing. Anatomical measurements included the volume and CT density of the lungs and the volume of the major airways, along with the diameters of the trachea, left bronchus and right bronchus. From these measurements, functional parameters such as functional residual capacity and tidal volume were calculated. Significant differences between the wild-type and TIMP-3 knockout groups were observed for measurements of CT density over the entire lung, indicating increased air content in the lungs of TIMP-3 knockout mice. These results demonstrate retrospective respiratory-gated micro-CT, providing images at multiple respiratory phases that can be analyzed quantitatively to investigate anatomical changes in murine models of emphysema.

  10. Pediatric Artificial Lung: A Low-Resistance Pumpless Artificial Lung Alleviates an Acute Lamb Model of Increased Right Ventricle Afterload.

    PubMed

    Alghanem, Fares; Bryner, Benjamin S; Jahangir, Emilia M; Fernando, Uditha P; Trahanas, John M; Hoffman, Hayley R; Bartlett, Robert H; Rojas-Peña, Alvaro; Hirschl, Ronald B

    Lung disease in children often results in pulmonary hypertension and right heart failure. The availability of a pediatric artificial lung (PAL) would open new approaches to the management of these conditions by bridging to recovery in acute disease or transplantation in chronic disease. This study investigates the efficacy of a novel PAL in alleviating an animal model of pulmonary hypertension and increased right ventricle afterload. Five juvenile lambs (20-30 kg) underwent PAL implantation in a pulmonary artery to left atrium configuration. Induction of disease involved temporary, reversible occlusion of the right main pulmonary artery. Hemodynamics, pulmonary vascular input impedance, and right ventricle efficiency were measured under 1) baseline, 2) disease, and 3) disease + PAL conditions. The disease model altered hemodynamics variables in a manner consistent with pulmonary hypertension. Subsequent PAL attachment improved pulmonary artery pressure (p = 0.018), cardiac output (p = 0.050), pulmonary vascular input impedance (Z.0 p = 0.028; Z.1 p = 0.058), and right ventricle efficiency (p = 0.001). The PAL averaged resistance of 2.3 ± 0.8 mm Hg/L/min and blood flow of 1.3 ± 0.6 L/min. This novel low-resistance PAL can alleviate pulmonary hypertension in an acute animal model and demonstrates potential for use as a bridge to lung recovery or transplantation in pediatric patients with significant pulmonary hypertension refractory to medical therapies.

  11. Osthole prevents intestinal ischemia-reperfusion-induced lung injury in a rodent model.

    PubMed

    Mo, Li-Qun; Chen, Ye; Song, Li; Wu, Gang-Ming; Tang, Ni; Zhang, Ying-Ying; Wang, Xiao-Bin; Liu, Ke-Xuan; Zhou, Jun

    2014-06-15

    Intestinal ischemia-reperfusion (II/R) is associated with high morbidity and mortality. The aim of this study was to investigate the effects of osthole on lung injury and mortality induced by II/R. A rat model of II/R was induced by clamping the superior mesenteric artery for 90 min followed by reperfusion for 240 min. Osthole was administrated intraperitoneally at 30 min before intestinal ischemia (10 or 50 mg/kg). The survival rate and mean arterial pressure were observed. Blood samples were obtained for blood gas analyses. Lung injury was assessed by the histopathologic changes (hematoxylin and eosin staining), lung wet-to-dry weight ratio, and pulmonary permeability index. The levels of reactive oxygen species, malondialdehyde, interleukin 6, and tumor necrosis factor α, as well as the activities of superoxide dismutase and myeloperoxidase in lung were measured. The survival rate, ratio of arterial oxygen tension to fraction of inspired oxygen, and mean arterial pressure decreased significantly after II/R. Results also indicated that II/R-induced severe lung injury evidenced by increase in pathologic scores, lung wet-to-dry weight ratio, and pulmonary permeability index, which was accompanied by increases in the levels of pulmonary reactive oxygen species, malondialdehyde, interleukin 6, tumor necrosis factor α, and the pulmonary myeloperoxidase activity and a decrease in superoxide dismutase activity. Osthole could significantly ameliorate lung injury and improve the previously mentioned variables. These findings indicated that osthole could attenuate the lung injury induced by II/R in rats, at least in part, by inhibiting inflammatory response and oxidative stress. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models.

    PubMed

    Bridgeman, Victoria L; Vermeulen, Peter B; Foo, Shane; Bilecz, Agnes; Daley, Frances; Kostaras, Eleftherios; Nathan, Mark R; Wan, Elaine; Frentzas, Sophia; Schweiger, Thomas; Hegedus, Balazs; Hoetzenecker, Konrad; Renyi-Vamos, Ferenc; Kuczynski, Elizabeth A; Vasudev, Naveen S; Larkin, James; Gore, Martin; Dvorak, Harold F; Paku, Sandor; Kerbel, Robert S; Dome, Balazs; Reynolds, Andrew R

    2017-02-01

    Anti-angiogenic therapies have shown limited efficacy in the clinical management of metastatic disease, including lung metastases. Moreover, the mechanisms via which tumours resist anti-angiogenic therapies are poorly understood. Importantly, rather than utilizing angiogenesis, some metastases may instead incorporate pre-existing vessels from surrounding tissue (vessel co-option). As anti-angiogenic therapies were designed to target only new blood vessel growth, vessel co-option has been proposed as a mechanism that could drive resistance to anti-angiogenic therapy. However, vessel co-option has not been extensively studied in lung metastases, and its potential to mediate resistance to anti-angiogenic therapy in lung metastases is not established. Here, we examined the mechanism of tumour vascularization in 164 human lung metastasis specimens (composed of breast, colorectal and renal cancer lung metastasis cases). We identified four distinct histopathological growth patterns (HGPs) of lung metastasis (alveolar, interstitial, perivascular cuffing, and pushing), each of which vascularized via a different mechanism. In the alveolar HGP, cancer cells invaded the alveolar air spaces, facilitating the co-option of alveolar capillaries. In the interstitial HGP, cancer cells invaded the alveolar walls to co-opt alveolar capillaries. In the perivascular cuffing HGP, cancer cells grew by co-opting larger vessels of the lung. Only in the pushing HGP did the tumours vascularize by angiogenesis. Importantly, vessel co-option occurred with high frequency, being present in >80% of the cases examined. Moreover, we provide evidence that vessel co-option mediates resistance to the anti-angiogenic drug sunitinib in preclinical lung metastasis models. Assuming that our interpretation of the data is correct, we conclude that vessel co-option in lung metastases occurs through at least three distinct mechanisms, that vessel co-option occurs frequently in lung metastases, and that vessel

  13. Animal models of asthma: innovative methods of lung research and new pharmacological targets.

    PubMed

    Braun, Armin; Tschernig, Thomas

    2006-06-01

    Allergic diseases like bronchial asthma are increasing in societies with western lifestyle. In the last years substantial progress was made in the understanding of the underlying mechanisms and explanations like the hygiene hypothesis were developed. However the exact mechanisms of the physiological and immunological events in the lung leading to bronchial asthma are still not fully understood. Therefore, animal models of asthma have been established and improved to study the complex cellular interactions in vivo. Since mice became the most frequently used animal species the methods for detecting lung physiology, e.g. lung function measurements were adapted to the small size of the murine lung. Laser-dissection and precision cut lung slices have become common techniques to get a view into distinct lung compartments and cells. In addition genomic and proteomic approaches are now used widely. On the other hand a major conclusion of the workshop stated that more than one species is necessary in research and for pharmacological screening in asthma and COPD. The resulting new understanding in the mechanisms of asthma pathogenesis has lead to a rapid identification of novel pharmaceutical targets for treatment of the disease.

  14. RECONSTRUCTION OF HUMAN LUNG MORPHOLOGY MODELS FROM MAGNETIC RESONANCE IMAGES

    EPA Science Inventory


    Reconstruction of Human Lung Morphology Models from Magnetic Resonance Images
    T. B. Martonen (Experimental Toxicology Division, U.S. EPA, Research Triangle Park, NC 27709) and K. K. Isaacs (School of Public Health, University of North Carolina, Chapel Hill, NC 27514)

  15. Multi-Modal Imaging in a Mouse Model of Orthotopic Lung Cancer

    PubMed Central

    Patel, Priya; Kato, Tatsuya; Ujiie, Hideki; Wada, Hironobu; Lee, Daiyoon; Hu, Hsin-pei; Hirohashi, Kentaro; Ahn, Jin Young; Zheng, Jinzi; Yasufuku, Kazuhiro

    2016-01-01

    Background Investigation of CF800, a novel PEGylated nano-liposomal imaging agent containing indocyanine green (ICG) and iohexol, for real-time near infrared (NIR) fluorescence and computed tomography (CT) image-guided surgery in an orthotopic lung cancer model in nude mice. Methods CF800 was intravenously administered into 13 mice bearing the H460 orthotopic human lung cancer. At 48 h post-injection (peak imaging agent accumulation time point), ex vivo NIR and CT imaging was performed. A clinical NIR imaging system (SPY®, Novadaq) was used to measure fluorescence intensity of tumor and lung. Tumor-to-background-ratios (TBR) were calculated in inflated and deflated states. The mean Hounsfield unit (HU) of lung tumor was quantified using the CT data set and a semi-automated threshold-based method. Histological evaluation using H&E, the macrophage marker F4/80 and the endothelial cell marker CD31, was performed, and compared to the liposomal fluorescence signal obtained from adjacent tissue sections Results The fluorescence TBR measured when the lung is in the inflated state (2.0 ± 0.58) was significantly greater than in the deflated state (1.42 ± 0.380 (n = 7, p<0.003). Mean fluorescent signal in tumor was highly variable across samples, (49.0 ± 18.8 AU). CT image analysis revealed greater contrast enhancement in lung tumors (a mean increase of 110 ± 57 HU) when CF800 is administered compared to the no contrast enhanced tumors (p = 0.0002). Conclusion Preliminary data suggests that the high fluorescence TBR and CT tumor contrast enhancement provided by CF800 may have clinical utility in localization of lung cancer during CT and NIR image-guided surgery. PMID:27584018

  16. Efficient generation of functional CFTR-expressing airway epithelial cells from human pluripotent stem cells.

    PubMed

    Wong, Amy P; Chin, Stephanie; Xia, Sunny; Garner, Jodi; Bear, Christine E; Rossant, Janet

    2015-03-01

    Airway epithelial cells are of great interest for research on lung development, regeneration and disease modeling. This protocol describes how to generate cystic fibrosis (CF) transmembrane conductance regulator protein (CFTR)-expressing airway epithelial cells from human pluripotent stem cells (PSCs). The stepwise approach from PSC culture to differentiation into progenitors and then mature epithelia with apical CFTR activity is outlined. Human PSCs that were inefficient at endoderm differentiation using our previous lung differentiation protocol were able to generate substantial lung progenitor cell populations. Augmented CFTR activity can be observed in all cultures as early as at 35 d of differentiation, and full maturation of the cells in air-liquid interface cultures occurs in <5 weeks. This protocol can be used for drug discovery, tissue regeneration or disease modeling.

  17. Application of artificial neural network model combined with four biomarkers in auxiliary diagnosis of lung cancer.

    PubMed

    Duan, Xiaoran; Yang, Yongli; Tan, Shanjuan; Wang, Sihua; Feng, Xiaolei; Cui, Liuxin; Feng, Feifei; Yu, Songcheng; Wang, Wei; Wu, Yongjun

    2017-08-01

    The purpose of the study was to explore the application of artificial neural network model in the auxiliary diagnosis of lung cancer and compare the effects of back-propagation (BP) neural network with Fisher discrimination model for lung cancer screening by the combined detections of four biomarkers of p16, RASSF1A and FHIT gene promoter methylation levels and the relative telomere length. Real-time quantitative methylation-specific PCR was used to detect the levels of three-gene promoter methylation, and real-time PCR method was applied to determine the relative telomere length. BP neural network and Fisher discrimination analysis were used to establish the discrimination diagnosis model. The levels of three-gene promoter methylation in patients with lung cancer were significantly higher than those of the normal controls. The values of Z(P) in two groups were 2.641 (0.008), 2.075 (0.038) and 3.044 (0.002), respectively. The relative telomere lengths of patients with lung cancer (0.93 ± 0.32) were significantly lower than those of the normal controls (1.16 ± 0.57), t = 4.072, P < 0.001. The areas under the ROC curve (AUC) and 95 % CI of prediction set from Fisher discrimination analysis and BP neural network were 0.670 (0.569-0.761) and 0.760 (0.664-0.840). The AUC of BP neural network was higher than that of Fisher discrimination analysis, and Z(P) was 0.76. Four biomarkers are associated with lung cancer. BP neural network model for the prediction of lung cancer is better than Fisher discrimination analysis, and it can provide an excellent and intelligent diagnosis tool for lung cancer.

  18. Lung Motion Model Validation Experiments, Free-Breathing Tissue Densitometry, and Ventilation Mapping using Fast Helical CT Imaging

    NASA Astrophysics Data System (ADS)

    Dou, Hsiang-Tai

    The uncertainties due to respiratory motion present significant challenges to accurate characterization of cancerous tissues both in terms of imaging and treatment. Currently available clinical lung imaging techniques are subject to inferior image quality and incorrect motion estimation, with consequences that can systematically impact the downstream treatment delivery and outcome. The main objective of this thesis is the development of the techniques of fast helical computed tomography (CT) imaging and deformable image registration for the radiotherapy applications in accurate breathing motion modeling, lung tissue density modeling and ventilation imaging. Fast helical CT scanning was performed on 64-slice CT scanner using the shortest available gantry rotation time and largest pitch value such that scanning of the thorax region amounts to just two seconds, which is less than typical breathing cycle in humans. The scanning was conducted under free breathing condition. Any portion of the lung anatomy undergoing such scanning protocol would be irradiated for only a quarter second, effectively removing any motion induced image artifacts. The resulting CT data were pristine volumetric images that record the lung tissue position and density in a fraction of the breathing cycle. Following our developed protocol, multiple fast helical CT scans were acquired to sample the tissue positions in different breathing states. To measure the tissue displacement, deformable image registration was performed that registers the non-reference images to the reference one. In modeling breathing motion, external breathing surrogate signal was recorded synchronously with the CT image slices. This allowed for the tissue-specific displacement to be modeled as parametrization of the recorded breathing signal using the 5D lung motion model. To assess the accuracy of the motion model in describing tissue position change, the model was used to simulate the original high-pitch helical CT scan

  19. Effect of one-lung ventilation on end-tidal carbon dioxide during cardiopulmonary resuscitation in a pig model of cardiac arrest.

    PubMed

    Ryu, Dong Hyun; Jung, Yong Hun; Jeung, Kyung Woon; Lee, Byung Kook; Jeong, Young Won; Yun, Jong Geun; Lee, Dong Hun; Lee, Sung Min; Heo, Tag; Min, Yong Il

    2018-01-01

    Unrecognized endobronchial intubation frequently occurs after emergency intubation. However, no study has evaluated the effect of one-lung ventilation on end-tidal carbon dioxide (ETCO2) during cardiopulmonary resuscitation (CPR). We compared the hemodynamic parameters, blood gases, and ETCO2 during one-lung ventilation with those during conventional two-lung ventilation in a pig model of CPR, to determine the effect of the former on ETCO2. A randomized crossover study was conducted in 12 pigs intubated with double-lumen endobronchial tube to achieve lung separation. During CPR, the animals underwent three 5-min ventilation trials based on a randomized crossover design: left-lung, right-lung, or two-lung ventilation. Arterial blood gases were measured at the end of each ventilation trial. Ventilation was provided using the same tidal volume throughout the ventilation trials. Comparison using generalized linear mixed model revealed no significant group effects with respect to aortic pressure, coronary perfusion pressure, and carotid blood flow; however, significant group effect in terms of ETCO2 was found (P < 0.001). In the post hoc analyses, ETCO2 was lower during the right-lung ventilation than during the two-lung (P = 0.006) or left-lung ventilation (P < 0.001). However, no difference in ETCO2 was detected between the left-lung and two-lung ventilations. The partial pressure of arterial carbon dioxide (PaCO2), partial pressure of arterial oxygen (PaO2), and oxygen saturation (SaO2) differed among the three types of ventilation (P = 0.003, P = 0.001, and P = 0.001, respectively). The post hoc analyses revealed a higher PaCO2, lower PaO2, and lower SaO2 during right-lung ventilation than during two-lung or left-lung ventilation. However, the levels of these blood gases did not differ between the left-lung and two-lung ventilations. In a pig model of CPR, ETCO2 was significantly lower during right-lung ventilation than during two-lung ventilation. However

  20. Design of a numerical model of lung by means of a special boundary condition in the truncated branches.

    PubMed

    Tena, Ana F; Fernández, Joaquín; Álvarez, Eduardo; Casan, Pere; Walters, D Keith

    2017-06-01

    The need for a better understanding of pulmonary diseases has led to increased interest in the development of realistic computational models of the human lung. To minimize computational cost, a reduced geometry model is used for a model lung airway geometry up to generation 16. Truncated airway branches require physiologically realistic boundary conditions to accurately represent the effect of the removed airway sections. A user-defined function has been developed, which applies velocities mapped from similar locations in fully resolved airway sections. The methodology can be applied in any general purpose computational fluid dynamics code, with the only limitation that the lung model must be symmetrical in each truncated branch. Unsteady simulations have been performed to verify the operation of the model. The test case simulates a spirometry because the lung is obliged to rapidly perform both inspiration and expiration. Once the simulation was completed, the obtained pressure in the lower level of the lung was used as a boundary condition. The output velocity, which is a numerical spirometry, was compared with the experimental spirometry for validation purposes. This model can be applied for a wide range of patient-specific resolution levels. If the upper airway generations have been constructed from a computed tomography scan, it would be possible to quickly obtain a complete reconstruction of the lung specific to a specific person, which would allow individualized therapies. Copyright © 2016 John Wiley & Sons, Ltd.

  1. Orthotopic lung cancer murine model by nonoperative transbronchial approach.

    PubMed

    Nakajima, Takahiro; Anayama, Takashi; Matsuda, Yasushi; Hwang, David M; McVeigh, Patrick Z; Wilson, Brian C; Zheng, Gang; Keshavjee, Shaf; Yasufuku, Kazuhiro

    2014-05-01

    The aim of this work was to establish a novel orthotopic human non-small cell lung cancer (NSCLC) murine xenograft model by a nonsurgical, transbronchial approach. Male athymic nude mice and human NSCLC cell lines, including A549, H460, and H520 were used. Under direct visualization of the vocal cords, a 23-gauge blunt-tip slightly curved metal catheter was introduced into the trachea to the bronchus, and 2.5×10(5) tumor cells mixed with Matrigel (BD Biosciences, Mississauga, Ontario, Canada) were administered into the lung. Mice were monitored using weekly microcomputed tomography scans for tumor formation. When the tumor size reached more than 4 mm in diameter, the animals were euthanized, and the tumor tissue was evaluated histopathologically. Of 37 mice studied, 34 were confirmed to have tumor formation: 29 developed solitary tumors and 5 had multifocal lesions. There was no evidence of extrapleural dissemination or effusion. Transbronchial delivery of tumor cells enabled the establishment of a novel orthotopic human NSCLC murine xenograft model. This clinically relevant preclinical model bearing a solitary nodule is of value for a variety of in vivo research studies. Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  2. Attenuation of Lipopolysaccharide-Induced Lung Vascular Stiffening by Lipoxin Reduces Lung Inflammation

    PubMed Central

    Meng, Fanyong; Mambetsariev, Isa; Tian, Yufeng; Beckham, Yvonne; Meliton, Angelo; Leff, Alan; Gardel, Margaret L.; Allen, Michael J.; Birukov, Konstantin G.

    2015-01-01

    Reversible changes in lung microstructure accompany lung inflammation, although alterations in tissue micromechanics and their impact on inflammation remain unknown. This study investigated changes in extracellular matrix (ECM) remodeling and tissue stiffness in a model of LPS-induced inflammation and examined the role of lipoxin analog 15-epi-lipoxin A4 (eLXA4) in the reduction of stiffness-dependent exacerbation of the inflammatory process. Atomic force microscopy measurements of live lung slices were used to directly measure local tissue stiffness changes induced by intratracheal injection of LPS. Effects of LPS on ECM properties and inflammatory response were evaluated in an animal model of LPS-induced lung injury, live lung tissue slices, and pulmonary endothelial cell (EC) culture. In vivo, LPS increased perivascular stiffness in lung slices monitored by atomic force microscopy and stimulated expression of ECM proteins fibronectin, collagen I, and ECM crosslinker enzyme, lysyl oxidase. Increased stiffness and ECM remodeling escalated LPS-induced VCAM1 and ICAM1 expression and IL-8 production by lung ECs. Stiffness-dependent exacerbation of inflammatory signaling was confirmed in pulmonary ECs grown on substrates with high and low stiffness. eLXA4 inhibited LPS-increased stiffness in lung cross sections, attenuated stiffness-dependent enhancement of EC inflammatory activation, and restored lung compliance in vivo. This study shows that increased local vascular stiffness exacerbates lung inflammation. Attenuation of local stiffening of lung vasculature represents a novel mechanism of lipoxin antiinflammatory action. PMID:24992633

  3. Toward the modeling of mucus draining from human lung: role of airways deformation on air-mucus interaction

    PubMed Central

    Mauroy, Benjamin; Flaud, Patrice; Pelca, Dominique; Fausser, Christian; Merckx, Jacques; Mitchell, Barrett R.

    2015-01-01

    Chest physiotherapy is an empirical technique used to help secretions to get out of the lung whenever stagnation occurs. Although commonly used, little is known about the inner mechanisms of chest physiotherapy and controversies about its use are coming out regularly. Thus, a scientific validation of chest physiotherapy is needed to evaluate its effects on secretions. We setup a quasi-static numerical model of chest physiotherapy based on thorax and lung physiology and on their respective biophysics. We modeled the lung with an idealized deformable symmetric bifurcating tree. Bronchi and their inner fluids mechanics are assumed axisymmetric. Static data from the literature is used to build a model for the lung's mechanics. Secretions motion is the consequence of the shear constraints apply by the air flow. The input of the model is the pressure on the chest wall at each time, and the output is the bronchi geometry and air and secretions properties. In the limit of our model, we mimicked manual and mechanical chest physiotherapy techniques. We show that for secretions to move, air flow has to be high enough to overcome secretion resistance to motion. Moreover, the higher the pressure or the quicker it is applied, the higher is the air flow and thus the mobilization of secretions. However, pressures too high are efficient up to a point where airways compressions prevents air flow to increase any further. Generally, the first effects of manipulations is a decrease of the airway tree hydrodynamic resistance, thus improving ventilation even if secretions do not get out of the lungs. Also, some secretions might be pushed deeper into the lungs; this effect is stronger for high pressures and for mechanical chest physiotherapy. Finally, we propose and tested two a dimensional numbers that depend on lung properties and that allow to measure the efficiency and comfort of a manipulation. PMID:26300780

  4. The rabbit as a model for studying lung disease and stem cell therapy.

    PubMed

    Kamaruzaman, Nurfatin Asyikhin; Kardia, Egi; Kamaldin, Nurulain 'Atikah; Latahir, Ahmad Zaeri; Yahaya, Badrul Hisham

    2013-01-01

    No single animal model can reproduce all of the human features of both acute and chronic lung diseases. However, the rabbit is a reliable model and clinically relevant facsimile of human disease. The similarities between rabbits and humans in terms of airway anatomy and responses to inflammatory mediators highlight the value of this species in the investigation of lung disease pathophysiology and in the development of therapeutic agents. The inflammatory responses shown by the rabbit model, especially in the case of asthma, are comparable with those that occur in humans. The allergic rabbit model has been used extensively in drug screening tests, and this model and humans appear to be sensitive to similar drugs. In addition, recent studies have shown that the rabbit serves as a good platform for cell delivery for the purpose of stem-cell-based therapy.

  5. The Rabbit as a Model for Studying Lung Disease and Stem Cell Therapy

    PubMed Central

    Kamaruzaman, Nurfatin Asyikhin; Kamaldin, Nurulain ‘Atikah; Latahir, Ahmad Zaeri; Yahaya, Badrul Hisham

    2013-01-01

    No single animal model can reproduce all of the human features of both acute and chronic lung diseases. However, the rabbit is a reliable model and clinically relevant facsimile of human disease. The similarities between rabbits and humans in terms of airway anatomy and responses to inflammatory mediators highlight the value of this species in the investigation of lung disease pathophysiology and in the development of therapeutic agents. The inflammatory responses shown by the rabbit model, especially in the case of asthma, are comparable with those that occur in humans. The allergic rabbit model has been used extensively in drug screening tests, and this model and humans appear to be sensitive to similar drugs. In addition, recent studies have shown that the rabbit serves as a good platform for cell delivery for the purpose of stem-cell-based therapy. PMID:23653896

  6. A preclinical rodent model of acute radiation-induced lung injury after ablative focal irradiation reflecting clinical stereotactic body radiotherapy.

    PubMed

    Hong, Zhen-Yu; Lee, Hae-June; Choi, Won Hoon; Lee, Yoon-Jin; Eun, Sung Ho; Lee, Jung Il; Park, Kwangwoo; Lee, Ji Min; Cho, Jaeho

    2014-07-01

    In a previous study, we established an image-guided small-animal micro-irradiation system mimicking clinical stereotactic body radiotherapy (SBRT). The goal of this study was to develop a rodent model of acute phase lung injury after ablative irradiation. A radiation dose of 90 Gy was focally delivered to the left lung of C57BL/6 mice using a small animal stereotactic irradiator. At days 1, 3, 5, 7, 9, 11 and 14 after irradiation, the lungs were perfused with formalin for fixation and paraffin sections were stained with hematoxylin and eosin (H&E) and Masson's trichrome. At days 7 and 14 after irradiation, micro-computed tomography (CT) images of the lung were taken and lung functional measurements were performed with a flexiVent™ system. Gross morphological injury was evident 9 days after irradiation of normal lung tissues and dynamic sequential events occurring during the acute phase were validated by histopathological analysis. CT images of the mouse lungs indicated partial obstruction located in the peripheral area of the left lung. Significant alteration in inspiratory capacity and tissue damping were detected on day 14 after irradiation. An animal model of radiation-induced lung injury (RILI) in the acute phase reflecting clinical stereotactic body radiotherapy was established and validated with histopathological and functional analysis. This model enhances our understanding of the dynamic sequential events occurring in the acute phase of radiation-induced lung injury induced by ablative dose focal volume irradiation.

  7. Predicting lung dosimetry of inhaled particleborne benzo[a]pyrene using physiologically based pharmacokinetic modeling

    PubMed Central

    Campbell, Jerry; Franzen, Allison; Van Landingham, Cynthia; Lumpkin, Michael; Crowell, Susan; Meredith, Clive; Loccisano, Anne; Gentry, Robinan; Clewell, Harvey

    2016-01-01

    Abstract Benzo[a]pyrene (BaP) is a by-product of incomplete combustion of fossil fuels and plant/wood products, including tobacco. A physiologically based pharmacokinetic (PBPK) model for BaP for the rat was extended to simulate inhalation exposures to BaP in rats and humans including particle deposition and dissolution of absorbed BaP and renal elimination of 3-hydroxy benzo[a]pyrene (3-OH BaP) in humans. The clearance of particle-associated BaP from lung based on existing data in rats and dogs suggest that the process is bi-phasic. An initial rapid clearance was represented by BaP released from particles followed by a slower first-order clearance that follows particle kinetics. Parameter values for BaP-particle dissociation were estimated using inhalation data from isolated/ventilated/perfused rat lungs and optimized in the extended inhalation model using available rat data. Simulations of acute inhalation exposures in rats identified specific data needs including systemic elimination of BaP metabolites, diffusion-limited transfer rates of BaP from lung tissue to blood and the quantitative role of macrophage-mediated and ciliated clearance mechanisms. The updated BaP model provides very good prediction of the urinary 3-OH BaP concentrations and the relative difference between measured 3-OH BaP in nonsmokers versus smokers. This PBPK model for inhaled BaP is a preliminary tool for quantifying lung BaP dosimetry in rat and humans and was used to prioritize data needs that would provide significant model refinement and robust internal dosimetry capabilities. PMID:27569524

  8. A Minimal Path Searching Approach for Active Shape Model (ASM)-based Segmentation of the Lung.

    PubMed

    Guo, Shengwen; Fei, Baowei

    2009-03-27

    We are developing a minimal path searching method for active shape model (ASM)-based segmentation for detection of lung boundaries on digital radiographs. With the conventional ASM method, the position and shape parameters of the model points are iteratively refined and the target points are updated by the least Mahalanobis distance criterion. We propose an improved searching strategy that extends the searching points in a fan-shape region instead of along the normal direction. A minimal path (MP) deformable model is applied to drive the searching procedure. A statistical shape prior model is incorporated into the segmentation. In order to keep the smoothness of the shape, a smooth constraint is employed to the deformable model. To quantitatively assess the ASM-MP segmentation, we compare the automatic segmentation with manual segmentation for 72 lung digitized radiographs. The distance error between the ASM-MP and manual segmentation is 1.75 ± 0.33 pixels, while the error is 1.99 ± 0.45 pixels for the ASM. Our results demonstrate that our ASM-MP method can accurately segment the lung on digital radiographs.

  9. A minimal path searching approach for active shape model (ASM)-based segmentation of the lung

    NASA Astrophysics Data System (ADS)

    Guo, Shengwen; Fei, Baowei

    2009-02-01

    We are developing a minimal path searching method for active shape model (ASM)-based segmentation for detection of lung boundaries on digital radiographs. With the conventional ASM method, the position and shape parameters of the model points are iteratively refined and the target points are updated by the least Mahalanobis distance criterion. We propose an improved searching strategy that extends the searching points in a fan-shape region instead of along the normal direction. A minimal path (MP) deformable model is applied to drive the searching procedure. A statistical shape prior model is incorporated into the segmentation. In order to keep the smoothness of the shape, a smooth constraint is employed to the deformable model. To quantitatively assess the ASM-MP segmentation, we compare the automatic segmentation with manual segmentation for 72 lung digitized radiographs. The distance error between the ASM-MP and manual segmentation is 1.75 +/- 0.33 pixels, while the error is 1.99 +/- 0.45 pixels for the ASM. Our results demonstrate that our ASM-MP method can accurately segment the lung on digital radiographs.

  10. A Minimal Path Searching Approach for Active Shape Model (ASM)-based Segmentation of the Lung

    PubMed Central

    Guo, Shengwen; Fei, Baowei

    2013-01-01

    We are developing a minimal path searching method for active shape model (ASM)-based segmentation for detection of lung boundaries on digital radiographs. With the conventional ASM method, the position and shape parameters of the model points are iteratively refined and the target points are updated by the least Mahalanobis distance criterion. We propose an improved searching strategy that extends the searching points in a fan-shape region instead of along the normal direction. A minimal path (MP) deformable model is applied to drive the searching procedure. A statistical shape prior model is incorporated into the segmentation. In order to keep the smoothness of the shape, a smooth constraint is employed to the deformable model. To quantitatively assess the ASM-MP segmentation, we compare the automatic segmentation with manual segmentation for 72 lung digitized radiographs. The distance error between the ASM-MP and manual segmentation is 1.75 ± 0.33 pixels, while the error is 1.99 ± 0.45 pixels for the ASM. Our results demonstrate that our ASM-MP method can accurately segment the lung on digital radiographs. PMID:24386531

  11. Lung Cancer Risk Models for Screening (R package: lcrisks)

    Cancer.gov

    In both the absence and presence of screening, the R package lcrisks, calculates individual risks of lung cancer and lung cancer death based on covariates: age, education, sex, race, smoking intensity/duration/quit-years, Body Mass Index, family history of lung-cancer, and self-reported emphysema. In the presence of CT screening akin to the NLST (3 yearly screens, 5 years of follow-up), it uses the covariates to estimate risk of false-positive CT screen as well as the reduction in risk of lung cancer death and increase in risk of lung cancer screening.

  12. SU-F-R-44: Modeling Lung SBRT Tumor Response Using Bayesian Network Averaging

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Diamant, A; Ybarra, N; Seuntjens, J

    2016-06-15

    Purpose: The prediction of tumor control after a patient receives lung SBRT (stereotactic body radiation therapy) has proven to be challenging, due to the complex interactions between an individual’s biology and dose-volume metrics. Many of these variables have predictive power when combined, a feature that we exploit using a graph modeling approach based on Bayesian networks. This provides a probabilistic framework that allows for accurate and visually intuitive predictive modeling. The aim of this study is to uncover possible interactions between an individual patient’s characteristics and generate a robust model capable of predicting said patient’s treatment outcome. Methods: We investigatedmore » a cohort of 32 prospective patients from multiple institutions whom had received curative SBRT to the lung. The number of patients exhibiting tumor failure was observed to be 7 (event rate of 22%). The serum concentration of 5 biomarkers previously associated with NSCLC (non-small cell lung cancer) was measured pre-treatment. A total of 21 variables were analyzed including: dose-volume metrics with BED (biologically effective dose) correction and clinical variables. A Markov Chain Monte Carlo technique estimated the posterior probability distribution of the potential graphical structures. The probability of tumor failure was then estimated by averaging the top 100 graphs and applying Baye’s rule. Results: The optimal Bayesian model generated throughout this study incorporated the PTV volume, the serum concentration of the biomarker EGFR (epidermal growth factor receptor) and prescription BED. This predictive model recorded an area under the receiver operating characteristic curve of 0.94(1), providing better performance compared to competing methods in other literature. Conclusion: The use of biomarkers in conjunction with dose-volume metrics allows for the generation of a robust predictive model. The preliminary results of this report demonstrate that it is

  13. In Vivo Evaluation of Lung Microwave Ablation in a Porcine Tumor Mimic Model

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Planche, Olivier, E-mail: oli.hrp@gmail.com; Teriitehau, Christophe; Boudabous, Sana

    2013-02-15

    To evaluate the microwave ablation of created tumor mimics in the lung of a large animal model (pigs), with examination of the ablative synergy of multiple antennas. Fifty-six tumor-mimic models of various sizes were created in 15 pigs by using barium-enriched minced collected thigh muscle injected into the lung of the same animal. Tumors were ablated under fluoroscopic guidance by single-antenna and multiple-antenna microwaves. Thirty-five tumor models were treated in 11 pigs with a single antenna at 75 W for 15 min, with 15 measuring 20 mm in diameter, 10 measuring 30 mm, and 10 measuring 40 mm. Mean circularitymore » of the single-antenna ablation zones measured 0.64 {+-} 0.12, with a diameter of 35.7 {+-} 8.7 mm along the axis of the antenna and 32.7 {+-} 12.8 mm perpendicular to the feeding point. Multiple-antenna delivery of 75 W for 15 min caused intraprocedural death of 2 animals; modified protocol to 60 W for 10 min resulted in an ablation zone with a diameter of 43.0 {+-} 7.7 along the axis of the antenna and 54.8 {+-} 8.5 mm perpendicular to the feeding point; circularity was 0.70 {+-} 0.10. A single microwave antenna can create ablation zones large enough to cover lung tumor mimic models of {<=}4 cm with no heat sink effect from vessels of {<=}6 mm. Synergic use of 3 antennas allows ablation of larger volumes than single-antenna or radiofrequency ablation, but great caution must be taken when 3 antennas are used simultaneously in the lung in clinical practice.« less

  14. Fractal Geometry Enables Classification of Different Lung Morphologies in a Model of Experimental Asthma

    NASA Astrophysics Data System (ADS)

    Obert, Martin; Hagner, Stefanie; Krombach, Gabriele A.; Inan, Selcuk; Renz, Harald

    2015-06-01

    Animal models represent the basis of our current understanding of the pathophysiology of asthma and are of central importance in the preclinical development of drug therapies. The characterization of irregular lung shapes is a major issue in radiological imaging of mice in these models. The aim of this study was to find out whether differences in lung morphology can be described by fractal geometry. Healthy and asthmatic mouse groups, before and after an acute asthma attack induced by methacholine, were studied. In vivo flat-panel-based high-resolution Computed Tomography (CT) was used for mice's thorax imaging. The digital image data of the mice's lungs were segmented from the surrounding tissue. After that, the lungs were divided by image gray-level thresholds into two additional subsets. One subset contained basically the air transporting bronchial system. The other subset corresponds mainly to the blood vessel system. We estimated the fractal dimension of all sets of the different mouse groups using the mass radius relation (mrr). We found that the air transporting subset of the bronchial lung tissue enables a complete and significant differentiation between all four mouse groups (mean D of control mice before methacholine treatment: 2.64 ± 0.06; after treatment: 2.76 ± 0.03; asthma mice before methacholine treatment: 2.37 ± 0.16; after treatment: 2.71 ± 0.03; p < 0.05). We conclude that the concept of fractal geometry allows a well-defined, quantitative numerical and objective differentiation of lung shapes — applicable most likely also in human asthma diagnostics.

  15. An individual risk prediction model for lung cancer based on a study in a Chinese population.

    PubMed

    Wang, Xu; Ma, Kewei; Cui, Jiuwei; Chen, Xiao; Jin, Lina; Li, Wei

    2015-01-01

    Early detection and diagnosis remains an effective yet challenging approach to improve the clinical outcome of patients with cancer. Low-dose computed tomography screening has been suggested to improve the diagnosis of lung cancer in high-risk individuals. To make screening more efficient, it is necessary to identify individuals who are at high risk. We conducted a case-control study to develop a predictive model for identification of such high-risk individuals. Clinical data from 705 lung cancer patients and 988 population-based controls were used for the development and evaluation of the model. Associations between environmental variants and lung cancer risk were analyzed with a logistic regression model. The predictive accuracy of the model was determined by calculating the area under the receiver operating characteristic curve and the optimal operating point. Our results indicate that lung cancer risk factors included older age, male gender, lower education level, family history of cancer, history of chronic obstructive pulmonary disease, lower body mass index, smoking cigarettes, a diet with less seafood, vegetables, fruits, dairy products, soybean products and nuts, a diet rich in meat, and exposure to pesticides and cooking emissions. The area under the curve was 0.8851 and the optimal operating point was obtained. With a cutoff of 0.35, the false positive rate, true positive rate, and Youden index were 0.21, 0.87, and 0.66, respectively. The risk prediction model for lung cancer developed in this study could discriminate high-risk from low-risk individuals.

  16. Modeling the Arrest of Tissue Growth in Epithelia

    NASA Astrophysics Data System (ADS)

    Golden, Alexander; Lubensky, David

    The mechanisms of control and eventual arrest of growth of tissues is an area that has received considerable attention, both experimentally and in the development of quantitative models. In particular, the Drosophila wing disc epithelium appears to robustly arrive at a unique final size. One mechanism that has the potential to play a role in the eventual cessation of growth is mechanical feedback from stresses induced by nonuniform growth. There is experimental support for an effect on the tissue growth rate by such mechanical stresses, and a number of numerical or cell-based models have been proposed that show that the arrest of growth can be achieved by mechanical feedback. We introduce an analytic framework that allows us to understand different coarse-grained feedback mechanisms on the same terms. We use the framework to distinguish between families of models that do not have a unique final size and those that do and give rough estimates for how much variability in the eventual organ size can be expected in models that do not have a unique final size. NSF Grant DMR-1056456.

  17. Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury.

    PubMed

    Rizzo, Alicia N; Sammani, Saad; Esquinca, Adilene E; Jacobson, Jeffrey R; Garcia, Joe G N; Letsiou, Eleftheria; Dudek, Steven M

    2015-12-01

    Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), an illness characterized by life-threatening vascular leak, is a significant cause of morbidity and mortality in critically ill patients. Recent preclinical studies and clinical observations have suggested a potential role for the chemotherapeutic agent imatinib in restoring vascular integrity. Our prior work demonstrates differential effects of imatinib in mouse models of ALI, namely attenuation of LPS-induced lung injury but exacerbation of ventilator-induced lung injury (VILI). Because of the critical role of mechanical ventilation in the care of patients with ARDS, in the present study we pursued an assessment of the effectiveness of imatinib in a "two-hit" model of ALI caused by combined LPS and VILI. Imatinib significantly decreased bronchoalveolar lavage protein, total cells, neutrophils, and TNF-α levels in mice exposed to LPS plus VILI, indicating that it attenuates ALI in this clinically relevant model. In subsequent experiments focusing on its protective role in LPS-induced lung injury, imatinib attenuated ALI when given 4 h after LPS, suggesting potential therapeutic effectiveness when given after the onset of injury. Mechanistic studies in mouse lung tissue and human lung endothelial cells revealed that imatinib inhibits LPS-induced NF-κB expression and activation. Overall, these results further characterize the therapeutic potential of imatinib against inflammatory vascular leak. Copyright © 2015 the American Physiological Society.

  18. Modeling accumulations of particles in lung during chronic inhalation exposures that lead to impaired clearance

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wolff, R.K.; Griffith, W.C. Jr.; Cuddihy, R.G.

    Chronic inhalation of insoluble particles of low toxicity that produce substantial lung burdens of particles, or inhalation of particles that are highly toxic to the lung, can impair clearance. This report describes model calculations of accumulations in lung of inhaled low-toxicity diesel exhaust soot and high-toxicity Ga2O3 particles. Lung burdens of diesel soot were measured periodically during a 24-mo exposure to inhaled diesel exhaust at soot concentrations of 0, 0.35, 3.5, and 7 mg m-3, 7 h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y after a 4-wk exposure to 23 mg Ga2O3 m-3, 2more » h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y both studies using inhaled radiolabeled tracer particles. Simulation models fit the observed lung burdens of diesel soot in rats exposed to the 3.5- and 7-mg m-3 concentrations of soot only if it was assumed that clearance remained normal for several months, then virtually stopped. Impaired clearance from high-toxicity particles occurred early after accumulations of a low burden, but that from low-toxicity particles was evident only after months of exposure, when high burdens had accumulated in lung. The impairment in clearances of Ga2O3 particles and radiolabeled tracers was similar, but the impairment in clearance of diesel soot and radiolabeled tracers differed in magnitude. This might have been related to differences in particle size and composition between the tracers and diesel soot. Particle clearance impairment should be considered both in the design of chronic exposures of laboratory animals to inhaled particles and in extrapolating the results to people.« less

  19. Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma

    PubMed Central

    Schneeberger, Valentina E.; Ren, Yuan; Luetteke, Noreen; Huang, Qingling; Chen, Liwei; Lawrence, Harshani R.; Lawrence, Nicholas J.; Haura, Eric B.; Koomen, John M.; Coppola, Domenico; Wu, Jie

    2015-01-01

    Epidermal growth factor receptor (EGFR) mutants drive lung tumorigenesis and are targeted for therapy. However, resistance to EGFR inhibitors has been observed, in which the mutant EGFR remains active. Thus, it is important to uncover mediators of EGFR mutant-driven lung tumors to develop new treatment strategies. The protein tyrosine phosphatase (PTP) Shp2 mediates EGF signaling. Nevertheless, it is unclear if Shp2 is activated by oncogenic EGFR mutants in lung carcinoma or if inhibiting the Shp2 PTP activity can suppress EGFR mutant-induced lung adenocarcinoma. Here, we generated transgenic mice containing a doxycycline (Dox)-inducible PTP-defective Shp2 mutant (tetO-Shp2CSDA). Using the rat Clara cell secretory protein (CCSP)-rtTA-directed transgene expression in the type II lung pneumocytes of transgenic mice, we found that the Gab1-Shp2 pathway was activated by EGFRL858R in the lungs of transgenic mice. Consistently, the Gab1-Shp2 pathway was activated in human lung adenocarcinoma cells containing mutant EGFR. Importantly, Shp2CSDA inhibited EGFRL858R-induced lung adenocarcinoma in transgenic animals. Analysis of lung tissues showed that Shp2CSDA suppressed Gab1 tyrosine phosphorylation and Gab1-Shp2 association, suggesting that Shp2 modulates a positive feedback loop to regulate its own activity. These results show that inhibition of the Shp2 PTP activity impairs mutant EGFR signaling and suppresses EGFRL858R-driven lung adenocarcinoma. PMID:25730908

  20. Stochastic rat lung dosimetry for inhaled radon progeny: a surrogate for the human lung for lung cancer risk assessment.

    PubMed

    Winkler-Heil, R; Hussain, M; Hofmann, W

    2015-05-01

    Laboratory rats are frequently used in inhalation studies as a surrogate for human exposures. The objective of the present study was therefore to develop a stochastic dosimetry model for inhaled radon progeny in the rat lung, to predict bronchial dose distributions and to compare them with corresponding dose distributions in the human lung. The most significant difference between human and rat lungs is the branching structure of the bronchial tree, which is relatively symmetric in the human lung, but monopodial in the rat lung. Radon progeny aerosol characteristics used in the present study encompass conditions typical for PNNL and COGEMA rat inhalation studies, as well as uranium miners and human indoor exposure conditions. It is shown here that depending on exposure conditions and modeling assumptions, average bronchial doses in the rat lung ranged from 5.4 to 7.3 mGy WLM(-1). If plotted as a function of airway generation, bronchial dose distributions exhibit a significant maximum in large bronchial airways. If, however, plotted as a function of airway diameter, then bronchial doses are much more uniformly distributed throughout the bronchial tree. Comparisons between human and rat exposures indicate that rat bronchial doses are slightly higher than human bronchial doses by about a factor of 1.3, while lung doses, averaged over the bronchial (BB), bronchiolar (bb) and alveolar-interstitial (AI) regions, are higher by about a factor of about 1.6. This supports the current view that the rat lung is indeed an appropriate surrogate for the human lung in case of radon-induced lung cancers. Furthermore, airway diameter seems to be a more appropriate morphometric parameter than airway generations to relate bronchial doses to bronchial carcinomas.

  1. The Effect of Different Doses of Cigarette Smoke in a Mouse Lung Tumor Model

    PubMed Central

    Santiago, Ludmilla Nadir; de Camargo Fenley, Juliana; Braga, Lúcia Campanario; Cordeiro, José Antônio; Cury, Patrícia M.

    2009-01-01

    Few studies have used Balb/c mice as an animal model for lung carcinogenesis. In this study, we investigated the effect of different doses of cigarette smoking in the urethane-induced Balb/c mouse lung cancer model. After injection of 3mg/kg urethane intraperitoneally, the mice were then exposed to tobacco smoke once or twice a day, five times a week, in a closed chamber. The animals were randomly divided into four groups. The control group (G0) received urethane only. The experimental groups (G1, G2 and G3) received urethane and exposure to the smoke of 3 cigarettes for 10 minutes once a day, 3 cigarettes for 10 minutes twice a day, and 6 cigarettes for 10 minutes twice a day, respectively. The mice were sacrificed after 16 weeks of exposure, and the number of nodules and hyperplasia in the lungs was counted. The results showed no statistically significant difference in the mean number of nodules and hyperplasia among the different groups, suggesting that the Balb/c mice are not suitable to study the pathogenesis of tobacco smoking-induced tumor progression in the lungs. PMID:19079653

  2. Lung mass density analysis using deep neural network and lung ultrasound surface wave elastography.

    PubMed

    Zhou, Boran; Zhang, Xiaoming

    2018-05-23

    Lung mass density is directly associated with lung pathology. Computed Tomography (CT) evaluates lung pathology using the Hounsfield unit (HU) but not lung density directly. We have developed a lung ultrasound surface wave elastography (LUSWE) technique to measure the surface wave speed of superficial lung tissue. The objective of this study was to develop a method for analyzing lung mass density of superficial lung tissue using a deep neural network (DNN) and synthetic data of wave speed measurements with LUSWE. The synthetic training dataset of surface wave speed, excitation frequency, lung mass density, and viscoelasticity from LUSWE (788,000 in total) was used to train the DNN model. The DNN was composed of 3 hidden layers of 1024 neurons for each layer and trained for 10 epochs with a batch size of 4096 and a learning rate of 0.001 with three types of optimizers. The test dataset (4000) of wave speeds at three excitation frequencies (100, 150, and 200 Hz) and shear elasticity of superficial lung tissue was used to predict the lung density and evaluate its accuracy compared with predefined lung mass densities. This technique was then validated on a sponge phantom experiment. The obtained results showed that predictions matched well with test dataset (validation accuracy is 0.992) and experimental data in the sponge phantom experiment. This method may be useful to analyze lung mass density by using the DNN model together with the surface wave speed and lung stiffness measurements. Copyright © 2018 Elsevier B.V. All rights reserved.

  3. A Graphical Model of Smoking-Induced Global Instability in Lung Cancer.

    PubMed

    Wang, Yanbo; Qian, Weikang; Yuan, Bo

    2018-01-01

    Smoking is the major cause of lung cancer and the leading cause of cancer-related death in the world. The most current view about lung cancer is no longer limited to individual genes being mutated by any carcinogenic insults from smoking. Instead, tumorigenesis is a phenotype conferred by many systematic and global alterations, leading to extensive heterogeneity and variation for both the genotypes and phenotypes of individual cancer cells. Thus, strategically it is foremost important to develop a methodology to capture any consistent and global alterations presumably shared by most of the cancerous cells for a given population. This is particularly true that almost all of the data collected from solid cancers (including lung cancers) are usually distant apart over a large span of temporal or even spatial contexts. Here, we report a multiple non-Gaussian graphical model to reconstruct the gene interaction network using two previously published gene expression datasets. Our graphical model aims to selectively detect gross structural changes at the level of gene interaction networks. Our methodology is extensively validated, demonstrating good robustness, as well as the selectivity and specificity expected based on our biological insights. In summary, gene regulatory networks are still relatively stable during presumably the early stage of neoplastic transformation. But drastic structural differences can be found between lung cancer and its normal control, including the gain of functional modules for cellular proliferations such as EGFR and PDGFRA, as well as the lost of the important IL6 module, supporting their roles as potential drug targets. Interestingly, our method can also detect early modular changes, with the ALDH3A1 and its associated interactions being strongly implicated as a potential early marker, whose activations appear to alter LCN2 module as well as its interactions with the important TP53-MDM2 circuitry. Our strategy using the graphical model to

  4. Microarray Meta-Analysis Identifies Acute Lung Injury Biomarkers in Donor Lungs That Predict Development of Primary Graft Failure in Recipients

    PubMed Central

    Haitsma, Jack J.; Furmli, Suleiman; Masoom, Hussain; Liu, Mingyao; Imai, Yumiko; Slutsky, Arthur S.; Beyene, Joseph; Greenwood, Celia M. T.; dos Santos, Claudia

    2012-01-01

    Objectives To perform a meta-analysis of gene expression microarray data from animal studies of lung injury, and to identify an injury-specific gene expression signature capable of predicting the development of lung injury in humans. Methods We performed a microarray meta-analysis using 77 microarray chips across six platforms, two species and different animal lung injury models exposed to lung injury with or/and without mechanical ventilation. Individual gene chips were classified and grouped based on the strategy used to induce lung injury. Effect size (change in gene expression) was calculated between non-injurious and injurious conditions comparing two main strategies to pool chips: (1) one-hit and (2) two-hit lung injury models. A random effects model was used to integrate individual effect sizes calculated from each experiment. Classification models were built using the gene expression signatures generated by the meta-analysis to predict the development of lung injury in human lung transplant recipients. Results Two injury-specific lists of differentially expressed genes generated from our meta-analysis of lung injury models were validated using external data sets and prospective data from animal models of ventilator-induced lung injury (VILI). Pathway analysis of gene sets revealed that both new and previously implicated VILI-related pathways are enriched with differentially regulated genes. Classification model based on gene expression signatures identified in animal models of lung injury predicted development of primary graft failure (PGF) in lung transplant recipients with larger than 80% accuracy based upon injury profiles from transplant donors. We also found that better classifier performance can be achieved by using meta-analysis to identify differentially-expressed genes than using single study-based differential analysis. Conclusion Taken together, our data suggests that microarray analysis of gene expression data allows for the detection of

  5. MAG-EPA resolves lung inflammation in an allergic model of asthma.

    PubMed

    Morin, C; Fortin, S; Cantin, A M; Rousseau, É

    2013-09-01

    Asthma is a chronic disease characterized by airways hyperresponsiveness, inflammation and airways remodelling involving reversible bronchial obstruction. Omega-3 fatty acids and their derivatives are known to reduce inflammation in several tissues including lung. The effects of eicosapentaenoic acid monoacylglyceride (MAG-EPA), a newly synthesized EPA derivative, were determined on the resolution of lung inflammation and airway hyperresponsiveness in an in vivo model of allergic asthma. Ovalbumin (OVA)-sensitized guinea-pigs were treated or not with MAG-EPA administered per os. Isometric tension measurements, histological analyses, homogenate preparation for Western blot experiments or total RNA extraction for RT-PCR were performed to assess the effect of MAG-EPA treatments. Mechanical tension measurements revealed that oral MAG-EPA treatments reduced methacholine (MCh)-induced bronchial hyperresponsiveness in OVA-sensitized guinea-pigs. Moreover, MAG-EPA treatments also decreased Ca(2+) hypersensitivity of bronchial smooth muscle. Histological analyses and leucocyte counts in bronchoalveolar lavages revealed that oral MAG-EPA treatments led to less inflammatory cell recruitment in the lung of OVA-sensitized guinea-pigs when compared with lungs from control animals. Results also revealed a reduction in mucin production and MUC5AC expression level in OVA-sensitized animals treated with MAG-EPA. Following MAG-EPA treatments, the transcript levels of pro-inflammatory markers such as IL-5, eotaxin, IL-13 and IL-4 were markedly reduced. Moreover, per os MAG-EPA administrations reduced COX2 over-expression in OVA-sensitized animals. We demonstrate that MAG-EPA reduces airway hyperresponsiveness and lung inflammation in OVA-sensitized animals, a finding consistent with a decrease in IL-4, IL-5, IL-13, COX-2 and MUC5AC expression levels in the lung. The present data suggest that MAG-EPA represents a new potential therapeutic strategy for resolving inflammation in allergic

  6. Lung tumor promotion by chromium-containing welding particulate matter in a mouse model.

    PubMed

    Zeidler-Erdely, Patti C; Meighan, Terence G; Erdely, Aaron; Battelli, Lori A; Kashon, Michael L; Keane, Michael; Antonini, James M

    2013-09-05

    Epidemiology suggests that occupational exposure to welding particulate matter (PM) may increase lung cancer risk. However, animal studies are lacking to conclusively link welding with an increased risk. PM derived from stainless steel (SS) welding contains carcinogenic metals such as hexavalent chromium and nickel. We hypothesized that welding PM may act as a tumor promoter and increase lung tumor multiplicity in vivo. Therefore, the capacity of chromium-containing gas metal arc (GMA)-SS welding PM to promote lung tumors was evaluated using a two-stage (initiation-promotion) model in lung tumor susceptible A/J mice. Male mice (n = 28-30/group) were treated either with the initiator 3-methylcholanthrene (MCA;10 μg/g; IP) or vehicle (corn oil) followed by 5 weekly pharyngeal aspirations of GMA-SS (340 or 680 μg/exposure) or PBS. Lung tumors were enumerated at 30 weeks post-initiation. MCA initiation followed by GMA-SS welding PM exposure promoted tumor multiplicity in both the low (12.1 ± 1.5 tumors/mouse) and high (14.0 ± 1.8 tumors/mouse) exposure groups significantly above MCA/sham (4.77 ± 0.7 tumors/mouse; p = 0.0001). Multiplicity was also highly significant (p < 0.004) across all individual lung regions of GMA-SS-exposed mice. No exposure effects were found in the corn oil groups at 30 weeks. Histopathology confirmed the gross findings and revealed increased inflammation and a greater number of malignant lesions in the MCA/welding PM-exposed groups. GMA-SS welding PM acts as a lung tumor promoter in vivo. Thus, this study provides animal evidence to support the epidemiological data that show welders have an increased lung cancer risk.

  7. A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis.

    PubMed

    Le Saux, Claude Jourdan; Davy, Philip; Brampton, Christopher; Ahuja, Seema S; Fauce, Steven; Shivshankar, Pooja; Nguyen, Hieu; Ramaseshan, Mahesh; Tressler, Robert; Pirot, Zhu; Harley, Calvin B; Allsopp, Richard

    2013-01-01

    The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

  8. Equation Discovery for Model Identification in Respiratory Mechanics of the Mechanically Ventilated Human Lung

    NASA Astrophysics Data System (ADS)

    Ganzert, Steven; Guttmann, Josef; Steinmann, Daniel; Kramer, Stefan

    Lung protective ventilation strategies reduce the risk of ventilator associated lung injury. To develop such strategies, knowledge about mechanical properties of the mechanically ventilated human lung is essential. This study was designed to develop an equation discovery system to identify mathematical models of the respiratory system in time-series data obtained from mechanically ventilated patients. Two techniques were combined: (i) the usage of declarative bias to reduce search space complexity and inherently providing the processing of background knowledge. (ii) A newly developed heuristic for traversing the hypothesis space with a greedy, randomized strategy analogical to the GSAT algorithm. In 96.8% of all runs the applied equation discovery system was capable to detect the well-established equation of motion model of the respiratory system in the provided data. We see the potential of this semi-automatic approach to detect more complex mathematical descriptions of the respiratory system from respiratory data.

  9. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury

    NASA Astrophysics Data System (ADS)

    Joo, Su-Yeon; Park, Mi-Ju; Kim, Kyun-Ha; Choi, Hee-Jung; Chung, Tae-Wook; Kim, Yong Jin; Kim, Joung Hee; Kim, Keuk-Jun; Joo, Myungsoo; Ha, Ki-Tae

    2016-08-01

    Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation.

  10. Conditions for NIR fluorescence-guided tumor resectioning in preclinical lung cancer model (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Kim, Minji; Quan, Yuhua; Choi, Byeong Hyun; Choi, Yeonho; Kim, Hyun Koo; Kim, Beop-Min

    2016-03-01

    Pulmonary nodule could be identified by intraoperative fluorescence imaging system from systemic injection of indocyanine green (ICG) which achieves enhanced permeability and retention (EPR) effects. This study was performed to evaluate optimal injection time of ICG for detecting cancer during surgery in rabbit lung cancer model. VX2 carcinoma cell was injected in rabbit lung under fluoroscopic computed tomography-guidance. Solitary lung cancer was confirmed on positron emitting tomography with CT (PET/CT) 2 weeks after inoculation. ICG was administered intravenously and fluorescent intensity of lung tumor was measured using the custom-built intraoperative color and fluorescence merged imaging system (ICFIS) for 15 hours. Solitary lung cancer was resected through thoracoscopic version of ICFIS. ICG was observed in all animals. Because Lung has fast blood pulmonary circulation, Fluorescent signal showed maximum intensity earlier than previous studies in other organs. Fluorescent intensity showed maximum intensity within 6-9 hours in rabbit lung cancer. Overall, Fluorescent intensity decreased with increasing time, however, all tumors were detectable using fluorescent images until 12 hours. In conclusion, while there had been studies in other organs showed that optimal injection time was at least 24 hours before operation, this study showed shorter optimal injection time at lung cancer. Since fluorescent signal showed the maximum intensity within 6-9 hours, cancer resection could be performed during this time. This data informed us that optimal injection time of ICG should be evaluated in each different solid organ tumor for fluorescent image guided surgery.

  11. The European Thoracic Surgery Database project: modelling the risk of in-hospital death following lung resection.

    PubMed

    Berrisford, Richard; Brunelli, Alessandro; Rocco, Gaetano; Treasure, Tom; Utley, Martin

    2005-08-01

    To identify pre-operative factors associated with in-hospital mortality following lung resection and to construct a risk model that could be used prospectively to inform decisions and retrospectively to enable fair comparisons of outcomes. Data were submitted to the European Thoracic Surgery Database from 27 units in 14 countries. We analysed data concerning all patients that had a lung resection. Logistic regression was used with a random sample of 60% of cases to identify pre-operative factors associated with in-hospital mortality and to build a model of risk. The resulting model was tested on the remaining 40% of patients. A second model based on age and ppoFEV1% was developed for risk of in-hospital death amongst tumour resection patients. Of the 3426 adult patients that had a first lung resection for whom mortality data were available, 66 died within the same hospital admission. Within the data used for model development, dyspnoea (according to the Medical Research Council classification), ASA (American Society of Anaesthesiologists) score, class of procedure and age were found to be significantly associated with in-hospital death in a multivariate analysis. The logistic model developed on these data displayed predictive value when tested on the remaining data. Two models of the risk of in-hospital death amongst adult patients undergoing lung resection have been developed. The models show predictive value and can be used to discern between high-risk and low-risk patients. Amongst the test data, the model developed for all diagnoses performed well at low risk, underestimated mortality at medium risk and overestimated mortality at high risk. The second model for resection of lung neoplasms was developed after establishing the performance of the first model and so could not be tested robustly. That said, we were encouraged by its performance over the entire range of estimated risk. The first of these two models could be regarded as an evaluation based on

  12. Development of an Ex Vivo Porcine Lung Model for Studying Growth, Virulence, and Signaling of Pseudomonas aeruginosa

    PubMed Central

    Muruli, Aneesha; Higgins, Steven; Diggle, Stephen P.

    2014-01-01

    Research into chronic infection by bacterial pathogens, such as Pseudomonas aeruginosa, uses various in vitro and live host models. While these have increased our understanding of pathogen growth, virulence, and evolution, each model has certain limitations. In vitro models cannot recapitulate the complex spatial structure of host organs, while experiments on live hosts are limited in terms of sample size and infection duration for ethical reasons; live mammal models also require specialized facilities which are costly to run. To address this, we have developed an ex vivo pig lung (EVPL) model for quantifying Pseudomonas aeruginosa growth, quorum sensing (QS), virulence factor production, and tissue damage in an environment that mimics a chronically infected cystic fibrosis (CF) lung. In a first test of our model, we show that lasR mutants, which do not respond to 3-oxo-C12-homoserine lactone (HSL)-mediated QS, exhibit reduced virulence factor production in EVPL. We also show that lasR mutants grow as well as or better than a corresponding wild-type strain in EVPL. lasR mutants frequently and repeatedly arise during chronic CF lung infection, but the evolutionary forces governing their appearance and spread are not clear. Our data are not consistent with the hypothesis that lasR mutants act as social “cheats” in the lung; rather, our results support the hypothesis that lasR mutants are more adapted to the lung environment. More generally, this model will facilitate improved studies of microbial disease, especially studies of how cells of the same and different species interact in polymicrobial infections in a spatially structured environment. PMID:24866798

  13. Titanium dioxide nanoparticle impact and translocation through ex vivo, in vivo and in vitro gut epithelia

    PubMed Central

    2014-01-01

    Background TiO2 particles are commonly used as dietary supplements and may contain up to 36% of nano-sized particles (TiO2-NPs). Still impact and translocation of NPs through the gut epithelium is poorly documented. Results We show that, in vivo and ex vivo, agglomerates of TiO2-NPs cross both the regular ileum epithelium and the follicle-associated epithelium (FAE) and alter the paracellular permeability of the ileum and colon epithelia. In vitro, they accumulate in M-cells and mucus-secreting cells, much less in enterocytes. They do not cause overt cytotoxicity or apoptosis. They translocate through a model of FAE only, but induce tight junctions remodeling in the regular ileum epithelium, which is a sign of integrity alteration and suggests paracellular passage of NPs. Finally we prove that TiO2-NPs do not dissolve when sequestered up to 24 h in gut cells. Conclusions Taken together these data prove that TiO2-NPs would possibly translocate through both the regular epithelium lining the ileum and through Peyer’s patches, would induce epithelium impairment, and would persist in gut cells where they would possibly induce chronic damage. PMID:24666995

  14. Sodium citrate inhibits the proliferation of human gastric adenocarcinoma epithelia cells

    PubMed Central

    Xia, Yuan; Zhang, Xulong; Bo, Agula; Sun, Juan; Li, Minhui

    2018-01-01

    The objective of the present study was to investigate the cytotoxic effects of sodium citrate on human gastric adenocarcinoma epithelia AGS cells. Numerous cytotoxicity-associated sodium citrate-induced effects were assessed, including cell viability and proliferation, cytokine expression and caspase activity. In vitro studies demonstrated that incubation with sodium citrate (>3.125 mM) inhibited AGS cell viability and proliferation in a dose-dependent manner. Incubation with sodium citrate for 24 h revealed that the levels of interleukin-1β (IL-1β), IL-8 and tumor necrosis factor increased with an increasing of dose of sodium citrate, whereas the IL-6 levels exhibited only a slight alteration. In addition, increases in caspase-3 and −9 activities were associated with increased duration of treatment and dosage of sodium citrate. Collectively, the results of the present study demonstrated that treatment with sodium citrate at higher concentrations or for longer durations exerts a cytotoxic effect on AGS cells via the induction of the intrinsic apoptosis pathway and the alteration in the levels of certain cytokines. PMID:29616124

  15. Airway segmentation and analysis for the study of mouse models of lung disease using micro-CT

    NASA Astrophysics Data System (ADS)

    Artaechevarria, X.; Pérez-Martín, D.; Ceresa, M.; de Biurrun, G.; Blanco, D.; Montuenga, L. M.; van Ginneken, B.; Ortiz-de-Solorzano, C.; Muñoz-Barrutia, A.

    2009-11-01

    Animal models of lung disease are gaining importance in understanding the underlying mechanisms of diseases such as emphysema and lung cancer. Micro-CT allows in vivo imaging of these models, thus permitting the study of the progression of the disease or the effect of therapeutic drugs in longitudinal studies. Automated analysis of micro-CT images can be helpful to understand the physiology of diseased lungs, especially when combined with measurements of respiratory system input impedance. In this work, we present a fast and robust murine airway segmentation and reconstruction algorithm. The algorithm is based on a propagating fast marching wavefront that, as it grows, divides the tree into segments. We devised a number of specific rules to guarantee that the front propagates only inside the airways and to avoid leaking into the parenchyma. The algorithm was tested on normal mice, a mouse model of chronic inflammation and a mouse model of emphysema. A comparison with manual segmentations of two independent observers shows that the specificity and sensitivity values of our method are comparable to the inter-observer variability, and radius measurements of the mainstem bronchi reveal significant differences between healthy and diseased mice. Combining measurements of the automatically segmented airways with the parameters of the constant phase model provides extra information on how disease affects lung function.

  16. Airways, vasculature, and interstitial tissue: anatomically informed computational modeling of human lungs for virtual clinical trials

    NASA Astrophysics Data System (ADS)

    Abadi, Ehsan; Sturgeon, Gregory M.; Agasthya, Greeshma; Harrawood, Brian; Hoeschen, Christoph; Kapadia, Anuj; Segars, W. P.; Samei, Ehsan

    2017-03-01

    This study aimed to model virtual human lung phantoms including both non-parenchymal and parenchymal structures. Initial branches of the non-parenchymal structures (airways, arteries, and veins) were segmented from anatomical data in each lobe separately. A volume-filling branching algorithm was utilized to grow the higher generations of the airways and vessels to the level of terminal branches. The diameters of the airways and vessels were estimated using established relationships between flow rates and diameters. The parenchyma was modeled based on secondary pulmonary lobule units. Polyhedral shapes with variable sizes were modeled, and the borders were assigned to interlobular septa. A heterogeneous background was added inside these units using a non-parametric texture synthesis algorithm which was informed by a high-resolution CT lung specimen dataset. A voxelized based CT simulator was developed to create synthetic helical CT images of the phantom with different pitch values. Results showed the progressive degradation in depiction of lung details with increased pitch. Overall, the enhanced lung models combined with the XCAT phantoms prove to provide a powerful toolset to perform virtual clinical trials in the context of thoracic imaging. Such trials, not practical using clinical datasets or simplistic phantoms, can quantitatively evaluate and optimize advanced imaging techniques towards patient-based care.

  17. Identification of Keratinocyte Growth Factor as a Target of microRNA-155 in Lung Fibroblasts: Implication in Epithelial-Mesenchymal Interactions

    PubMed Central

    Chevalier, Benoit; Puisségur, Marie-Pierre; Lebrigand, Kevin; Robbe-Sermesant, Karine; Bertero, Thomas; Lino Cardenas, Christian L.; Courcot, Elisabeth; Rios, Géraldine; Fourre, Sandra; Lo-Guidice, Jean-Marc; Marcet, Brice; Cardinaud, Bruno; Barbry, Pascal; Mari, Bernard

    2009-01-01

    Background Epithelial-mesenchymal interactions are critical in regulating many aspects of vertebrate embryo development, and for the maintenance of homeostatic equilibrium in adult tissues. The interactions between epithelium and mesenchyme are believed to be mediated by paracrine signals such as cytokines and extracellular matrix components secreted from fibroblasts that affect adjacent epithelia. In this study, we sought to identify the repertoire of microRNAs (miRNAs) in normal lung human fibroblasts and their potential regulation by the cytokines TNF-α, IL-1β and TGF-β. Methodology/Principal Findings MiR-155 was significantly induced by inflammatory cytokines TNF-α and IL-1β while it was down-regulated by TGF-β. Ectopic expression of miR-155 in human fibroblasts induced modulation of a large set of genes related to “cell to cell signalling”, “cell morphology” and “cellular movement”. This was consistent with an induction of caspase-3 activity and with an increase in cell migration in fibroblasts tranfected with miR-155. Using different miRNA bioinformatic target prediction tools, we found a specific enrichment for miR-155 predicted targets among the population of down-regulated transcripts. Among fibroblast-selective targets, one interesting hit was keratinocyte growth factor (KGF, FGF-7), a member of the fibroblast growth factor (FGF) family, which owns two potential binding sites for miR-155 in its 3′-UTR. Luciferase assays experimentally validated that miR-155 can efficiently target KGF 3′-UTR. Site-directed mutagenesis revealed that only one out of the 2 potential sites was truly functional. Functional in vitro assays experimentally validated that miR-155 can efficiently target KGF 3′-UTR. Furthermore, in vivo experiments using a mouse model of lung fibrosis showed that miR-155 expression level was correlated with the degree of lung fibrosis. Conclusions/Significance Our results strongly suggest a physiological function of miR-155 in

  18. Daily propranolol prevents prolonged mobilization of hematopoietic progenitor cells in a rat model of lung contusion, hemorrhagic shock, and chronic stress.

    PubMed

    Bible, Letitia E; Pasupuleti, Latha V; Gore, Amy V; Sifri, Ziad C; Kannan, Kolenkode B; Mohr, Alicia M

    2015-09-01

    Propranolol has been shown previously to decrease the mobilization of hematopoietic progenitor cells (HPCs) after acute injury in rodent models; however, this acute injury model does not reflect the prolonged period of critical illness after severe trauma. Using our novel lung contusion/hemorrhagic shock/chronic restraint stress model, we hypothesize that daily administration of propranolol will decrease prolonged mobilization of HPCs without worsening lung healing. Male Sprague-Dawley rats underwent 6 days of restraint stress after undergoing lung contusion or lung contusion/hemorrhagic shock. Restraint stress consisted of a daily 2-hour period of restraint interrupted every 30 minutes by alarms and repositioning. Each day after the period of restraint stress, the rats received intraperitoneal propranolol (10 mg/kg). On day 7, peripheral blood was analyzed for granulocyte-colony stimulating factor (G-CSF) and stromal cell-derived factor 1 via enzyme-linked immunosorbent assay and for mobilization of HPCs using c-kit and CD71 flow cytometry. The lungs were examined histologically to grade injury. Seven days after lung contusion and lung contusion/hemorrhagic shock, the addition of chronic restraint stress significantly increased the mobilization of HPC, which was associated with persistently increased levels of G-CSF and increased lung injury scores. The addition of propranolol to lung contusion/chronic restraint stress and lung contusion/hemorrhagic shock/chronic restraint stress models greatly decreased HPC mobilization and restored G-CSF levels to that of naïve animals without worsening lung injury scores. The daily administration of propranolol after both lung contusion and lung contusion/hemorrhagic shock subjected to chronic restraint stress decreased the prolonged mobilization of HPC from the bone marrow and decreased plasma G-CSF levels. Despite the decrease in mobilization of HPC, lung healing did not worsen. Alleviating chronic stress with propranolol

  19. Lung function and airway inflammation in rats following exposure to combustion products of carbon-graphite/epoxy composite material: comparison to a rodent model of acute lung injury.

    PubMed

    Whitehead, Gregory S; Grasman, Keith A; Kimmel, Edgar C

    2003-02-01

    Pulmonary function and inflammation in the lungs of rodents exposed by inhalation to carbon/graphite/epoxy advanced composite material (ACM) combustion products were compared to that of a rodent model of acute lung injury (ALI) produced by pneumotoxic paraquat dichloride. This investigation was undertaken to determine if short-term exposure to ACM smoke induces ALI; and to determine if smoke-related responses were similar to the pathogenic mechanisms of a model of lung vascular injury. We examined the time-course for mechanical lung function, infiltration of inflammatory cells into the lung, and the expression of three inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2 (MIP-2) and interferon-gamma (IFN-gamma). Male Fischer-344 rats were either exposed to 26.8-29.8 g/m(3) nominal concentrations of smoke or were given i.p. injections of paraquat dichloride. Measurements were determined at 1, 2, 3, and 7 days post exposure. In the smoke-challenged rats, there were no changes in lung function indicative of ALI throughout the 7-day observation period, despite the acute lethality of the smoke atmosphere. However, the animals showed signs of pulmonary inflammation. The expression of TNF-alpha was significantly increased in the lavage fluid 1 day following exposure, which preceded the maximum leukocyte infiltration. MIP-2 levels were significantly increased in lavage fluid at days 2, 3, and 7. This followed the leukocyte infiltration. IFN-gamma was significantly increased in the lung tissue at day 7, which occurred during the resolution of the inflammatory response. The paraquat, which was also lethal to a small percentage of the animals, caused several physiologic changes characteristic of ALI, including significant decreases in lung compliance, lung volumes/capacities, distribution of ventilation, and gas exchange capacity. The expression of TNF-alpha and MIP-2 increased significantly in the lung tissue as well as in the

  20. Stochastic dosimetry model for radon progeny in the rat lung.

    PubMed

    Winkler-HeiI, R; Hofmann, W; Hussain, M

    2014-07-01

    The stochastic dosimetry model presented here considers the distinctly asymmetric, stochastic branching pattern reported in morphometric measurements. This monopodial structure suggests that an airway diameter is a more appropriate morphometric parameter to classify bronchial dose distributions for inhaled radon progeny than the commonly assigned airway generation numbers. Bronchial doses were calculated for the typical exposure conditions reported for the Pacific Northwest National Laboratory rat inhalation studies, yielding an average bronchial dose of 7.75 mGy WLM(-1). If plotted as functions of airway generations, the resulting dose distributions are highest in the central bronchial airways, while significantly decreasing towards peripheral generations. However, if plotted as functions of airway diameters, doses are much more uniformly distributed among bronchial airways. The comparison between rat and human lungs indicates that dose conversion coefficients for the rat lung are higher than the corresponding values for the human lung by a factor of 1.34 for the experimental PNNL exposure conditions, and of 1.25 for typical human indoor conditions. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  1. Efficient, non-toxic anion transport by synthetic carriers in cells and epithelia

    NASA Astrophysics Data System (ADS)

    Li, Hongyu; Valkenier, Hennie; Judd, Luke W.; Brotherhood, Peter R.; Hussain, Sabir; Cooper, James A.; Jurček, Ondřej; Sparkes, Hazel A.; Sheppard, David N.; Davis, Anthony P.

    2016-01-01

    Transmembrane anion transporters (anionophores) have potential for new modes of biological activity, including therapeutic applications. In particular they might replace the activity of defective anion channels in conditions such as cystic fibrosis. However, data on the biological effects of anionophores are scarce, and it remains uncertain whether such molecules are fundamentally toxic. Here, we report a biological study of an extensive series of powerful anion carriers. Fifteen anionophores were assayed in single cells by monitoring anion transport in real time through fluorescence emission from halide-sensitive yellow fluorescent protein. A bis-(p-nitrophenyl)ureidodecalin shows especially promising activity, including deliverability, potency and persistence. Electrophysiological tests show strong effects in epithelia, close to those of natural anion channels. Toxicity assays yield negative results in three cell lines, suggesting that promotion of anion transport may not be deleterious to cells. We therefore conclude that synthetic anion carriers are realistic candidates for further investigation as treatments for cystic fibrosis.

  2. Lung volumes and emphysema in smokers with interstitial lung abnormalities.

    PubMed

    Washko, George R; Hunninghake, Gary M; Fernandez, Isis E; Nishino, Mizuki; Okajima, Yuka; Yamashiro, Tsuneo; Ross, James C; Estépar, Raúl San José; Lynch, David A; Brehm, John M; Andriole, Katherine P; Diaz, Alejandro A; Khorasani, Ramin; D'Aco, Katherine; Sciurba, Frank C; Silverman, Edwin K; Hatabu, Hiroto; Rosas, Ivan O

    2011-03-10

    Cigarette smoking is associated with emphysema and radiographic interstitial lung abnormalities. The degree to which interstitial lung abnormalities are associated with reduced total lung capacity and the extent of emphysema is not known. We looked for interstitial lung abnormalities in 2416 (96%) of 2508 high-resolution computed tomographic (HRCT) scans of the lung obtained from a cohort of smokers. We used linear and logistic regression to evaluate the associations between interstitial lung abnormalities and HRCT measurements of total lung capacity and emphysema. Interstitial lung abnormalities were present in 194 (8%) of the 2416 HRCT scans evaluated. In statistical models adjusting for relevant covariates, interstitial lung abnormalities were associated with reduced total lung capacity (-0.444 liters; 95% confidence interval [CI], -0.596 to -0.292; P<0.001) and a lower percentage of emphysema defined by lung-attenuation thresholds of -950 Hounsfield units (-3%; 95% CI, -4 to -2; P<0.001) and -910 Hounsfield units (-10%; 95% CI, -12 to -8; P<0.001). As compared with participants without interstitial lung abnormalities, those with abnormalities were more likely to have a restrictive lung deficit (total lung capacity <80% of the predicted value; odds ratio, 2.3; 95% CI, 1.4 to 3.7; P<0.001) and were less likely to meet the diagnostic criteria for chronic obstructive pulmonary disease (COPD) (odds ratio, 0.53; 95% CI, 0.37 to 0.76; P<0.001). The effect of interstitial lung abnormalities on total lung capacity and emphysema was dependent on COPD status (P<0.02 for the interactions). Interstitial lung abnormalities were positively associated with both greater exposure to tobacco smoke and current smoking. In smokers, interstitial lung abnormalities--which were present on about 1 of every 12 HRCT scans--were associated with reduced total lung capacity and a lesser amount of emphysema. (Funded by the National Institutes of Health and the Parker B. Francis Foundation

  3. A hybrid patient-specific biomechanical model based image registration method for the motion estimation of lungs.

    PubMed

    Han, Lianghao; Dong, Hua; McClelland, Jamie R; Han, Liangxiu; Hawkes, David J; Barratt, Dean C

    2017-07-01

    This paper presents a new hybrid biomechanical model-based non-rigid image registration method for lung motion estimation. In the proposed method, a patient-specific biomechanical modelling process captures major physically realistic deformations with explicit physical modelling of sliding motion, whilst a subsequent non-rigid image registration process compensates for small residuals. The proposed algorithm was evaluated with 10 4D CT datasets of lung cancer patients. The target registration error (TRE), defined as the Euclidean distance of landmark pairs, was significantly lower with the proposed method (TRE = 1.37 mm) than with biomechanical modelling (TRE = 3.81 mm) and intensity-based image registration without specific considerations for sliding motion (TRE = 4.57 mm). The proposed method achieved a comparable accuracy as several recently developed intensity-based registration algorithms with sliding handling on the same datasets. A detailed comparison on the distributions of TREs with three non-rigid intensity-based algorithms showed that the proposed method performed especially well on estimating the displacement field of lung surface regions (mean TRE = 1.33 mm, maximum TRE = 5.3 mm). The effects of biomechanical model parameters (such as Poisson's ratio, friction and tissue heterogeneity) on displacement estimation were investigated. The potential of the algorithm in optimising biomechanical models of lungs through analysing the pattern of displacement compensation from the image registration process has also been demonstrated. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Respiratory Tract Lung Geometry and Dosimetry Model for Male Sprague-Dawley Rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Miller, Frederick J.; Asgharian, Bahman; Schroeter, Jeffry D.

    2015-07-24

    While inhalation toxicological studies of various compounds have been conducted using a number of different strains of rats, mechanistic dosimetry models have only had tracheobronchial (TB) structural data for Long-Evans rats, detailed morphometric data on the alveolar region of Sprague-Dawley rats and limited alveolar data on other strains. Based upon CT imaging data for two male Sprague-Dawley rats, a 15-generation, symmetric typical path model was developed for the TB region. Literature data for the alveolar region of Sprague-Dawley rats were analyzed to develop an eight-generation model, and the two regions were joined to provide a complete lower respiratory tract modelmore » for Sprague-Dawley rats. The resulting lung model was used to examine particle deposition in Sprague-Dawley rats and to compare these results with predicted deposition in Long-Evans rats. Relationships of various physiologic variables and lung volumes were either developed in this study or extracted from the literature to provide the necessary input data for examining particle deposition. While the lengths, diameters and branching angles of the TB airways differed between the two Sprague-Dawley rats, the predicted deposition patterns in the three major respiratory tract regions were very similar. Between Sprague-Dawley and Long-Evans rats, significant differences in TB and alveolar predicted deposition fractions were observed over a wide range of particle sizes, with TB deposition fractions being up to 3- to 4-fold greater in Sprague-Dawley rats and alveolar deposition being significantly greater in Long-Evans rats. Thus, strain-specific lung geometry models should be used for particle deposition calculations and interspecies dose comparisons.« less

  5. Respiratory tract lung geometry and dosimetry model for male Sprague-Dawley rats.

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Miller, Frederick J.; Asgharian, Bahman; Schroeter, Jeffry D.

    2014-08-26

    While inhalation toxicological studies of various compounds have been conducted using a number of different strains of rats, mechanistic dosimetry models have only had tracheobronchial (TB) structural data for Long-Evans rats, detailed morphometric data on the alveolar region of Sprague-Dawley rats and limited alveolar data on other strains. Based upon CT imaging data for two male Sprague-Dawley rats, a 15-generation, symmetric typical path model was developed for the TB region. Literature data for the alveolar region of Sprague-Dawley rats were analyzed to develop an eight-generation model, and the two regions were joined to provide a complete lower respiratory tract modelmore » for Sprague-Dawley rats. The resulting lung model was used to examine particle deposition in Sprague-Dawley rats and to compare these results with predicted deposition in Long-Evans rats. Relationships of various physiologic variables and lung volumes were either developed in this study or extracted from the literature to provide the necessary input data for examining particle deposition. While the lengths, diameters and branching angles of the TB airways differed between the two Sprague- Dawley rats, the predicted deposition patterns in the three major respiratory tract regions were very similar. Between Sprague-Dawley and Long-Evans rats, significant differences in TB and alveolar predicted deposition fractions were observed over a wide range of particle sizes, with TB deposition fractions being up to 3- to 4-fold greater in Sprague-Dawley rats and alveolar deposition being significantly greater in Long-Evans rats. Thus, strain-specific lung geometry models should be used for particle deposition calculations and interspecies dose comparisons.« less

  6. [Development of the lung cancer diagnostic system].

    PubMed

    Lv, You-Jiang; Yu, Shou-Yi

    2009-07-01

    To develop a lung cancer diagnosis system. A retrospective analysis was conducted in 1883 patients with primary lung cancer or benign pulmonary diseases (pneumonia, tuberculosis, or pneumonia pseudotumor). SPSS11.5 software was used for data processing. For the relevant factors, a non-factor Logistic regression analysis was used followed by establishment of the regression model. Microsoft Visual Studio 2005 system development platform and VB.Net corresponding language were used to develop the lung cancer diagnosis system. The non-factor multi-factor regression model showed a goodness-of-fit (R2) of the model of 0.806, with a diagnostic accuracy for benign lung diseases of 92.8%, a diagnostic accuracy for lung cancer of 89.0%, and an overall accuracy of 90.8%. The model system for early clinical diagnosis of lung cancer has been established.

  7. A parametric model for the changes in the complex valued conductivity of a lung during tidal breathing

    NASA Astrophysics Data System (ADS)

    Nordebo, Sven; Dalarsson, Mariana; Khodadad, Davood; Müller, Beat; Waldmann, Andreas D.; Becher, Tobias; Frerichs, Inez; Sophocleous, Louiza; Sjöberg, Daniel; Seifnaraghi, Nima; Bayford, Richard

    2018-05-01

    Classical homogenization theory based on the Hashin–Shtrikman coated ellipsoids is used to model the changes in the complex valued conductivity (or admittivity) of a lung during tidal breathing. Here, the lung is modeled as a two-phase composite material where the alveolar air-filling corresponds to the inclusion phase. The theory predicts a linear relationship between the real and the imaginary parts of the change in the complex valued conductivity of a lung during tidal breathing, and where the loss cotangent of the change is approximately the same as of the effective background conductivity and hence easy to estimate. The theory is illustrated with numerical examples based on realistic parameter values and frequency ranges used with electrical impedance tomography (EIT). The theory may be potentially useful for imaging and clinical evaluations in connection with lung EIT for respiratory management and control.

  8. Anti-sFlt-1 Therapy Preserves Lung Alveolar and Vascular Growth in Antenatal Models of Bronchopulmonary Dysplasia.

    PubMed

    Wallace, Bradley; Peisl, Amelie; Seedorf, Gregory; Nowlin, Taylor; Kim, Christina; Bosco, Jennifer; Kenniston, Jon; Keefe, Dennis; Abman, Steven H

    2018-03-15

    Pregnancies complicated by antenatal stress, including preeclampsia (PE) and chorioamnionitis (CA), increase the risk for bronchopulmonary dysplasia (BPD) in preterm infants, but biologic mechanisms linking prenatal factors with BPD are uncertain. Levels of sFlt-1 (soluble fms-like tyrosine kinase 1), an endogenous antagonist to VEGF (vascular endothelial growth factor), are increased in amniotic fluid and maternal blood in PE and associated with CA. Because impaired VEGF signaling has been implicated in the pathogenesis of BPD, we hypothesized that fetal exposure to sFlt-1 decreases lung growth and causes abnormal lung structure and pulmonary hypertension during infancy. To test this hypothesis, we studied the effects of anti-sFlt-1 monoclonal antibody (mAb) treatment on lung growth in two established antenatal models of BPD that mimic PE and CA induced by intraamniotic (i.a.) injections of sFlt-1 or endotoxin, respectively. In experimental PE, mAb was administered by three different approaches, including antenatal treatment by either i.a. instillation or maternal uterine artery infusion, or by postnatal intraperitoneal injections. With each strategy, mAb therapy improved infant lung structure as assessed by radial alveolar count, vessel density, right ventricular hypertrophy, and lung function. As found in the PE model, the adverse lung effects of i.a. endotoxin were also reduced by antenatal or postnatal mAb therapy. We conclude that treatment with anti-sFlt-1 mAb preserves lung structure and function and prevents right ventricular hypertrophy in two rat models of BPD of antenatal stress and speculate that early mAb therapy may provide a novel strategy for the prevention of BPD.

  9. Using Dual Fluorescence Reporting Genes to Establish an In Vivo Imaging Model of Orthotopic Lung Adenocarcinoma in Mice.

    PubMed

    Lai, Cheng-Wei; Chen, Hsiao-Ling; Yen, Chih-Ching; Wang, Jiun-Long; Yang, Shang-Hsun; Chen, Chuan-Mu

    2016-12-01

    Lung adenocarcinoma is characterized by a poor prognosis and high mortality worldwide. In this study, we purposed to use the live imaging techniques and a reporter gene that generates highly penetrative near-infrared (NIR) fluorescence to establish a preclinical animal model that allows in vivo monitoring of lung cancer development and provides a non-invasive tool for the research on lung cancer pathogenesis and therapeutic efficacy. A human lung adenocarcinoma cell line (A549), which stably expressed the dual fluorescence reporting gene (pCAG-iRFP-2A-Venus), was used to generate subcutaneous or orthotopic lung cancer in nude mice. Cancer development was evaluated by live imaging via the NIR fluorescent signals from iRFP, and the signals were verified ex vivo by the green fluorescence of Venus from the gross lung. The tumor-bearing mice received miR-16 nucleic acid therapy by intranasal administration to demonstrate therapeutic efficacy in this live imaging system. For the subcutaneous xenografts, the detection of iRFP fluorescent signals revealed delicate changes occurring during tumor growth that are not distinguishable by conventional methods of tumor measurement. For the orthotopic xenografts, the positive correlation between the in vivo iRFP signal from mice chests and the ex vivo green fluorescent signal from gross lung tumors and the results of the suppressed tumorigenesis by miR-16 treatment indicated that lung tumor size can be accurately quantified by the emission of NIR fluorescence. In addition, orthotopic lung tumor localization can be accurately visualized using iRFP fluorescence tomography in vivo, thus revealing the trafficking of lung tumor cells. We introduced a novel dual fluorescence lung cancer model that provides a non-invasive option for preclinical research via the use of NIR fluorescence in live imaging of lung.

  10. A Lagrangian Approach for Calculating Microsphere Deposition in a One-Dimensional Lung-Airway Model.

    PubMed

    Vaish, Mayank; Kleinstreuer, Clement

    2015-09-01

    Using the open-source software openfoam as the solver, a novel approach to calculate microsphere transport and deposition in a 1D human lung-equivalent trumpet model (TM) is presented. Specifically, for particle deposition in a nonlinear trumpetlike configuration a new radial force has been developed which, along with the regular drag force, generates particle trajectories toward the wall. The new semi-empirical force is a function of any given inlet volumetric flow rate, micron-particle diameter, and lung volume. Particle-deposition fractions (DFs) in the size range from 2 μm to 10 μm are in agreement with experimental datasets for different laminar and turbulent inhalation flow rates as well as total volumes. Typical run times on a single processor workstation to obtain actual total deposition results at comparable accuracy are 200 times less than that for an idealized whole-lung geometry (i.e., a 3D-1D model with airways up to 23rd generation in single-path only).

  11. Lung tumor promotion by chromium-containing welding particulate matter in a mouse model

    PubMed Central

    2013-01-01

    Background Epidemiology suggests that occupational exposure to welding particulate matter (PM) may increase lung cancer risk. However, animal studies are lacking to conclusively link welding with an increased risk. PM derived from stainless steel (SS) welding contains carcinogenic metals such as hexavalent chromium and nickel. We hypothesized that welding PM may act as a tumor promoter and increase lung tumor multiplicity in vivo. Therefore, the capacity of chromium-containing gas metal arc (GMA)-SS welding PM to promote lung tumors was evaluated using a two-stage (initiation-promotion) model in lung tumor susceptible A/J mice. Methods Male mice (n = 28-30/group) were treated either with the initiator 3-methylcholanthrene (MCA;10 μg/g; IP) or vehicle (corn oil) followed by 5 weekly pharyngeal aspirations of GMA-SS (340 or 680 μg/exposure) or PBS. Lung tumors were enumerated at 30 weeks post-initiation. Results MCA initiation followed by GMA-SS welding PM exposure promoted tumor multiplicity in both the low (12.1 ± 1.5 tumors/mouse) and high (14.0 ± 1.8 tumors/mouse) exposure groups significantly above MCA/sham (4.77 ± 0.7 tumors/mouse; p = 0.0001). Multiplicity was also highly significant (p < 0.004) across all individual lung regions of GMA-SS-exposed mice. No exposure effects were found in the corn oil groups at 30 weeks. Histopathology confirmed the gross findings and revealed increased inflammation and a greater number of malignant lesions in the MCA/welding PM-exposed groups. Conclusions GMA-SS welding PM acts as a lung tumor promoter in vivo. Thus, this study provides animal evidence to support the epidemiological data that show welders have an increased lung cancer risk. PMID:24107379

  12. Predicting survival across chronic interstitial lung disease: the ILD-GAP model.

    PubMed

    Ryerson, Christopher J; Vittinghoff, Eric; Ley, Brett; Lee, Joyce S; Mooney, Joshua J; Jones, Kirk D; Elicker, Brett M; Wolters, Paul J; Koth, Laura L; King, Talmadge E; Collard, Harold R

    2014-04-01

    Risk prediction is challenging in chronic interstitial lung disease (ILD) because of heterogeneity in disease-specific and patient-specific variables. Our objective was to determine whether mortality is accurately predicted in patients with chronic ILD using the GAP model, a clinical prediction model based on sex, age, and lung physiology, that was previously validated in patients with idiopathic pulmonary fibrosis. Patients with idiopathic pulmonary fibrosis (n=307), chronic hypersensitivity pneumonitis (n=206), connective tissue disease-associated ILD (n=281), idiopathic nonspecific interstitial pneumonia (n=45), or unclassifiable ILD (n=173) were selected from an ongoing database (N=1,012). Performance of the previously validated GAP model was compared with novel prediction models in each ILD subtype and the combined cohort. Patients with follow-up pulmonary function data were used for longitudinal model validation. The GAP model had good performance in all ILD subtypes (c-index, 74.6 in the combined cohort), which was maintained at all stages of disease severity and during follow-up evaluation. The GAP model had similar performance compared with alternative prediction models. A modified ILD-GAP Index was developed for application across all ILD subtypes to provide disease-specific survival estimates using a single risk prediction model. This was done by adding a disease subtype variable that accounted for better adjusted survival in connective tissue disease-associated ILD, chronic hypersensitivity pneumonitis, and idiopathic nonspecific interstitial pneumonia. The GAP model accurately predicts risk of death in chronic ILD. The ILD-GAP model accurately predicts mortality in major chronic ILD subtypes and at all stages of disease.

  13. Prenatal administration of neuropeptide bombesin promotes lung development in a rat model of nitrofen-induced congenital diaphragmatic hernia.

    PubMed

    Sakai, Kohei; Kimura, Osamu; Furukawa, Taizo; Fumino, Shigehisa; Higuchi, Koji; Wakao, Junko; Kimura, Koseki; Aoi, Shigeyoshi; Masumoto, Kouji; Tajiri, Tatsuro

    2014-12-01

    Fetal medical treatment to improve lung hypoplasia in congenital diaphragmatic hernia (CDH) has yet to be established. The neuropeptide bombesin (BBS) might play an important role in lung development. The present study aims to determine whether prenatally administered BBS could be useful to promote fetal lung development in a rat model of nitrofen-induced CDH. Pregnant rats were administered with nitrofen (100mg) on gestation day 9.5 (E9.5). BBS (50mg/kg/day) was then daily infused intraperitoneally from E14, and fetal lungs were harvested on E21. The expression of PCNA was assessed by both immunohistochemical staining and RT-PCR to determine the amount of cell proliferation. Lung maturity was assessed as the expression of TTF-1, a marker of alveolar epithelial cell type II. The lung-body-weight ratio was significantly increased in CDH/BBS(+) compared with CDH/BBS(-) (p<0.05). The number of cells stained positive for PCNA and TTF-1 was significantly decreased in CDH/BBS(+) compared with CDH/BBS(-) (p<0.01). The TTF-1 mRNA expression levels were significantly decreased in CDH/BBS(+) compared with CDH/BBS(-) (p<0.05). Prenatally administered BBS promotes lung development in a rat model of nitrofen-induced CDH. Neuropeptide BBS could help to rescue lung hypoplasia in fetal CDH. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Calcium homeostasis in crustacea: the evolving role of branchial, renal, digestive and hypodermal epithelia.

    PubMed

    Wheatly, M G

    1999-06-01

    Crustaceans serve as an ideal model for the study of calcium homeostasis due to their natural molting cycle. Demineralization and remineralization of the calcified cuticle is accompanied by bidirectional Ca transfer across the primary Ca transporting epithelia: gills, antennal gland (kidney), digestive system, and cuticular hypodermis. The review will demonstrate how a continuum of crustaceans can be used as a paradigm for the evolution of Ca transport mechanisms. Generally speaking, aquatic crustaceans rely primarily on branchial Ca uptake and accordingly are affected by water Ca content; terrestrial crustaceans rely on intake of dietary Ca across the digestive epithelium. Synchrony of mineralization at the cuticle vs. storage sites will be presented Physiological and behavioral adaptations have evolved to optimize Ca balance during the molting cycle in different Ca environments. Intracellular Ca regulation reveals common mechanisms of apical and basolateral membrane transport as well as intracellular sequestration. Regulation of cell Ca concentration will be discussed in intermolt and during periods of the molting cycle when transepithelial Ca flux is significantly elevated. Molecular characterization of the sarco-/endoplasmic reticular Ca pump in aquatic species reveals the presence of two isoforms that originate from a single gene. This gene is differentially expressed during the molting cycle. Gene expression may be regulated by a suite of hormones including ecdysone, calcitonin, and vitamin D. Perspectives for future research are presented.

  15. Semi-Solid and Solid Dosage Forms for the Delivery of Phage Therapy to Epithelia.

    PubMed

    Brown, Teagan L; Petrovski, Steve; Chan, Hiu Tat; Angove, Michael J; Tucci, Joseph

    2018-02-26

    The delivery of phages to epithelial surfaces for therapeutic outcomes is a realistic proposal, and indeed one which is being currently tested in clinical trials. This paper reviews some of the known research on formulation of phages into semi-solid dosage forms such as creams, ointments and pastes, as well as solid dosage forms such as troches (or lozenges and pastilles) and suppositories/pessaries, for delivery to the epithelia. The efficacy and stability of these phage formulations is discussed, with a focus on selection of optimal semi-solid bases for phage delivery. Issues such as the need for standardisation of techniques for formulation as well as for assessment of efficacy are highlighted. These are important when trying to compare results from a range of experiments and across different delivery bases.

  16. Semi-Solid and Solid Dosage Forms for the Delivery of Phage Therapy to Epithelia

    PubMed Central

    Petrovski, Steve; Chan, Hiu Tat; Angove, Michael J.; Tucci, Joseph

    2018-01-01

    The delivery of phages to epithelial surfaces for therapeutic outcomes is a realistic proposal, and indeed one which is being currently tested in clinical trials. This paper reviews some of the known research on formulation of phages into semi-solid dosage forms such as creams, ointments and pastes, as well as solid dosage forms such as troches (or lozenges and pastilles) and suppositories/pessaries, for delivery to the epithelia. The efficacy and stability of these phage formulations is discussed, with a focus on selection of optimal semi-solid bases for phage delivery. Issues such as the need for standardisation of techniques for formulation as well as for assessment of efficacy are highlighted. These are important when trying to compare results from a range of experiments and across different delivery bases. PMID:29495355

  17. A newly developed solution enhances thirty-hour preservation in a canine lung transplantation model.

    PubMed

    Liu, C J; Ueda, M; Kosaka, S; Hirata, T; Yokomise, H; Inui, K; Hitomi, S; Wada, H

    1996-09-01

    Ischemia and reperfusion cause the production of oxygen free radicals. These damage grafts or disrupt normal vascular homeostatic mechanisms, with a parallel reduction in endothelial nitric oxide and adenosine 3',5'-cyclic monophosphate levels. We hypothesized that lung preservation failure may be related to these events. To improve lung preservation, we prepared a new ET-Kyoto solution, which contains N-acetylcysteine (a radical scavenger), nitroglycerin (to elevate the nitric oxide level), and dibutyryl adenosine 3',5'-cyclic monophosphate (to elevate the adenosine 3',5'-cyclic monophosphate level) and examined its efficacy in a canine single-lung transplantation model. Lungs were flushed with new ET-Kyoto solution (group I, n = 9), basal ET-Kyoto solution (group II, n = 6), basal ET-Kyoto solution plus ethanol and propylene glycol (solvents of nitroglycerin; group III, n = 6), or low-potassium dextran glucose solution (group IV, n = 6), and stored at 4 degrees C for 30 hours. After left single-lung transplantation, the right main bronchus and right pulmonary artery were ligated and the functions of the transplanted lung were assessed for 6 hours. Arterial oxygen tension was significantly higher in group I than in groups II, III, and IV (p < 0.05). Peak inspiratory pressure and wet-to-dry lung weight ratio were significantly lower in group I than in groups II and IV (p < 0.01). Histologic and ultrastructural studies showed better preservation in group I than in groups II, III, and IV. We conclude that the new ET-Kyoto solution provides enhanced 30-hour lung preservation.

  18. Automatic lung tumor segmentation on PET/CT images using fuzzy Markov random field model.

    PubMed

    Guo, Yu; Feng, Yuanming; Sun, Jian; Zhang, Ning; Lin, Wang; Sa, Yu; Wang, Ping

    2014-01-01

    The combination of positron emission tomography (PET) and CT images provides complementary functional and anatomical information of human tissues and it has been used for better tumor volume definition of lung cancer. This paper proposed a robust method for automatic lung tumor segmentation on PET/CT images. The new method is based on fuzzy Markov random field (MRF) model. The combination of PET and CT image information is achieved by using a proper joint posterior probability distribution of observed features in the fuzzy MRF model which performs better than the commonly used Gaussian joint distribution. In this study, the PET and CT simulation images of 7 non-small cell lung cancer (NSCLC) patients were used to evaluate the proposed method. Tumor segmentations with the proposed method and manual method by an experienced radiation oncologist on the fused images were performed, respectively. Segmentation results obtained with the two methods were similar and Dice's similarity coefficient (DSC) was 0.85 ± 0.013. It has been shown that effective and automatic segmentations can be achieved with this method for lung tumors which locate near other organs with similar intensities in PET and CT images, such as when the tumors extend into chest wall or mediastinum.

  19. A comprehensive computational human lung model incorporating inter-acinar dependencies: Application to spontaneous breathing and mechanical ventilation.

    PubMed

    Roth, Christian J; Ismail, Mahmoud; Yoshihara, Lena; Wall, Wolfgang A

    2017-01-01

    In this article, we propose a comprehensive computational model of the entire respiratory system, which allows simulating patient-specific lungs under different ventilation scenarios and provides a deeper insight into local straining and stressing of pulmonary acini. We include novel 0D inter-acinar linker elements to respect the interplay between neighboring alveoli, an essential feature especially in heterogeneously distended lungs. The model is applicable to healthy and diseased patient-specific lung geometries. Presented computations in this work are based on a patient-specific lung geometry obtained from computed tomography data and composed of 60,143 conducting airways, 30,072 acini, and 140,135 inter-acinar linkers. The conducting airways start at the trachea and end before the respiratory bronchioles. The acini are connected to the conducting airways via terminal airways and to each other via inter-acinar linkers forming a fully coupled anatomically based respiratory model. Presented numerical examples include simulation of breathing during a spirometry-like test, measurement of a quasi-static pressure-volume curve using a supersyringe maneuver, and volume-controlled mechanical ventilation. The simulations show that our model incorporating inter-acinar dependencies successfully reproduces physiological results in healthy and diseased states. Moreover, within these scenarios, a deeper insight into local pressure, volume, and flow rate distribution in the human lung is investigated and discussed. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  20. hPSC-derived lung and intestinal organoids as models of human fetal tissue

    PubMed Central

    Aurora, Megan; Spence, Jason R.

    2016-01-01

    In vitro human pluripotent stem cell (hPSC) derived tissues are excellent models to study certain aspects of normal human development. Current research in the field of hPSC derived tissues reveals these models to be inherently fetal-like on both a morphological and gene expression level. In this review we briefly discuss current methods for differentiating lung and intestinal tissue from hPSCs into individual 3-dimensional units called organoids. We discuss how these methods mirror what is known about in vivo signaling pathways of the developing embryo. Additionally, we will review how the inherent immaturity of these models lends them to be particularly valuable in the study of immature human tissues in the clinical setting of premature birth. Human lung organoids (HLOs) and human intestinal organoids (HIOs) not only model normal development, but can also be utilized to study several important diseases of prematurity such as respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), and necrotizing enterocolitis (NEC). PMID:27287882

  1. Double-hit mouse model of cigarette smoke priming for acute lung injury.

    PubMed

    Sakhatskyy, Pavlo; Wang, Zhengke; Borgas, Diana; Lomas-Neira, Joanne; Chen, Yaping; Ayala, Alfred; Rounds, Sharon; Lu, Qing

    2017-01-01

    Epidemiological studies indicate that cigarette smoking (CS) increases the risk and severity of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). The mechanism is not understood, at least in part because of lack of animal models that reproduce the key features of the CS priming process. In this study, using two strains of mice, we characterized a double-hit mouse model of ALI induced by CS priming of injury caused by lipopolysaccharide (LPS). C57BL/6 and AKR mice were preexposed to CS briefly (3 h) or subacutely (3 wk) before intratracheal instillation of LPS and ALI was assessed 18 h after LPS administration by measuring lung static compliance, lung edema, vascular permeability, inflammation, and alveolar apoptosis. We found that as little as 3 h of exposure to CS enhanced LPS-induced ALI in both strains of mice. Similar exacerbating effects were observed after 3 wk of preexposure to CS. However, there was a strain difference in susceptibility to CS priming for ALI, with a greater effect in AKR mice. The key features we observed suggest that 3 wk of CS preexposure of AKR mice is a reproducible, clinically relevant animal model that is useful for studying mechanisms and treatment of CS priming for a second-hit-induced ALI. Our data also support the concept that increased susceptibility to ALI/ARDS is an important adverse health consequence of CS exposure that needs to be taken into consideration when treating critically ill individuals.

  2. Double-hit mouse model of cigarette smoke priming for acute lung injury

    PubMed Central

    Sakhatskyy, Pavlo; Wang, Zhengke; Borgas, Diana; Lomas-Neira, Joanne; Chen, Yaping; Ayala, Alfred; Rounds, Sharon

    2016-01-01

    Epidemiological studies indicate that cigarette smoking (CS) increases the risk and severity of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). The mechanism is not understood, at least in part because of lack of animal models that reproduce the key features of the CS priming process. In this study, using two strains of mice, we characterized a double-hit mouse model of ALI induced by CS priming of injury caused by lipopolysaccharide (LPS). C57BL/6 and AKR mice were preexposed to CS briefly (3 h) or subacutely (3 wk) before intratracheal instillation of LPS and ALI was assessed 18 h after LPS administration by measuring lung static compliance, lung edema, vascular permeability, inflammation, and alveolar apoptosis. We found that as little as 3 h of exposure to CS enhanced LPS-induced ALI in both strains of mice. Similar exacerbating effects were observed after 3 wk of preexposure to CS. However, there was a strain difference in susceptibility to CS priming for ALI, with a greater effect in AKR mice. The key features we observed suggest that 3 wk of CS preexposure of AKR mice is a reproducible, clinically relevant animal model that is useful for studying mechanisms and treatment of CS priming for a second-hit-induced ALI. Our data also support the concept that increased susceptibility to ALI/ARDS is an important adverse health consequence of CS exposure that needs to be taken into consideration when treating critically ill individuals. PMID:27864287

  3. Interstitial distribution of charged macromolecules in the dog lung: a kinetic model.

    PubMed

    Parker, J C; Miniati, M; Pitt, R; Taylor, A E

    1987-01-01

    A mathematic model was constructed to investigate conflicting physiologic data concerning the charge effect of continuous capillaries to macromolecules in the lung. We simulated the equilibration kinetics of lactate dehydrogenase (MR 4.2 nM) isozymes LDH 1 (pI = 5.0) and LDH 5 (pI = 7.9) between plasma and lymph using previously measured permeability coefficients, lung tissue distribution volumes (VA) and plasma concentrations (CP) in lung tissue. Our hypothesis is that the fixed anionic charges in interstitium, basement membrane, and cell surfaces determine equilibration rather than charged membrane effects at the capillary barrier, so the same capillary permeability coefficients were used for both isozymes. Capillary filtration rates and protein fluxes were calculated using conventional flux equations. Initial conditions at baseline and increased left atrial pressures (PLA) were those measured in animal studies. Simulated equilibration of isozymes over 30 h in the model at baseline capillary pressures accurately predicted the observed differences in lymph/plasma concentration ratios (CL/CP) between isotopes at 4 h and equilibration of these ratios at 24 h. Quantitative prediction of isozyme CL/CP ratios was also obtained at increased PLA. However, an additional cation selective compartment representing the surface glycocalyx was required to accurately simulate the initial higher transcapillary clearances of cationic LDH 5. Thus experimental data supporting the negative barrier, positive barrier, and no charge barrier hypotheses were accurately reproduced by the model using only the observed differences in interstitial partitioning of isozymes without differences in capillary selectivity.

  4. Secreted aspartic proteases are not required for invasion of reconstituted human epithelia by Candida albicans.

    PubMed

    Lermann, Ulrich; Morschhäuser, Joachim

    2008-11-01

    A well-known virulence attribute of the human-pathogenic yeast Candida albicans is the secretion of aspartic proteases (Saps), which may contribute to colonization and infection of different host niches by degrading tissue barriers, destroying host defence molecules, or digesting proteins for nutrient supply. The role of individual Sap isoenzymes, which are encoded by a large gene family, for the pathogenicity of C. albicans has been investigated by assessing the virulence of mutants lacking specific SAP genes and by studying the expression pattern of the SAP genes in various models of superficial and systemic infections. We used a recombination-based genetic reporter system to detect the induction of the SAP1-SAP6 genes during infection of reconstituted human vaginal epithelium. Only SAP5, but none of the other tested SAP genes, was detectably activated in this in vitro infection model. To directly address the importance of the SAP1-SAP6 genes for invasion of reconstituted human epithelia (RHE), we constructed a set of mutants of the wild-type C. albicans model strain SC5314 in which either single or multiple SAP genes were specifically deleted. Even mutants lacking all of the SAP1-SAP3 or the SAP4-SAP6 genes displayed the same capacity to invade and damage both oral and vaginal RHE as their wild-type parental strain, in contrast to a nonfilamentous efg1Delta mutant that was avirulent under these conditions. We therefore conclude from these results that the secreted aspartic proteases Sap1p-Sap6p are not required for invasion of RHE by C. albicans.

  5. The Effects of Smoking on the Developing Lung: Insights from a Biologic Model for Lung Development, Homeostasis, and Repair

    PubMed Central

    Asotra, Kamlesh; Torday, John S.

    2010-01-01

    There is extensive epidemiologic and experimental evidence from both animal and human studies that demonstrates detrimental long-term pulmonary outcomes in the offspring of mothers who smoke during pregnancy. However, the molecular mechanisms underlying these associations are not understood. Therefore, it is not surprising that that there is no effective intervention to prevent the damaging effects of perinatal smoke exposure. Using a biologic model of lung development, homeostasis, and repair, we have determined that in utero nicotine exposure disrupts specific molecular paracrine communications between epithelium and interstitium that are driven by parathyroid hormone-related protein and peroxisome proliferator-activated receptor (PPAR)γ, resulting in transdifferentiation of lung lipofibroblasts to myofibroblasts, i.e., the conversion of the lipofibroblast phenotype to a cell type that is not conducive to alveolar homeostasis, and is the cellular hallmark of chronic lung disease, including asthma. Furthermore, we have shown that by molecularly targeting PPARγ expression, nicotine-induced lung injury can not only be significantly averted, it can also be reverted. The concept outlined by us differs from the traditional paradigm of teratogenic and toxicological effects of tobacco smoke that has been proposed in the past. We have argued that since nicotine alters the normal homeostatic epithelial-mesenchymal paracrine signaling in the developing alveolus, rather than causing totally disruptive structural changes, it offers a unique opportunity to prevent, halt, and/or reverse this process through targeted molecular manipulations. PMID:19641967

  6. Creation of Lung-Targeted Dexamethasone Immunoliposome and Its Therapeutic Effect on Bleomycin-Induced Lung Injury in Rats

    PubMed Central

    Li, Nan; Hu, Yang; Zhang, Yuan; Xu, Jin-Fu; Li, Xia; Ren, Jie; Su, Bo; Yuan, Wei-Zhong; Teng, Xin-Rong; Zhang, Rong-Xuan; Jiang, Dian-hua; Mulet, Xavier; Li, Hui-Ping

    2013-01-01

    Objective Acute lung injury (ALI), is a major cause of morbidity and mortality, which is routinely treated with the administration of systemic glucocorticoids. The current study investigated the distribution and therapeutic effect of a dexamethasone(DXM)-loaded immunoliposome (NLP) functionalized with pulmonary surfactant protein A (SP-A) antibody (SPA-DXM-NLP) in an animal model. Methods DXM-NLP was prepared using film dispersion combined with extrusion techniques. SP-A antibody was used as the lung targeting agent. Tissue distribution of SPA-DXM-NLP was investigated in liver, spleen, kidney and lung tissue. The efficacy of SPA-DXM-NLP against lung injury was assessed in a rat model of bleomycin-induced acute lung injury. Results The SPA-DXM-NLP complex was successfully synthesized and the particles were stable at 4°C. Pulmonary dexamethasone levels were 40 times higher with SPA-DXM-NLP than conventional dexamethasone injection. Administration of SPA-DXM-NLP significantly attenuated lung injury and inflammation, decreased incidence of infection, and increased survival in animal models. Conclusions The administration of SPA-DXM-NLP to animal models resulted in increased levels of DXM in the lungs, indicating active targeting. The efficacy against ALI of the immunoliposomes was shown to be superior to conventional dexamethasone administration. These results demonstrate the potential of actively targeted glucocorticoid therapy in the treatment of lung disease in clinical practice. PMID:23516459

  7. Maternal inflammation modulates infant immune response patterns to viral lung challenge in a murine model.

    PubMed

    Gleditsch, Dorothy D; Shornick, Laurie P; Van Steenwinckel, Juliette; Gressens, Pierre; Weisert, Ryan P; Koenig, Joyce M

    2014-07-01

    Chorioamnionitis, an inflammatory gestational disorder, commonly precedes preterm delivery. Preterm infants may be at particular risk for inflammation-related morbidity related to infection, although the pathogenic mechanisms are unclear. We hypothesized that maternal inflammation modulates immune programming to drive postnatal inflammatory processes. We used a novel combined murine model to treat late gestation dams with low-dose lipopolysaccharide (LPS) and to secondarily challenge exposed neonates or weanlings with Sendai virus (SeV) lung infection. Multiple organs were analyzed to characterize age-specific postnatal immune and inflammatory responses. Maternal LPS treatment enhanced innate immune populations in the lungs, livers, and/or spleens of exposed neonates or weanlings. Secondary lung SeV infection variably affected neutrophil, macrophage, and dendritic cell proportions in multiple organs of exposed pups. Neonatal lung infection induced brain interleukin (IL)-4 expression, although this response was muted in LPS-exposed pups. Adaptive immune cells, including lung, lymph node, and thymic lymphocytes and lung CD4 cells expressing FoxP3, interferon (IFN)-γ, or IL-17, were variably prominent in LPS-exposed pups. Maternal inflammation modifies postnatal immunity and augments systemic inflammatory responses to viral lung infection in an age-specific manner. We speculate that inflammatory modulation of the developing immune system contributes to chronic morbidity and mortality in preterm infants.

  8. Controlled lung reperfusion to reduce pulmonary ischaemia/reperfusion injury after cardiopulmonary bypass in a porcine model.

    PubMed

    Slottosch, Ingo; Liakopoulos, Oliver; Kuhn, Elmar; Deppe, Antje; Lopez-Pastorini, Alberto; Schwarz, David; Neef, Klaus; Choi, Yeong-Hoon; Sterner-Kock, Anja; Jung, Kristina; Mühlfeld, Christian; Wahlers, Thorsten

    2014-12-01

    Ischaemia/reperfusion (I/R) injury of the lungs contributes to pulmonary dysfunction after cardiac surgery with cardiopulmonary bypass (CPB), leading to increased morbidity and mortality of patients. This study investigated the value of controlled lung reperfusion strategies on lung ischaemia-reperfusion injury in a porcine CPB model. Pigs were subjected to routine CPB for 120 min with 60 min of blood cardioplegic cardiac arrest (CCA). Following CCA, the uncontrolled reperfusion (UR, n = 6) group was conventionally weaned from CPB. Two groups underwent controlled lung reperfusion strategies (CR group: controlled reperfusion conditions, n = 6; MR group: controlled reperfusion conditions and modified reperfusate, n = 6) via the pulmonary artery before CPB weaning. Sham-operated pigs (n = 7) served as controls. Animals were followed up until 4 h after CPB. Pulmonary function, haemodynamics, markers of inflammation, endothelial injury and oxidative stress as well as morphological lung alterations were analysed. CPB (UR group) induced deterioration of pulmonary function (lung mechanics, oxygenation index and lung oedema). Also, controlled lung reperfusion groups (CR and MR) presented with pulmonary dysfunction after CPB. However, compared with UR, controlled lung reperfusion strategies (CR and MR) improved lung mechanics and reduced markers of oxidative stress, but without alteration of haemodynamics, oxygenation, inflammation, endothelial injury and lung morphology. Both controlled reperfusion groups were similar without relevant differences. Controlled lung reperfusion strategies attenuated a decrease in lung mechanics and an increase in oxidative stress, indicating an influence on CPB-related pulmonary injury. However, they failed to avoid completely CPB-related lung injury, implying the need for additional strategies given the multifactorial pathophysiology of postoperative pulmonary dysfunction. © The Author 2014. Published by Oxford University Press on behalf of

  9. Identification of ADAM 31: a protein expressed in Leydig cells and specialized epithelia.

    PubMed

    Liu, L; Smith, J W

    2000-06-01

    A family of proteins containing a disintegrin and metalloproteinase domain (ADAMs) has been identified recently. Here, we report the identification of a novel member of the ADAM protein family from mouse. This protein is designated ADAM 31. The complementary DNA sequence of ADAM 31 predicts a transmembrane protein with metalloproteinase, disintegrin, cysteine-rich, and cytoplasmic domains. Messenger RNA encoding ADAM 31 was most abundant in testes, but was also detected in many other tissues. More significantly, the antibodies raised against ADAM 31 reveal that the protein has a unique and restricted expression pattern. ADAM 31 is expressed in Leydig cells of the testes, but unlike many other ADAMs, it is not found on developing sperm. Furthermore, ADAM 31 is highly expressed on four types of specialized epithelia: the cauda epididymidis, the vas deferens, the convoluted tubules of the kidney, and the parietal cells of the stomach.

  10. Inhibitory effect of kefiran on ovalbumin-induced lung inflammation in a murine model of asthma.

    PubMed

    Kwon, Ok-Kyoung; Ahn, Kyung-Seop; Lee, Mee-Young; Kim, So-Young; Park, Bo-Young; Kim, Mi-Kyoung; Lee, In-Young; Oh, Sei-Ryang; Lee, Hyeong-Kyu

    2008-12-01

    Kefiran is a major component of kefir which is a microbial symbiont mixture that produces jelly-like grains. This study aimed to evaluate the therapeutic availability of kefiran on the ovalbumin-induced asthma mouse model in which airway inflammation and airway hyper-responsiveness were found in the lung. BALB/c mice sensitized and challenged to ovalbumin were treated intra-gastrically with kefiran 1 hour before the ovalbumin challenge. Kefiran significantly suppressed ovalbumin-induced airway hyper-responsiveness (AHR) to inhaled methacholine. Administration of kefiran significantly inhibited the release of both eosinophils and other inflammatory cells into bronchoalveolar lavage (BAL) fluid and lung tissue which was measured by Diff-Quik. Interleukin-4 (IL-4) and interleukin-5 (IL-5) were also reduced to normal levels after administration of kefiran in BAL fluid. Histological studies demonstrate that kefiran substantially inhibited ovalbumin-induced eosinophilia in lung tissue by H&E staining and goblet cell hyperplasia in the airway by PAS staining. Taken above data, kefiran may be useful for the treatment of inflammation of lung tissue and airway hyper-responsiveness in a murine model and may have therapeutic potential for the treatment of allergic bronchial asthma.

  11. Adeno-Associated Virus Type 6 (AAV6) Vectors Mediate Efficient Transduction of Airway Epithelial Cells in Mouse Lungs Compared to That of AAV2 Vectors

    PubMed Central

    Halbert, Christine L.; Allen, James M.; Miller, A. Dusty

    2001-01-01

    Although vectors derived from adeno-associated virus type 2 (AAV2) promote gene transfer and expression in many somatic tissues, studies with animal models and cultured cells show that the apical surface of airway epithelia is resistant to transduction by AAV2 vectors. Approaches to increase transduction rates include increasing the amount of vector and perturbing the integrity of the epithelia. In this study, we explored the use of vectors based on AAV6 to increase transduction rates in airways. AAV vectors were made using combinations of rep, cap, and packaged genomes from AAV2 or AAV6. The packaged genomes encoded human placental alkaline phosphatase and contained terminal repeat sequences from AAV2 or AAV6. We found that transduction efficiency was primarily dependent on the source of Cap protein, defined here as the vector pseudotype. The AAV6 and AAV2 pseudotype vectors exhibited different tropisms in tissue-cultured cells, and cell transduction by AAV6 vectors was not inhibited by heparin, nor did they compete for entry in a transduction assay, indicating that AAV6 and AAV2 capsid bind different receptors. In vivo analysis of vectors showed that AAV2 pseudotype vectors gave high transduction rates in alveolar cells but much lower rates in the airway epithelium. In contrast, the AAV6 pseudotype vectors exhibited much more efficient transduction of epithelial cells in large and small airways, showing up to 80% transduction in some airways. These results, combined with our previous results showing lower immunogenicity of AAV6 than of AAV2 vectors, indicate that AAV6 vectors may provide significant advantages over AAV2 for gene therapy of lung diseases like cystic fibrosis. PMID:11413329

  12. Human fetal lung morphometry at autopsy with new modeling to quantitate structural maturity.

    PubMed

    Lipsett, Jill

    2017-06-01

    To demonstrate a simplified morphometric procedure, including a new model for acinar structural maturity, applicable to autopsy fetal lung and present reference values for these parameters. Cases with autopsy consent for research were studied. To simplify analysis only critical morphometric parameters were measured to allow calculation of gas-exchange surface area. A total of 58 fetuses, 16-40 weeks were included. Subjects were rejected with any condition predisposing to pulmonary hypo/hyperplasia, significant maceration, or if lung weight/bodyweight or microscopy identified pulmonary hypoplasia or lung growth disorders. Lungs were inflation fixed, weights and volumes determined, sampled, then returned to the body. Volume densities (V V ) of parenchyma/non-parenchyma and air-space/gas-exchange tissue, gas-exchange surface density (S V ), and total surface area (SA) were determined. The number, mean radius, and septal thickness of modeled airspace-spheres were calculated. Equations were generated for each parameter function of gestation and bodyweight. From 16 to 40-week weights and volumes increased as power functions from ∼4 g/mL to ∼90 g/mL. Parenchyma/non-parenchyma changed little-75:25 (16 weeks) to 71:29 (term). Parenchyma was 10% airspace:90% tissue early and 50:50 by term. Gas-exchange S V increased from 175 to 450 cm 2 /cm 3 and total SA increased from 0.059 to 4.793 m 2 . There were 3.31 × 10 6 airspace-spheres, 12 µ radius, septal thickness 30 µ at 16 weeks, increasing to 56.92 × 10 6 , 26 µ radius, septal thickness 13 µ by term. Morphometry can feasibly be performed at autopsy, providing more informative quantitative data on lung structural development than current methods utilized. This reference data set compares well with published data. © 2017 Wiley Periodicals, Inc.

  13. Shrinking lung syndrome as a manifestation of pleuritis: a new model based on pulmonary physiological studies.

    PubMed

    Henderson, Lauren A; Loring, Stephen H; Gill, Ritu R; Liao, Katherine P; Ishizawar, Rumey; Kim, Susan; Perlmutter-Goldenson, Robin; Rothman, Deborah; Son, Mary Beth F; Stoll, Matthew L; Zemel, Lawrence S; Sandborg, Christy; Dellaripa, Paul F; Nigrovic, Peter A

    2013-03-01

    The pathophysiology of shrinking lung syndrome (SLS) is poorly understood. We sought to define the structural basis for this condition through the study of pulmonary mechanics in affected patients. Since 2007, most patients evaluated for SLS at our institutions have undergone standardized respiratory testing including esophageal manometry. We analyzed these studies to define the physiological abnormalities driving respiratory restriction. Chest computed tomography data were post-processed to quantify lung volume and parenchymal density. Six cases met criteria for SLS. All presented with dyspnea as well as pleurisy and/or transient pleural effusions. Chest imaging results were free of parenchymal disease and corrected diffusing capacities were normal. Total lung capacities were 39%-50% of predicted. Maximal inspiratory pressures were impaired at high lung volumes, but not low lung volumes, in 5 patients. Lung compliance was strikingly reduced in all patients, accompanied by increased parenchymal density. Patients with SLS exhibited symptomatic and/or radiographic pleuritis associated with 2 characteristic physiological abnormalities: (1) impaired respiratory force at high but not low lung volumes; and (2) markedly decreased pulmonary compliance in the absence of identifiable interstitial lung disease. These findings suggest a model in which pleural inflammation chronically impairs deep inspiration, for example through neural reflexes, leading to parenchymal reorganization that impairs lung compliance, a known complication of persistently low lung volumes. Together these processes could account for the association of SLS with pleuritis as well as the gradual symptomatic and functional progression that is a hallmark of this syndrome.

  14. Micro-imaging of the Mouse Lung via MRI

    NASA Astrophysics Data System (ADS)

    Wang, Wei

    Quantitative measurement of lung microstructure is of great significance in assessment of pulmonary disease, particularly in the earliest stages. Conventional stereological assessment of ex-vivo fixed tissue specimens under the microscope has a long and successful tradition and is regarded as a gold standard, but the invasive nature limits its applications and the practicality of use in longitudinal studies. The technique for diffusion MRI-based 3He lung morphometry was previously developed and validated for human lungs, and was recently extended to ex-vivo mouse lungs. The technique yields accurate, quantitative information about the microstructure and geometry of acinar airways. In this dissertation, the 3He lung morphometry technique is for the first time successfully implemented for in-vivo studies of mice. It can generate spatially-resolved maps of parameters that reveal the microstructure of mouse lung. Results in healthy mice indicate excellent agreement between in-vivo morphometry via 3He MRI and microscopic morphometry after sacrifice. The implementation and validation of 3He morphometry in healthy mice open up new avenues for application of the technique as a precise, noninvasive, in-vivo biomarker of changes in lung microstructure, within various mouse models of lung disease. We have applied 3He morphometry to the Sendai mouse model of lung disease. Specifically, the Sendai-virus model of chronic obstructive lung disease has demonstrated an innate immune response in mouse airways that exhibits similarities to the chronic airway inflammation in human COPD and asthma, but the effect on distal lung parenchyma had not been investigated. We imaged the time course and regional distribution of mouse lung microstructural changes in vivo after Sendai virus (SeV) infection with 1H and 3He diffusion MRI. 1H MR images detected the SeV-induced pulmonary inflammation in vivo and 3He lung morphometry showed modest increase in alveolar duct radius distal to airway

  15. Long non-coding RNA expression patterns in lung tissues of chronic cigarette smoke induced COPD mouse model.

    PubMed

    Zhang, Haiyun; Sun, Dejun; Li, Defu; Zheng, Zeguang; Xu, Jingyi; Liang, Xue; Zhang, Chenting; Wang, Sheng; Wang, Jian; Lu, Wenju

    2018-05-15

    Long non-coding RNAs (lncRNAs) have critical regulatory roles in protein-coding gene expression. Aberrant expression profiles of lncRNAs have been observed in various human diseases. In this study, we investigated transcriptome profiles in lung tissues of chronic cigarette smoke (CS)-induced COPD mouse model. We found that 109 lncRNAs and 260 mRNAs were significantly differential expressed in lungs of chronic CS-induced COPD mouse model compared with control animals. GO and KEGG analyses indicated that differentially expressed lncRNAs associated protein-coding genes were mainly involved in protein processing of endoplasmic reticulum pathway, and taurine and hypotaurine metabolism pathway. The combination of high throughput data analysis and the results of qRT-PCR validation in lungs of chronic CS-induced COPD mouse model, 16HBE cells with CSE treatment and PBMC from patients with COPD revealed that NR_102714 and its associated protein-coding gene UCHL1 might be involved in the development of COPD both in mouse and human. In conclusion, our study demonstrated that aberrant expression profiles of lncRNAs and mRNAs existed in lungs of chronic CS-induced COPD mouse model. From animal models perspective, these results might provide further clues to investigate biological functions of lncRNAs and their potential target protein-coding genes in the pathogenesis of COPD.

  16. Central focused convolutional neural networks: Developing a data-driven model for lung nodule segmentation.

    PubMed

    Wang, Shuo; Zhou, Mu; Liu, Zaiyi; Liu, Zhenyu; Gu, Dongsheng; Zang, Yali; Dong, Di; Gevaert, Olivier; Tian, Jie

    2017-08-01

    Accurate lung nodule segmentation from computed tomography (CT) images is of great importance for image-driven lung cancer analysis. However, the heterogeneity of lung nodules and the presence of similar visual characteristics between nodules and their surroundings make it difficult for robust nodule segmentation. In this study, we propose a data-driven model, termed the Central Focused Convolutional Neural Networks (CF-CNN), to segment lung nodules from heterogeneous CT images. Our approach combines two key insights: 1) the proposed model captures a diverse set of nodule-sensitive features from both 3-D and 2-D CT images simultaneously; 2) when classifying an image voxel, the effects of its neighbor voxels can vary according to their spatial locations. We describe this phenomenon by proposing a novel central pooling layer retaining much information on voxel patch center, followed by a multi-scale patch learning strategy. Moreover, we design a weighted sampling to facilitate the model training, where training samples are selected according to their degree of segmentation difficulty. The proposed method has been extensively evaluated on the public LIDC dataset including 893 nodules and an independent dataset with 74 nodules from Guangdong General Hospital (GDGH). We showed that CF-CNN achieved superior segmentation performance with average dice scores of 82.15% and 80.02% for the two datasets respectively. Moreover, we compared our results with the inter-radiologists consistency on LIDC dataset, showing a difference in average dice score of only 1.98%. Copyright © 2017. Published by Elsevier B.V.

  17. Three dimensional computed tomography lung modeling is useful in simulation and navigation of lung cancer surgery.

    PubMed

    Ikeda, Norihiko; Yoshimura, Akinobu; Hagiwara, Masaru; Akata, Soichi; Saji, Hisashi

    2013-01-01

    The number of minimally invasive operations, such as video-assisted thoracoscopic surgery (VATS) lobectomy or segmentectomy, has enormously increased in recent years. These operations require extreme knowledge of the anatomy of pulmonary vessels and bronchi in each patient, and surgeons must carefully dissect the branches of pulmonary vessels during operation. Thus, foreknowledge of the anatomy of each patient would greatly contribute to the safety and accuracy of the operation. The development of multi-detector computed tomography (MDCT) has promoted three dimensional (3D) images of lung structures. It is possible to see the vascular and bronchial structures from the view of the operator; therefore, it is employed for preoperative simulation as well as navigation during operation. Due to advances in software, even small vessels can be accurately imaged, which is useful in performing segmentectomy. Surgical simulation and navigation systems based on high quality 3D lung modeling, including vascular and bronchial structures, can be used routinely to enhance the safety operation, education of junior staff, as well as providing a greater sense of security to the operators.

  18. Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma

    PubMed Central

    McFadden, David G.; Politi, Katerina; Bhutkar, Arjun; Chen, Frances K.; Song, Xiaoling; Pirun, Mono; Santiago, Philip M.; Kim-Kiselak, Caroline; Platt, James T.; Lee, Emily; Hodges, Emily; Rosebrock, Adam P.; Bronson, Roderick T.; Socci, Nicholas D.; Hannon, Gregory J.; Jacks, Tyler; Varmus, Harold

    2016-01-01

    Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity. PMID:27702896

  19. Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma.

    PubMed

    McFadden, David G; Politi, Katerina; Bhutkar, Arjun; Chen, Frances K; Song, Xiaoling; Pirun, Mono; Santiago, Philip M; Kim-Kiselak, Caroline; Platt, James T; Lee, Emily; Hodges, Emily; Rosebrock, Adam P; Bronson, Roderick T; Socci, Nicholas D; Hannon, Gregory J; Jacks, Tyler; Varmus, Harold

    2016-10-18

    Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

  20. Targeting Interleukin-13 with Tralokinumab Attenuates Lung Fibrosis and Epithelial Damage in a Humanized SCID Idiopathic Pulmonary Fibrosis Model

    PubMed Central

    Zhang, Huilan; Oak, Sameer R.; Coelho, Ana Lucia; Herath, Athula; Flaherty, Kevin R.; Lee, Joyce; Bell, Matt; Knight, Darryl A.; Martinez, Fernando J.; Sleeman, Matthew A.; Herzog, Erica L.; Hogaboam, Cory M.

    2014-01-01

    The aberrant fibrotic and repair responses in the lung are major hallmarks of idiopathic pulmonary fibrosis (IPF). Numerous antifibrotic strategies have been used in the clinic with limited success, raising the possibility that an effective therapeutic strategy in this disease must inhibit fibrosis and promote appropriate lung repair mechanisms. IL-13 represents an attractive target in IPF, but its disease association and mechanism of action remains unknown. In the present study, an overexpression of IL-13 and IL-13 pathway markers was associated with IPF, particularly a rapidly progressive form of this disease. Targeting IL-13 in a humanized experimental model of pulmonary fibrosis using tralokinumab (CAT354) was found to therapeutically block aberrant lung remodeling in this model. However, targeting IL-13 was also found to promote lung repair and to restore epithelial integrity. Thus, targeting IL-13 inhibits fibrotic processes and enhances repair processes in the lung. PMID:24325475

  1. Anti-Aspergillus Activities of the Respiratory Epithelium in Health and Disease.

    PubMed

    Bertuzzi, Margherita; Hayes, Gemma E; Icheoku, Uju J; van Rhijn, Norman; Denning, David W; Osherov, Nir; Bignell, Elaine M

    2018-01-08

    Respiratory epithelia fulfil multiple roles beyond that of gaseous exchange, also acting as primary custodians of lung sterility and inflammatory homeostasis. Inhaled fungal spores pose a continual antigenic, and potentially pathogenic, challenge to lung integrity against which the human respiratory mucosa has developed various tolerance and defence strategies. However, respiratory disease and immune dysfunction frequently render the human lung susceptible to fungal diseases, the most common of which are the aspergilloses, a group of syndromes caused by inhaled spores of Aspergillus fumigatus . Inhaled Aspergillus spores enter into a multiplicity of interactions with respiratory epithelia, the mechanistic bases of which are only just becoming recognized as important drivers of disease, as well as possible therapeutic targets. In this mini-review we examine current understanding of Aspergillus -epithelial interactions and, based upon the very latest developments in the field, we explore two apparently opposing schools of thought which view epithelial uptake of Aspergillus spores as either a curative or disease-exacerbating event.

  2. The Emulsified PFC Oxycyte® Improved Oxygen Content and Lung Injury Score in a Swine Model of Oleic Acid Lung Injury (OALI).

    PubMed

    Haque, Ashraful; Scultetus, Anke H; Arnaud, Francoise; Dickson, Leonora J; Chun, Steve; McNamee, George; Auker, Charles R; McCarron, Richard M; Mahon, Richard T

    2016-12-01

    Perfluorocarbons (PFCs) can transport 50 times more oxygen than human plasma. Their properties may be advantageous in preservation of tissue viability in oxygen-deprived states, such as in acute lung injury. We hypothesized that an intravenous dose of the PFC emulsion Oxycyte ® would improve tissue oxygenation and thereby mitigate the effects of acute lung injury. Intravenous oleic acid (OA) was used to induce lung injury in anesthetized and instrumented Yorkshire swine assigned to three experimental groups: (1) PFC post-OA received Oxycyte ® (5 ml/kg) 45 min after oleic acid-induced lung injury (OALI); (2) PFC pre-OA received Oxycyte ® 45 min before OALI; and (3) Controls which received equivalent dose of normal saline. Animals were observed for 3 h after OALI began, and then euthanized. The median survival times for PFC post-OA, PFC pre-OA, and control were 240, 87.5, and 240 min, respectively (p = 0.001). Mean arterial pressure and mean pulmonary arterial pressure were both higher in the PFC post-OA (p < 0.001 for both parameters). Oxygen content was significantly different between PFC post-OA and the control (p = 0.001). Histopathological grading of lung injury indicated that edema and congestion was significantly less severe in the PFC post-OA compared to control (p = 0.001). The intravenous PFC Oxycyte ® improves blood oxygen content and lung histology when used as a treatment after OALI, while Oxycyte ® used prior to OALI was associated with increased mortality. Further exploration in other injury models is indicated.

  3. Simulation of parametric model towards the fixed covariate of right censored lung cancer data

    NASA Astrophysics Data System (ADS)

    Afiqah Muhamad Jamil, Siti; Asrul Affendi Abdullah, M.; Kek, Sie Long; Ridwan Olaniran, Oyebayo; Enera Amran, Syahila

    2017-09-01

    In this study, simulation procedure was applied to measure the fixed covariate of right censored data by using parametric survival model. The scale and shape parameter were modified to differentiate the analysis of parametric regression survival model. Statistically, the biases, mean biases and the coverage probability were used in this analysis. Consequently, different sample sizes were employed to distinguish the impact of parametric regression model towards right censored data with 50, 100, 150 and 200 number of sample. R-statistical software was utilised to develop the coding simulation with right censored data. Besides, the final model of right censored simulation was compared with the right censored lung cancer data in Malaysia. It was found that different values of shape and scale parameter with different sample size, help to improve the simulation strategy for right censored data and Weibull regression survival model is suitable fit towards the simulation of survival of lung cancer patients data in Malaysia.

  4. Potential usefulness of a topic model-based categorization of lung cancers as quantitative CT biomarkers for predicting the recurrence risk after curative resection

    NASA Astrophysics Data System (ADS)

    Kawata, Y.; Niki, N.; Ohmatsu, H.; Satake, M.; Kusumoto, M.; Tsuchida, T.; Aokage, K.; Eguchi, K.; Kaneko, M.; Moriyama, N.

    2014-03-01

    In this work, we investigate a potential usefulness of a topic model-based categorization of lung cancers as quantitative CT biomarkers for predicting the recurrence risk after curative resection. The elucidation of the subcategorization of a pulmonary nodule type in CT images is an important preliminary step towards developing the nodule managements that are specific to each patient. We categorize lung cancers by analyzing volumetric distributions of CT values within lung cancers via a topic model such as latent Dirichlet allocation. Through applying our scheme to 3D CT images of nonsmall- cell lung cancer (maximum lesion size of 3 cm) , we demonstrate the potential usefulness of the topic model-based categorization of lung cancers as quantitative CT biomarkers.

  5. Anchored PDE4 regulates chloride conductance in wild-type and ΔF508-CFTR human airway epithelia

    PubMed Central

    Blanchard, Elise; Zlock, Lorna; Lao, Anna; Mika, Delphine; Namkung, Wan; Xie, Moses; Scheitrum, Colleen; Gruenert, Dieter C.; Verkman, Alan S.; Finkbeiner, Walter E.; Conti, Marco; Richter, Wito

    2014-01-01

    Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that impair its expression and/or chloride channel function. Here, we provide evidence that type 4 cyclic nucleotide phosphodiesterases (PDE4s) are critical regulators of the cAMP/PKA-dependent activation of CFTR in primary human bronchial epithelial cells. In non-CF cells, PDE4 inhibition increased CFTR activity under basal conditions (ΔISC 7.1 μA/cm2) and after isoproterenol stimulation (increased ΔISC from 13.9 to 21.0 μA/cm2) and slowed the return of stimulated CFTR activity to basal levels by >3-fold. In cells homozygous for ΔF508-CFTR, the most common mutation found in CF, PDE4 inhibition alone produced minimal channel activation. However, PDE4 inhibition strongly amplified the effects of CFTR correctors, drugs that increase expression and membrane localization of CFTR, and/or CFTR potentiators, drugs that increase channel gating, to reach ∼25% of the chloride conductance observed in non-CF cells. Biochemical studies indicate that PDE4s are anchored to CFTR and mediate a local regulation of channel function. Taken together, our results implicate PDE4 as an important determinant of CFTR activity in airway epithelia, and support the use of PDE4 inhibitors to potentiate the therapeutic benefits of CFTR correctors and potentiators.—Blanchard, E., Zlock, L., Lao, A., Mika, D., Namkung, W., Xie, M., Scheitrum, C., Gruenert, D.C., Verkman, A.S., Finkbeiner, W.E., Conti, M., Richter, W. Anchored PDE4 regulates chloride conductance in wild type and ΔF508-CFTR human airway epithelia. PMID:24200884

  6. Immunomodulatory Effects of Mixed Hematopoietic Chimerism: Immune Tolerance in Canine Model of Lung Transplantation

    PubMed Central

    Nash;, Richard A.; Yunosov;, Murad; Abrams;, Kraig; Hwang;, Billanna; Castilla-Llorente;, Cristina; Chen;, Peter; Farivar;, Alexander S.; Georges;, George E.; Hackman;, Robert C.; Lamm;, Wayne J.E.; Lesnikova;, Marina; Ochs;, Hans D.; Randolph-Habecker;, Julie; Ziegler;, Stephen F.; Storb;, Rainer; Storer;, Barry; Madtes;, David K.; Glenny;, Robb; Mulligan, Michael S.

    2010-01-01

    Long-term survival after lung transplantation is limited by acute and chronic graft rejection. Induction of immune tolerance by first establishing mixed hematopoietic chimerism (MC) is a promising strategy to improve outcomes. In a preclinical canine model, stable MC was established in recipients after reduced-intensity conditioning and hematopoietic cell transplantation from a DLA-identical donor. Delayed lung transplantation was performed from the stem cell donor without pharmacological immunosuppression. Lung graft survival without loss of function was prolonged in chimeric (n=5) vs. nonchimeric (n=7) recipients (p≤0.05, Fisher’s test). There were histological changes consistent with low grade rejection in 3/5 of the lung grafts in chimeric recipients at ≥1 year. Chimeric recipients after lung transplantation had a normal immune response to a T-dependent antigen. Compared to normal dogs, there were significant increases of CD4+INFγ+, CD4+IL-4+ and CD8+ INFγ+ T-cell subsets in the blood (p <0.0001 for each of the 3 T-cell subsets). Markers for regulatory T-cell subsets including foxP3, IL10 and TGFβ were also increased in CD3+ T cells from the blood and peripheral tissues of chimeric recipients after lung transplantation. Establishing MC is immunomodulatory and observed changes were consistent with activation of both the effector and regulatory immune response. PMID:19422333

  7. [Water-cooled laser sealing of lung tissue in an ex-vivo ventilated porcine lung model].

    PubMed

    Tonoyan, T; Prisadov, G; Menges, P; Herrmann, K; Bobrov, P; Linder, A

    2014-06-01

    Laser resections of lung metastases are followed by air leaks from the parenchymal defect. Large surfaces after metastasectomy are closed by sutures or sealants while smaller areas are frequently sealed thermally by cautery or laser. In this study two different techniques of thermal sealing of lung tissue with laser light are investigated. Carbonisation of lung tissue during thermal sealing appears at temperatures higher than 180 °C. Hypothetically this is contraproductive to haemo- as well as to pneumostasis. In this experimental study thermal laser sealing with and without carbonisation is investigated. In one series tissue temperatures higher than 100 °C are avoided by water dropping from the tip of the light guide onto the parenchymal leak. In the other series carbonisation appeared because the laser light was applied in the non-contact mode without tissue cooling. The characteristics of the laser were 40 W, 1350 nm continuous mode. Air leaks (Vt) were measured with a simple and fast technique with high precision. The sealing effect of either series was defined as S = (1-Vt/V0) and the difference of S was statistically examined. The basic values V0 before sealing were about the same in both series. The air leaks Vt after 15, 30 and 45 s of sealing varied significantly in both series (p = 0.03). During simultaneous cooling the sealing effect was increasing with the duration of laser application, while it became worse in the series without cooling. Histological examination of the sealing zone showed only coagulation of the tissue, while ruptured alveolae could be seen more often in the non-cooled sealing area. It could be shown in the ex-vivo lung model that laser sealing of parenchymal leaks is improved by simultaneous cooling during laser application. Non cooled laser sealing seems to heat up the tissue abruptly and create carbonisation followed by multiple ruptures of alveola and small airways. In accordance with our clinical experience this

  8. Computed tomography screening for lung cancer: results of ten years of annual screening and validation of cosmos prediction model.

    PubMed

    Veronesi, G; Maisonneuve, P; Rampinelli, C; Bertolotti, R; Petrella, F; Spaggiari, L; Bellomi, M

    2013-12-01

    It is unclear how long low-dose computed tomographic (LDCT) screening should continue in populations at high risk of lung cancer. We assessed outcomes and the predictive ability of the COSMOS prediction model in volunteers screened for 10 years. Smokers and former smokers (>20 pack-years), >50 years, were enrolled over one year (2000-2001), receiving annual LDCT for 10 years. The frequency of screening-detected lung cancers was compared with COSMOS and Bach risk model estimates. Among 1035 recruited volunteers (71% men, mean age 58 years) compliance was 65% at study end. Seventy-one (6.95%) lung cancers were diagnosed, 12 at baseline. Disease stage was: IA in 48 (66.6%); IB in 6; IIA in 5; IIB in 2; IIIA in 5; IIIB in 1; IV in 5; and limited small cell cancer in 3. Five- and ten-year survival were 64% and 57%, respectively, 84% and 65% for stage I. Ten (12.1%) received surgery for a benign lesion. The number of lung cancers detected during the first two screening rounds was close to that predicted by the COSMOS model, while the Bach model accurately predicted frequency from the third year on. Neither cancer frequency nor proportion at stage I decreased over 10 years, indicating that screening should not be discontinued. Most cancers were early stage, and overall survival was high. Only a limited number of invasive procedures for benign disease were performed. The Bach model - designed to predict symptomatic cancers - accurately predicted cancer frequency from the third year, suggesting that overdiagnosis is a minor problem in lung cancer screening. The COSMOS model - designed to estimate screening-detected lung cancers - accurately predicted cancer frequency at baseline and second screening round. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  9. Effect of CPAP in a Mouse Model of Hyperoxic Neonatal Lung Injury

    PubMed Central

    Reyburn, Brent; Fiore, Juliann M. Di; Raffay, Thomas; Martin, Richard J.; Y.S., Prakash; Jafri, Anjum; MacFarlane, Peter M.

    2015-01-01

    Background Continuous positive airway pressure [CPAP] and supplemental oxygen have become the mainstay of neonatal respiratory support in preterm infants. Although oxygen therapy is associated with respiratory morbidities including bronchopulmonary dysplasia [BPD], the long-term effects of CPAP on lung function are largely unknown. We used a hyperoxia-induced mouse model of BPD to explore the effects of daily CPAP during the first week of life on later respiratory system mechanics. Objective To test the hypothesis that daily CPAP in a newborn mouse model of BPD improves longer term respiratory mechanics. Methods Mouse pups from C57BL/6 pregnant dams were exposed to room air [RA] or hyperoxia [50% O2, 24hrs/day] for the first postnatal week with or without exposure to daily CPAP [6cmH2O, 3hrs/day]. Respiratory system resistance [Rrs] and compliance [Crs] were measured following a subsequent 2 week period of room RA recovery. Additional measurements included radial alveolar counts and macrophage counts. Results Mice exposed to hyperoxia had significantly elevated Rrs, decreased Crs, reduced alveolarization, and increased macrophage counts at three weeks compared to RA treated mice. Daily CPAP treatment significantly improved Rrs, Crs and alveolarization, and decreased lung macrophage infiltration in hyperoxia-exposed pups. Conclusions We have demonstrated that daily CPAP had a longer term benefit on baseline respiratory system mechanics in a neonatal mouse model of BPD. We speculate that this beneficial effect of CPAP was the consequence of a decrease in the inflammatory response and resultant alveolar injury associated with hyperoxic newborn lung injury. PMID:26394387

  10. Development of ferret as a human lung cancer model by injecting4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

    USDA-ARS?s Scientific Manuscript database

    Development of new animal lung cancer models that are relevant to human lung carcinogenesis is important for lung cancer research. Previously we have shown the induction of lung tumor in ferrets (Mustela putorius furo) exposed to both tobacco smoke and a tobacco carcinogen (4-(N-methyl-N-nitrosamino...

  11. Neonatal lungs: maturational changes in lung resistivity spectra.

    PubMed

    Brown, B H; Primhak, R A; Smallwood, R H; Milnes, P; Narracott, A J; Jackson, M J

    2002-09-01

    The electrical resistivity of lung tissue can be related to the structure and composition of the tissue and also to the air content. Electrical impedance tomographic measurements have been used on 155 normal children over the first three years of life and 25 pre-term infants, to determine the absolute resistivity of lung tissue as a function of frequency. The results show consistent changes with increasing age in both lung tissue resistivity (5.8 ohm m at birth to 20.9 ohm m at 3 years of age) and in the changes of resistivity with frequency (Cole parameter ratio R/S=0.41 at birth and 0.84 at 3 years of age). Comparison with a lung model showed that the measurements are consistent with maturational changes in the number and size of alveoli, the extracapillary blood volume and the size of the extracapillary vessels. However, the results show that the process of maturation is not complete at the age of three years.

  12. A three-compartment model of osmotic water exchange in the lung microvasculature.

    PubMed

    Seale, K T; Harris, T R

    2000-08-01

    A bolus injection of hypertonic NaCl into the pulmonary arterial circulation of an isolated perfused dog lung causes the osmotic movement of water first into, and then out of the capillary. The associated changes in blood constituent concentrations and density are referred to as the osmotic transient (OT). Measurement of the sound conduction velocity of effluent blood during an OT is a highly sensitive way to monitor water movement between the vascular and extravascular spaces. It was our objective to develop a mathematical model that adequately describes this transient change in the sound conduction velocity and evaluate its application under conditions of homogeneous and heterogeneous capillary flow distributions. The model accounts for osmotic water exchange between the capillary and two parallel extravascular compartments, and includes as parameters the osmotic conductances (sigmaK1 ,sigmaK2) of the two compartments. The osmotic conductance parameters incorporate the filtration coefficient for water and reflection coefficient for salt for the two pathways of water exchange. The partition of total extravascular lung water (EVLW) between the two extravascular compartments is a third parameter of the model. The homogeneous model parameter estimates (per gram wet lung weight +/-95% confidence limits) from the best-fit analysis of a typical curve were sigmaK1=2.15 +/-0.07, sigmaK2 = 0.03 + 0.00 [ml h(-1) (mosmol/liter)(-1) g(-1)] and V1 = 23.83+/-0.12 ml, with a coefficient of variation (CV) of 0.08. The heterogeneous parameter estimates for a capillary transit time distribution with mean transit time (MTTc) = 1.72 s, and relative dispersion (RDc) = 0.35 were KI = 2.38+/-0.05, or K2 = 0.03+/-0.00 [ml h(-1) (mosmol/liter)(-1) g(-1)], V1 = 23.91+/-0.08 ml, and CV=0.05. EVLW was 42.1 ml for both models. We conclude that the three-compartment mathematical model adequately describes a typical OT under both homogeneous and heterogeneous blood flow assumptions.

  13. A one-dimensional model for the propagation of transient pressure waves through the lung.

    PubMed

    Grimal, Quentin; Watzky, Alexandre; Naili, Salah

    2002-08-01

    The propagation of pressure waves in the lung has been investigated by many authors concerned with respiratory physiology, ultrasound medical techniques or thoracic impact injuries. In most of the theoretical studies, the lung has been modeled as an isotropic and homogeneous medium, and by using Hooke's constitutive law (see e.g. Ganesan et al. Respir. Physiol. 110 (1997) 19; Jahed et al. J. Appl. Physiol. 66 (1989) 2675; Grimal et al. C.R. Acad. Sci., Paris 329 (IIb) (2001) 655-662), or more elaborated material laws (see, e.g. Bush and Challener (Proceedings of the International Research Council on Biokinetics Impacts (IRCOBI), Bergish-gladbach, 1988); Stuhmiller et al. J. Trauma 28 (1988) S132; Yang and Wang, Finite element modeling of the human thorax. Web page: http://wwwils.nlm.nih.gov/research/visible/vhpconf98/AUTHORS/YANG/YANG.HTM.). The hypothesis of homogeneous medium may be inappropriate for certain problems. Because of its foam-like structure, the behavior of the lung-even if the air and the soft tissue are assumed to behave like linearly elastic materials-is susceptible to be frequency dependent. In the present study, the lung is viewed as a one-dimensional stack of air and soft tissue layers; wave propagation in such a stack can be investigated in an equivalent mass-spring chain (El-Raheb (J. Acoust. Soc. Am. 94 (1993) 172; Int. J. Solids Struct. 34 (1997) 2969), where the masses and springs, respectively, represent the alveolar walls and alveolar gas. Results are presented in the time and frequency domains. The frequency dependence (cutoff frequency, variations in phase velocity) of the lung model is found to be highly dependent on the mean alveolar size. We found that short pulses induced by high velocity impacts (bullet stopped by a bulletproof jacket) can be highly distorted during the propagation. The pressure differential between two alveoli is discussed as a possible injury criterion.

  14. Mint3 in bone marrow-derived cells promotes lung metastasis in breast cancer model mice.

    PubMed

    Hara, Toshiro; Murakami, Yoshinori; Seiki, Motoharu; Sakamoto, Takeharu

    2017-08-26

    Breast cancer is one of the most common cancers in women in the world. Although breast cancer is well treatable at the early stage, patients with distant metastases show a poor prognosis. Data from recent studies using transplantation models indicate that Mint3/APBA3 might promote breast cancer malignancy. However, whether Mint3 indeed contributes to tumor development, progression, or metastasis in vivo remains unclear. To address this, here we examined whether Mint3 depletion affects tumor malignancy in MMTV-PyMT breast cancer model mice. In MMTV-PyMT mice, Mint3 depletion did not affect tumor onset and tumor growth, but attenuated lung metastases. Experimental lung metastasis of breast cancer Met-1 cells derived from MMTV-PyMT mice also decreased in Mint3-depleted mice, indicating that host Mint3 expression affected lung metastasis of MMTV-PyMT-derived breast cancer cells. Further bone marrow transplant experiments revealed that Mint3 in bone marrow-derived cells promoted lung metastasis in MMTV-PyMT mice. Thus, targeting Mint3 in bone marrow-derived cells might be a good strategy for preventing metastasis and improving the prognosis of breast cancer patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury.

    PubMed

    Ribeiro, A; Almeida, V I; Costola-de-Souza, C; Ferraz-de-Paula, V; Pinheiro, M L; Vitoretti, L B; Gimenes-Junior, J A; Akamine, A T; Crippa, J A; Tavares-de-Lima, W; Palermo-Neto, J

    2015-02-01

    We have previously shown that the prophylactic treatment with cannabidiol (CBD) reduces inflammation in a model of acute lung injury (ALI). In this work we analyzed the effects of the therapeutic treatment with CBD in mice subjected to the model of lipopolysaccharide (LPS)-induced ALI on pulmonary mechanics and inflammation. CBD (20 and 80 mg/kg) was administered (i.p.) to mice 6 h after LPS-induced lung inflammation. One day (24 h) after the induction of inflammation the assessment of pulmonary mechanics and inflammation were analyzed. The results show that CBD decreased total lung resistance and elastance, leukocyte migration into the lungs, myeloperoxidase activity in the lung tissue, protein concentration and production of pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) in the bronchoalveolar lavage supernatant. Thus, we conclude that CBD administered therapeutically, i.e. during an ongoing inflammatory process, has a potent anti-inflammatory effect and also improves the lung function in mice submitted to LPS-induced ALI. Therefore the present and previous data suggest that in the future cannabidiol might become a useful therapeutic tool for the attenuation and treatment of inflammatory lung diseases.

  16. Cost-effectiveness of gemcitabine in stage IV non-small cell lung cancer: an estimate using the Population Health Model lung cancer module.

    PubMed

    Evans, W K

    1997-04-01

    Statistics Canada (Ottawa, Ontario, Canada) is in the process of developing the Population Health Model to simulate the health and common illnesses of Canadians. The Population Health Model incorporates a lung cancer module that is based on contemporary Canadian practice. This microsimulation model can be used to estimate the total direct care costs of treating all lung cancer cases diagnosed in Canada and to evaluate the cost and cost-effectiveness of new therapeutic interventions as they are introduced into practice. Gemcitabine, a new nucleoside analogue with a broad spectrum of antitumor activity, is about to be introduced on the Canadian market. The Population Health Model has been used to estimate the cost-effectiveness of gemcitabine in the management of lung cancer over a range of drug doses per treatment cycle starting at 1,000 mg/m2 weekly x 3, as well as potential survival benefits. The survival of stage IV non-small cell lung cancer (NSCLC) patients treated on an international trial of gemcitabine (EO-18) was used to estimate the potential survival gain relative to the survival of stage IV NSCLC patients managed with best supportive care on a randomized trial conducted by the National Cancer Institute of Canada (BR 5). Sensitivity analyses were performed assuming that the survival gain was 25% or 50% less than that reported in the EO-18 trial. The perspective of the economic analysis is that of the government as payer in a universal health care system, and all costs are expressed in 1993 Canadian dollars. Based on the apparent survival advantage of the EO-18 trial in comparison to best supportive care, the cost per life-year gained ranged from $632 to $9,285, depending on the dose per treatment cycle. At the highest dose per cycle (2,000 mg/m2) and with survival reduced by 50% as compared with the EO-18 result, the cost per life-year gained was estimated to be $17,390. From these estimates of direct care costs in the Canadian health care system

  17. Effects of Chinese medicinal herbs on a rat model of chronic Pseudomonas aeruginosa lung infection.

    PubMed

    Song, Z; Johansen, H K; Moser, C; Høiby, N

    1996-05-01

    The aim of the study was to evaluate the effects of two kinds of Chinese medicinal herbs, Isatis tinctoria L (ITL) and Daphne giraldii Nitsche (DGN), on a rat model of chronic Pseudomonas aeruginosa lung infection mimicking cystic fibrosis (CF). Compared to the control group, both drugs were able to reduce the incidence of lung abscess (p < 0.05) and to decrease the severity of the macroscopic pathology in lungs (p < 0.05). In the great majority of the rats, the herbs altered the inflammatory response in the lungs from an acute type inflammation, dominated by polymorphonuclear leukocytes (PMN), to a chronic type inflammation, dominated by mononuclear leukocytes (MN). DGN also improved the clearance of P. aeruginosa from the lungs (p < 0.03) compared with the control group. There were no significant differences between the control group and the two herbal groups with regard to serum IgG and IgA anti-P. aeruginosa sonicate antibodies. However, the IgM concentration in the ITL group was significantly lower than in the control group (p < 0.03). These results suggest that the two medicinal herbs might be helpful to CF patients with chronic P. aeruginosa lung infection, DGN being the most favorable.

  18. Can Stem Cells be Used to Generate New Lungs? Ex Vivo Lung Bioengineering with Decellularized Whole Lung Scaffolds

    PubMed Central

    Wagner, Darcy E.; Bonvillain, Ryan W.; Jensen, Todd J.; Girard, Eric D.; Bunnell, Bruce A.; Finck, Christine M.; Hoffman, Andrew M.; Weiss, Daniel J.

    2013-01-01

    For patients with end-stage lung diseases, lung transplantation is the only available therapeutic option. However, the number of suitable donor lungs is insufficient and lung transplants are complicated by significant graft failure and complications of immunosuppressive regimens. An alternative to classic organ replacement is desperately needed. Engineering of bioartificial organs using either natural or synthetic scaffolds is an exciting new potential option for generation of functional pulmonary tissue for human clinical application. Natural organ scaffolds can be generated by decellularization of native tissues; these acellular scaffolds retain the native organ ultrastructure and can be seeded with autologous cells toward the goal of regenerating functional tissues. Several decellularization strategies have been employed for lung, however, there is no consensus on the optimal approach. A variety of cell types have been investigated as potential candidates for effective recellularization of acellular lung scaffolds. Candidate cells that might be best utilized are those which can be easily and reproducibly isolated, expanded in vitro, seeded onto decellularized matrices, induced to differentiate into pulmonary lineage cells, and which survive to functional maturity. Whole lung cell suspensions, endogenous progenitor cells, embryonic and adult stem cells, and induced pluripotent stem (iPS) cells have been investigated for their applicability to repopulate acellular lung matrices. Ideally, patient-derived autologous cells would be used for lung recellularization as they have the potential to reduce the need for post-transplant immunosuppression. Several studies have performed transplantation of rudimentary bioengineered lung scaffolds in animal models with limited, short-term functionality but much further study is needed. PMID:23614471

  19. Lung deformations and radiation-induced regional lung collapse in patients treated with stereotactic body radiation therapy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Diot, Quentin, E-mail: quentin.diot@ucdenver.edu; Kavanagh, Brian; Vinogradskiy, Yevgeniy

    2015-11-15

    Purpose: To differentiate radiation-induced fibrosis from regional lung collapse outside of the high dose region in patients treated with stereotactic body radiation therapy (SBRT) for lung tumors. Methods: Lung deformation maps were computed from pre-treatment and post-treatment computed tomography (CT) scans using a point-to-point translation method. Fifty anatomical landmarks inside the lung (vessel or airway branches) were matched on planning and follow-up scans for the computation process. Two methods using the deformation maps were developed to differentiate regional lung collapse from fibrosis: vector field and Jacobian methods. A total of 40 planning and follow-ups CT scans were analyzed for 20more » lung SBRT patients. Results: Regional lung collapse was detected in 15 patients (75%) using the vector field method, in ten patients (50%) using the Jacobian method, and in 12 patients (60%) by radiologists. In terms of sensitivity and specificity the Jacobian method performed better. Only weak correlations were observed between the dose to the proximal airways and the occurrence of regional lung collapse. Conclusions: The authors presented and evaluated two novel methods using anatomical lung deformations to investigate lung collapse and fibrosis caused by SBRT treatment. Differentiation of these distinct physiological mechanisms beyond what is usually labeled “fibrosis” is necessary for accurate modeling of lung SBRT-induced injuries. With the help of better models, it becomes possible to expand the therapeutic benefits of SBRT to a larger population of lung patients with large or centrally located tumors that were previously considered ineligible.« less

  20. Rebuilding the Injured Lung

    PubMed Central

    2015-01-01

    The 57th annual Thomas L. Petty Aspen Lung Conference, entitled “Rebuilding the Injured Lung,” was held from June 4 to 7, 2014 at the Gant Conference Center in Aspen, Colorado. Investigators from a wide range of disciplines and perspectives convened to discuss the biology of lung injury, how the lung repairs itself, how and why repair fails, and how the repair process can be enhanced. Among the challenges identified in the course of the conference was how to develop more predictive experimental models that capture the multidimensional complexity of lung injury and repair in a tractable manner. From such approaches that successfully fuse the biological and physical sciences, the group envisioned that new therapies for acute and chronic lung injury would emerge. The discussion of experimental therapeutics ranged from pharmaceuticals and cells that interdict fibrosis and enhance repair to a de novo lung derived from stem cells repopulating a decellularized matrix. PMID:25830839

  1. Impact of mechanical stress on ion transport in native lung epithelium (Xenopus laevis): short-term activation of Na+, Cl (-) and K+ channels.

    PubMed

    Bogdan, Roman; Veith, Christine; Clauss, Wolfgang; Fronius, Martin

    2008-09-01

    Epithelia, in general, and the lung epithelium, in particular, are exposed to mechanical forces, but little is known about their impact on pulmonary ion transport. In our present study, we employed transepithelial ion transport measurements on Xenopus lung preparations using custom-built Ussing chambers. Tissues were exposed to mechanical stress by increasing the water column (5 cm) at one side of the tissues. Apical exposure to hydrostatic pressure significantly decreased the short circuit current (I (SC): 24 +/- 1%, n = 152), slightly decreased the transepithelial resistance (R (T): 7 +/- 2%, n = 152), but increased the apical membrane capacitance (C (M): 16 +/- 6%, n = 9). The pressure-induced effect was sensitive to Na+ (amiloride), Cl(-) (DIDS, NFA, NPPB) and K+ channel blockers (Ba2+), glibenclamide). Further on, it was accompanied by increased extracellular ATP levels. The results show that mechanical stress leads to an activation of Na+, Cl(-), and K+ conductances in a native pulmonary epithelium resulting in a net decrease of ion absorption. This could be of considerable interest, since an altered ion transport may contribute to pathophysiological conditions, e.g., the formation of pulmonary edema during artificial ventilation.

  2. PGE(2) activation of apical membrane Cl(-) channels in A6 epithelia: impedance analysis.

    PubMed Central

    Păunescu, T G; Helman, S I

    2001-01-01

    Measurements of transepithelial electrical impedance of continuously short-circuited A6 epithelia were made at audio frequencies (0.244 Hz to 10.45 kHz) to investigate the time course and extent to which prostaglandin E(2) (PGE(2)) modulates Cl(-) transport and apical membrane capacitance in this cell-cultured model epithelium. Apical and basolateral membrane resistances were determined by nonlinear curve-fitting of the impedance vectors at relatively low frequencies (<50 Hz) to equations (Păunescu, T. G., and S. I. Helman. 2001. Biophys. J. 81:838--851) where depressed Nyquist impedance semicircles were characteristic of the membrane impedances under control Na(+)-transporting and amiloride-inhibited conditions. In all tissues (control, amiloride-blocked, and amiloride-blocked and furosemide-pretreated), PGE(2) caused relatively small (< approximately 3 microA/cm(2)) and rapid (<60 s) maximal increase of chloride current due to activation of a rather large increase of apical membrane conductance that preceded significant activation of Na(+) transport through amiloride-sensitive epithelial Na(+) channels (ENaCs). Apical membrane capacitance was frequency-dependent with a Cole-Cole dielectric dispersion whose relaxation frequency was near 150 Hz. Analysis of the time-dependent changes of the complex frequency-dependent equivalent capacitance of the cells at frequencies >1.5 kHz revealed that the mean 9.8% increase of capacitance caused by PGE(2) was not correlated in time with activation of chloride conductance, but rather correlated with activation of apical membrane Na(+) transport. PMID:11463630

  3. Radiobiological modeling of two stereotactic body radiotherapy schedules in patients with stage I peripheral non-small cell lung cancer.

    PubMed

    Huang, Bao-Tian; Lin, Zhu; Lin, Pei-Xian; Lu, Jia-Yang; Chen, Chuang-Zhen

    2016-06-28

    This study aims to compare the radiobiological response of two stereotactic body radiotherapy (SBRT) schedules for patients with stage I peripheral non-small cell lung cancer (NSCLC) using radiobiological modeling methods. Volumetric modulated arc therapy (VMAT)-based SBRT plans were designed using two dose schedules of 1 × 34 Gy (34 Gy in 1 fraction) and 4 × 12 Gy (48 Gy in 4 fractions) for 19 patients diagnosed with primary stage I NSCLC. Dose to the gross target volume (GTV), planning target volume (PTV), lung and chest wall (CW) were converted to biologically equivalent dose in 2 Gy fraction (EQD2) for comparison. Five different radiobiological models were employed to predict the tumor control probability (TCP) value. Three additional models were utilized to estimate the normal tissue complication probability (NTCP) value for the lung and the modified equivalent uniform dose (mEUD) value to the CW. Our result indicates that the 1 × 34 Gy dose schedule provided a higher EQD2 dose to the tumor, lung and CW. Radiobiological modeling revealed that the TCP value for the tumor, NTCP value for the lung and mEUD value for the CW were 7.4% (in absolute value), 7.2% (in absolute value) and 71.8% (in relative value) higher on average, respectively, using the 1 × 34 Gy dose schedule.

  4. [The efficacy of traditional Chinese medicin in animal model of lung injury induced by paraquat: a meta-analysis].

    PubMed

    Wang, Lei; Hong, Guangliang; Li, Dong; Chen, Xiao; Han, Wenwen; Lu, Zhongqiu

    2014-06-01

    To systematically review the effect of traditional Chinese medicine (TCM) in an animal model of lung injury induced by paraquat (PQ), and to provide a theoretical basis for future clinical trials. The Wanfang, CNKI, VIP, PubMed/MEDLINE, EMBASE database (from January 1979 to September 2012) were searched. All papers concerning TCM in animal model of lung injury induced by PQ were retrieved. Study selection and data extraction were performed on the basis of Cochrane systematic review methods. Weighted mean difference (WMD) and 95% confidence interval (95%CI) with random effects model was adopted to investigate the effect of TCM on lung injury induced by PQ. Eighteen papers involving 1 188 rats met our criteria. Meta-analysis showed that TCM could improve the lung coefficiency (WMD -0.07, 95%CI -0.14 to -0.01, P=0.03), reduce lung wet/dry weight ratio (WMD -1.15, 95%CI -2.03 to -0.27, P=0.01), increase the serum superoxide dismutase (SOD) activity (WMD 56.08, 95%CI 23.46 to 88.70, P=0.000 8), improve plasma glutathione peroxidase (GSH-Px) level (WMD 26.64, 95%CI 18.95 to 34.33, P<0.000 01), and lower serum malondialdehyde(MDA) level (WMD -0.65, 95%CI -1.00 to -0.30, P=0.000 2), however there was no significant difference in the level of serum tumor necrosis factor-α (TNF-α) and hydroxyproline(HYP) level between TCM and controls (TNF-α: WMD -25.15, 95%CI -54.87 to 4.57, P=0.10; HYP: WMD -0.11, 95%CI -2.71 to 0.48, P=0.17). These findings demonstrate the efficacy of TCM in animal models of lung injury induced by PQ. However taking account of heterogeneity, the efficacy should be interpreted with caution.

  5. Aerobic Exercise Decreases Lung Inflammation by IgE Decrement in an OVA Mice Model.

    PubMed

    Camargo Hizume-Kunzler, Deborah; Greiffo, Flavia R; Fortkamp, Bárbara; Ribeiro Freitas, Gabriel; Keller Nascimento, Juliana; Regina Bruggemann, Thayse; Melo Avila, Leonardo; Perini, Adenir; Bobinski, Franciane; Duarte Silva, Morgana; Rocha Lapa, Fernanda; Paula Vieira, Rodolfo; Vargas Horewicz, Verônica; Soares Dos Santos, Adair Roberto; Cattelan Bonorino, Kelly

    2017-06-01

    Aerobic exercise (AE) reduces lung function decline and risk of exacerbations in asthmatic patients. However, the inflammatory lung response involved in exercise during the sensitization remains unclear. Therefore, we evaluated the effects of exercise for 2 weeks in an experimental model of sensitization and single ovalbumin-challenge. Mice were divided into 4 groups: mice non-sensitized and not submitted to exercise (Sedentary, n=10); mice non-sensitized and submitted to exercise (Exercise, n=10); mice sensitized and exposed to ovalbumin (OVA, n=10); and mice sensitized, submitted to exercise and exposed to OVA (OVA+Exercise, n=10). 24 h after the OVA/saline exposure, we counted inflammatory cells from bronchoalveolar fluid (BALF), lung levels of total IgE, IL-4, IL-5, IL-10 and IL-1ra, measurements of OVA-specific IgG1 and IgE, and VEGF and NOS-2 expression via western blotting. AE reduced cell counts from BALF in the OVA group (p<0.05), total IgE, IL-4 and IL-5 lung levels and OVA-specific IgE and IgG1 titers (p<0.05). There was an increase of NOS-2 expression, IL-10 and IL-1ra lung levels in the OVA groups (p<0.05). Our results showed that AE attenuated the acute lung inflammation, suggesting immunomodulatory properties on the sensitization process in the early phases of antigen presentation in asthma. © Georg Thieme Verlag KG Stuttgart · New York.

  6. A Prediction Model for ROS1-Rearranged Lung Adenocarcinomas based on Histologic Features

    PubMed Central

    Zheng, Jing; Kong, Mei; Sun, Ke; Wang, Bo; Chen, Xi; Ding, Wei; Zhou, Jianying

    2016-01-01

    Aims To identify the clinical and histological characteristics of ROS1-rearranged non-small-cell lung carcinomas (NSCLCs) and build a prediction model to prescreen suitable patients for molecular testing. Methods and Results We identified 27 cases of ROS1-rearranged lung adenocarcinomas in 1165 patients with NSCLCs confirmed by real-time PCR and FISH and performed univariate and multivariate analyses to identify predictive factors associated with ROS1 rearrangement and finally developed prediction model. Detected with ROS1 immunochemistry, 59 cases of 1165 patients had a certain degree of ROS1 expression. Among these cases, 19 cases (68%, 19/28) with 3+ and 8 cases (47%, 8/17) with 2+ staining were ROS1 rearrangement verified by real-time PCR and FISH. In the resected group, the acinar-predominant growth pattern was the most commonly observed (57%, 8/14), while in the biopsy group, solid patterns were the most frequently observed (78%, 7/13). Based on multiple logistic regression analysis, we determined that female sex, cribriform structure and the presence of psammoma body were the three most powerful indicators of ROS1 rearrangement, and we have developed a predictive model for the presence of ROS1 rearrangements in lung adenocarcinomas. Conclusions Female, cribriform structure and presence of psammoma body were the three most powerful indicator of ROS1 rearrangement status, and predictive formula was helpful in screening ROS1-rearranged NSCLC, especially for ROS1 immunochemistry equivocal cases. PMID:27648828

  7. A Prediction Model for ROS1-Rearranged Lung Adenocarcinomas based on Histologic Features.

    PubMed

    Zhou, Jianya; Zhao, Jing; Zheng, Jing; Kong, Mei; Sun, Ke; Wang, Bo; Chen, Xi; Ding, Wei; Zhou, Jianying

    2016-01-01

    To identify the clinical and histological characteristics of ROS1-rearranged non-small-cell lung carcinomas (NSCLCs) and build a prediction model to prescreen suitable patients for molecular testing. We identified 27 cases of ROS1-rearranged lung adenocarcinomas in 1165 patients with NSCLCs confirmed by real-time PCR and FISH and performed univariate and multivariate analyses to identify predictive factors associated with ROS1 rearrangement and finally developed prediction model. Detected with ROS1 immunochemistry, 59 cases of 1165 patients had a certain degree of ROS1 expression. Among these cases, 19 cases (68%, 19/28) with 3+ and 8 cases (47%, 8/17) with 2+ staining were ROS1 rearrangement verified by real-time PCR and FISH. In the resected group, the acinar-predominant growth pattern was the most commonly observed (57%, 8/14), while in the biopsy group, solid patterns were the most frequently observed (78%, 7/13). Based on multiple logistic regression analysis, we determined that female sex, cribriform structure and the presence of psammoma body were the three most powerful indicators of ROS1 rearrangement, and we have developed a predictive model for the presence of ROS1 rearrangements in lung adenocarcinomas. Female, cribriform structure and presence of psammoma body were the three most powerful indicator of ROS1 rearrangement status, and predictive formula was helpful in screening ROS1-rearranged NSCLC, especially for ROS1 immunochemistry equivocal cases.

  8. A Validated Clinical Risk Prediction Model for Lung Cancer in Smokers of All Ages and Exposure Types: A HUNT Study.

    PubMed

    Markaki, Maria; Tsamardinos, Ioannis; Langhammer, Arnulf; Lagani, Vincenzo; Hveem, Kristian; Røe, Oluf Dimitri

    2018-05-01

    Lung cancer causes >1·6 million deaths annually, with early diagnosis being paramount to effective treatment. Here we present a validated risk assessment model for lung cancer screening. The prospective HUNT2 population study in Norway examined 65,237 people aged >20years in 1995-97. After a median of 15·2years, 583 lung cancer cases had been diagnosed; 552 (94·7%) ever-smokers and 31 (5·3%) never-smokers. We performed multivariable analyses of 36 candidate risk predictors, using multiple imputation of missing data and backwards feature selection with Cox regression. The resulting model was validated in an independent Norwegian prospective dataset of 45,341 ever-smokers, in which 675 lung cancers had been diagnosed after a median follow-up of 11·6years. Our final HUNT Lung Cancer Model included age, pack-years, smoking intensity, years since smoking cessation, body mass index, daily cough, and hours of daily indoors exposure to smoke. External validation showed a 0·879 concordance index (95% CI [0·866-0·891]) with an area under the curve of 0·87 (95% CI [0·85-0·89]) within 6years. Only 22% of ever-smokers would need screening to identify 81·85% of all lung cancers within 6years. Our model of seven variables is simple, accurate, and useful for screening selection. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  9. Epidemiology of Lung Cancer

    PubMed Central

    Brock, Malcolm V.; Ford, Jean G.; Samet, Jonathan M.; Spivack, Simon D.

    2013-01-01

    Background: Ever since a lung cancer epidemic emerged in the mid-1900s, the epidemiology of lung cancer has been intensively investigated to characterize its causes and patterns of occurrence. This report summarizes the key findings of this research. Methods: A detailed literature search provided the basis for a narrative review, identifying and summarizing key reports on population patterns and factors that affect lung cancer risk. Results: Established environmental risk factors for lung cancer include smoking cigarettes and other tobacco products and exposure to secondhand tobacco smoke, occupational lung carcinogens, radiation, and indoor and outdoor air pollution. Cigarette smoking is the predominant cause of lung cancer and the leading worldwide cause of cancer death. Smoking prevalence in developing nations has increased, starting new lung cancer epidemics in these nations. A positive family history and acquired lung disease are examples of host factors that are clinically useful risk indicators. Risk prediction models based on lung cancer risk factors have been developed, but further refinement is needed to provide clinically useful risk stratification. Promising biomarkers of lung cancer risk and early detection have been identified, but none are ready for broad clinical application. Conclusions: Almost all lung cancer deaths are caused by cigarette smoking, underscoring the need for ongoing efforts at tobacco control throughout the world. Further research is needed into the reasons underlying lung cancer disparities, the causes of lung cancer in never smokers, the potential role of HIV in lung carcinogenesis, and the development of biomarkers. PMID:23649439

  10. Local Origin of Mesenchymal Cells in a Murine Orthotopic Lung Transplantation Model of Bronchiolitis Obliterans

    PubMed Central

    Mimura, Takeshi; Walker, Natalie; Aoki, Yoshiro; Manning, Casey M.; Murdock, Benjamin J.; Myers, Jeffery L.; Lagstein, Amir; Osterholzer, John J.; Lama, Vibha N.

    2016-01-01

    Bronchiolitis obliterans is the leading cause of chronic graft failure and long-term mortality in lung transplant recipients. Here, we used a novel murine model to characterize allograft fibrogenesis within a whole-lung microenvironment. Unilateral left lung transplantation was performed in mice across varying degrees of major histocompatibility complex mismatch combinations. B6D2F1/J (a cross between C57BL/6J and DBA/2J) (Haplotype H2b/d) lungs transplanted into DBA/2J (H2d) recipients were identified to show histopathology for bronchiolitis obliterans in all allogeneic grafts. Time course analysis showed an evolution from immune cell infiltration of the bronchioles and vessels at day 14, consistent with acute rejection and lymphocytic bronchitis, to subepithelial and intraluminal fibrotic lesions of bronchiolitis obliterans by day 28. Allografts at day 28 showed a significantly higher hydroxyproline content than the isografts (33.21 ± 1.89 versus 22.36 ± 2.33 μg/mL). At day 40 the hydroxyproline content had increased further (48.91 ± 7.09 μg/mL). Flow cytometric analysis was used to investigate the origin of mesenchymal cells in fibrotic allografts. Collagen I–positive cells (89.43% ± 6.53%) in day 28 allografts were H2Db positive, showing their donor origin. This novel murine model shows consistent and reproducible allograft fibrogenesis in the context of single-lung transplantation and represents a major step forward in investigating mechanisms of chronic graft failure. PMID:25848843

  11. Development of New Mouse Lung Tumor Models Expressing EGFR T790M Mutants Associated with Clinical Resistance to Kinase Inhibitors

    PubMed Central

    Regales, Lucia; Balak, Marissa N.; Gong, Yixuan; Politi, Katerina; Sawai, Ayana; Le, Carl; Koutcher, Jason A.; Solit, David B.; Rosen, Neal; Zakowski, Maureen F.; Pao, William

    2007-01-01

    Background The EGFR T790M mutation confers acquired resistance to kinase inhibitors in human EGFR mutant lung adenocarcinoma, is occasionally detected before treatment, and may confer genetic susceptibility to lung cancer. Methodology/Principal Findings To study further its role in lung tumorigenesis, we developed mice with inducible expression in type II pneumocytes of EGFRT790M alone or together with a drug-sensitive L858R mutation. Both transgenic lines develop lung adenocarcinomas that require mutant EGFR for tumor maintenance but are resistant to an EGFR kinase inhibitor. EGFRL858R+T790M-driven tumors are transiently targeted by hsp90 inhibition. Notably, EGFRT790M-expressing animals develop tumors with longer latency than EGFRL858R+T790M-bearing mice and in the absence of additional kinase domain mutations. Conclusions/Significance These new mouse models of mutant EGFR-dependent lung adenocarcinomas provide insight into clinical observations. The models should also be useful for developing improved therapies for patients with lung cancers harboring EGFRT790M alone or in conjunction with drug-sensitive EGFR kinase domain mutations. PMID:17726540

  12. Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors.

    PubMed

    Regales, Lucia; Balak, Marissa N; Gong, Yixuan; Politi, Katerina; Sawai, Ayana; Le, Carl; Koutcher, Jason A; Solit, David B; Rosen, Neal; Zakowski, Maureen F; Pao, William

    2007-08-29

    The EGFR T790M mutation confers acquired resistance to kinase inhibitors in human EGFR mutant lung adenocarcinoma, is occasionally detected before treatment, and may confer genetic susceptibility to lung cancer. To study further its role in lung tumorigenesis, we developed mice with inducible expression in type II pneumocytes of EGFR(T790M) alone or together with a drug-sensitive L858R mutation. Both transgenic lines develop lung adenocarcinomas that require mutant EGFR for tumor maintenance but are resistant to an EGFR kinase inhibitor. EGFR(L858R+T790M)-driven tumors are transiently targeted by hsp90 inhibition. Notably, EGFR(T790M)-expressing animals develop tumors with longer latency than EGFR(L858R+T790M)-bearing mice and in the absence of additional kinase domain mutations. These new mouse models of mutant EGFR-dependent lung adenocarcinomas provide insight into clinical observations. The models should also be useful for developing improved therapies for patients with lung cancers harboring EGFR(T790M) alone or in conjunction with drug-sensitive EGFR kinase domain mutations.

  13. The effects of exogenous surfactant treatment in a murine model of two-hit lung injury.

    PubMed

    Zambelli, Vanessa; Bellani, Giacomo; Amigoni, Maria; Grassi, Alice; Scanziani, Margherita; Farina, Francesca; Latini, Roberto; Pesenti, Antonio

    2015-02-01

    Because pulmonary endogenous surfactant is altered during acute respiratory distress syndrome, surfactant replacement may improve clinical outcomes. However, trials of surfactant use have had mixed results. We designed this animal model of unilateral (right) lung injury to explore the effect of exogenous surfactant administered to the injured lung on inflammation in the injured and noninjured lung. Mice underwent hydrochloric acid instillation (1.5 mL/kg) into the right bronchus and prolonged (7 hours) mechanical ventilation (25 mL/kg). After 3 hours, mice were treated with 1 mL/kg exogenous surfactant (Curosurf®) (surf group) or sterile saline (NaCl 0.9%) (vehicle group) in the injured (right) lung or did not receive any treatment (hydrochloric acid, ventilator-induced lung injury). Gas exchange, lung compliance, and bronchoalveolar inflammation (cells, albumin, and cytokines) were evaluated. After a significant analysis of variance (ANOVA) test, Tukey post hoc test was used for statistical analysis. At least 8 to 10 mice in each group were analyzed for each evaluated variable. Surfactant treatment significantly increased both the arterial oxygen tension to fraction of inspired oxygen ratio and respiratory system static compliance (P = 0.027 and P = 0.007, respectively, for surf group versus vehicle). Surfactant therapy increased indices of inflammation in the acid-injured lung compared with vehicle: inflammatory cells (685 [602-773] and 216 [125-305] × 1000/mL, respectively; P < 0.001) and albumin in bronchoalveolar lavage (BAL) (1442 ± 588 and 743 ± 647 μg/mL, respectively; P = 0.027). These differences were not found (P = 0.96 and P = 0.54) in the contralateral (uninjured) lung (inflammatory cells 131 [78-195] and 119 [87-149] × 1000/mL and albumin 135 ± 100 and 173 ± 115 μg/mL). Exogenous surfactant administration to an acid-injured right lung improved gas exchange and whole respiratory system compliance. However, markers of inflammation increased in

  14. A modeling study of the effect of gravity on airflow distribution and particle deposition in the lung.

    PubMed

    Asgharian, Bahman; Price, Owen; Oberdörster, Gunter

    2006-06-01

    Inhalation of particles generated as a result of thermal degradation from fire or smoke, as may occur on spacecraft, is of major health concern to space-faring countries. Knowledge of lung airflow and particle transport under different gravity environments is required to addresses this concern by providing information on particle deposition. Gravity affects deposition of particles in the lung in two ways. First, the airflow distribution among airways is changed in different gravity environments. Second, particle losses by sedimentation are enhanced with increasing gravity. In this study, a model of airflow distribution in the lung that accounts for the influence of gravity was used for a mathematical description of particle deposition in the human lung to calculate lobar, regional, and local deposition of particles in different gravity environments. The lung geometry used in the mathematical model contained five lobes that allowed the assessment of lobar ventilation distribution and variation of particle deposition. At zero gravity, it was predicted that all lobes of the lung expanded and contracted uniformly, independent of body position. Increased gravity in the upright position increased the expansion of the upper lobes and decreased expansion of the lower lobes. Despite a slight increase in predicted deposition of ultrafine particles in the upper lobes with decreasing gravity, deposition of ultrafine particles was generally predicted to be unaffected by gravity. Increased gravity increased predicted deposition of fine and coarse particles in the tracheobronchial region, but that led to a reduction or even elimination of deposition in the alveolar region for coarse particles. The results from this study show that existing mathematical models of particle deposition at 1 G can be extended to different gravity environments by simply correcting for a gravity constant. Controlled studies in astronauts on future space missions are needed to validate these predictions.

  15. Hydrogen coadministration slows the development of COPD-like lung disease in a cigarette smoke-induced rat model.

    PubMed

    Liu, Xiaoyu; Ma, Cuiqing; Wang, Xiaoyu; Wang, Wenjing; Li, Zhu; Wang, Xiansheng; Wang, Pengyu; Sun, Wuzhuang; Xue, Baojian

    2017-01-01

    Chronic obstructive pulmonary disease (COPD) is a progressive pulmonary disease caused by harmful gases or particles. Recent studies have shown that 2% hydrogen or hydrogen water is effective in the treatment and prevention of a variety of diseases. This study investigated the beneficial effects and the possible mechanisms of different hydrogen concentrations on COPD. A rat COPD model was established through smoke exposure methods, and inhalation of different concentrations of hydrogen was used as the intervention. The daily condition of rats and the weight changes were observed; lung function and right ventricular hypertrophy index were assessed. Also, white blood cells were assessed in bronchoalveolar lavage fluid. Pathologic changes in the lung tissue were analyzed using light microscopy and electron microscopy; cardiovascular structure and pulmonary arterial pressure changes in rats were observed using ultrasonography. Tumor necrosis factor alpha, interleukin (IL)-6, IL-17, IL-23, matrix metalloproteinase-12, tissue inhibitor of metalloproteinase-1, caspase-3, caspase-8 protein, and mRNA levels in the lung tissue were determined using immunohistochemistry, Western blot, and real-time polymerase chain reaction. The results showed that hydrogen inhalation significantly reduced the number of inflammatory cells in the bronchoalveolar lavage fluid, and the mRNA and protein expression levels of tumor necrosis factor alpha, IL-6, IL-17, IL-23, matrix metalloproteinase-12, caspase-3, and caspase-8, but increased the tissue inhibitor of metalloproteinase-1 expression. Furthermore, hydrogen inhalation ameliorated lung pathology, lung function, and cardiovascular function and reduced the right ventricular hypertrophy index. Inhalation of 22% and 41.6% hydrogen showed better outcome than inhalation of 2% hydrogen. These results suggest that hydrogen inhalation slows the development of COPD-like lung disease in a cigarette smoke-induced rat model. Higher concentrations of

  16. Hydrogen coadministration slows the development of COPD-like lung disease in a cigarette smoke-induced rat model

    PubMed Central

    Liu, Xiaoyu; Ma, Cuiqing; Wang, Xiaoyu; Wang, Wenjing; Li, Zhu; Wang, Xiansheng; Wang, Pengyu; Sun, Wuzhuang; Xue, Baojian

    2017-01-01

    Background Chronic obstructive pulmonary disease (COPD) is a progressive pulmonary disease caused by harmful gases or particles. Recent studies have shown that 2% hydrogen or hydrogen water is effective in the treatment and prevention of a variety of diseases. This study investigated the beneficial effects and the possible mechanisms of different hydrogen concentrations on COPD. Methods A rat COPD model was established through smoke exposure methods, and inhalation of different concentrations of hydrogen was used as the intervention. The daily condition of rats and the weight changes were observed; lung function and right ventricular hypertrophy index were assessed. Also, white blood cells were assessed in bronchoalveolar lavage fluid. Pathologic changes in the lung tissue were analyzed using light microscopy and electron microscopy; cardiovascular structure and pulmonary arterial pressure changes in rats were observed using ultrasonography. Tumor necrosis factor alpha, interleukin (IL)-6, IL-17, IL-23, matrix metalloproteinase-12, tissue inhibitor of metalloproteinase-1, caspase-3, caspase-8 protein, and mRNA levels in the lung tissue were determined using immunohistochemistry, Western blot, and real-time polymerase chain reaction. Results The results showed that hydrogen inhalation significantly reduced the number of inflammatory cells in the bronchoalveolar lavage fluid, and the mRNA and protein expression levels of tumor necrosis factor alpha, IL-6, IL-17, IL-23, matrix metalloproteinase-12, caspase-3, and caspase-8, but increased the tissue inhibitor of metalloproteinase-1 expression. Furthermore, hydrogen inhalation ameliorated lung pathology, lung function, and cardiovascular function and reduced the right ventricular hypertrophy index. Inhalation of 22% and 41.6% hydrogen showed better outcome than inhalation of 2% hydrogen. Conclusion These results suggest that hydrogen inhalation slows the development of COPD-like lung disease in a cigarette smoke

  17. Redistribution of pulmonary blood flow impacts thermodilution-based extravascular lung water measurements in a model of acute lung injury

    PubMed Central

    Easley, R. Blaine; Mulreany, Daniel G.; Lancaster, Christopher T.; Custer, Jason W.; Fernandez-Bustamante, Ana; Colantuoni, Elizabeth; Simon, Brett A.

    2009-01-01

    Background Studies using transthoracic thermodilution have demonstrated increased extravascular lung water (EVLW) measurements attributed to progression of edema and flooding during sepsis and acute lung injury. We hypothesize that redistribution of pulmonary blood flow can cause increased apparent EVLW secondary to increased perfusion of thermally silent tissue, not increased lung edema. Methods Anesthetized, mechanically ventilated canines were instrumented with PiCCO® (Pulsion Medical, Munich, Germany) catheters and underwent lung injury by repetitive saline lavage. Hemodynamic and respiratory physiologic data were recorded. After stabilized lung injury, endotoxin was administered to inactivate hypoxic pulmonary vasoconstriction. Computerized tomographic imaging was performed to quantify in vivo lung volume, total tissue (fluid) and air content, and regional distribution of blood flow. Results Lavage injury caused an increase in airway pressures and decreased arterial oxygen content with minimal hemodynamic effects. EVLW and shunt fraction increased after injury and then markedly following endotoxin administration. Computerized tomographic measurements quantified an endotoxin-induced increase in pulmonary blood flow to poorly aerated regions with no change in total lung tissue volume. Conclusions The abrupt increase in EVLW and shunt fraction after endotoxin administration is consistent with inactivation of hypoxic pulmonary vasoconstriction and increased perfusion to already flooded lung regions that were previously thermally silent. Computerized tomographic studies further demonstrate in vivo alterations in regional blood flow (but not lung water) and account for these alterations in shunt fraction and EVLW. PMID:19809280

  18. miR‐34b‐5p inhibition attenuates lung inflammation and apoptosis in an LPS‐induced acute lung injury mouse model by targeting progranulin

    PubMed Central

    Xie, Wang; Lu, Qingchun; Wang, Kailing; Lu, Jingjing; Gu, Xia; Zhu, Dongyi; Liu, Fanglei

    2018-01-01

    Inflammation and apoptosis play important roles in the initiation and progression of acute lung injury (ALI). Our previous study has shown that progranulin (PGRN) exerts lung protective effects during LPS‐induced ALI. Here, we have investigated the potential roles of PGRN‐targeting microRNAs (miRNAs) in regulating inflammation and apoptosis in ALI and have highlighted the important role of PGRN. LPS‐induced lung injury and the protective roles of PGRN in ALI were first confirmed. The function of miR‐34b‐5p in ALI was determined by transfection of a miR‐34b‐5p mimic or inhibitor in intro and in vivo. The PGRN level gradually increased and subsequently significantly decreased, reaching its lowest value by 24 hr; PGRN was still elevated compared to the control. The change was accompanied by a release of inflammatory mediators and accumulation of inflammatory cells in the lungs. Using bioinformatics analysis and RT‐PCR, we demonstrated that, among 12 putative miRNAs, the kinetics of the miR‐34b‐5p levels were closely associated with PGRN expression in the lung homogenates. The gain‐ and loss‐of‐function analysis, dual‐luciferase reporter assays, and rescue experiments confirmed that PGRN was the functional target of miR‐34b‐5p. Intravenous injection of miR‐34b‐5p antagomir in vivo significantly inhibited miR‐34b‐5p up‐regulation, reduced inflammatory cytokine release, decreased alveolar epithelial cell apoptosis, attenuated lung inflammation, and improved survival by targeting PGRN during ALI. miR‐34b‐5p knockdown attenuates lung inflammation and apoptosis in an LPS‐induced ALI mouse model by targeting PGRN. This study shows that miR‐34b‐5p and PGRN may be potential targets for ALI treatments. PMID:29150939

  19. Scaling of lunge feeding in rorqual whales: an integrated model of engulfment duration.

    PubMed

    Potvin, J; Goldbogen, J A; Shadwick, R E

    2010-12-07

    Rorqual whales (Balaenopteridae) obtain their food by lunge feeding, a dynamic process that involves the intermittent engulfment and filtering of large amounts of water and prey. During a lunge, whales accelerate to high speed and open their mouth wide, thereby exposing a highly distensible buccal cavity to the flow and facilitating its inflation. Unsteady hydrodynamic models suggest that the muscles associated with the ventral groove blubber undergo eccentric contraction in order to stiffen and control the inflation of the buccal cavity; in doing so the engulfed water mass is accelerated forward as the whale's body slows down. Although the basic mechanics of lunge feeding are relatively well known, the scaling of this process remains poorly understood, particularly with regards to its duration (from mouth opening to closure). Here we formulate a new theory of engulfment time which integrates prey escape behavior with the mechanics of the whale's body, including lunge speed and acceleration, gape angle dynamics, and the controlled inflation of the buccal cavity. Given that the complex interaction between these factors must be highly coordinated in order to maximize engulfment volume, the proposed formulation rests on the scenario of Synchronized Engulfment, whereby the filling of the cavity (posterior to the temporomandibular joint) coincides with the moment of maximum gape. When formulated specifically for large rorquals feeding on krill, our analysis predicts that engulfment time increases with body size, but in amounts dictated by the specifics of krill escape and avoidance kinematics. The predictions generated by the model are corroborated by limited empirical data on a species-specific basis, particularly for humpback and blue whales chasing krill. A sensitivity analysis applied to all possible sized fin whales also suggests that engulfment duration and lunge speed will increase intra-specifically with body size under a wide range of predator-prey scenarios

  20. The effects of exogenous surfactant administration on ventilation-induced inflammation in mouse models of lung injury.

    PubMed

    Puntorieri, Valeria; Hiansen, Josh Qua; McCaig, Lynda A; Yao, Li-Juan; Veldhuizen, Ruud A W; Lewis, James F

    2013-11-20

    Mechanical ventilation (MV) is an essential supportive therapy for acute lung injury (ALI); however it can also contribute to systemic inflammation. Since pulmonary surfactant has anti-inflammatory properties, the aim of the study was to investigate the effect of exogenous surfactant administration on ventilation-induced systemic inflammation. Mice were randomized to receive an intra-tracheal instillation of a natural exogenous surfactant preparation (bLES, 50 mg/kg) or no treatment as a control. MV was then performed using the isolated and perfused mouse lung (IPML) set up. This model allowed for lung perfusion during MV. In experiment 1, mice were exposed to mechanical ventilation only (tidal volume =20 mL/kg, 2 hours). In experiment 2, hydrochloric acid or air was instilled intra-tracheally four hours before applying exogenous surfactant and ventilation (tidal volume =5 mL/kg, 2 hours). For both experiments, exogenous surfactant administration led to increased total and functional surfactant in the treated groups compared to the controls. Exogenous surfactant administration in mice exposed to MV only did not affect peak inspiratory pressure (PIP), lung IL-6 levels and the development of perfusate inflammation compared to non-treated controls. Acid injured mice exposed to conventional MV showed elevated PIP, lung IL-6 and protein levels and greater perfusate inflammation compared to air instilled controls. Instillation of exogenous surfactant did not influence the development of lung injury. Moreover, exogenous surfactant was not effective in reducing the concentration of inflammatory cytokines in the perfusate. The data indicates that exogenous surfactant did not mitigate ventilation-induced systemic inflammation in our models. Future studies will focus on altering surfactant composition to improve its immuno-modulating activity.

  1. A model of mechanical interactions between heart and lungs.

    PubMed

    Fontecave Jallon, Julie; Abdulhay, Enas; Calabrese, Pascale; Baconnier, Pierre; Gumery, Pierre-Yves

    2009-12-13

    To study the mechanical interactions between heart, lungs and thorax, we propose a mathematical model combining a ventilatory neuromuscular model and a model of the cardiovascular system, as described by Smith et al. (Smith, Chase, Nokes, Shaw & Wake 2004 Med. Eng. Phys.26, 131-139. (doi:10.1016/j.medengphy.2003.10.001)). The respiratory model has been adapted from Thibault et al. (Thibault, Heyer, Benchetrit & Baconnier 2002 Acta Biotheor. 50, 269-279. (doi:10.1023/A:1022616701863)); using a Liénard oscillator, it allows the activity of the respiratory centres, the respiratory muscles and rib cage internal mechanics to be simulated. The minimal haemodynamic system model of Smith includes the heart, as well as the pulmonary and systemic circulation systems. These two modules interact mechanically by means of the pleural pressure, calculated in the mechanical respiratory system, and the intrathoracic blood volume, calculated in the cardiovascular model. The simulation by the proposed model provides results, first, close to experimental data, second, in agreement with the literature results and, finally, highlighting the presence of mechanical cardiorespiratory interactions.

  2. A Biomathematical Model of Pneumococcal Lung Infection and Antibiotic Treatment in Mice.

    PubMed

    Schirm, Sibylle; Ahnert, Peter; Wienhold, Sandra; Mueller-Redetzky, Holger; Nouailles-Kursar, Geraldine; Loeffler, Markus; Witzenrath, Martin; Scholz, Markus

    2016-01-01

    Pneumonia is considered to be one of the leading causes of death worldwide. The outcome depends on both, proper antibiotic treatment and the effectivity of the immune response of the host. However, due to the complexity of the immunologic cascade initiated during infection, the latter cannot be predicted easily. We construct a biomathematical model of the murine immune response during infection with pneumococcus aiming at predicting the outcome of antibiotic treatment. The model consists of a number of non-linear ordinary differential equations describing dynamics of pneumococcal population, the inflammatory cytokine IL-6, neutrophils and macrophages fighting the infection and destruction of alveolar tissue due to pneumococcus. Equations were derived by translating known biological mechanisms and assuming certain response kinetics. Antibiotic therapy is modelled by a transient depletion of bacteria. Unknown model parameters were determined by fitting the predictions of the model to data sets derived from mice experiments of pneumococcal lung infection with and without antibiotic treatment. Time series of pneumococcal population, debris, neutrophils, activated epithelial cells, macrophages, monocytes and IL-6 serum concentrations were available for this purpose. The antibiotics Ampicillin and Moxifloxacin were considered. Parameter fittings resulted in a good agreement of model and data for all experimental scenarios. Identifiability of parameters is also estimated. The model can be used to predict the performance of alternative schedules of antibiotic treatment. We conclude that we established a biomathematical model of pneumococcal lung infection in mice allowing predictions regarding the outcome of different schedules of antibiotic treatment. We aim at translating the model to the human situation in the near future.

  3. Developing Novel Therapeutic Approaches in Small Cell Lung Carcinoma Using Genetically Engineered Mouse Models and Human Circulating Tumor Cells

    DTIC Science & Technology

    2014-10-01

    AD_________________ Award Number: W81XWH-13-1-0325 TITLE: Developing Novel Therapeutic Approaches in Small Cell Lung Carcinoma Using ...Genetically Engineered Mouse Models and Human Circulating Tumor Cells PRINCIPAL INVESTIGATOR: Jeffrey Engelman MD PhD CONTRACTING ORGANIZATION ...Novel Therapeutic Approaches in Small Cell Lung 5a. CONTRACT NUMBER W81XWH-13-1-0325 Carcinoma Using Genetically Engineered Mouse Models and 5b

  4. Acute Lung Injury and Persistent Small Airway Disease in a Rabbit Model of Chlorine Inhalation

    PubMed Central

    Musah, Sadiatu; Schlueter, Connie F.; Humphrey, David M.; Powell, Karen S.; Roberts, Andrew M.; Hoyle, Gary W.

    2016-01-01

    Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbits were extubated and were allowed to survive for up to 24 h after exposure to 800 ppm chlorine for 4 min to study acute effects or up to 7 days after exposure to 400 ppm for 8 min to study longer term effects. Acute effects observed 6 or 24 h after inhalation of 800 ppm chlorine for 4 min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400 ppm chlorine for 8 min, rabbits exhibited mild hypoxemia, increased area of pressure-volume loops, and airway hyperreactivity. Lung histology 7 days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury. PMID:27913141

  5. Acute lung injury and persistent small airway disease in a rabbit model of chlorine inhalation.

    PubMed

    Musah, Sadiatu; Schlueter, Connie F; Humphrey, David M; Powell, Karen S; Roberts, Andrew M; Hoyle, Gary W

    2017-01-15

    Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbits were extubated and were allowed to survive for up to 24h after exposure to 800ppm chlorine for 4min to study acute effects or up to 7days after exposure to 400ppm for 8min to study longer term effects. Acute effects observed 6 or 24h after inhalation of 800ppm chlorine for 4min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400ppm chlorine for 8min, rabbits exhibited mild hypoxemia, increased area of pressure-volume loops, and airway hyperreactivity. Lung histology 7days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Treatment with Entinostat Heals Experimental Cholera by Affecting Physical and Chemical Barrier Functions of Intestinal Epithelia.

    PubMed

    Sarker, Protim; Banik, Atanu; Stromberg, Roger; Gudmundsson, Gudmundur H; Raqib, Rubhana; Agerberth, Birgitta

    2017-07-01

    We have shown previously that oral treatment with sodium butyrate or phenylbutyrate in an experimental model of shigellosis improves clinical outcomes and induces the expression of the antimicrobial peptide CAP-18 in the large intestinal epithelia. In a subsequent study, we found that entinostat, an aroylated phenylenediamine compound, has similar therapeutic potential against shigellosis. In this study, we aimed to evaluate entinostat as a potential candidate for host-directed therapy against cholera in an experimental model. Vibrio cholerae -infected rabbits were treated with two different dose regimens of entinostat: either 0.5 mg twice daily for 2 days or 1 mg once daily for 2 days. The effects of treatment on clinical outcomes and V. cholerae shedding (CFU count in stool) were observed. Immunohistochemical analysis was carried out to assess CAP-18 expression in ileal and jejunal mucosae. The serum zonulin level was measured by an enzyme-linked immunosorbent assay (ELISA) to evaluate gut permeability. Infection of rabbits with V. cholerae downregulated CAP-18 expression in the ileal epithelium; the expression was replenished by oral treatment with entinostat at either dose regimen. The level of zonulin, a marker of gut permeability, in serum was upregulated after infection, and this upregulation was counteracted after treatment with entinostat. Entinostat treatment also led to recovery from cholera and a decline in the V. cholerae count in stool. In conclusion, the improved clinical outcome of cholera for rabbits treated with entinostat is associated with the induction of CAP-18 and the reduction of gut epithelial permeability. Copyright © 2017 American Society for Microbiology.

  7. In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line

    PubMed Central

    Nanjo, Shigeki; Nakagawa, Takayuki; Takeuchi, Shinji; Kita, Kenji; Fukuda, Koji; Nakada, Mitsutoshi; Uehara, Hisanori; Nishihara, Hiroshi; Hara, Eiji; Uramoto, Hidetaka; Tanaka, Fumihiro; Yano, Seiji

    2015-01-01

    EML4-ALK lung cancer accounts for approximately 3–7% of non-small-cell lung cancer cases. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. In this study, we found that the lung adenocarcinoma cell line A925L expresses an EML4-ALK gene fusion (variant 5a, E2:A20) and is sensitive to the ALK inhibitors crizotinib and alectinib. We further established highly tumorigenic A925LPE3 cells, which also have the EML4-ALK gene fusion (variant 5a) and are sensitive to ALK inhibitors. By using A925LPE3 cells with luciferase gene transfection, we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, whereas alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments. PMID:25581823

  8. Functional Invariant NKT Cells in Pig Lungs Regulate the Airway Hyperreactivity: A Potential Animal Model

    PubMed Central

    Manickam, Cordelia; Khatri, Mahesh; Rauf, Abdul; Li, Xiangming; Tsuji, Moriya; Rajashekara, Gireesh; Dwivedi, Varun

    2015-01-01

    Important roles played by invariant natural killer T (iNKT) cells in asthma pathogenesis have been demonstrated. We identified functional iNKT cells and CD1d molecules in pig lungs. Pig iNKT cells cultured in the presence of α-GalCer proliferated and secreted Th1 and Th2 cytokines. Like in other animal models, direct activation of pig lung iNKT cells using α-GalCer resulted in acute airway hyperreactivity (AHR). Clinically, acute AHR-induced pigs had increased respiratory rate, enhanced mucus secretion in the airways, fever, etc. In addition, we observed petechial hemorrhages, infiltration of CD4+ cells, and increased Th2 cytokines in AHR-induced pig lungs. Ex vivo proliferated iNKT cells of asthma induced pigs in the presence of C-glycoside analogs of α-GalCer had predominant Th2 phenotype and secreted more of Th2 cytokine, IL-4. Thus, baby pigs may serve as a useful animal model to study iNKT cell-mediated AHR caused by various environmental and microbial CD1d-specific glycolipid antigens. PMID:21042929

  9. Evaluating the impacts of screening and smoking cessation programmes on lung cancer in a high-burden region of the USA: a simulation modelling study

    PubMed Central

    Tramontano, Angela C; Sheehan, Deirdre F; McMahon, Pamela M; Dowling, Emily C; Holford, Theodore R; Ryczak, Karen; Lesko, Samuel M; Levy, David T; Kong, Chung Yin

    2016-01-01

    Objective While the US Preventive Services Task Force has issued recommendations for lung cancer screening, its effectiveness at reducing lung cancer burden may vary at local levels due to regional variations in smoking behaviour. Our objective was to use an existing model to determine the impacts of lung cancer screening alone or in addition to increased smoking cessation in a US region with a relatively high smoking prevalence and lung cancer incidence. Setting Computer-based simulation model. Participants Simulated population of individuals 55 and older based on smoking prevalence and census data from Northeast Pennsylvania. Interventions Hypothetical lung cancer control from 2014 to 2050 through (1) screening with CT, (2) intensified smoking cessation or (3) a combination strategy. Primary and secondary outcome measures Primary outcomes were lung cancer mortality rates. Secondary outcomes included number of people eligible for screening and number of radiation-induced lung cancers. Results Combining lung cancer screening with increased smoking cessation would yield an estimated 8.1% reduction in cumulative lung cancer mortality by 2050. Our model estimated that the number of screening-eligible individuals would progressively decrease over time, indicating declining benefit of a screening-only programme. Lung cancer screening achieved a greater mortality reduction in earlier years, but was later surpassed by smoking cessation. Conclusions Combining smoking cessation programmes with lung cancer screening would provide the most benefit to a population, especially considering the growing proportion of patients ineligible for screening based on current recommendations. PMID:26928026

  10. Variable tidal volumes improve lung protective ventilation strategies in experimental lung injury.

    PubMed

    Spieth, Peter M; Carvalho, Alysson R; Pelosi, Paolo; Hoehn, Catharina; Meissner, Christoph; Kasper, Michael; Hübler, Matthias; von Neindorff, Matthias; Dassow, Constanze; Barrenschee, Martina; Uhlig, Stefan; Koch, Thea; de Abreu, Marcelo Gama

    2009-04-15

    Noisy ventilation with variable Vt may improve respiratory function in acute lung injury. To determine the impact of noisy ventilation on respiratory function and its biological effects on lung parenchyma compared with conventional protective mechanical ventilation strategies. In a porcine surfactant depletion model of lung injury, we randomly combined noisy ventilation with the ARDS Network protocol or the open lung approach (n = 9 per group). Respiratory mechanics, gas exchange, and distribution of pulmonary blood flow were measured at intervals over a 6-hour period. Postmortem, lung tissue was analyzed to determine histological damage, mechanical stress, and inflammation. We found that, at comparable minute ventilation, noisy ventilation (1) improved arterial oxygenation and reduced mean inspiratory peak airway pressure and elastance of the respiratory system compared with the ARDS Network protocol and the open lung approach, (2) redistributed pulmonary blood flow to caudal zones compared with the ARDS Network protocol and to peripheral ones compared with the open lung approach, (3) reduced histological damage in comparison to both protective ventilation strategies, and (4) did not increase lung inflammation or mechanical stress. Noisy ventilation with variable Vt and fixed respiratory frequency improves respiratory function and reduces histological damage compared with standard protective ventilation strategies.

  11. Sidestream Smoke Exposure Increases the Susceptibility of Airway Epithelia to Adenoviral Infection

    PubMed Central

    Sharma, Priyanka; Kolawole, Abimbola O.; Core, Susan B.; Kajon, Adriana E.; Excoffon, Katherine J. D. A.

    2012-01-01

    Background Although significant epidemiological evidence indicates that cigarette smoke exposure increases the incidence and severity of viral infection, the molecular mechanisms behind the increased susceptibility of the respiratory tract to viral pathogens are unclear. Adenoviruses are non-enveloped DNA viruses and important causative agents of acute respiratory disease. The Coxsackievirus and adenovirus receptor (CAR) is the primary receptor for many adenoviruses. We hypothesized that cigarette smoke exposure increases epithelial susceptibility to adenovirus infection by increasing the abundance of apical CAR. Methodology and Findings Cultured human airway epithelial cells (CaLu-3) were used as a model to investigate the effect of sidestream cigarette smoke (SSS), mainstream cigarette smoke (MSS), or control air exposure on the susceptibility of polarized respiratory epithelia to adenoviral infection. Using a Cultex air-liquid interface exposure system, we have discovered novel differences in epithelial susceptibility between SSS and MSS exposures. SSS exposure upregulates an eight-exon isoform of CAR and increases adenoviral entry from the apical surface whilst MSS exposure is similar to control air exposure. Additionally, the level of cellular glycogen synthase kinase 3β (GSK3β) is downregulated by SSS exposure and treatment with a specific GSK3β inhibitor recapitulates the effects of SSS exposure on CAR expression and viral infection. Conclusions This is the first time that SSS exposure has been shown to directly enhance the susceptibility of a polarized epithelium to infection by a common respiratory viral pathogen. This work provides a novel understanding of the impact of SSS on the burden of respiratory viral infections and may lead to new strategies to alter viral infections. Moreover, since GSK3β inhibitors are under intense clinical investigation as therapeutics for a diverse range of diseases, studies such as these might provide insight to extend

  12. Modeling the lung: Design and development of tissue engineered macro- and micro-physiologic lung models for research use.

    PubMed

    Nichols, Joan E; Niles, Jean A; Vega, Stephanie P; Argueta, Lissenya B; Eastaway, Adriene; Cortiella, Joaquin

    2014-09-01

    Respiratory tract specific cell populations, or tissue engineered in vitro grown human lung, have the potential to be used as research tools to mimic physiology, toxicology, pathology, as well as infectious diseases responses of cells or tissues. Studies related to respiratory tract pathogenesis or drug toxicity testing in the past made use of basic systems where single cell populations were exposed to test agents followed by evaluations of simple cellular responses. Although these simple single-cell-type systems provided good basic information related to cellular responses, much more can be learned from cells grown in fabricated microenvironments which mimic in vivo conditions in specialized microfabricated chambers or by human tissue engineered three-dimensional (3D) models which allow for more natural interactions between cells. Recent advances in microengineering technology, microfluidics, and tissue engineering have provided a new approach to the development of 2D and 3D cell culture models which enable production of more robust human in vitro respiratory tract models. Complex models containing multiple cell phenotypes also provide a more reasonable approximation of what occurs in vivo without the confounding elements in the dynamic in vivo environment. The goal of engineering good 3D human models is the formation of physiologically functional respiratory tissue surrogates which can be used as pathogenesis models or in the case of 2D screening systems for drug therapy evaluation as well as human toxicity testing. We hope that this manuscript will serve as a guide for development of future respiratory tract model systems as well as a review of conventional models. © 2014 by the Society for Experimental Biology and Medicine.

  13. Cystic Fibrosis Transmembrane Conductance Regulator Potentiation as a Therapeutic Strategy for Pulmonary Edema: A Proof-of-Concept Study in Pigs.

    PubMed

    Li, Xiaopeng; Vargas Buonfiglio, Luis G; Adam, Ryan J; Stoltz, David A; Zabner, Joseph; Comellas, Alejandro P

    2017-12-01

    To determine the feasibility of using a cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX-770/Kalydeco, Vertex Pharmaceuticals, Boston, MA), as a therapeutic strategy for treating pulmonary edema. Prospective laboratory animal investigation. Animal research laboratory. Newborn and 3 days to 1 week old pigs. Hydrostatic pulmonary edema was induced in pigs by acute volume overload. Ivacaftor was nebulized into the lung immediately after volume overload. Grams of water per grams of dry lung tissue were determined in the lungs harvested 1 hour after volume overload. Ivacaftor significantly improved alveolar liquid clearance in isolated pig lung lobes ex vivo and reduced edema in a volume overload in vivo pig model of hydrostatic pulmonary edema. To model hydrostatic pressure-induced edema in vitro, we developed a method of applied pressure to the basolateral surface of alveolar epithelia. Elevated hydrostatic pressure resulted in decreased cystic fibrosis transmembrane conductance regulator activity and liquid absorption, an effect which was partially reversed by cystic fibrosis transmembrane conductance regulator potentiation with ivacaftor. Cystic fibrosis transmembrane conductance regulator potentiation by ivacaftor is a novel therapeutic approach for pulmonary edema.

  14. Dexpanthenol therapy reduces lung damage in a hyperoxic lung injury in neonatal rats.

    PubMed

    Ozdemir, Ramazan; Demirtas, Gulsum; Parlakpinar, Hakan; Polat, Alaadin; Tanbag, Kevser; Taslidere, Elif; Karadag, Ahmet

    2016-01-01

    Dexpanthenol (Dxp) plays a major role in cellular defense and in repair systems against oxidative stress and inflammatory response and it has not yet been evaluated in treatment of bronchopulmonary dysplasia (BPD). We tested the hypothesis that proposes whether Dxp decreases the severity of lung injury in an animal model of BPD. Forty rat pups were divided into four groups: control, control + Dxp, hyperoxia and hyperoxia + Dxp. All animals were processed for lung histology and tissue analysis. The degree of lung inflammation, oxidative and antioxidant capacity was assessed from lung homogenates. Lung injury score and alveol diameter increased in the hyperoxia group (p < 0.001). Median level of malondialdehyde, total oxidant status and oxidative stress indexes was significantly higher in the hyperoxia group compared to the other groups. The median superoxide dismutase activity in the hyperoxia group was notably less than those of control + Dxp and hyperoxia + Dxp groups (p < 0.01). Similarly, lung catalase, glutathione (GSH) peroxidase and reduced GSH activities in the hyperoxia group were significantly lower than other groups. Furthermore, the hyperoxia + Dxp group had lower tumor necrosis factor-α and interleukin-1β median levels compared to the hyperoxia group (p = 0.007). Dxp treatment results in less emphysematous change as well as decrease in inflammation and oxidative stress markers in an animal model of BPD.

  15. A Bayesian network approach for modeling local failure in lung cancer

    NASA Astrophysics Data System (ADS)

    Oh, Jung Hun; Craft, Jeffrey; Lozi, Rawan Al; Vaidya, Manushka; Meng, Yifan; Deasy, Joseph O.; Bradley, Jeffrey D.; El Naqa, Issam

    2011-03-01

    Locally advanced non-small cell lung cancer (NSCLC) patients suffer from a high local failure rate following radiotherapy. Despite many efforts to develop new dose-volume models for early detection of tumor local failure, there was no reported significant improvement in their application prospectively. Based on recent studies of biomarker proteins' role in hypoxia and inflammation in predicting tumor response to radiotherapy, we hypothesize that combining physical and biological factors with a suitable framework could improve the overall prediction. To test this hypothesis, we propose a graphical Bayesian network framework for predicting local failure in lung cancer. The proposed approach was tested using two different datasets of locally advanced NSCLC patients treated with radiotherapy. The first dataset was collected retrospectively, which comprises clinical and dosimetric variables only. The second dataset was collected prospectively in which in addition to clinical and dosimetric information, blood was drawn from the patients at various time points to extract candidate biomarkers as well. Our preliminary results show that the proposed method can be used as an efficient method to develop predictive models of local failure in these patients and to interpret relationships among the different variables in the models. We also demonstrate the potential use of heterogeneous physical and biological variables to improve the model prediction. With the first dataset, we achieved better performance compared with competing Bayesian-based classifiers. With the second dataset, the combined model had a slightly higher performance compared to individual physical and biological models, with the biological variables making the largest contribution. Our preliminary results highlight the potential of the proposed integrated approach for predicting post-radiotherapy local failure in NSCLC patients.

  16. Effect of shape and size of lung and chest wall on stresses in the lung

    NASA Technical Reports Server (NTRS)

    Vawter, D. L.; Matthews, F. L.; West, J. B.

    1975-01-01

    To understand better the effect of shape and size of lung and chest wall on the distribution of stresses, strains, and surface pressures, we analyzed a theoretical model using the technique of finite elements. First we investigated the effects of changing the chest wall shape during expansion, and second we studied lungs of a variety of inherent shapes and sizes. We found that, in general, the distributions of alveolar size, mechanical stresses, and surface pressures in the lungs were dominated by the weight of the lung and that changing the shape of the lung or chest wall had relatively little effect. Only at high states of expansion where the lung was very stiff did changing the shape of the chest wall cause substantial changes. Altering the inherent shape of the lung generally had little effect but the topographical differences in stresses and surface pressures were approximately proportional to lung height. The results are generally consistent with those found in the dog by Hoppin et al (1969).

  17. Humidification of base flow gas during adult high-frequency oscillatory ventilation: an experimental study using a lung model.

    PubMed

    Shiba, Naoki; Nagano, Osamu; Hirayama, Takahiro; Ichiba, Shingo; Ujike, Yoshihito

    2012-01-01

    In adult high-frequency oscillatory ventilation (HFOV) with an R100 artificial ventilator, exhaled gas from patient's lung may warm the temperature probe and thereby disturb the humidification of base flow (BF) gas. We measured the humidity of BF gas during HFOV with frequencies of 6, 8 and 10 Hz, maximum stroke volumes (SV) of 285, 205, and 160 ml at the respective frequencies, and, BFs of 20, 30, 40 l/min using an original lung model. The R100 device was equipped with a heated humidifier, Hummax Ⅱ, consisting of a porous hollow fiber in circuit. A 50-cm length of circuit was added between temperature probe (located at 50 cm proximal from Y-piece) and the hollow fiber. The lung model was made of a plastic container and a circuit equipped with another Hummax Ⅱ. The lung model temperature was controlled at 37℃. The Hummax Ⅱ of the R100 was inactivated in study-1 and was set at 35℃ or 37℃ in study-2. The humidity was measured at the distal end of the added circuit in study-1 and at the proximal end in study-2. In study-1, humidity was detected at 6 Hz (SV 285 ml) and BF 20 l/min, indicating the direct reach of the exhaled gas from the lung model to the temperature probe. In study-2 the absolute humidity of the BF gas decreased by increasing SV and by increasing BF and it was low with setting of 35℃. In this study setting, increasing the SV induced significant reduction of humidification of the BF gas during HFOV with R100.

  18. Hyperglycemia impedes lung bacterial clearance in a murine model of cystic fibrosis-related diabetes

    PubMed Central

    Hunt, William R.; Zughaier, Susu M.; Guentert, Dana E.; Shenep, Melissa A.; Koval, Michael; McCarty, Nael A.

    2013-01-01

    Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity associated with cystic fibrosis (CF), impacting more than half of patients over age 30. CFRD is clinically significant, portending accelerated decline in lung function, more frequent pulmonary exacerbations, and increased mortality. Despite the profound morbidity associated with CFRD, little is known about the underlying CFRD-related pulmonary pathology. Our aim was to develop a murine model of CFRD to explore the hypothesis that elevated glucose in CFRD is associated with reduced lung bacterial clearance. A diabetic phenotype was induced in gut-corrected CF transmembrane conductance regulator (CFTR) knockout mice (CFKO) and their CFTR-expressing wild-type littermates (WT) utilizing streptozotocin. Mice were subsequently challenged with an intratracheal inoculation of Pseudomonas aeruginosa (PAO1) (75 μl of 1–5 × 106 cfu/ml) for 18 h. Bronchoalveolar lavage fluid was collected for glucose concentration and cell counts. A portion of the lung was homogenized and cultured as a measure of the remaining viable PAO1 inoculum. Diabetic mice had increased airway glucose compared with nondiabetic mice. The ability to clear bacteria from the lung was significantly reduced in diabetic WT mice and control CFKO mice. Critically, bacterial clearance by diabetic CFKO mice was significantly more diminished compared with nondiabetic CFKO mice, despite an even more robust recruitment of neutrophils to the airways. This finding that CFRD mice boast an exaggerated, but less effective, inflammatory cell response to intratracheal PAO1 challenge presents a novel and useful murine model to help identify therapeutic strategies that promote bacterial clearance in CFRD. PMID:24097557

  19. P2 purinoceptors regulate calcium-activated chloride and fluid transport in 31EG4 mammary epithelia.

    PubMed

    Blaug, Sasha; Rymer, Jodi; Jalickee, Stephen; Miller, Sheldon S

    2003-04-01

    It has been reported that secretory mammary epithelial cells (MEC) release ATP, UTP, and UDP upon mechanical stimulation. Here we examined the physiological changes caused by ATP/UTP in nontransformed, clonal mouse mammary epithelia (31EG4 cells). In control conditions, transepithelial potential (apical side negative) and resistance were -4.4 +/- 1.3 mV (mean +/- SD, n = 12) and 517.7 +/- 39.4 Omega. cm(2), respectively. The apical membrane potential was -43.9 +/- 1.7 mV, and the ratio of apical to basolateral membrane resistance (R(A)/R(B)) was 3.5 +/- 0.2. Addition of ATP or UTP to the apical or basolateral membranes caused large voltage and resistance changes with an EC(50) of approximately 24 microM (apical) and approximately 30 microM (basal). Apical ATP/UTP (100 microM) depolarized apical membrane potential by 17.6 +/- 0.8 mV (n = 7) and decreased R(A)/R(B) by a factor of approximately 3. The addition of adenosine to either side (100 microM) had no effect on any of these parameters. The ATP/UTP responses were partially inhibited by DIDS and suramin and mediated by a transient increase in free intracellular Ca(2+) concentration (427 +/- 206 nM; 15-25 microM ATP, apical; n = 6). This Ca(2+) increase was blocked by cyclopiazonic acid, by BAPTA, or by xestospongin C. 31EG4 MEC monolayers also secreted or absorbed fluid in the resting state, and ATP or UTP increased fluid secretion by 5.6 +/- 3 microl x cm(-2) x h(-1) (n = 10). Pharmacology experiments indicate that 31EG4 epithelia contain P2Y(2) purinoceptors on the apical and basolateral membranes, which upon activation stimulate apical Ca(2+)-dependent Cl channels and cause fluid secretion across the monolayer. This suggests that extracellular nucleotides could play a fundamental role in mammary gland paracrine signaling and the regulation of milk composition in vivo.

  20. Development of an experimental model of brain tissue heterotopia in the lung

    PubMed Central

    Quemelo, Paulo Roberto Veiga; Sbragia, Lourenço; Peres, Luiz Cesar

    2007-01-01

    Summary The presence of heterotopic brain tissue in the lung is a rare abnormality. The cases reported thus far are usually associated with neural tube defects (NTD). As there are no reports of experimental models of NTD that present this abnormality, the objective of the present study was to develop a surgical method of brain tissue heterotopia in the lung. We used 24 pregnant Swiss mice divided into two groups of 12 animals each, denoted 17GD and 18GD according to the gestational day (GD) when caesarean section was performed to collect the fetuses. Surgery was performed on the 15th GD, one fetus was removed by hysterectomy and its brain tissue was cut into small fragments and implanted in the lung of its litter mates. Thirty-four live fetuses were obtained from the 17GD group. Of these, eight (23.5%) were used as control (C), eight (23.5%) were sham operated (S) and 18 (52.9%) were used for pulmonary brain tissue implantation (PBI). Thirty live fetuses were obtained from the females of the 18GD group. Of these, eight (26.6%) were C, eight (26.6%) S and 14 (46.6%) were used for PBI. Histological examination of the fetal trunks showed implantation of GFAP-positive brain tissue in 85% of the fetuses of the 17GD group and in 100% of those of the 18GD group, with no significant difference between groups for any of the parameters analysed. The experimental model proved to be efficient and of relatively simple execution, showing complete integration of the brain tissue with pulmonary and pleural tissue and thus representing a model that will permit the study of different aspects of cell implantation and interaction. PMID:17877535

  1. MRI and CT lung biomarkers: Towards an in vivo understanding of lung biomechanics.

    PubMed

    Young, Heather M; Eddy, Rachel L; Parraga, Grace

    2017-09-29

    The biomechanical properties of the lung are necessarily dependent on its structure and function, both of which are complex and change over time and space. This makes in vivo evaluation of lung biomechanics and a deep understanding of lung biomarkers, very challenging. In patients and animal models of lung disease, in vivo evaluations of lung structure and function are typically made at the mouth and include spirometry, multiple-breath gas washout tests and the forced oscillation technique. These techniques, and the biomarkers they provide, incorporate the properties of the whole organ system including the parenchyma, large and small airways, mouth, diaphragm and intercostal muscles. Unfortunately, these well-established measurements mask regional differences, limiting their ability to probe the lung's gross and micro-biomechanical properties which vary widely throughout the organ and its subcompartments. Pulmonary imaging has the advantage in providing regional, non-invasive measurements of healthy and diseased lung, in vivo. Here we summarize well-established and emerging lung imaging tools and biomarkers and how they may be used to generate lung biomechanical measurements. We review well-established and emerging lung anatomical, microstructural and functional imaging biomarkers generated using synchrotron x-ray tomographic-microscopy (SRXTM), micro-x-ray computed-tomography (micro-CT), clinical CT as well as magnetic resonance imaging (MRI). Pulmonary imaging provides measurements of lung structure, function and biomechanics with high spatial and temporal resolution. Imaging biomarkers that reflect the biomechanical properties of the lung are now being validated to provide a deeper understanding of the lung that cannot be achieved using measurements made at the mouth. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. The effect of CSF-1 administration on lung maturation in a mouse model of neonatal hyperoxia exposure.

    PubMed

    Jones, Christina V; Alikhan, Maliha A; O'Reilly, Megan; Sozo, Foula; Williams, Timothy M; Harding, Richard; Jenkin, Graham; Ricardo, Sharon D

    2014-09-06

    Lung immaturity due to preterm birth is a significant complication affecting neonatal health. Despite the detrimental effects of supplemental oxygen on alveolar formation, it remains an important treatment for infants with respiratory distress. Macrophages are traditionally associated with the propagation of inflammatory insults, however increased appreciation of their diversity has revealed essential functions in development and regeneration. Macrophage regulatory cytokine Colony-Stimulating Factor-1 (CSF-1) was investigated in a model of neonatal hyperoxia exposure, with the aim of promoting macrophages associated with alveologenesis to protect/rescue lung development and function. Neonatal mice were exposed to normoxia (21% oxygen) or hyperoxia (Hyp; 65% oxygen); and administered CSF-1 (0.5 μg/g, daily × 5) or vehicle (PBS) in two treatment regimes; 1) after hyperoxia from postnatal day (P)7-11, or 2) concurrently with five days of hyperoxia from P1-5. Lung structure, function and macrophages were assessed using alveolar morphometry, barometric whole-body plethysmography and flow cytometry. Seven days of hyperoxia resulted in an 18% decrease in body weight and perturbation of lung structure and function. In regime 1, growth restriction persisted in the Hyp + PBS and Hyp + CSF-1 groups, although perturbations in respiratory function were resolved by P35. CSF-1 increased CSF-1R+/F4/80+ macrophage number by 34% at P11 compared to Hyp + PBS, but was not associated with growth or lung structural rescue. In regime 2, five days of hyperoxia did not cause initial growth restriction in the Hyp + PBS and Hyp + CSF-1 groups, although body weight was decreased at P35 with CSF-1. CSF-1 was not associated with increased macrophages, or with functional perturbation in the adult. Overall, CSF-1 did not rescue the growth and lung defects associated with hyperoxia in this model; however, an increase in CSF-1R+ macrophages was not associated with an

  3. Adjusting tidal volume to stress index in an open lung condition optimizes ventilation and prevents overdistension in an experimental model of lung injury and reduced chest wall compliance.

    PubMed

    Ferrando, Carlos; Suárez-Sipmann, Fernando; Gutierrez, Andrea; Tusman, Gerardo; Carbonell, Jose; García, Marisa; Piqueras, Laura; Compañ, Desamparados; Flores, Susanie; Soro, Marina; Llombart, Alicia; Belda, Francisco Javier

    2015-01-13

    The stress index (SI), a parameter derived from the shape of the pressure-time curve, can identify injurious mechanical ventilation. We tested the hypothesis that adjusting tidal volume (VT) to a non-injurious SI in an open lung condition avoids hypoventilation while preventing overdistension in an experimental model of combined lung injury and low chest-wall compliance (Ccw). Lung injury was induced by repeated lung lavages using warm saline solution, and Ccw was reduced by controlled intra-abdominal air-insufflation in 22 anesthetized, paralyzed and mechanically ventilated pigs. After injury animals were recruited and submitted to a positive end-expiratory pressure (PEEP) titration trial to find the PEEP level resulting in maximum compliance. During a subsequent four hours of mechanical ventilation, VT was adjusted to keep a plateau pressure (Pplat) of 30 cmH2O (Pplat-group, n = 11) or to a SI between 0.95 and 1.05 (SI-group, n = 11). Respiratory rate was adjusted to maintain a 'normal' PaCO2 (35 to 65 mmHg). SI, lung mechanics, arterial-blood gases haemodynamics pro-inflammatory cytokines and histopathology were analyzed. In addition Computed Tomography (CT) data were acquired at end expiration and end inspiration in six animals. PaCO2 was significantly higher in the Pplat-group (82 versus 53 mmHg, P = 0.01), with a resulting lower pH (7.19 versus 7.34, P = 0.01). We observed significant differences in VT (7.3 versus 5.4 mlKg(-1), P = 0.002) and Pplat values (30 versus 35 cmH2O, P = 0.001) between the Pplat-group and SI-group respectively. SI (1.03 versus 0.99, P = 0.42) and end-inspiratory transpulmonary pressure (PTP) (17 versus 18 cmH2O, P = 0.42) were similar in the Pplat- and SI-groups respectively, without differences in overinflated lung areas at end- inspiration in both groups. Cytokines and histopathology showed no differences. Setting tidal volume to a non-injurious stress index in an open lung condition improves

  4. Variable Ventilation Improved Respiratory System Mechanics and Ameliorated Pulmonary Damage in a Rat Model of Lung Ischemia-Reperfusion.

    PubMed

    Soluri-Martins, André; Moraes, Lillian; Santos, Raquel S; Santos, Cintia L; Huhle, Robert; Capelozzi, Vera L; Pelosi, Paolo; Silva, Pedro L; de Abreu, Marcelo Gama; Rocco, Patricia R M

    2017-01-01

    Lung ischemia-reperfusion injury remains a major complication after lung transplantation. Variable ventilation (VV) has been shown to improve respiratory function and reduce pulmonary histological damage compared to protective volume-controlled ventilation (VCV) in different models of lung injury induced by endotoxin, surfactant depletion by saline lavage, and hydrochloric acid. However, no study has compared the biological impact of VV vs. VCV in lung ischemia-reperfusion injury, which has a complex pathophysiology different from that of other experimental models. Thirty-six animals were randomly assigned to one of two groups: (1) ischemia-reperfusion (IR), in which the left pulmonary hilum was completely occluded and released after 30 min; and (2) Sham, in which animals underwent the same surgical manipulation but without hilar clamping. Immediately after surgery, the left (IR-injured) and right (contralateral) lungs from 6 animals per group were removed, and served as non-ventilated group (NV) for molecular biology analysis. IR and Sham groups were further randomized to one of two ventilation strategies: VCV ( n = 6/group) [tidal volume (V T ) = 6 mL/kg, positive end-expiratory pressure (PEEP) = 2 cmH 2 O, fraction of inspired oxygen (FiO 2 ) = 0.4]; or VV, which was applied on a breath-to-breath basis as a sequence of randomly generated V T values ( n = 1200; mean V T = 6 mL/kg), with a 30% coefficient of variation. After 5 min of ventilation and at the end of a 2-h period (Final), respiratory system mechanics and arterial blood gases were measured. At Final, lungs were removed for histological and molecular biology analyses. Respiratory system elastance and alveolar collapse were lower in VCV than VV (mean ± SD, VCV 3.6 ± 1.3 cmH 2 0/ml and 2.0 ± 0.8 cmH 2 0/ml, p = 0.005; median [interquartile range], VCV 20.4% [7.9-33.1] and VV 5.4% [3.1-8.8], p = 0.04, respectively). In left lungs of IR animals, VCV increased the expression of interleukin-6 and

  5. Variable Ventilation Improved Respiratory System Mechanics and Ameliorated Pulmonary Damage in a Rat Model of Lung Ischemia-Reperfusion

    PubMed Central

    Soluri-Martins, André; Moraes, Lillian; Santos, Raquel S.; Santos, Cintia L.; Huhle, Robert; Capelozzi, Vera L.; Pelosi, Paolo; Silva, Pedro L.; de Abreu, Marcelo Gama; Rocco, Patricia R. M.

    2017-01-01

    Lung ischemia-reperfusion injury remains a major complication after lung transplantation. Variable ventilation (VV) has been shown to improve respiratory function and reduce pulmonary histological damage compared to protective volume-controlled ventilation (VCV) in different models of lung injury induced by endotoxin, surfactant depletion by saline lavage, and hydrochloric acid. However, no study has compared the biological impact of VV vs. VCV in lung ischemia-reperfusion injury, which has a complex pathophysiology different from that of other experimental models. Thirty-six animals were randomly assigned to one of two groups: (1) ischemia-reperfusion (IR), in which the left pulmonary hilum was completely occluded and released after 30 min; and (2) Sham, in which animals underwent the same surgical manipulation but without hilar clamping. Immediately after surgery, the left (IR-injured) and right (contralateral) lungs from 6 animals per group were removed, and served as non-ventilated group (NV) for molecular biology analysis. IR and Sham groups were further randomized to one of two ventilation strategies: VCV (n = 6/group) [tidal volume (VT) = 6 mL/kg, positive end-expiratory pressure (PEEP) = 2 cmH2O, fraction of inspired oxygen (FiO2) = 0.4]; or VV, which was applied on a breath-to-breath basis as a sequence of randomly generated VT values (n = 1200; mean VT = 6 mL/kg), with a 30% coefficient of variation. After 5 min of ventilation and at the end of a 2-h period (Final), respiratory system mechanics and arterial blood gases were measured. At Final, lungs were removed for histological and molecular biology analyses. Respiratory system elastance and alveolar collapse were lower in VCV than VV (mean ± SD, VCV 3.6 ± 1.3 cmH20/ml and 2.0 ± 0.8 cmH20/ml, p = 0.005; median [interquartile range], VCV 20.4% [7.9–33.1] and VV 5.4% [3.1–8.8], p = 0.04, respectively). In left lungs of IR animals, VCV increased the expression of interleukin-6 and intercellular

  6. Evaluating the impacts of screening and smoking cessation programmes on lung cancer in a high-burden region of the USA: a simulation modelling study.

    PubMed

    Tramontano, Angela C; Sheehan, Deirdre F; McMahon, Pamela M; Dowling, Emily C; Holford, Theodore R; Ryczak, Karen; Lesko, Samuel M; Levy, David T; Kong, Chung Yin

    2016-02-29

    While the US Preventive Services Task Force has issued recommendations for lung cancer screening, its effectiveness at reducing lung cancer burden may vary at local levels due to regional variations in smoking behaviour. Our objective was to use an existing model to determine the impacts of lung cancer screening alone or in addition to increased smoking cessation in a US region with a relatively high smoking prevalence and lung cancer incidence. Computer-based simulation model. Simulated population of individuals 55 and older based on smoking prevalence and census data from Northeast Pennsylvania. Hypothetical lung cancer control from 2014 to 2050 through (1) screening with CT, (2) intensified smoking cessation or (3) a combination strategy. Primary outcomes were lung cancer mortality rates. Secondary outcomes included number of people eligible for screening and number of radiation-induced lung cancers. Combining lung cancer screening with increased smoking cessation would yield an estimated 8.1% reduction in cumulative lung cancer mortality by 2050. Our model estimated that the number of screening-eligible individuals would progressively decrease over time, indicating declining benefit of a screening-only programme. Lung cancer screening achieved a greater mortality reduction in earlier years, but was later surpassed by smoking cessation. Combining smoking cessation programmes with lung cancer screening would provide the most benefit to a population, especially considering the growing proportion of patients ineligible for screening based on current recommendations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  7. Home energy efficiency and radon related risk of lung cancer: modelling study

    PubMed Central

    Milner, James; Shrubsole, Clive; Das, Payel; Jones, Benjamin; Ridley, Ian; Chalabi, Zaid; Hamilton, Ian; Armstrong, Ben; Davies, Michael

    2014-01-01

    Objective To investigate the effect of reducing home ventilation as part of household energy efficiency measures on deaths from radon related lung cancer. Design Modelling study. Setting England. Intervention Home energy efficiency interventions, motivated in part by targets for reducing greenhouse gases, which entail reduction in uncontrolled ventilation in keeping with good practice guidance. Main outcome measures Modelled current and future distributions of indoor radon levels for the English housing stock and associated changes in life years due to lung cancer mortality, estimated using life tables. Results Increasing the air tightness of dwellings (without compensatory purpose-provided ventilation) increased mean indoor radon concentrations by an estimated 56.6%, from 21.2 becquerels per cubic metre (Bq/m3) to 33.2 Bq/m3. After the lag in lung cancer onset, this would result in an additional annual burden of 4700 life years lost and (at peak) 278 deaths. The increases in radon levels for the millions of homes that would contribute most of the additional burden are below the threshold at which radon remediation measures are cost effective. Fitting extraction fans and trickle ventilators to restore ventilation will help offset the additional burden but only if the ventilation related energy efficiency gains are lost. Mechanical ventilation systems with heat recovery may lower radon levels and the risk of cancer while maintaining the advantage of energy efficiency for the most airtight dwellings but there is potential for a major adverse impact on health if such systems fail. Conclusion Unless specific remediation is used, reducing the ventilation of dwellings will improve energy efficiency only at the expense of population wide adverse impact on indoor exposure to radon and risk of lung cancer. The implications of this and other consequences of changes to ventilation need to be carefully evaluated to ensure that the desirable health and environmental benefits of

  8. SU-E-J-163: A Biomechanical Lung Model for Respiratory Motion Study

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Liu, X; Belcher, AH; Grelewicz, Z

    2015-06-15

    Purpose: This work presents a biomechanical model to investigate the complex respiratory motion for the lung tumor tracking in radiosurgery by computer simulation. Methods: The models include networked massspring-dampers to describe the tumor motion, different types of surrogate signals, and the force generated by the diaphragm. Each mass-springdamper has the same mechanical structure and each model can have different numbers of mass-spring-dampers. Both linear and nonlinear stiffness parameters were considered, and the damping ratio was tuned in a range so that the tumor motion was over-damped (no natural tumor oscillation occurs without force from the diaphragm). The simulation was runmore » by using ODE45 (ordinary differential equations by Runge-Kutta method) in MATLAB, and all time courses of motions and inputs (force) were generated and compared. Results: The curvature of the motion time courses around their peaks was sensitive to the damping ratio. Therefore, the damping ratio can be determined based on the clinical data of a high sampling rate. The peak values of different signals and the time the peaks occurred were compared, and it was found that the diaphragm force had a time lead over the tumor motion, and the lead time (0.1–0.4 seconds) depended on the distance between the tumor and the diaphragm. Conclusion: We reported a model based analysis approach for the spatial and temporal relation between the motion of the lung tumor and the surrogate signals. Due to the phase lead of the diaphragm in comparing with the lung tumor motion, the measurement of diaphragm motion (or its electromyography signal) can be used as a beam gating signal in radiosurgery, and it can also be an additional surrogate signal for better tumor motion tracking. The research is funded by the American Cancer Society (ACS) grant. The grant name is: Frameless SRS Based on Robotic Head Motion Cancellation. The grant number is: RSG-13-313-01-CCE.« less

  9. [Expression of HIF1-alpha on myocardium and lung in rats model of asphyxia death].

    PubMed

    Zhang, Geng-qian; Zhou, Bin; Du, Bing; Yang, Zhi-hui; Zhang, Bei-lei; Zhu, Yin-hua; Zhang, Lin

    2006-12-01

    To investigate the expression of HIF1-alpha in heart and lung tissue died from asphyxia. The rats model of asphyxia death was constructed by hanging, different asphyxia groups and control group sets were made according the postmortem time (0,2,6,24 h), immunohistochemistry and half-quantitative RT-PCR methods were used to investigate expression of HIF1-alpha and mRNA changes on heart and lung tissue. The positive staining of HIF1-alpha could be observed in the myocardium and lung tissue. Significant differences were found between the groups of asphyxia and their corresponding control group. HIF1-alpha expression was found in all the asphyxia groups while it was only expressed in the control groups of 2 h, 6 h and 24 h. Nucleic positive staining could be detected in all the asphyxia groups but none was found in the control groups. RT-PCR showed that the expression of mRNA between 0 h asphyxia group and 0 h control group were equal in both cardic muscle and lung, but elevated expression in groups of 2,6,24h compared to their control groups. The nuclear positive staining of HIF1-alpha in heart and lung can be a special character of suffocation death.

  10. In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line.

    PubMed

    Nanjo, Shigeki; Nakagawa, Takayuki; Takeuchi, Shinji; Kita, Kenji; Fukuda, Koji; Nakada, Mitsutoshi; Uehara, Hisanori; Nishihara, Hiroshi; Hara, Eiji; Uramoto, Hidetaka; Tanaka, Fumihiro; Yano, Seiji

    2015-03-01

    EML4-ALK lung cancer accounts for approximately 3-7% of non-small-cell lung cancer cases. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. In this study, we found that the lung adenocarcinoma cell line A925L expresses an EML4-ALK gene fusion (variant 5a, E2:A20) and is sensitive to the ALK inhibitors crizotinib and alectinib. We further established highly tumorigenic A925LPE3 cells, which also have the EML4-ALK gene fusion (variant 5a) and are sensitive to ALK inhibitors. By using A925LPE3 cells with luciferase gene transfection, we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, whereas alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  11. Computationally efficient analysis of particle transport and deposition in a human whole-lung-airway model. Part I: Theory and model validation.

    PubMed

    Kolanjiyil, Arun V; Kleinstreuer, Clement

    2016-12-01

    Computational predictions of aerosol transport and deposition in the human respiratory tract can assist in evaluating detrimental or therapeutic health effects when inhaling toxic particles or administering drugs. However, the sheer complexity of the human lung, featuring a total of 16 million tubular airways, prohibits detailed computer simulations of the fluid-particle dynamics for the entire respiratory system. Thus, in order to obtain useful and efficient particle deposition results, an alternative modeling approach is necessary where the whole-lung geometry is approximated and physiological boundary conditions are implemented to simulate breathing. In Part I, the present new whole-lung-airway model (WLAM) represents the actual lung geometry via a basic 3-D mouth-to-trachea configuration while all subsequent airways are lumped together, i.e., reduced to an exponentially expanding 1-D conduit. The diameter for each generation of the 1-D extension can be obtained on a subject-specific basis from the calculated total volume which represents each generation of the individual. The alveolar volume was added based on the approximate number of alveoli per generation. A wall-displacement boundary condition was applied at the bottom surface of the first-generation WLAM, so that any breathing pattern due to the negative alveolar pressure can be reproduced. Specifically, different inhalation/exhalation scenarios (rest, exercise, etc.) were implemented by controlling the wall/mesh displacements to simulate realistic breathing cycles in the WLAM. Total and regional particle deposition results agree with experimental lung deposition results. The outcomes provide critical insight to and quantitative results of aerosol deposition in human whole-lung airways with modest computational resources. Hence, the WLAM can be used in analyzing human exposure to toxic particulate matter or it can assist in estimating pharmacological effects of administered drug-aerosols. As a practical

  12. Protective ventilation reduces Pseudomonas aeruginosa growth in lung tissue in a porcine pneumonia model.

    PubMed

    Sperber, Jesper; Nyberg, Axel; Lipcsey, Miklos; Melhus, Åsa; Larsson, Anders; Sjölin, Jan; Castegren, Markus

    2017-08-31

    Mechanical ventilation with positive end expiratory pressure and low tidal volume, i.e. protective ventilation, is recommended in patients with acute respiratory distress syndrome. However, the effect of protective ventilation on bacterial growth during early pneumonia in non-injured lungs is not extensively studied. The main objectives were to compare two different ventilator settings on Pseudomonas aeruginosa growth in lung tissue and the development of lung injury. A porcine model of severe pneumonia was used. The protective group (n = 10) had an end expiratory pressure of 10 cm H 2 O and a tidal volume of 6 ml x kg -1 . The control group (n = 10) had an end expiratory pressure of 5 cm H 2 O and a tidal volume of 10 ml x kg -1 . 10 11 colony forming units of Pseudomonas aeruginosa were inoculated intra-tracheally at baseline, after which the experiment continued for 6 h. Two animals from each group received only saline, and served as sham animals. Lung tissue samples from each animal were used for bacterial cultures and wet-to-dry weight ratio measurements. The protective group displayed lower numbers of Pseudomonas aeruginosa (p < 0.05) in the lung tissue, and a lower wet-to-dry ratio (p < 0.01) than the control group. The control group deteriorated in arterial oxygen tension/inspired oxygen fraction, whereas the protective group was unchanged (p < 0.01). In early phase pneumonia, protective ventilation with lower tidal volume and higher end expiratory pressure has the potential to reduce the pulmonary bacterial burden and the development of lung injury.

  13. Lung cell fiber evanescent wave spectroscopic biosensing of inhalation health hazards.

    PubMed

    Riley, Mark R; Lucas, Pierre; Le Coq, David; Juncker, Christophe; Boesewetter, Dianne E; Collier, Jayne L; DeRosa, Diana M; Katterman, Matthew E; Boussard-Plédel, Catherine; Bureau, Bruno

    2006-11-05

    Health risks associated with the inhalation of biological materials have been a topic of great concern; however, there are no rapid and automatable methods available to evaluate the potential health impact of inhaled materials. Here we describe a novel approach to evaluate the potential toxic effects of materials evaluated through cell-based spectroscopic analysis. Anchorage-dependent cells are grown on the surface of optical fibers transparent to infrared light. The probe system is composed of a single chalcogenide fiber (composed of Te, As, and Se) acting as both the sensor and transmission line for infrared optical signals. The cells are exposed to potential toxins and alterations of cellular composition are monitored through their impact on cellular spectral features. The signal is collected via evanescent wave absorption along the tapered sensing zone of the fiber through spectral changes between 3,000 and 600 cm(-1) (3,333-16,666 nm). Cell physiology, composition, and function are non-invasively tracked through monitoring infrared light absorption by the cell layer. This approach is demonstrated with an immortalized lung cell culture (A549, human lung carcinoma epithelia) in response to a variety of inhalation hazards including gliotoxin (a fungal metabolite), etoposide (a genotoxin), and methyl methansesulfonate (MMS, an alkylating agent). Gliotoxin impacts cell metabolism, etoposide impacts nucleic acids and the cell cycle, and MMS impacts nucleic acids and induces an immune response. This spectroscopic method is sensitive, non-invasive, and provides information on a wide range of cellular damage and response mechanisms and could prove useful for cell response screening of pharmaceuticals or for toxicological evaluations. (c) 2006 Wiley Periodicals, Inc.

  14. PR-Set7 is degraded in a conditional Cul4A transgenic mouse model of lung cancer

    DOE PAGES

    Wang, Yang; Xu, Zhidong; Mao, Jian -Hua; ...

    2015-06-01

    Background and objective. Maintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. PR-Set7 (also known as Set8) is a cell cycle regulated enzyme that catalyses monomethylation of histone 4 at Lys20 (H4K20me1) to promote chromosome condensation and prevent DNA damage. Recent studies show that CRL4CDT2-mediated ubiquitylation of PR-Set7 leads to its degradation during S phase and after DNA damage. This might occur to ensure appropriate changes in chromosome structure during the cell cycle or to preserve genome integrity after DNA damage. Methods. We developed a new model of lung tumor developmentmore » in mice harboring a conditionally expressed allele of Cul4A. We have therefore used a mouse model to demonstrate for the first time that Cul4A is oncogenic in vivo. With this model, staining of PR-Set7 in the preneoplastic and tumor lesions in AdenoCre-induced mouse lungs was performed. Meanwhile we identified higher protein level changes of γ-tubulin and pericentrin by IHC. Results. The level of PR-Set7 down-regulated in the preneoplastic and adenocarcinomous lesions following over-expression of Cul4A. We also identified higher levels of the proteins pericentrin and γ-tubulin in Cul4A mouse lungs induced by AdenoCre. Conclusion. PR-Set7 is a direct target of Cul4A for degradation and involved in the formation of lung tumors in the conditional Cul4A transgenic mouse model.« less

  15. PR-Set7 is degraded in a conditional Cul4A transgenic mouse model of lung cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wang, Yang; Xu, Zhidong; Mao, Jian -Hua

    Background and objective. Maintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. PR-Set7 (also known as Set8) is a cell cycle regulated enzyme that catalyses monomethylation of histone 4 at Lys20 (H4K20me1) to promote chromosome condensation and prevent DNA damage. Recent studies show that CRL4CDT2-mediated ubiquitylation of PR-Set7 leads to its degradation during S phase and after DNA damage. This might occur to ensure appropriate changes in chromosome structure during the cell cycle or to preserve genome integrity after DNA damage. Methods. We developed a new model of lung tumor developmentmore » in mice harboring a conditionally expressed allele of Cul4A. We have therefore used a mouse model to demonstrate for the first time that Cul4A is oncogenic in vivo. With this model, staining of PR-Set7 in the preneoplastic and tumor lesions in AdenoCre-induced mouse lungs was performed. Meanwhile we identified higher protein level changes of γ-tubulin and pericentrin by IHC. Results. The level of PR-Set7 down-regulated in the preneoplastic and adenocarcinomous lesions following over-expression of Cul4A. We also identified higher levels of the proteins pericentrin and γ-tubulin in Cul4A mouse lungs induced by AdenoCre. Conclusion. PR-Set7 is a direct target of Cul4A for degradation and involved in the formation of lung tumors in the conditional Cul4A transgenic mouse model.« less

  16. Synthetic Secoisolariciresinol Diglucoside (LGM2605) Protects Human Lung in an Ex Vivo Model of Proton Radiation Damage.

    PubMed

    Velalopoulou, Anastasia; Chatterjee, Shampa; Pietrofesa, Ralph A; Koziol-White, Cynthia; Panettieri, Reynold A; Lin, Liyong; Tuttle, Stephen; Berman, Abigail; Koumenis, Constantinos; Christofidou-Solomidou, Melpo

    2017-11-25

    Radiation therapy for the treatment of thoracic malignancies has improved significantly by directing of the proton beam in higher doses on the targeted tumor while normal tissues around the tumor receive much lower doses. Nevertheless, exposure of normal tissues to protons is known to pose a substantial risk in long-term survivors, as confirmed by our work in space-relevant exposures of murine lungs to proton radiation. Thus, radioprotective strategies are being sought. We established that LGM2605 is a potent protector from radiation-induced lung toxicity and aimed in the current study to extend the initial findings of space-relevant, proton radiation-associated late lung damage in mice by looking at acute changes in human lung. We used an ex vivo model of organ culture where tissue slices of donor living human lung were kept in culture and exposed to proton radiation. We exposed donor human lung precision-cut lung sections (huPCLS), pretreated with LGM2605, to 4 Gy proton radiation and evaluated them 30 min and 24 h later for gene expression changes relevant to inflammation, oxidative stress, and cell cycle arrest, and determined radiation-induced senescence, inflammation, and oxidative tissue damage. We identified an LGM2605-mediated reduction of proton radiation-induced cellular senescence and associated cell cycle changes, an associated proinflammatory phenotype, and associated oxidative tissue damage. This is a first report on the effects of proton radiation and of the radioprotective properties of LGM2605 on human lung.

  17. Synthetic Secoisolariciresinol Diglucoside (LGM2605) Protects Human Lung in an Ex Vivo Model of Proton Radiation Damage

    PubMed Central

    Velalopoulou, Anastasia; Chatterjee, Shampa; Pietrofesa, Ralph A.; Koziol-White, Cynthia; Panettieri, Reynold A.; Lin, Liyong; Tuttle, Stephen; Berman, Abigail; Koumenis, Constantinos; Christofidou-Solomidou, Melpo

    2017-01-01

    Radiation therapy for the treatment of thoracic malignancies has improved significantly by directing of the proton beam in higher doses on the targeted tumor while normal tissues around the tumor receive much lower doses. Nevertheless, exposure of normal tissues to protons is known to pose a substantial risk in long-term survivors, as confirmed by our work in space-relevant exposures of murine lungs to proton radiation. Thus, radioprotective strategies are being sought. We established that LGM2605 is a potent protector from radiation-induced lung toxicity and aimed in the current study to extend the initial findings of space-relevant, proton radiation-associated late lung damage in mice by looking at acute changes in human lung. We used an ex vivo model of organ culture where tissue slices of donor living human lung were kept in culture and exposed to proton radiation. We exposed donor human lung precision-cut lung sections (huPCLS), pretreated with LGM2605, to 4 Gy proton radiation and evaluated them 30 min and 24 h later for gene expression changes relevant to inflammation, oxidative stress, and cell cycle arrest, and determined radiation-induced senescence, inflammation, and oxidative tissue damage. We identified an LGM2605-mediated reduction of proton radiation-induced cellular senescence and associated cell cycle changes, an associated proinflammatory phenotype, and associated oxidative tissue damage. This is a first report on the effects of proton radiation and of the radioprotective properties of LGM2605 on human lung. PMID:29186841

  18. Antitumor immune activity by chemokine CX3CL1 in an orthotopic implantation of lung cancer model in vivo.

    PubMed

    Kee, Ji-Ye; Arita, Yoshihisa; Shinohara, Kanna; Ohashi, Yasukata; Sakurai, Hiroaki; Saiki, Ikuo; Koizumi, Keiichi

    2013-01-01

    Due to their chemoattractant properties stimulating the accumulation of infiltrating immune cells in tumors, chemokines are known to have antitumor effects. Fractalkine, a unique CX3C chemokine, is expressed in activated endothelial cells, while its receptor, CX3CR1, is expressed in cytolytic immune cells, such as natural killer cells, monocytes and some CD8 + T cells. The biological properties of cancer cells are affected by the implantation organ and differences in immune systems, requiring cancer implantation in orthotopic organs in an in vivo experiment. To develop new therapy strategies for lung cancer, an animal model reflecting the clinical features of lung cancer was previously established. This study aimed to determine whether CX3CL1-induced biological functions should be used for immune cell-based gene therapy of lung cancer in the orthotopic implantation model. An orthotopic intrapulmonary implantation of CX3CL1-stable expression in mouse lung cancer (LLC-CX3CL1) was performed to analyze growth. Results showed a significant decrease in tumor growth in the lung compared to the control cells (LLC-mock). Furthermore, the antitumor effects of CX3CL1 were derived from natural killer cell activities in the depletion experiment in vivo . Therefore, CX3CL1 has the potential of a useful therapeutic target in lung cancer.

  19. Exogenous surfactant preserves lung function and reduces alveolar Evans blue dye influx in a rat model of ventilation-induced lung injury.

    PubMed

    Verbrugge, S J; Vazquez de Anda, G; Gommers, D; Neggers, S J; Sorm, V; Böhm, S H; Lachmann, B

    1998-08-01

    Changes in pulmonary edema infiltration and surfactant after intermittent positive pressure ventilation with high peak inspiratory lung volumes have been well described. To further elucidate the role of surfactant changes, the authors tested the effect of different doses of exogenous surfactant preceding high peak inspiratory lung volumes on lung function and lung permeability. Five groups of Sprague-Dawley rats (n = 6 per group) were subjected to 20 min of high peak inspiratory lung volumes. Before high peak inspiratory lung volumes, four of these groups received intratracheal administration of saline or 50, 100, or 200 mg/kg body weight surfactant; one group received no intratracheal administration. Gas exchange was measured during mechanical ventilation. A sixth group served as nontreated, nonventilated controls. After death, all lungs were excised, and static pressure-volume curves and total lung volume at a transpulmonary pressure of 5 cm H2O were recorded. The Gruenwald index and the steepest part of the compliance curve (Cmax) were calculated. A bronchoalveolar lavage was performed; surfactant small and large aggregate total phosphorus and minimal surface tension were measured. In a second experiment in five groups of rats (n = 6 per group), lung permeability for Evans blue dye was measured. Before 20 min of high peak inspiratory lung volumes, three groups received intratracheal administration of 100, 200, or 400 mg/ kg body weight surfactant; one group received no intratracheal administration. A fifth group served as nontreated, nonventilated controls. Exogenous surfactant at a dose of 200 mg/kg preserved total lung volume at a pressure of 5 cm H2O, maximum compliance, the Gruenwald Index, and oxygenation after 20 min of mechanical ventilation. The most active surfactant was recovered in the group that received 200 mg/kg surfactant, and this dose reduced minimal surface tension of bronchoalveolar lavage to control values. Alveolar influx of Evans blue dye

  20. The application of the sinusoidal model to lung cancer patient respiratory motion

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    George, R.; Vedam, S.S.; Chung, T.D.

    2005-09-15

    Accurate modeling of the respiratory cycle is important to account for the effect of organ motion on dose calculation for lung cancer patients. The aim of this study is to evaluate the accuracy of a respiratory model for lung cancer patients. Lujan et al. [Med. Phys. 26(5), 715-720 (1999)] proposed a model, which became widely used, to describe organ motion due to respiration. This model assumes that the parameters do not vary between and within breathing cycles. In this study, first, the correlation of respiratory motion traces with the model f(t) as a function of the parameter n(n=1,2,3) was undertakenmore » for each breathing cycle from 331 four-minute respiratory traces acquired from 24 lung cancer patients using three breathing types: free breathing, audio instruction, and audio-visual biofeedback. Because cos{sup 2} and cos{sup 4} had similar correlation coefficients, and cos{sup 2} and cos{sup 1} have a trigonometric relationship, for simplicity, the cos{sup 1} value was consequently used for further analysis in which the variations in mean position (z{sub 0}), amplitude of motion (b) and period ({tau}) with and without biofeedback or instructions were investigated. For all breathing types, the parameter values, mean position (z{sub 0}), amplitude of motion (b), and period ({tau}) exhibited significant cycle-to-cycle variations. Audio-visual biofeedback showed the least variations for all three parameters (z{sub 0}, b, and {tau}). It was found that mean position (z{sub 0}) could be approximated with a normal distribution, and the amplitude of motion (b) and period ({tau}) could be approximated with log normal distributions. The overall probability density function (pdf) of f(t) for each of the three breathing types was fitted with three models: normal, bimodal, and the pdf of a simple harmonic oscillator. It was found that the normal and the bimodal models represented the overall respiratory motion pdfs with correlation values from 0.95 to 0.99, whereas

  1. Recurrent milk aspiration produces changes in airway mechanics, lung eosinophilia, and goblet cell hyperplasia in a murine model.

    PubMed

    Janahi, I A; Elidemir, O; Shardonofsky, F R; Abu-Hassan, M N; Fan, L L; Larsen, G L; Blackburn, M R; Colasurdo, G N

    2000-12-01

    Recurrent aspiration of milk into the respiratory tract has been implicated in the pathogenesis of a variety of inflammatory lung disorders including asthma. However, the lack of animal models of aspiration-induced lung injury has limited our knowledge of the pathophysiological characteristics of this disorder. This study was designed to evaluate the effects of recurrent milk aspiration on airway mechanics and lung cells in a murine model. Under light anesthesia, BALB/c mice received daily intranasal instillations of whole cow's milk (n = 7) or sterile physiologic saline (n = 9) for 10 d. Respiratory system resistance (Rrs) and dynamic elastance (Edyn,rs) were measured in anesthetized, tracheotomized, paralyzed and mechanically ventilated mice 24 h after the last aspiration of milk. Rrs and Edyn,rs were derived from transrespiratory and plethysmographic pressure signals. In addition, airway responses to increasing concentrations of i.v. methacholine (Mch) were determined. Airway responses were measured in terms of PD(100) (dose of Mch causing 100% increase from baseline Rrs) and Rrs,max (% increase from baseline at the maximal plateau response) and expressed as % control (mean +/- SE). We found recurrent milk aspiration did not affect Edyn and baseline Rrs values. However, airway responses to Mch were increased after milk aspiration when compared with control mice. These changes in airway mechanics were associated with an increased percentage of lymphocytes and eosinophils in the bronchoalveolar lavage, mucus production, and lung inflammation. Our findings suggest that recurrent milk aspiration leads to alterations in airway function, lung eosinophilia, and goblet cell hyperplasia in a murine model.

  2. Retention and clearance of inhaled ceramic fibres in rat lungs and development of a dissolution model.

    PubMed Central

    Yamato, H; Hori, H; Tanaka, I; Higashi, T; Morimoto, Y; Kido, M

    1994-01-01

    Male Wistar rats were exposed to aluminium silicate ceramic fibres by inhalation to study pulmonary deposition, clearance, and dissolution of the fibres. Rats were killed at one day, one month, three months, and six months after the termination of exposure. After exposure, fibres greater than 50 microns in length were seen with a scanning electron microscope in the alveolar region of the lung. Fibres were recovered from the lungs with a low temperature ashing technique and their number, diameter, and length were measured by scanning electron microscopy. The number of fibres remaining in the lungs declined exponentially with time after exposure and their silicon content also fell. The geometric median diameter of fibres decreased linearly with time. By six months after exposure, the surface of fibres recovered from the lungs had an eroded appearance. The results suggest that ceramic fibres are physically cleared from the lung and that they show signs of dissolution. Finally, the results were used to develop a theoretical model of fibre dissolution that gives a satisfactory fit to the experimental data. Images Figure 1 Figure 2 Figure 5 PMID:8199672

  3. Human Bocavirus Type-1 Capsid Facilitates the Transduction of Ferret Airways by Adeno-Associated Virus Genomes.

    PubMed

    Yan, Ziying; Feng, Zehua; Sun, Xingshen; Zhang, Yulong; Zou, Wei; Wang, Zekun; Jensen-Cody, Chandler; Liang, Bo; Park, Soo-Yeun; Qiu, Jianming; Engelhardt, John F

    2017-08-01

    Human bocavirus type-1 (HBoV1) has a high tropism for the apical membrane of human airway epithelia. The packaging of a recombinant adeno-associated virus 2 (rAAV2) genome into HBoV1 capsid produces a chimeric vector (rAAV2/HBoV1) that also efficiently transduces human airway epithelia. As such, this vector is attractive for use in gene therapies to treat lung diseases such as cystic fibrosis. However, preclinical development of rAAV2/HBoV1 vectors has been hindered by the fact that humans are the only known host for HBoV1 infection. This study reports that rAAV2/HBoV1 vector is capable of efficiently transducing the lungs of both newborn (3- to 7-day-old) and juvenile (29-day-old) ferrets, predominantly in the distal airways. Analyses of in vivo, ex vivo, and in vitro models of the ferret proximal airway demonstrate that infection of this particular region is less effective than it is in humans. Studies of vector binding and endocytosis in polarized ferret proximal airway epithelial cultures revealed that a lack of effective vector endocytosis is the main cause of inefficient transduction in vitro. While transgene expression declined proportionally with growth of the ferrets following infection at 7 days of age, reinfection of ferrets with rAAV2/HBoV1 at 29 days gave rise to approximately 5-fold higher levels of transduction than observed in naive infected 29-day-old animals. The findings presented here lay the foundation for clinical development of HBoV1 capsid-based vectors for lung gene therapy in cystic fibrosis using ferret models.

  4. Evaluation of the chemical model of vestibular lesions induced by arsanilate in rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Vignaux, G.; Univ Caen, Caen, F-14000; Chabbert, C.

    Several animal models of vestibular deficits that mimic the human pathology phenotype have previously been developed to correlate the degree of vestibular injury to cognate vestibular deficits in a time-dependent manner. Sodium arsanilate is one of the most commonly used substances for chemical vestibular lesioning, but it is not well described in the literature. In the present study, we used histological and functional approaches to conduct a detailed exploration of the model of vestibular lesions induced by transtympanic injection of sodium arsanilate in rats. The arsanilate-induced damage was restricted to the vestibular sensory organs without affecting the external ear, themore » oropharynx, or Scarpa's ganglion. This finding strongly supports the absence of diffusion of arsanilate into the external ear or Eustachian tubes, or through the eighth cranial nerve sheath leading to the brainstem. One of the striking observations of the present study is the complete restructuring of the sensory epithelia into a non sensory epithelial monolayer observed at 3 months after arsanilate application. This atrophy resembles the monolayer epithelia observed postmortem in the vestibular epithelia of patients with a history of lesioned vestibular deficits such as labyrinthectomy, antibiotic treatment, vestibular neuritis, or Ménière's disease. In cases of Ménière's disease, aminoglycosides, and platinum-based chemotherapy, vestibular hair cells are destroyed, regardless of the physiopathological process, as reproduced with the arsanilate model of vestibular lesion. These observations, together with those presented in this study of arsanilate vestibular toxicity, suggest that this atrophy process relies on a common mechanism of degeneration of the sensory epithelia.« less

  5. Improved biochemical preservation of lung slices during cold storage.

    PubMed

    Bull, D A; Connors, R C; Reid, B B; Albanil, A; Stringham, J C; Karwande, S V

    2000-05-15

    Development of lung preservation solutions typically requires whole-organ models which are animal and labor intensive. These models rely on physiologic rather than biochemical endpoints, making accurate comparison of the relative efficacy of individual solution components difficult. We hypothesized that lung slices could be used to assess preservation of biochemical function during cold storage. Whole rat lungs were precision cut into slices with a thickness of 500 microm and preserved at 4 degrees C in the following solutions: University of Wisconsin (UW), Euro-Collins (EC), low-potassium-dextran (LPD), Kyoto (K), normal saline (NS), or a novel lung preservation solution (NPS) developed using this model. Lung biochemical function was assessed by ATP content (etamol ATP/mg wet wt) and capacity for protein synthesis (cpm/mg protein) immediately following slicing (0 h) and at 6, 12, 18, and 24 h of cold storage. Six slices were assayed at each time point for each solution. The data were analyzed using analysis of variance and are presented as means +/- SD. ATP content was significantly higher in the lung slices stored in NPS compared with all other solutions at each time point (P < 0.0001). Protein synthesis was significantly higher in the lung slices stored in NPS compared with all other solutions at 6, 12, and 18 h of preservation (P < 0.05). This lung slice model allows the rapid and efficient screening of lung preservation solutions and their components using quantifiable biochemical endpoints. Using this model, we have developed a novel solution that improves the biochemical preservation of lung slices during cold storage. Copyright 2000 Academic Press.

  6. A simple analogue of lung mechanics.

    PubMed

    Sherman, T F

    1993-12-01

    A model of the chest and lungs can be easily constructed from a bottle of water, a balloon, a syringe, a rubber stopper, glass and rubber tubing, and clamps. The model is a more exact analogue of the body than the classic apparatus of Hering in two respects: 1) the pleurae and intrapleural fluid are represented by water rather than air, and 2) the subatmospheric "intrapleural" pressure is created by the elasticity of the "lung" (balloon) rather than by a vacuum pump. With this model, students can readily see how the lung is inflated and deflated by movements of the "diaphragm and chest" (syringe plunger) and how intrapleural pressures change as this is accomplished.

  7. Lung transplantation and interstitial lung disease.

    PubMed

    Alalawi, Raed; Whelan, Timothy; Bajwa, Ravinder S; Hodges, Tony N

    2005-09-01

    Interstitial lung disease includes a heterogeneous group of disorders that leads to respiratory insufficiency and death in a significant number of patients. Lung transplantation is a therapeutic option in select candidates. The indications, transplant procedure options, and outcomes continue to evolve. Various recipient comorbidities influence the choice of procedure in patients with interstitial lung disease. Single lung transplants are used as the procedure of choice and bilateral transplants are reserved for patients with suppurative lung disease and patients with pulmonary hypertension. Issues unique to patients with interstitial lung disease affect the morbidity, mortality and recurrence of the disease. Lung transplantation is an effective therapy for respiratory failure in interstitial lung disease with survival following transplant being similar to that achieved in transplant recipients with other diseases.

  8. Impact of endotracheal tube shortening on work of breathing in neonatal and pediatric in vitro lung models.

    PubMed

    Mohr, Rebecca; Thomas, Jörg; Cannizzaro, Vincenzo; Weiss, Markus; Schmidt, Alexander R

    2017-09-01

    Work of breathing accounts for a significant proportion of total oxygen consumption in neonates and infants. Endotracheal tube inner diameter and length significantly affect airflow resistance and thus work of breathing. While endotracheal tube shortening reduces endotracheal tube resistance, the impact on work of breathing in mechanically ventilated neonates and infants remains unknown. The objective of this in vitro study was to quantify the effect of endotracheal tube shortening on work of breathing in simulated pediatric lung settings. We hypothesized that endotracheal tube shortening significantly reduces work of breathing. We used the Active-Servo-Lung 5000 to simulate different clinical scenarios in mechanically ventilated infants and neonates under spontaneous breathing with and without pressure support. Endotracheal tube size, lung resistance, and compliance, as well as respiratory settings such as respiratory rate and tidal volume were weight and age adapted for each lung model. Work of breathing was measured before and after maximal endotracheal tube shortening and the reduction of the daily energy demand calculated. Tube shortening with and without pressure support decreased work of breathing to a maximum of 10.1% and 8.1%, respectively. As a result, the calculated reduction of total daily energy demand by endotracheal tube shortening was between 0.002% and 0.02%. In this in vitro lung model, endotracheal tube shortening had minimal effects on work of breathing. Moreover, the calculated percentage reduction of the total daily energy demand after endotracheal tube shortening was minimal. © 2017 John Wiley & Sons Ltd.

  9. A completely automated processing pipeline for lung and lung lobe segmentation and its application to the LIDC-IDRI data base

    NASA Astrophysics Data System (ADS)

    Blaffert, Thomas; Wiemker, Rafael; Barschdorf, Hans; Kabus, Sven; Klinder, Tobias; Lorenz, Cristian; Schadewaldt, Nicole; Dharaiya, Ekta

    2010-03-01

    Automated segmentation of lung lobes in thoracic CT images has relevance for various diagnostic purposes like localization of tumors within the lung or quantification of emphysema. Since emphysema is a known risk factor for lung cancer, both purposes are even related to each other. The main steps of the segmentation pipeline described in this paper are the lung detector and the lung segmentation based on a watershed algorithm, and the lung lobe segmentation based on mesh model adaptation. The segmentation procedure was applied to data sets of the data base of the Image Database Resource Initiative (IDRI) that currently contains over 500 thoracic CT scans with delineated lung nodule annotations. We visually assessed the reliability of the single segmentation steps, with a success rate of 98% for the lung detection and 90% for lung delineation. For about 20% of the cases we found the lobe segmentation not to be anatomically plausible. A modeling confidence measure is introduced that gives a quantitative indication of the segmentation quality. For a demonstration of the segmentation method we studied the correlation between emphysema score and malignancy on a per-lobe basis.

  10. Lung Cancer and Lung Transplantation.

    PubMed

    Brand, Timothy; Haithcock, Benjamin

    2018-02-01

    Lung transplantation remains a viable option for patients with endstage pulmonary disease. Despite removing the affected organ and replacing both lungs, the risk of lung malignancies still exists. Regardless of the mode of entry, lung cancer affects the prognosis in these patients and diligence is required. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Unsupervised segmentation of lung fields in chest radiographs using multiresolution fractal feature vector and deformable models.

    PubMed

    Lee, Wen-Li; Chang, Koyin; Hsieh, Kai-Sheng

    2016-09-01

    Segmenting lung fields in a chest radiograph is essential for automatically analyzing an image. We present an unsupervised method based on multiresolution fractal feature vector. The feature vector characterizes the lung field region effectively. A fuzzy c-means clustering algorithm is then applied to obtain a satisfactory initial contour. The final contour is obtained by deformable models. The results show the feasibility and high performance of the proposed method. Furthermore, based on the segmentation of lung fields, the cardiothoracic ratio (CTR) can be measured. The CTR is a simple index for evaluating cardiac hypertrophy. After identifying a suspicious symptom based on the estimated CTR, a physician can suggest that the patient undergoes additional extensive tests before a treatment plan is finalized.

  12. Modelling of cardiac-related changes in lung resistivity measured with EITS.

    PubMed

    Zhao, T X; Brown, B H; Nopp, P; Wang, W; Leathard, A D; Lu, L Q

    1996-11-01

    Resistivity data from 9.6 kHZ to 1.2 MHz were recorded from eight normal subjects using an electrical impedance tomographic spectroscopy (EITS) system and then averaged to a mean cardiac cycle using the ECG gating technique. The Cole-Cole model, that is, extracellular resistance R connected in parallel with intracellular resistance S and membrane capacitance C in series, with a distribution parameter a, was applied to model the frequency characteristics and to produce parametric images. During systole, SC and RC were found to decrease and FR increase. The changes in R/S were not consistent among the subjects. We estimated the peak changes in R, S and C to be -2.5%, -3.3% and -7.6% respectively. The results can be explained by considering the blood vessels as spheres of different sizes with blood inside them. The decrease in R during systole might be caused by the increased blood content in relatively large vessels, whereas that in S by the increased blood volume in relatively small vessels. The capacitance of blood is normally smaller than that of lung tissue, whereas FR blood is higher than that of lung tissue. Hence, as blood content increases, C should decrease and FR increase.

  13. Integrated lung tissue mechanics one piece at a time: Computational modeling across the scales of biology.

    PubMed

    Burrowes, Kelly S; Iravani, Amin; Kang, Wendy

    2018-01-12

    The lung is a delicately balanced and highly integrated mechanical system. Lung tissue is continuously exposed to the environment via the air we breathe, making it susceptible to damage. As a consequence, respiratory diseases present a huge burden on society and their prevalence continues to rise. Emergent function is produced not only by the sum of the function of its individual components but also by the complex feedback and interactions occurring across the biological scales - from genes to proteins, cells, tissue and whole organ - and back again. Computational modeling provides the necessary framework for pulling apart and putting back together the pieces of the body and organ systems so that we can fully understand how they function in both health and disease. In this review, we discuss models of lung tissue mechanics spanning from the protein level (the extracellular matrix) through to the level of cells, tissue and whole organ, many of which have been developed in isolation. This is a vital step in the process but to understand the emergent behavior of the lung, we must work towards integrating these component parts and accounting for feedback across the scales, such as mechanotransduction. These interactions will be key to unlocking the mechanisms occurring in disease and in seeking new pharmacological targets and improving personalized healthcare. Copyright © 2018 Elsevier Ltd. All rights reserved.

  14. Experimental investigation and numerical simulation of 3He gas diffusion in simple geometries: implications for analytical models of 3He MR lung morphometry.

    PubMed

    Parra-Robles, J; Ajraoui, S; Deppe, M H; Parnell, S R; Wild, J M

    2010-06-01

    Models of lung acinar geometry have been proposed to analytically describe the diffusion of (3)He in the lung (as measured with pulsed gradient spin echo (PGSE) methods) as a possible means of characterizing lung microstructure from measurement of the (3)He ADC. In this work, major limitations in these analytical models are highlighted in simple diffusion weighted experiments with (3)He in cylindrical models of known geometry. The findings are substantiated with numerical simulations based on the same geometry using finite difference representation of the Bloch-Torrey equation. The validity of the existing "cylinder model" is discussed in terms of the physical diffusion regimes experienced and the basic reliance of the cylinder model and other ADC-based approaches on a Gaussian diffusion behaviour is highlighted. The results presented here demonstrate that physical assumptions of the cylinder model are not valid for large diffusion gradient strengths (above approximately 15 mT/m), which are commonly used for (3)He ADC measurements in human lungs. (c) 2010 Elsevier Inc. All rights reserved.

  15. Computationally efficient analysis of particle transport and deposition in a human whole-lung-airway model. Part II: Dry powder inhaler application.

    PubMed

    Kolanjiyil, Arun V; Kleinstreuer, Clement; Sadikot, Ruxana T

    2017-05-01

    Pulmonary drug delivery is becoming a favored route for administering drugs to treat both lung and systemic diseases. Examples of lung diseases include asthma, cystic fibrosis and chronic obstructive pulmonary disease (COPD) as well as respiratory distress syndrome (ARDS) and pulmonary fibrosis. Special respiratory drugs are administered to the lungs, using an appropriate inhaler device. Next to the pressurized metered-dose inhaler (pMDI), the dry powder inhaler (DPI) is a frequently used device because of the good drug stability and a minimal need for patient coordination. Specific DPI-designs and operations greatly affect drug-aerosol formation and hence local lung deposition. Simulating the fluid-particle dynamics after use of a DPI allows for the assessment of drug-aerosol deposition and can also assist in improving the device configuration and operation. In Part I of this study a first-generation whole lung-airway model (WLAM) was introduced and discussed to analyze particle transport and deposition in a human respiratory tract model. In the present Part II the drug-aerosols are assumed to be injected into the lung airways from a DPI mouth-piece, forming the mouth-inlet. The total as well as regional particle depositions in the WLAM, as inhaled from a DPI, were successfully compared with experimental data sets reported in the open literature. The validated modeling methodology was then employed to study the delivery of curcumin aerosols into lung airways using a commercial DPI. Curcumin has been implicated to possess high therapeutic potential as an antioxidant, anti-inflammatory and anti-cancer agent. However, efficacy of curcumin treatment is limited because of the low bioavailability of curcumin when ingested. Hence, alternative drug administration techniques, e.g., using inhalable curcumin-aerosols, are under investigation. Based on the present results, it can be concluded that use of a DPI leads to low lung deposition efficiencies because large amounts of

  16. Green tea polyphenol extract attenuates lung injury in experimental model of carrageenan-induced pleurisy in mice

    PubMed Central

    Di Paola, Rosanna; Mazzon, Emanuela; Muià, Carmelo; Genovese, Tiziana; Menegazzi, Marta; Zaffini, Raffaela; Suzuki, Hisanory; Cuzzocrea, Salvatore

    2005-01-01

    Here we investigate the effects of the green tea extract in an animal model of acute inflammation, carrageenan-induced pleurisy. We report here that green tea extract (given at 25 mg/kg i.p. bolus 1 h prior to carrageenan), exerts potent anti-inflammatory effects in an animal model of acute inflammation in vivo. Injection of carrageenan (2%) into the pleural cavity of mice elicited an acute inflammatory response characterized by fluid accumulation in the pleural cavity that contained many neutrophils (PMNs), an infiltration of PMNs in lung tissues and increased production of nitrite/nitrate, tumour necrosis factor alpha. All parameters of inflammation were attenuated by green tea extract treatment. Furthermore, carrageenan induced an up-regulation of the adhesion molecule ICAM-1, as well as nitrotyrosine and poly (ADP-ribose) synthetase (PARS) formation, as determined by immunohistochemical analysis of lung tissues. Staining for the ICAM-1, nitrotyrosine, and PARS was reduced by green tea extract. Our results clearly demonstrate that treatment with green tea extract exerts a protective effect and offers a novel therapeutic approach for the management of lung injury. PMID:15987519

  17. Analysis of point-to-point lung motion with full inspiration and expiration CT data using non-linear optimization method: optimal geometric assumption model for the effective registration algorithm

    NASA Astrophysics Data System (ADS)

    Kim, Namkug; Seo, Joon Beom; Heo, Jeong Nam; Kang, Suk-Ho

    2007-03-01

    The study was conducted to develop a simple model for more robust lung registration of volumetric CT data, which is essential for various clinical lung analysis applications, including the lung nodule matching in follow up CT studies, semi-quantitative assessment of lung perfusion, and etc. The purpose of this study is to find the most effective reference point and geometric model based on the lung motion analysis from the CT data sets obtained in full inspiration (In.) and expiration (Ex.). Ten pairs of CT data sets in normal subjects obtained in full In. and Ex. were used in this study. Two radiologists were requested to draw 20 points representing the subpleural point of the central axis in each segment. The apex, hilar point, and center of inertia (COI) of each unilateral lung were proposed as the reference point. To evaluate optimal expansion point, non-linear optimization without constraints was employed. The objective function is sum of distances from the line, consist of the corresponding points between In. and Ex. to the optimal point x. By using the nonlinear optimization, the optimal points was evaluated and compared between reference points. The average distance between the optimal point and each line segment revealed that the balloon model was more suitable to explain the lung expansion model. This lung motion analysis based on vector analysis and non-linear optimization shows that balloon model centered on the center of inertia of lung is most effective geometric model to explain lung expansion by breathing.

  18. A Risk Stratification Model for Lung Cancer Based on Gene Coexpression Network and Deep Learning

    PubMed Central

    2018-01-01

    Risk stratification model for lung cancer with gene expression profile is of great interest. Instead of previous models based on individual prognostic genes, we aimed to develop a novel system-level risk stratification model for lung adenocarcinoma based on gene coexpression network. Using multiple microarray, gene coexpression network analysis was performed to identify survival-related networks. A deep learning based risk stratification model was constructed with representative genes of these networks. The model was validated in two test sets. Survival analysis was performed using the output of the model to evaluate whether it could predict patients' survival independent of clinicopathological variables. Five networks were significantly associated with patients' survival. Considering prognostic significance and representativeness, genes of the two survival-related networks were selected for input of the model. The output of the model was significantly associated with patients' survival in two test sets and training set (p < 0.00001, p < 0.0001 and p = 0.02 for training and test sets 1 and 2, resp.). In multivariate analyses, the model was associated with patients' prognosis independent of other clinicopathological features. Our study presents a new perspective on incorporating gene coexpression networks into the gene expression signature and clinical application of deep learning in genomic data science for prognosis prediction. PMID:29581968

  19. Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models.

    PubMed

    Baker, Amanda F; Hanke, Neale T; Sands, Barbara J; Carbajal, Liliana; Anderl, Janet L; Garland, Linda L

    2014-12-31

    Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models. A diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ. CFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC50 values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC50 values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP). CFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC.

  20. High-frequency percussive ventilation attenuates lung injury in a rabbit model of gastric juice aspiration.

    PubMed

    Allardet-Servent, Jérôme; Bregeon, Fabienne; Delpierre, Stéphane; Steinberg, Jean-Guillaume; Payan, Marie-José; Ravailhe, Sylvie; Papazian, Laurent

    2008-01-01

    To test the effects of high-frequency percussive ventilation (HFPV) compared with high-frequency oscillatory ventilation (HFOV) and low-volume conventional mechanical ventilation (LVCMV), on lung injury course in a gastric juice aspiration model. Prospective, randomized, controlled, in-vivo animal study. University animal research laboratory. Forty-three New Zealand rabbits. Lung injury was induced by intratracheal instillation of human gastric juice in order to achieve profound hypoxaemia (PaO2/FIO2< or =50). Animals were ventilated for 4h after randomization in one of the following four groups: HFPV (median pressure 15cmH2O); LVCMV (VT 6mlkg(-1) and PEEP set to reach 15cmH2O plateau pressure); HFOV (mean pressure 15cmH2O); and a high-volume control group HVCMV (VT 12ml kg(-1) and ZEEP). Static respiratory compliance increased after the ventilation period in the HFPV, LVMCV and HFOV groups, in contrast with the HVCMV group. PaO2/FIO2 improved similarly in the HFPV, LVCMV and HFOV groups, and remained lower in the HVCMV group than in the three others. Lung oedema, myeloperoxidase and histological lung injury score were higher in the HVCMV group, but not different among all others. Arterial lactate markedly increased after 4h of ventilation in the HVCMV group, while lower but similar levels were observed in the three other groups. HFPV, like HFOV and protective CMV, improves respiratory mechanics and oxygenation, and attenuates lung damage. The HFPV provides attractive lung protection, but further studies should confirm these results before introducing HFPV into the clinical arena.