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Sample records for lung epithelia model

  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. 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

    2016-11-04

    The apical surface liquid layer (ASL) 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 (ENaC) is believed to be the dominating mechanism to cope with increases in ASL volumes. Alternative mechanisms, in particular increases in epithelial water permeability (Posm), 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 (hTEpC), both cultivated at air liquid interface conditions, were used as models for the lung epithelium. AVE was established by adding isotonic solution onto the apical surface of differentiated lung epithelia and time course of ASL volume restoration was assessed by the D2O dilution method. Concomitant ion transport was investigated in Ussing chambers. We identified a low resorptive state (lowRS) immediately after AVE, which coincided with proteolytic ion transport activation within 10 to 15 min after AVE. The main clearance of excess ASL occurred during a delayed (hours after AVE) high resorptive state (highRS), which did not correlate with ion transport activation. Instead, highRS onset coincided with an increase in Posm, which depended on aquapoprin upregulation. In summary, our data demonstrates that, besides to ion transport activation, modulation of Posm is a major mechanism to compensate long-term AVE in lung epithelia.

  3. 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

  4. 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.

  5. Value of Organoids from Comparative Epithelia Models

    PubMed Central

    Schwarz, Julia S.; de Jonge, Hugo R.; Forrest, John N.

    2015-01-01

    Organoids have tremendous therapeutic potential. They were recently defined as a collection of organ-specific cell types, which self-organize through cell-sorting, develop from stem cells, and perform an organ specific function. The ability to study organoid development and growth in culture and manipulate their genetic makeup makes them particularly suitable for studying development, disease, and drug efficacy. Organoids show great promise in personalized medicine. From a single patient biopsy, investigators can make hundreds of organoids with the genetic landscape of the patient of origin. This genetic similarity makes organoids an ideal system in which to test drug efficacy. While many investigators assume human organoids are the ultimate model system, we believe that the generation of epithelial organoids of comparative model organisms has great potential. Many key transport discoveries were made using marine organisms. In this paper, we describe how deriving organoids from the spiny dogfish shark, zebrafish, and killifish can contribute to the fields of comparative biology and disease modeling with future prospects for personalized medicine. PMID:26604860

  6. Effective viscosity and dynamics of spreading epithelia: a solvable model.

    PubMed

    Blanch-Mercader, C; Vincent, R; Bazellières, E; Serra-Picamal, X; Trepat, X; Casademunt, J

    2017-02-08

    Collective cell migration in spreading epithelia in controlled environments has become a landmark in our current understanding of fundamental biophysical processes in development, regeneration, wound healing or cancer. Epithelial monolayers are treated as thin layers of a viscous fluid that exert active traction forces on the substrate. The model is exactly solvable and shows a broad range of applicabilities for the quantitative analysis and interpretation of force microscopy data of monolayers from a variety of experiments and cell lines. In addition, the proposed model provides physical insights into how the biological regulation of the tissue is encoded in a reduced set of time-dependent physical parameters. In particular the temporal evolution of the effective viscosity entails a mechanosensitive regulation of adhesion. Besides, the observation of an effective elastic tensile modulus can be interpreted as an emergent phenomenon in an active fluid.

  7. Tobacco Carcinogen NNK Transporter MRP2 Regulates CFTR Function in Lung Epithelia: Implications for Lung Cancer

    PubMed Central

    Li, Chunying; Schuetz, John D.; Naren, Anjaparavanda P.

    2010-01-01

    Lung cancer is the leading cause of cancer death in the United States. About 85% of all lung cancers are linked to tobacco smoke, in which more than 50 lung carcinogens have been identified and one of the most abundant is 4-(methylnitrosamino)-1-(3-pyridyl)- 1-butanone (NNK). The human lung epithelium constitutes the first line of defense against tobacco specific carcinogens, in which apically-localized receptors, transporters, and ion channels in the airway may play a critical role in this native defense against tobacco smoke. Here we showed that multidrug resistance protein-2 (MRP2) and cystic fibrosis transmembrane conductance regulator (CFTR), two ATP-binding cassette (ABC) transporters, are localized to the apical surfaces of plasma membrane in polarized lung epithelial cells. We observed that there is a functional coupling between CFTR and MRP2 that may be mediated by PDZ proteins. We also observed the existence of a macromolecular complex containing CFTR, MRP2, and PDZ proteins, which might form the basis for the regulatory cooperation between these two ABC transporters. Our results have important implications for cigarette smoke-associated lung diseases (such as smoke-related emphysema, chronic obstructive pulmonary disease, and lung cancer). PMID:20089353

  8. Maternal alcohol ingestion reduces SP-A expression by pre-term fetal lung epithelia

    PubMed Central

    Lazic, Tatjana; Wyatt, Todd A; Matic, Milan; Meyerholz, David K; Grubor, Branka; Gallup, Jack M; Kersting, Karl W; Imerman, Paula M; Almeida-De-Macedo, Marcia; Ackermann, Mark R

    2007-01-01

    In addition to neurodevelopmental effects, alcohol consumption at high levels during pregnancy is associated with immunomodulation and premature birth. Premature birth, in turn, is associated with increased susceptibility to various infectious agents such as Respiratory Syncytial Virus (RSV). The initial line of pulmonary innate defense includes the mucociliary apparatus, which expels microorganisms trapped within the airway secretions. Surfactant proteins A and D (SP-A and SP-D, respectively) are additional components of pulmonary innate immunity and have an important role in pulmonary defense against inhaled pathogens. The purpose of this study was to determine if chronic alcohol consumption during the third trimester of pregnancy alters the function of the mucociliary apparatus and expression of SP-A and SP-D of fetal lung epithelia. Sixteen, date-mated ewes were assigned to two different groups; an ethanol exposed group in which ewes received ethanol through surgically implanted intra-abomasal cannula during the third trimester of pregnancy, and a control group in which ewes received the equivalent amount of water instead of ethanol. Within these two groups, ewes were further randomly assigned to a full-term group in which the lambs were naturally delivered, and a pre-term group in which the lambs were delivered prematurely via an abdominal incision and uterotomy. Ethanol was administered 5 times a week as a 40% solution at 1gr/kg of body weight. The mean maternal serum alcohol concentration (SAC) measured 6 hr post administration was 16.3 +/− 4.36 mg/dL. Tracheas from 6 full-term lambs were collected to assess ciliary beat frequency (CBF). The lung tissue from all (24) lambs was collected for immunohistochemistry (IHC) analysis of SP-A and SP-D protein production and fluorogenic real-time quantitative polymerase chain reaction analysis (qPCR) of SP-A and SP-D mRNA levels. Exposure to ethanol during pregnancy significantly blocked stimulated increase in CBF

  9. 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.

  10. Amiloride‐sensitive fluid resorption in NCI‐H441 lung epithelia depends on an apical Cl− conductance

    PubMed Central

    Korbmacher, Jonas P.; Michel, Christiane; Neubauer, Daniel; Thompson, Kristin; Mizaikoff, Boris; Frick, Manfred; Dietl, Paul; Wittekindt, Oliver H.

    2014-01-01

    Abstract Proper apical airway surface hydration is essential to maintain lung function. This hydration depends on well‐balanced water resorption and secretion. The mechanisms involved in resorption are still a matter of debate, especially as the measurement of transepithelial water transport remains challenging. In this study, we combined classical short circuit current (ISC) measurements with a novel D2O dilution method to correlate ion and water transport in order to reveal basic transport mechanisms in lung epithelia. D2O dilution method enabled precise analysis of water resorption with an unprecedented resolution. NCI‐H441 cells cultured at an air–liquid interface resorbed water at a rate of 1.5 ± 0.4 μL/(h cm2). Water resorption and ISC were reduced by almost 80% in the presence of the bulk Cl− channel inhibitor 5‐nitro‐2‐(3‐phenylpropylamino)benzoic acid (NPPB) or amiloride, a specific inhibitor of epithelial sodium channel (ENaC). However, water resorption and ISC were only moderately affected by forskolin or cystic fibrosis transmembrane regulator (CFTR) channel inhibitors (CFTRinh‐172 and glybenclamide). In line with previous studies, we demonstrate that water resorption depends on ENaC, and CFTR channels have only a minor but probably modulating effect on water resorption. However, the major ENaC‐mediated water resorption depends on an apical non‐CFTR Cl− conductance. PMID:24744880

  11. Protection of Cftr knockout mice from acute lung infection by a helper-dependent adenoviral vector expressing Cftr in airway epithelia

    PubMed Central

    Koehler, David R.; Sajjan, Umadevi; Chow, Yu-Hua; Martin, Bernard; Kent, Geraldine; Tanswell, A. Keith; McKerlie, Colin; Forstner, Janet F.; Hu, Jim

    2003-01-01

    We developed a helper-dependent adenoviral vector for cystic fibrosis lung gene therapy. The vector expresses cystic fibrosis transmembrane conductance regulator (Cftr) using control elements from cytokeratin 18. The vector expressed properly localized CFTR in cultured cells and in the airway epithelia of mice. Cftr RNA and protein were present in whole lung and bronchioles, respectively, for 28 days after a vector dose. Acute inflammation was minimal to moderate. To test the therapeutic potential of the vector, we challenged mice with a clinical strain of Burkholderia cepacia complex (Bcc). Cftr knockout mice (but not Cftr+/+ littermates) challenged with Bcc developed severe lung histopathology and had high lung bacteria counts. Cftr knockout mice receiving gene therapy 7 days before Bcc challenge had less severe histopathology, and the number of lung bacteria was reduced to the level seen in Cftr+/+ littermates. These data suggest that gene therapy could benefit cystic fibrosis patients by reducing susceptibility to opportunistic pathogens. PMID:14673110

  12. DNA methylation changes in human lung epithelia cells exposed to multi-walled carbon nanotubes.

    PubMed

    Sierra, Marta I; Rubio, Laura; Bayón, Gustavo F; Cobo, Isabel; Menendez, Pablo; Morales, Paula; Mangas, Cristina; Urdinguio, Rocio G; Lopez, Virginia; Valdes, Adolfo; Vales, Gerard; Marcos, Ricard; Torrecillas, Ramon; Fernández, Agustin F; Fraga, Mario F

    2017-09-13

    Humans are increasingly exposed to nanoparticles and, although many of their physiological effects have been described, the molecular mechanisms underlying them are still largely unknown. The present study aimed to determine the possible role of certain epigenetic mechanisms in the cellular response of human lung epithelial cells that are triggered by long-term exposure to titanium dioxide nanoparticles (TiO2NPs) and multi-walled carbon nanotubes (MWCNTs). The results showed that exposure to TiO2NPs had only minor effects on genome-wide DNA methylation. However, we identified 755 CpG sites showing consistent DNA hypomethylation in cells exposed to MWCNTs. These sites were mainly located at low density CpG regions and enhancers, and very frequently on the X chromosome. Our results thus suggest that long-term MWCNT exposure may have important effects on the epigenome.

  13. Adenosine deaminase 1 and concentrative nucleoside transporters 2 and 3 regulate adenosine on the apical surface of human airway epithelia: implications for inflammatory lung diseases.

    PubMed

    Hirsh, Andrew J; Stonebraker, Jaclyn R; van Heusden, Catja A; Lazarowski, Eduardo R; Boucher, Richard C; Picher, Maryse

    2007-09-11

    Adenosine is a multifaceted signaling molecule mediating key aspects of innate and immune lung defenses. However, abnormally high airway adenosine levels exacerbate inflammatory lung diseases. This study identifies the mechanisms regulating adenosine elimination from the apical surface of human airway epithelia. Experiments conducted on polarized primary cultures of nasal and bronchial epithelial cells showed that extracellular adenosine is eliminated by surface metabolism and cellular uptake. The conversion of adenosine to inosine was completely inhibited by the adenosine deaminase 1 (ADA1) inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). The reaction exhibited Km and Vmax values of 24 microM and 0.14 nmol x min(-1) x cm(-2). ADA1 (not ADA2) mRNA was detected in human airway epithelia. The adenosine/mannitol permeability coefficient ratio (18/1) indicated a minor contribution of paracellular absorption. Adenosine uptake was Na+-dependent and was inhibited by the concentrative nucleoside transporter (CNT) blocker phloridzin but not by the equilibrative nucleoside transporter (ENT) blocker dipyridamole. Apparent Km and Vmax values were 17 microM and 7.2 nmol x min(-1) x cm(-2), and transport selectivity was adenosine = inosine = uridine > guanosine = cytidine > thymidine. CNT3 mRNA was detected throughout the airways, while CNT2 was restricted to nasal epithelia. Inhibition of adenosine elimination by EHNA or phloridzin raised apical adenosine levels by >3-fold and stimulated IL-13 and MCP-1 secretion by 6-fold. These responses were reproduced by the adenosine receptor agonist 5'-(N-ethylcarboxamido)adenosine (NECA) and blocked by the adenosine receptor antagonist, 8-(p-sulfophenyl) theophylline (8-SPT). This study shows that adenosine elimination on human airway epithelia is mediated by ADA1, CNT2, and CNT3, which constitute important regulators of adenosine-mediated inflammation.

  14. 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...

  15. 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...

  16. Model Lungs.

    ERIC Educational Resources Information Center

    Taylor, Emma

    1991-01-01

    A cheap and simple model that can be made and used by pupils to study the human breathing mechanism is presented. A list of needed materials, procedures for construction, possible refinements, and method of use are included. (KR)

  17. Primary cultured cells as sensitive in vitro model for assessment of toxicants--comparison to hepatocytes and gill epithelia.

    PubMed

    Zhou, Bingsheng; Liu, Chunsheng; Wang, Jingxian; Lam, Paul K S; Wu, Rudolf S S

    2006-11-16

    In an effort to develop cultured cell models for toxicity screening and environmental biomonitoring, we compared primary cultured gill epithelia and hepatocytes from freshwater tilapia (Oreochromis niloticus) to assess their sensitivity to AhR agonist toxicants. Epithelia were cultured on permeable supports (terephthalate membranes, "filters") and bathed on the apical with waterborne toxicants (pseudo in vivo asymmetrical culture conditions). Hepatocytes were cultured in multi-well plates and exposed to toxicants in culture medium. Cytochrome P4501A (measured as 7-Ethoxyresorufin-O-deethylase, EROD) was selected as a biomarker. For cultured gill epithelia, the integrity of the epithelia remained unchanged on exposure to model toxicants, such as 1,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), benzo(a)pyrene B[a]P, polychlorinated biphenyl (PCB) mixture (Aroclor 1254), and polybrominated diphenyl ether (PBDE) mixture (DE71). A good concentration-dependent response of EROD activity was clearly observed in both cultured gill epithelia and hepatocytes. The time-course response of EROD was measured as early as 3h, and was maximal after 6h of exposure to TCDD, B[a]P and Aroclor 1254. The estimated 6h EC50 for TCDD, B[a]P, and Aroclor 1254 was 1.2 x 10(-9), 5.7 x 10(-8) and 6.6 x 10(-6)M. For the cultured hepatocytes, time-course study showed that a significant induction of EROD took place at 18 h, and the maximal induction of EROD was observed at 24h after exposure. The estimated 24h EC50 for TCDD, B[a]P, and Aroclor 1254 was 1.4 x 10(-9), 8.1 x 10(-8) and 7.3 x 10(-6)M. There was no induction or inhibition of EROD in DE71 exposure to both gill epithelia and hepatocytes. The results show that cultured gill epithelia more rapidly induce EROD and are slightly more sensitive than cultured hepatocytes, and could be used as a rapid and sensitive tool for screening chemicals and monitoring environmental AhR agonist toxicants.

  18. Development of an in vitro colonization model to investigate Staphylococcus aureus interactions with airway epithelia

    PubMed Central

    Kiedrowski, Megan R.; Paharik, Alexandra E.; Ackermann, Laynez W.; Shelton, Annie U.; Singh, Sachinkumar B.; Starner, Timothy D.; Horswill, Alexander R.

    2016-01-01

    SUMMARY Staphylococcus aureus is a bacterial pathogen responsible for a wide range of diseases and is also a human commensal colonizing the upper respiratory tract. Strains belonging to the clonal complex group CC30 are associated with colonization, although the colonization state itself is not clearly defined. In this work, we developed a co-culture model with S. aureus colonizing the apical surface of polarized human airway epithelial cells. The S. aureus are grown at the air-liquid interface to allow an in-depth evaluation of a simulated colonization state. Exposure to wild-type S. aureus bacteria or conditioned media killed airway epithelial cells within one day, while mutant S. aureus strains lacking alpha-toxin (hla) persisted on viable cells for at least two days. Recent S. aureus CC30 isolates are natural hla mutants, and we observed that these strains displayed reduced toxicity toward airway epithelial cells. Quantitative real-time PCR of known virulence factors showed the expression profile of S. aureus grown in co-culture correlates with results from previous human colonization studies. Microarray analysis indicated significant shifts in S. aureus physiology in the co-culture model toward lipid and amino acid metabolism. The development of the in vitro colonization model will enable further study of specific S. aureus interactions with the host epithelia. PMID:26566259

  19. Growth Regulation via Insulin-Like Growth Factor Binding Protein-4 and -2 in Association with Mutant K-ras in Lung Epithelia

    PubMed Central

    Sato, Hanako; Yazawa, Takuya; Suzuki, Takehisa; Shimoyamada, Hiroaki; Okudela, Koji; Ikeda, Masaichi; Hamada, Kenji; Yamada-Okabe, Hisafumi; Yao, Masayuki; Kubota, Yoshinobu; Takahashi, Takashi; Kamma, Hiroshi; Kitamura, Hitoshi

    2006-01-01

    Gain-of-function point mutations in K-ras affect early events in pulmonary bronchioloalveolar carcinoma. We investigated altered mRNA expression on K-Ras activation in human peripheral lung epithelial cells (HPL1A) using oligonucleotide microarrays. Mutated K-Ras stably expressed in HPL1A accelerated cell growth and induced the expression of insulin-like growth factor (IGF)-binding protein (IGFBP)-4 and IGFBP-2, which modulate cell growth via IGF. Other lung epithelial cell lines (NHBE and HPL1D) revealed the same phenomena as HPL1A by mutated K-ras transgene. Lung cancer cell growth was also accelerated by mutated K-ras gene transduction, whereas IGFBP-4/2 induction was weaker compared with mutated K-Ras-expressing lung epithelial cells. To understand the differences in IGFBP-4/2 inducibility via K-Ras-activated signaling between nonneoplastic lung epithelia and lung carcinoma, we addressed the mechanisms of IGFBP-4/2 transcriptional activation. Our results revealed that Egr-1, which is induced on activation of Ras-mitogen-activated protein kinase signaling, is crucial for transactivation of IGFBP-4/2. Furthermore, IGFBP-4 and IGFBP-2 promoters were often hypermethylated in lung carcinoma, yielding low basal expression/weak induction of IGFBP-4/2. These findings suggest that continuous K-Ras activation accelerates cell growth and evokes a feedback system through IGFBP-4/2 to prevent excessive growth. Moreover, this growth regulation is disrupted in lung cancers because of promoter hypermethylation of IGFBP-4/2 genes. PMID:17071580

  20. Risk considerations related to lung modeling

    SciTech Connect

    Masse, R.; Cross, F.T. )

    1989-01-01

    Improved lung models provide a more accurate assessment of dose from inhalation exposures and, therefore, more accurate dose-response relationships for risk evaluation and exposure limitation. Epidemiological data for externally irradiated persons indicate that the numbers of excess respiratory tract carcinomas differ in the upper airways, bronchi, and distal lung. Neither their histogenesis and anatomical location nor their progenitor cells are known with sufficient accuracy for accurate assessment of the microdosimetry. The nuclei of sensitive cells generally can be assumed to be distributed at random in the epithelium, beneath the mucus and tips of the beating cilia and cells. In stratified epithelia, basal cells may be considered the only cells at risk. Upper-airway tumors have been observed in both therapeutically irradiated patients and in Hiroshima-Nagasaki survivors. The current International Commission on Radiological Protection Lung-Model Task Group proposes that the upper airways and lung have a similar relative risk coefficient for cancer induction. The partition of the risk weighting factor, therefore, will be proportional to the spontaneous death rate from tumors, and 80% of the weighting factor for the respiratory tract should be attributed to the lung. For Weibel lung-model branching generations 0 to 16 and 17 to 23, the Task Group proposes an 80/20 partition of the risk, i.e., 64% and 16%, respectively, of the total risk. Regarding risk in animals, recent data in rats indicate a significantly lower effectiveness for lung-cancer induction at low doses from insoluble long-lived alpha-emitters than from Rn daughters. These findings are due, in part, to the fact that different regions of the lung are irradiated. Tumors in the lymph nodes are rare in people and animals exposed to radiation.44 references.

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

    PubMed Central

    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.

    2012-01-01

    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. PMID:22637155

  2. Improved development of somatic cell cloned bovine embryos by a mammary gland epithelia cells in vitro model.

    PubMed

    He, Xiao-Ying; Ma, Li-Bing; He, Xiao-Ning; Si, Wan-Tong; Zheng, Yue-Mao

    2016-06-30

    Previous studies have established a bovine mammary gland epithelia cells in vitro model by the adenovirus-mediated telomerase (hTERT-bMGEs). The present study was conducted to confirm whether hTERT-bMGEs were effective target cells to improve the efficiency of transgenic expression and somatic cell nuclear transfer (SCNT). To accomplish this, a mammary-specific vector encoding human lysozyme and green fluorescent protein was used to verify the transgenic efficiency of hTERT-bMGEs, and untreated bovine mammary gland epithelial cells (bMGEs) were used as a control group. The results showed that the hTERT-bMGEs group had much higher transgenic efficiency and protein expression than the bMGEs group. Furthermore, the nontransgenic and transgenic hTERT-bMGEs were used as donor cells to evaluate the efficiency of SCNT. There were no significant differences in rates of cleavage or blastocysts or hatched blastocysts of cloned embryos from nontransgenic hTERT-bMGEs at passage 18 and 28 groups (82.8% vs. 81.9%, 28.6% vs. 24.8%, 58.6% vs. 55.3%, respectively) and the transgenic group (80.8%, 26.5% and 53.4%); however, they were significantly higher than the bMGEs group (71.2%, 12.8% and 14.8%), (p < 0.05). We confirmed that hTERT-bMGEs could serve as effective target cells for improving development of somatic cell cloned cattle embryos.

  3. Improved development of somatic cell cloned bovine embryos by a mammary gland epithelia cells in vitro model

    PubMed Central

    Ma, Li-bing; He, Xiao-ning; Si, Wan-tong; Zheng, Yue-Mao

    2016-01-01

    Previous studies have established a bovine mammary gland epithelia cells in vitro model by the adenovirus-mediated telomerase (hTERT-bMGEs). The present study was conducted to confirm whether hTERT-bMGEs were effective target cells to improve the efficiency of transgenic expression and somatic cell nuclear transfer (SCNT). To accomplish this, a mammary-specific vector encoding human lysozyme and green fluorescent protein was used to verify the transgenic efficiency of hTERT-bMGEs, and untreated bovine mammary gland epithelial cells (bMGEs) were used as a control group. The results showed that the hTERT-bMGEs group had much higher transgenic efficiency and protein expression than the bMGEs group. Furthermore, the nontransgenic and transgenic hTERT-bMGEs were used as donor cells to evaluate the efficiency of SCNT. There were no significant differences in rates of cleavage or blastocysts or hatched blastocysts of cloned embryos from nontransgenic hTERT-bMGEs at passage 18 and 28 groups (82.8% vs. 81.9%, 28.6% vs. 24.8%, 58.6% vs. 55.3%, respectively) and the transgenic group (80.8%, 26.5% and 53.4%); however, they were significantly higher than the bMGEs group (71.2%, 12.8% and 14.8%), (p < 0.05). We confirmed that hTERT-bMGEs could serve as effective target cells for improving development of somatic cell cloned cattle embryos. PMID:26243608

  4. Exposure to Engineered Nanomaterial Results in Disruption of Brush Borders in Epithelia Models in vitro

    NASA Astrophysics Data System (ADS)

    Faust, James J.

    Engineered nanoparticles (NP; 10-9 m) have found use in a variety of consumer goods and medical devices because of the unique changes in material properties that occur when synthesized on the nanoscale. Although many definitions for nanoparticle exist, from the perspective of size, nanoparticle is defined as particles with diameters less than 100 nm in any external dimension. Examples of their use include titanium dioxide added as a pigment in products intended to be ingested by humans, silicon dioxide NPs are used in foods as an anticaking agent, and gold or iron oxide NPs can be used as vectors for drug delivery or contrast agents for specialized medical imaging. Although the intended use of these NPs is often to improve human health, it has come to the attention of investigators that NPs can have unintended or even detrimental effects on the organism. This work describes one such unintended effect of NP exposure from the perspective of exposure via the oral route. First, this Dissertation will explain an event referred to as brush border disruption that occurred after nanoparticles interacted with an in vitro model of the human intestinal epithelium. Second, this Dissertation will identify and characterize several consumer goods that were shown to contain titanium dioxide that are intended to be ingested. Third, this Dissertation shows that sedimentation due to gravity does not artifactually result in disruption of brush borders as a consequence of exposure to food grade titanium dioxide in vitro. Finally, this Dissertation will demonstrate that iron oxide nanoparticles elicited similar effects after exposure to an in vitro brush border expressing model of the human placenta. Together, these data suggest that brush border disruption is not an artifact of the material/cell culture model, but instead represents a bona fide biological response as a result of exposure to nanomaterial.

  5. Onset of nonlinearity in a stochastic model for auto-chemotactic advancing epithelia.

    PubMed

    Ben Amar, Martine; Bianca, Carlo

    2016-09-27

    We investigate the role of auto-chemotaxis in the growth and motility of an epithelium advancing on a solid substrate. In this process, cells create their own chemoattractant allowing communications among neighbours, thus leading to a signaling pathway. As known, chemotaxis provokes the onset of cellular density gradients and spatial inhomogeneities mostly at the front, a phenomenon able to predict some features revealed in in vitro experiments. A continuous model is proposed where the coupling between the cellular proliferation, the friction on the substrate and chemotaxis is investigated. According to our results, the friction and proliferation stabilize the front whereas auto-chemotaxis is a factor of destabilization. This antagonist role induces a fingering pattern with a selected wavenumber k0. However, in the planar front case, the translational invariance of the experimental set-up gives also a mode at k = 0 and the coupling between these two modes in the nonlinear regime is responsible for the onset of a Hopf-bifurcation. The time-dependent oscillations of patterns observed experimentally can be predicted simply in this continuous non-linear approach. Finally the effects of noise are also investigated below the instability threshold.

  6. Onset of nonlinearity in a stochastic model for auto-chemotactic advancing epithelia

    PubMed Central

    Ben Amar, Martine; Bianca, Carlo

    2016-01-01

    We investigate the role of auto-chemotaxis in the growth and motility of an epithelium advancing on a solid substrate. In this process, cells create their own chemoattractant allowing communications among neighbours, thus leading to a signaling pathway. As known, chemotaxis provokes the onset of cellular density gradients and spatial inhomogeneities mostly at the front, a phenomenon able to predict some features revealed in in vitro experiments. A continuous model is proposed where the coupling between the cellular proliferation, the friction on the substrate and chemotaxis is investigated. According to our results, the friction and proliferation stabilize the front whereas auto-chemotaxis is a factor of destabilization. This antagonist role induces a fingering pattern with a selected wavenumber k0. However, in the planar front case, the translational invariance of the experimental set-up gives also a mode at k = 0 and the coupling between these two modes in the nonlinear regime is responsible for the onset of a Hopf-bifurcation. The time-dependent oscillations of patterns observed experimentally can be predicted simply in this continuous non-linear approach. Finally the effects of noise are also investigated below the instability threshold. PMID:27669998

  7. Onset of nonlinearity in a stochastic model for auto-chemotactic advancing epithelia

    NASA Astrophysics Data System (ADS)

    Ben Amar, Martine; Bianca, Carlo

    2016-09-01

    We investigate the role of auto-chemotaxis in the growth and motility of an epithelium advancing on a solid substrate. In this process, cells create their own chemoattractant allowing communications among neighbours, thus leading to a signaling pathway. As known, chemotaxis provokes the onset of cellular density gradients and spatial inhomogeneities mostly at the front, a phenomenon able to predict some features revealed in in vitro experiments. A continuous model is proposed where the coupling between the cellular proliferation, the friction on the substrate and chemotaxis is investigated. According to our results, the friction and proliferation stabilize the front whereas auto-chemotaxis is a factor of destabilization. This antagonist role induces a fingering pattern with a selected wavenumber k0. However, in the planar front case, the translational invariance of the experimental set-up gives also a mode at k = 0 and the coupling between these two modes in the nonlinear regime is responsible for the onset of a Hopf-bifurcation. The time-dependent oscillations of patterns observed experimentally can be predicted simply in this continuous non-linear approach. Finally the effects of noise are also investigated below the instability threshold.

  8. The function of 7D-cadherins: a mathematical model predicts physiological importance for water transport through simple epithelia

    PubMed Central

    2011-01-01

    Background 7D-cadherins like LI-cadherin are cell adhesion molecules and represent exceptional members of the cadherin superfamily. Although LI-cadherin was shown to act as a functional Ca2+-dependent adhesion molecule, linking neighboring cells together, and to be dysregulated in a variety of diseases, the physiological role is still enigmatic. Interestingly 7D-cadherins occur only in the lateral plasma membranes of cells from epithelia of water transporting tissues like the gut, the liver or the kidney. Furthermore LI-cadherin was shown to exhibit a highly cooperative Ca2+-dependency of the binding activity. Thus it is tempting to assume that LI-cadherin regulates the water transport through the epithelium in a passive fashion by changing its binding activity in dependence on the extracellular Ca2+. Results We developed a simple mathematical model describing the epithelial lining of a lumen with a content of variable osmolarity covering an interstitium of constant osmolarity. The width of the lateral intercellular cleft was found to influence the water transport significantly. In the case of hypertonic luminal content a narrow cleft is necessary to further increase concentration of the luminal content. If the cleft is too wide, the water flux will change direction and water is transported into the lumen. Electron microscopic images show that in fact areas of the gut can be found where the lateral intercellular cleft is narrow throughout the lateral cell border whereas in other areas the lateral intercellular cleft is widened. Conclusions Our simple model clearly predicts that changes of the width of the lateral intercellular cleft can regulate the direction and efficiency of water transport through a simple epithelium. In a narrow cleft the cells can increase the concentration of osmotic active substances easily by active transport whereas if the cleft is wide, friction is reduced but the cells can hardly build up high osmotic gradients. It is now tempting to

  9. Methods for culture of human corneal and conjunctival epithelia.

    PubMed

    Spurr-Michaud, Sandra J; Gipson, Ilene K

    2013-01-01

    The surface of the eye is exposed to the outside world and is, thus, subject to surface abrasion, infections, and drying, cicatrizing diseases. Availability of in vitro methods for culture of the human corneal and conjunctival epithelia, which cover the ocular surface, is therefore important in understanding the biology of these epithelia and their response to disease/infections, as well as for providing human-relevant models for preclinical testing of potential therapeutic agents. The ensuing chapter describes several methods for primary culture of both corneal and conjunctival epithelia and culture of immortalized cell lines, and methods employed to induce differentiation in the cultured epithelia.

  10. Basolateral Mg2+ Extrusion via CNNM4 Mediates Transcellular Mg2+ Transport across Epithelia: A Mouse Model

    PubMed Central

    Miura, Jiro; Sato, Sunao; Toyosawa, Satoru; Furutani, Kazuharu; Kurachi, Yoshihisa; Omori, Yoshihiro; Furukawa, Takahisa; Tsuda, Tetsuya; Kuwabata, Susumu; Mizukami, Shin; Kikuchi, Kazuya; Miki, Hiroaki

    2013-01-01

    Transcellular Mg2+ transport across epithelia, involving both apical entry and basolateral extrusion, is essential for magnesium homeostasis, but molecules involved in basolateral extrusion have not yet been identified. Here, we show that CNNM4 is the basolaterally located Mg2+ extrusion molecule. CNNM4 is strongly expressed in intestinal epithelia and localizes to their basolateral membrane. CNNM4-knockout mice showed hypomagnesemia due to the intestinal malabsorption of magnesium, suggesting its role in Mg2+ extrusion to the inner parts of body. Imaging analyses revealed that CNNM4 can extrude Mg2+ by exchanging intracellular Mg2+ with extracellular Na+. Furthermore, CNNM4 mutations cause Jalili syndrome, characterized by recessive amelogenesis imperfecta with cone-rod dystrophy. CNNM4-knockout mice showed defective amelogenesis, and CNNM4 again localizes to the basolateral membrane of ameloblasts, the enamel-forming epithelial cells. Missense point mutations associated with the disease abolish the Mg2+ extrusion activity. These results demonstrate the crucial importance of Mg2+ extrusion by CNNM4 in organismal and topical regulation of magnesium. PMID:24339795

  11. Chromosomal Abnormalities in Non-Small Cell Lung Carcinomas and in Bronchial Epithelia of High-Risk Smokers Detected by Multi-Target Interphase Fluorescence in Situ Hybridization

    PubMed Central

    Santos Romeo, Maura; Sokolova, Irina A.; Morrison, Larry E.; Zeng, Chan; Barón, Anna E.; Hirsch, Fred R.; Miller, York E.; Franklin, Wilbur A.; Varella-Garcia, Marileila

    2003-01-01

    Human lung carcinogenesis is accompanied by complex chromosomal changes that may be detected in interphase cells by fluorescence in situ hybridization (FISH) assay using recently developed multitarget DNA probes. Touch preparations of 20 non-small cell lung carcinomas, sputum specimens from 3 patients with lung cancer and from 11 ex-smokers without lung cancer, and cultured benign bronchial epithelium of 42 high-risk smokers, 9 of whom had concurrent invasive carcinoma, were tested using a four-color FISH probe (LAVysion) targeting centromere 6, 5p15.2, 7p12 (EGFR), and 8q24 (MYC). Significantly high frequencies of abnormal cells were found in each of the 20 NSCLC (100%) and in the 3 sputum specimens from lung cancer patients. None of the cytologically normal sputa contained FISH abnormalities. Cultured bronchial epithelial cells from 11 of 42 patients (26%) were abnormal for at least one probe. Abnormal FISH patterns had no association with gender, presence of tumor or histology. Multicolor FISH can readily detect chromosomal abnormalities in imprints and sputa from lung carcinomas. Chromosomal aneusomy is also frequent in bronchial epithelial cells from long-term smokers. The prognostic significance of the multicolor LAVysion FISH probe set should be validated in a controlled clinical trial. PMID:12707375

  12. Chromosomal abnormalities in non-small cell lung carcinomas and in bronchial epithelia of high-risk smokers detected by multi-target interphase fluorescence in situ hybridization.

    PubMed

    Romeo, Maura Santos; Sokolova, Irina A; Morrison, Larry E; Zeng, Chan; Barón, Anna E; Hirsch, Fred R; Miller, York E; Franklin, Wilbur A; Varella-Garcia, Marileila

    2003-05-01

    Human lung carcinogenesis is accompanied by complex chromosomal changes that may be detected in interphase cells by fluorescence in situ hybridization (FISH) assay using recently developed multitarget DNA probes. Touch preparations of 20 non-small cell lung carcinomas, sputum specimens from 3 patients with lung cancer and from 11 ex-smokers without lung cancer, and cultured benign bronchial epithelium of 42 high-risk smokers, 9 of whom had concurrent invasive carcinoma, were tested using a four-color FISH probe (LAVysion) targeting centromere 6, 5p15.2, 7p12 (EGFR), and 8q24 (MYC). Significantly high frequencies of abnormal cells were found in each of the 20 NSCLC (100%) and in the 3 sputum specimens from lung cancer patients. None of the cytologically normal sputa contained FISH abnormalities. Cultured bronchial epithelial cells from 11 of 42 patients (26%) were abnormal for at least one probe. Abnormal FISH patterns had no association with gender, presence of tumor or histology. Multicolor FISH can readily detect chromosomal abnormalities in imprints and sputa from lung carcinomas. Chromosomal aneusomy is also frequent in bronchial epithelial cells from long-term smokers. The prognostic significance of the multicolor LAVysion FISH probe set should be validated in a controlled clinical trial.

  13. 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.

  14. A Spatial Model of Fluid Recycling in the Airways of the Lung

    PubMed Central

    Sharp, K.; Crampin, E.; Sneyd, J.

    2015-01-01

    The genetic disease cystic fibrosis (CF) is a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and results in viscous mucus and impaired mucociliary clearance leading to chronic recurring pulmonary infections. Although extensive experimental research has been conducted over the last few decades, CF lung pathophysiology remains controversial. There are two competing explanations for the observed depletion of periciliary liquid (PCL) in CF lungs. The low volume hypothesis assumes fluid hyperabsorption through surface epithelia due to an over-active Epithelial Na+ Channel (ENaC), and the low secretion hypothesis assumes inspissated mucins secreted from glands due to lack of serous fluid secreted from gland acini. We present a spatial mathematical model that reflects in vivo fluid recycling via submucosal gland (SMG) secretion, and absorption through surface epithelia. We then test the model in CF conditions by increasing ENaC open probability and decreasing SMG flux while simultaneously reducing CFTR open probability. Increasing ENaC activity only results in increased fluid absorption across surface epithelia, as seen in in vitro experiments. However, combining potential CF mechanisms results in markedly less fluid absorbed while providing the largest reduction in PCL volume, suggesting that a compromise in gland fluid secretion dominates over increased ENaC activity to decrease the amount of fluid transported transcellularly in CF lungs in vivo. Model results also indicate that a spatial model is necessary for an accurate calculation of total fluid transport, as the effects of spatial gradients can be severe, particularly in close proximity to the SMGs. PMID:26169010

  15. Human airway epithelia express catalytically active NEU3 sialidase.

    PubMed

    Lillehoj, Erik P; Hyun, Sang Won; Feng, Chiguang; Zhang, Lei; Liu, Anguo; Guang, Wei; Nguyen, Chinh; Sun, Wenji; Luzina, Irina G; Webb, Tonya J; Atamas, Sergei P; Passaniti, Antonino; Twaddell, William S; Puché, Adam C; Wang, Lai-Xi; Cross, Alan S; Goldblum, Simeon E

    2014-05-01

    Sialic acids on glycoconjugates play a pivotal role in many biological processes. In the airways, sialylated glycoproteins and glycolipids are strategically positioned on the plasma membranes of epithelia to regulate receptor-ligand, cell-cell, and host-pathogen interactions at the molecular level. We now demonstrate, for the first time, sialidase activity for ganglioside substrates in human airway epithelia. Of the four known mammalian sialidases, NEU3 has a substrate preference for gangliosides and is expressed at mRNA and protein levels at comparable abundance in epithelia derived from human trachea, bronchi, small airways, and alveoli. In small airway and alveolar epithelia, NEU3 protein was immunolocalized to the plasma membrane, cytosolic, and nuclear subcellular fractions. Small interfering RNA-induced silencing of NEU3 expression diminished sialidase activity for a ganglioside substrate by >70%. NEU3 immunostaining of intact human lung tissue could be localized to the superficial epithelia, including the ciliated brush border, as well as to nuclei. However, NEU3 was reduced in subepithelial tissues. These results indicate that human airway epithelia express catalytically active NEU3 sialidase.

  16. Modeling Mycobacterium tuberculosis early granuloma formation in experimental human lung tissue.

    PubMed

    Parasa, Venkata Ramanarao; Rahman, Muhammad Jubayer; Ngyuen Hoang, Anh Thu; Svensson, Mattias; Brighenti, Susanna; Lerm, Maria

    2014-02-01

    The widely used animal models for tuberculosis (TB) display fundamental differences from human TB. Therefore, a validated model that recapitulates human lung TB is attractive for TB research. Here, we describe a unique method for establishment of TB infection in an experimental human lung tissue model. The model is based on cell lines derived from human lungs and primary macrophages from peripheral blood, and displays characteristics of human lung tissue, including evenly integrated macrophages throughout the epithelium, production of extracellular matrix, stratified epithelia and mucus secretion. Establishment of experimental infection in the model tissue with Mycobacterium tuberculosis, the bacterium that causes TB, resulted in clustering of macrophages at the site of infection, reminiscent of early TB granuloma formation. We quantitated the extent of granuloma formation induced by different strains of mycobacteria and validated our model against findings in other TB models. We found that early granuloma formation is dependent on ESAT-6, which is secreted via the type VII secretion machinery of virulent mycobacteria. Our model, which can facilitate the discovery of the interactions between mycobacteria and host cells in a physiological environment, is the first lung tissue model described for TB.

  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. Luminal acetylcholine does not affect the activity of the CFTR in tracheal epithelia of pigs.

    PubMed

    Dittrich, Nikolaus P; Kummer, Wolfgang; Clauss, Wolfgang G; Fronius, Martin

    2015-11-01

    Fluid homeostasis mediated by the airway epithelium is required for proper lung function, and the CFTR (cystic fibrosis transmembrane conductance regulator) Cl(-) channel is crucial for these processes. Luminal acetylcholine (ACh) acts as an auto-/paracrine mediator to activate Cl(-) channels in airway epithelia and evidence exists showing that nicotinic ACh receptors activate CFTR in murine airway epithelia. The present study investigated whether or not luminal ACh regulates CFTR activity in airway epithelia of pigs, an emerging model for investigations of human airway disease and cystic fibrosis (CF) in particular. Transepithelial ion currents of freshly dissected pig tracheal preparations were measured with Ussing chambers. Application of luminal ACh (100 μM) induced an increase of the short-circuit current (I(SC)). The ACh effect was mimicked by muscarine and pilocarpine (100 μM each) and was sensitive to muscarinic receptor antagonists (atropine, 4-DAMP, pirenzepine). No changes of the I(SC) were observed by nicotine (100 μM) and ACh responses were not affected by nicotine or mecamylamine (25 μM). Luminal application of IBMX (I, 100 μM) and forskolin (F, 10 μM), increase the I(SC) and the I/F-induced current were decreased by the CFTR inhibitor GlyH-101 (GlyH, 50 μM) indicating increased CFTR activity by I/F. In contrast, GlyH did not affect the ACh-induced current, indicating that the ACh response does not involve the activation of the CFTR. Results from this study suggest that luminal ACh does not regulate the activity of the CFTR in tracheal epithelia of pigs which opposes observation from studies using mice airway epithelium.

  19. Proinflammatory cytokine secretion is suppressed by TMEM16A or CFTR channel activity in human cystic fibrosis bronchial epithelia

    PubMed Central

    Veit, Guido; Bossard, Florian; Goepp, Julie; Verkman, A. S.; Galietta, Luis J. V.; Hanrahan, John W.; Lukacs, Gergely L.

    2012-01-01

    Cystic fibrosis (CF) is caused by the functional expression defect of the CF transmembrane conductance regulator (CFTR) chloride channel at the apical plasma membrane. Impaired bacterial clearance and hyperactive innate immune response are hallmarks of the CF lung disease, yet the existence of and mechanism accounting for the innate immune defect that occurs before infection remain controversial. Inducible expression of either CFTR or the calcium-activated chloride channel TMEM16A attenuated the proinflammatory cytokines interleukin-6 (IL-6), IL-8, and CXCL1/2 in two human respiratory epithelial models under air–liquid but not liquid–liquid interface culture. Expression of wild-type but not the inactive G551D-CFTR indicates that secretion of the chemoattractant IL-8 is inversely proportional to CFTR channel activity in cftr∆F508/∆F508 immortalized and primary human bronchial epithelia. Similarly, direct but not P2Y receptor–mediated activation of TMEM16A attenuates IL-8 secretion in respiratory epithelia. Thus augmented proinflammatory cytokine secretion caused by defective anion transport at the apical membrane may contribute to the excessive and persistent lung inflammation in CF and perhaps in other respiratory diseases associated with documented down-regulation of CFTR (e.g., chronic obstructive pulmonary disease). Direct pharmacological activation of TMEM16A offers a potential therapeutic strategy to reduce the inflammation of CF airway epithelia. PMID:22973054

  20. Proinflammatory cytokine secretion is suppressed by TMEM16A or CFTR channel activity in human cystic fibrosis bronchial epithelia.

    PubMed

    Veit, Guido; Bossard, Florian; Goepp, Julie; Verkman, A S; Galietta, Luis J V; Hanrahan, John W; Lukacs, Gergely L

    2012-11-01

    Cystic fibrosis (CF) is caused by the functional expression defect of the CF transmembrane conductance regulator (CFTR) chloride channel at the apical plasma membrane. Impaired bacterial clearance and hyperactive innate immune response are hallmarks of the CF lung disease, yet the existence of and mechanism accounting for the innate immune defect that occurs before infection remain controversial. Inducible expression of either CFTR or the calcium-activated chloride channel TMEM16A attenuated the proinflammatory cytokines interleukin-6 (IL-6), IL-8, and CXCL1/2 in two human respiratory epithelial models under air-liquid but not liquid-liquid interface culture. Expression of wild-type but not the inactive G551D-CFTR indicates that secretion of the chemoattractant IL-8 is inversely proportional to CFTR channel activity in cftr(∆F508/∆F508) immortalized and primary human bronchial epithelia. Similarly, direct but not P2Y receptor-mediated activation of TMEM16A attenuates IL-8 secretion in respiratory epithelia. Thus augmented proinflammatory cytokine secretion caused by defective anion transport at the apical membrane may contribute to the excessive and persistent lung inflammation in CF and perhaps in other respiratory diseases associated with documented down-regulation of CFTR (e.g., chronic obstructive pulmonary disease). Direct pharmacological activation of TMEM16A offers a potential therapeutic strategy to reduce the inflammation of CF airway epithelia.

  1. Human lung ex vivo infection models.

    PubMed

    Hocke, Andreas C; Suttorp, Norbert; Hippenstiel, Stefan

    2017-03-01

    Pneumonia is counted among the leading causes of death worldwide. Viruses, bacteria and pathogen-related molecules interact with cells present in the human alveolus by numerous, yet poorly understood ways. Traditional cell culture models little reflect the cellular composition, matrix complexity and three-dimensional architecture of the human lung. Integrative animal models suffer from species differences, which are of particular importance for the investigation of zoonotic lung diseases. The use of cultured ex vivo infected human lung tissue may overcome some of these limitations and complement traditional models. The present review gives an overview of common bacterial lung infections, such as pneumococcal infection and of widely neglected pathogens modeled in ex vivo infected lung tissue. The role of ex vivo infected lung tissue for the investigation of emerging viral zoonosis including influenza A virus and Middle East respiratory syndrome coronavirus is discussed. Finally, further directions for the elaboration of such models are revealed. Overall, the introduced models represent meaningful and robust methods to investigate principles of pathogen-host interaction in original human lung tissue.

  2. Comparison of lung preservation solutions in human lungs using an ex vivo lung perfusion experimental model.

    PubMed

    Medeiros, Israel L; Pêgo-Fernandes, Paulo M; Mariani, Alessandro W; Fernandes, Flávio G; Unterpertinger, Fernando V; Canzian, Mauro; Jatene, Fabio B

    2012-09-01

    Experimental studies on lung preservation have always been performed using animal models. We present ex vivo lung perfusion as a new model for the study of lung preservation. Using human lungs instead of animal models may bring the results of experimental studies closer to what could be expected in clinical practice. Brain-dead donors whose lungs had been declined by transplantation teams were used. The cases were randomized into two groups. In Group 1, Perfadex®was used for pulmonary preservation, and in Group 2, LPDnac, a solution manufactured in Brazil, was used. An ex vivo lung perfusion system was used, and the lungs were ventilated and perfused after 10 hours of cold ischemia. The extent of ischemic-reperfusion injury was measured using functional and histological parameters. After reperfusion, the mean oxygenation capacity was 405.3 mmHg in Group 1 and 406.0 mmHg in Group 2 (p = 0.98). The mean pulmonary vascular resistance values were 697.6 and 378.3 dyn·s·cm-5, respectively (p =0.035). The mean pulmonary compliance was 46.8 cm H20 in Group 1 and 49.3 ml/cm H20 in Group 2 (p =0.816). The mean wet/dry weight ratios were 2.06 and 2.02, respectively (p=0.87). The mean Lung Injury Scores for the biopsy performed after reperfusion were 4.37 and 4.37 in Groups 1 and 2, respectively (p = 1.0), and the apoptotic cell counts were 118.75/mm² and 137.50/mm², respectively (p=0.71). The locally produced preservation solution proved to be as good as Perfadex®. The clinical use of LPDnac may reduce costs in our centers. Therefore, it is important to develop new models to study lung preservation.

  3. A novel marker for basal (stem) cells of mammalian stratified squamous epithelia and squamous cell carcinomas.

    PubMed

    Samuel, J; Noujaim, A A; Willans, D J; Brzezinska, G S; Haines, D M; Longenecker, B M

    1989-05-01

    We have developed a monoclonal antibody (174H.64) which selectively recognizes antigens shared by the basal cells of mammalian stratified squamous epithelium and squamous cell carcinoma (SCC). Histopathological studies of the frozen tissue sections demonstrated selective binding of this antibody to SCCs of human, bovine, canine, feline, and murine origin. Tumors of other histological types did not show reactivity with the antibody. In well-differentiated SCCs the peripheral layer of the tumor showed preferential binding of the antibody, suggesting that the antigens are associated with the proliferative compartment of the tumor. Studies on normal human tissues showed selective binding of the antibody to the basal layer of stratified squamous epithelia, thymic epithelial cells, and myoepithelial cells around breast ducts, while no antibody binding was observed for the suprabasal layers of stratified epithelia, simple epithelia, or tissues of nonepithelial origin. A similar pattern of antibody binding was also observed for bovine and murine skin with staining of the basal layer. The antigens detected by monoclonal antibody 174H.64 were characterized from cytoskeletal protein extracts of normal human keratinocytes as well as human and bovine SCC tissues by using an immunoblotting technique. The antigens detected in normal human keratinocytes consisted of two major protein bands of approximate molecular weights of 48,000-50,000 and 57,000. In bovine SCC tumor the antigen detected was the Mr 48,000-50,000 band and in the human SCC tumor it was the Mr 57,000 band. A murine lung SCC model was developed with a murine SCC cell line KLN-205. The lung tumor obtained was reactive against the antibody and showed selective staining of the peripheral layer of the tumor containing the stem cell population. The antigens described by monoclonal antibody 174H.64 appear to be molecules associated with the stem cell populations of normal stratified epithelium and squamous cell carcinoma.

  4. Interaction of tea polyphenols and food constituents with model gut epithelia: the protective role of the mucus gel layer.

    PubMed

    D'Agostino, Eleanor M; Rossetti, Damiano; Atkins, Derek; Ferdinando, Dudley; Yakubov, Gleb E

    2012-03-28

    The luminal surface of the gastrointestinal tract is covered by a mucus gel layer that acts to protect gut epithelial cells from the harsh luminal environment. This study investigated the use of two human colonic adenocarcinoma cell lines, HT29-MTX-E12 and HT29, as a model to mimic gut epithelium with and without a mucus gel layer. The effect of adding the tea polyphenols epigallocatechin gallate (EGCG) and epicatechin (EC) to the cells with subsequent examination of cell morphology and viability was assessed. EGCG, at the concentrations tested, was very toxic to the HT29 cells, but less toxic to the HT29-MTX-E12 cells, suggesting that the mucus gel layer on the HT29-MTX-E12 cells can protect the cells against EGCG toxicity. In contrast, EC had no effect on the viability of either the HT29 or HT29-MTX-E12 cells, suggesting that proteins within the mucus gel layer on the apical surface of gut epithelial cells may bind to the galloyl ring of EGCG. The effect of adding food-related ingredients with the ability to complex with EGCG, β-casein and maltodextrin, on cell viability was also examined. The presence of β-casein was very effective in protecting the cells against the toxicity effect of EGCG, but maltodextrin, at the concentration tested, was less effective in protecting against this toxicity. In conclusion, the results demonstrate that the mucus gel layer on HT29 human colonic adenocarcinoma cells may protect these cells against EGCG toxicity. In addition, the data showing reduced toxicity of EC compared to that of EGCG suggest that the cytotoxic effects of high polyphenol levels may be associated with the ability of polyphenols to interact with cellular proteins and mucins.

  5. 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.

  6. Development of Mouse Lung Deposition Models

    DTIC Science & Technology

    2015-07-01

    Particle inhalability in mice was lower than that in rats . In contrast, deposition of the same size particle was higher in mice nasal passages than...that in rats . Thus, fewer particles entered the mouse lung in comparison with rat particle inhalation. The penetration was severely limited for...geometry that was previously developed for humans, rats , and rhesus monkeys [6], [7]. Inputs to the model included lung geometry and volumes, and

  7. A Risk Model for Lung Cancer Incidence

    PubMed Central

    Hoggart, Clive; Brennan, Paul; Tjonneland, Anne; Vogel, Ulla; Overvad, Kim; Østergaard, Jane Nautrup; Kaaks, Rudolf; Canzian, Federico; Boeing, Heiner; Steffen, Annika; Trichopoulou, Antonia; Bamia, Christina; Trichopoulos, Dimitrios; Johansson, Mattias; Palli, Domenico; Krogh, Vittorio; Tumino, Rosario; Sacerdote, Carlotta; Panico, Salvatore; Boshuizen, Hendriek; Bueno-de-Mesquita, H. Bas; Peeters, Petra H.M.; Lund, Eiliv; Gram, Inger Torhild; Braaten, Tonje; Rodríguez, Laudina; Agudo, Antonio; Sanchez-Cantalejo, Emilio; Arriola, Larraitz; Chirlaque, Maria-Dolores; Barricarte, Aurelio; Rasmuson, Torgny; Khaw, Kay-Tee; Wareham, Nicholas; Allen, Naomi E.; Riboli, Elio; Vineis, Paolo

    2015-01-01

    Risk models for lung cancer incidence would be useful for prioritizing individuals for screening and participation in clinical trials of chemoprevention. We present a risk model for lung cancer built using prospective cohort data from a general population which predicts individual incidence in a given time period. We build separate risk models for current and former smokers using 169,035 ever smokers from the multicenter European Prospective Investigation into Cancer and Nutrition (EPIC) and considered a model for never smokers. The data set was split into independent training and test sets. Lung cancer incidence was modeled using survival analysis, stratifying by age started smoking, and for former smokers, also smoking duration. Other risk factors considered were smoking intensity, 10 occupational/environmental exposures previously implicated with lung cancer, and single-nucleotide polymorphisms at two loci identified by genome-wide association studies of lung cancer. Individual risk in the test set was measured by the predicted probability of lung cancer incidence in the year preceding last follow-up time, predictive accuracy was measured by the area under the receiver operator characteristic curve (AUC). Using smoking information alone gave good predictive accuracy: the AUC and 95% confidence interval in ever smokers was 0.843 (0.810–0.875), the Bach model applied to the same data gave an AUC of 0.775 (0.737–0.813). Other risk factors had negligible effect on the AUC, including never smokers for whom prediction was poor. Our model is generalizable and straightforward to implement. Its accuracy can be attributed to its modeling of lifetime exposure to smoking. PMID:22496387

  8. 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.

  9. Targeted Type 2 Alveolar Cell Depletion. A Dynamic Functional Model for Lung Injury Repair

    PubMed Central

    Garcia, Orquidea; Hiatt, Michael J.; Lundin, Amber; Lee, Jooeun; Reddy, Raghava; Navarro, Sonia; Kikuchi, Alex

    2016-01-01

    Type 2 alveolar epithelial cells (AEC2) are regarded as the progenitor population of the alveolus responsible for injury repair and homeostatic maintenance. Depletion of this population is hypothesized to underlie various lung pathologies. Current models of lung injury rely on either uncontrolled, nonspecific destruction of alveolar epithelia or on targeted, nontitratable levels of fixed AEC2 ablation. We hypothesized that discrete levels of AEC2 ablation would trigger stereotypical and informative patterns of repair. To this end, we created a transgenic mouse model in which the surfactant protein-C promoter drives expression of a mutant SR39TK herpes simplex virus-1 thymidine kinase specifically in AEC2. Because of the sensitivity of SR39TK, low doses of ganciclovir can be administered to these animals to induce dose-dependent AEC2 depletion ranging from mild (50%) to lethal (82%) levels. We demonstrate that specific levels of AEC2 depletion cause altered expression patterns of apoptosis and repair proteins in surviving AEC2 as well as distinct changes in distal lung morphology, pulmonary function, collagen deposition, and expression of remodeling proteins in whole lung that persist for up to 60 days. We believe SPCTK mice demonstrate the utility of cell-specific expression of the SR39TK transgene for exerting fine control of target cell depletion. Our data demonstrate, for the first time, that specific levels of type 2 alveolar epithelial cell depletion produce characteristic injury repair outcomes. Most importantly, use of these mice will contribute to a better understanding of the role of AEC2 in the initiation of, and response to, lung injury. PMID:26203800

  10. Hypo-Elastic Model for Lung Parenchyma

    SciTech Connect

    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 is characterized against published experimental data for dog lung. Future work includes non-elastic model behavior.

  11. Dysfunction of Nrf-2 in CF Epithelia Leads to Excess Intracellular H2O2 and Inflammatory Cytokine Production

    PubMed Central

    Chen, Junnan; Kinter, Michael; Shank, Samuel; Cotton, Calvin; Kelley, Thomas J.; Ziady, Assem G.

    2008-01-01

    Cystic fibrosis is characterized by recurring pulmonary exacerbations that lead to the deterioration of lung function and eventual lung failure. Excessive inflammatory responses by airway epithelia have been linked to the overproduction of the inflammatory cytokine IL-6 and IL-8. The mechanism by which this occurs is not fully understood, but normal IL-1β mediated activation of the production of these cytokines occurs via H2O2 dependent signaling. Therefore, we speculated that CFTR dysfunction causes alterations in the regulation of steady state H2O2. We found significantly elevated levels of H2O2 in three cultured epithelial cell models of CF, one primary and two immortalized. Increases in H2O2 heavily contributed to the excessive IL-6 and IL-8 production in CF epithelia. Proteomic analysis of three in vitro and two in vivo models revealed a decrease in antioxidant proteins that regulate H2O2 processing, by ≥2 fold in CF vs. matched normal controls. When cells are stimulated, differential expression in CF versus normal is enhanced; corresponding to an increase in H2O2 mediated production of IL-6 and IL-8. The cause of this redox imbalance is a decrease by ∼70% in CF cells versus normal in the expression and activity of the transcription factor Nrf-2. Inhibition of CFTR function in normal cells produced this phenotype, while N-acetyl cysteine, selenium, an activator of Nrf-2, and the overexpression of Nrf-2 all normalized H2O2 processing and decreased IL-6 and IL-8 to normal levels, in CF cells. We conclude that a paradoxical decrease in Nrf-2 driven antioxidant responses in CF epithelia results in an increase in steady state H2O2, which in turn contributes to the overproduction of the pro-inflammatory cytokines IL-6 and IL-8. Treatment with antioxidants can ameliorate exaggerated cytokine production without affecting normal responses. PMID:18846238

  12. Obstructive lung disease models: what is valid?

    PubMed

    Ferdinands, Jill M; Mannino, David M

    2008-12-01

    Use of disease simulation models has led to scrutiny of model methods and demand for evidence that models credibly simulate health outcomes. We sought to describe recent obstructive lung disease simulation models and their validation. Medline and EMBASE were used to identify obstructive lung disease simulation models published from January 2000 to June 2006. Publications were reviewed to assess model attributes and four types of validation: first-order (verification/debugging), second-order (comparison with studies used in model development), third-order (comparison with studies not used in model development), and predictive validity. Six asthma and seven chronic obstructive pulmonary disease models were identified. Seven (54%) models included second-order validation, typically by comparing observed outcomes to simulations of source study cohorts. Seven (54%) models included third-order validation, in which modeled outcomes were usually compared qualitatively for agreement with studies independent of the model. Validation endpoints included disease prevalence, exacerbation, and all-cause mortality. Validation was typically described as acceptable, despite near-universal absence of criteria for judging adequacy of validation. Although over half of recent obstructive lung disease simulation models report validation, inconsistencies in validation methods and lack of detailed reporting make assessing adequacy of validation difficult. For simulation modeling to be accepted as a tool for evaluating clinical and public health programs, models must be validated to credibly simulate health outcomes of interest. Defining the required level of validation and providing guidance for quantitative assessment and reporting of validation are important future steps in promoting simulation models as practical decision tools.

  13. In vitro models of lung toxicity.

    PubMed

    Fisher, G L; Placke, M E

    1987-12-01

    In vitro assays that emphasize cellular components critical to the host defense system have been developed to evaluate pulmonary toxicity and define deleterious changes in parenchymal cell populations. Assays that employ pulmonary alveolar macrophages (PAM) have demonstrated good correlation between macrophage toxicity and pulmonary fibrogenicity for many inorganic compounds. The PAM assays provide simple and inexpensive screens of potential respiratory tract toxicity. Many investigators screen chemicals for their ability to alter the mucosal epithelial cell conducting airways by performing tracheal organ cultures. The tracheal assays have also provided useful screens for Vitamin A analogues required for epithelial cell differentiation. Most recently, in vitro respiratory tract models have been extended to include whole-lung explants, an approach that allows for development of fibrosis and epithelial cell toxicity after in vitro exposure to inorganic and organic fibrogens. The whole-lung explant system appears to duplicate the in vivo response to a variety of lung toxins, including bleomycin, silica, and crocidolite asbestos. Together, these assays provide a description of potential toxicity to key components of the lung, emphasizing the pulmonary macrophage, conducting airways, and alveolar septae. It is expected that continued research in these models will enhance their predictive abilities and utility in risk assessment.

  14. Translational models of lung disease.

    PubMed

    Mercer, Paul F; Abbott-Banner, Katharine; Adcock, Ian M; Knowles, Richard G

    2015-02-01

    The 2nd Cross Company Respiratory Symposium (CCRS), held in Horsham, U.K. in 2012, brought together representatives from across the pharmaceutical industry with expert academics, in the common interest of improving the design and translational predictiveness of in vivo models of respiratory disease. Organized by the respiratory representatives of the European Federation of Pharmaceutical Industries and Federations (EFPIA) group of companies involved in the EU-funded project (U-BIOPRED), the aim of the symposium was to identify state-of-the-art improvements in the utility and design of models of respiratory disease, with a view to improving their translational potential and reducing wasteful animal usage. The respiratory research and development community is responding to the challenge of improving translation in several ways: greater collaboration and open sharing of data, careful selection of the species, complexity and chronicity of the models, improved practices in preclinical research, continued refinement in models of respiratory diseases and their sub-types, greater understanding of the biology underlying human respiratory diseases and their sub-types, and finally greater use of human (and especially disease-relevant) cells, tissues and explants. The present review highlights these initiatives, combining lessons from the symposium and papers published in Clinical Science arising from the symposium, with critiques of the models currently used in the settings of asthma, idiopathic pulmonary fibrosis and COPD. The ultimate hope is that this will contribute to a more rational, efficient and sustainable development of a range of new treatments for respiratory diseases that continue to cause substantial morbidity and mortality across the world.

  15. 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.

  16. Foxg1-Cre Mediated Lrp2 Inactivation in the Developing Mouse Neural Retina, Ciliary and Retinal Pigment Epithelia Models Congenital High Myopia

    PubMed Central

    Obry, Antoine; Santin, Mathieu D.; Ben-Yacoub, Sirine; Pâques, Michel; Amsellem-Levera, Sabine; Bribian, Ana; Simonutti, Manuel; Augustin, Sébastien; Debeir, Thomas; Sahel, José Alain; Christ, Annabel; de Castro, Fernando; Lehéricy, Stéphane; Cosette, Pascal; Kozyraki, Renata

    2015-01-01

    Myopia is a common ocular disorder generally due to increased axial length of the eye-globe. Its extreme form high myopia (HM) is a multifactorial disease leading to retinal and scleral damage, visual impairment or loss and is an important health issue. Mutations in the endocytic receptor LRP2 gene result in Donnai-Barrow (DBS) and Stickler syndromes, both characterized by HM. To clearly establish the link between Lrp2 and congenital HM we inactivated Lrp2 in the mouse forebrain including the neural retina and the retinal and ciliary pigment epithelia. High resolution in vivo MRI imaging and ophthalmological analyses showed that the adult Lrp2-deficient eyes were 40% longer than the control ones mainly due to an excessive elongation of the vitreal chamber. They had an apparently normal intraocular pressure and developed chorioretinal atrophy and posterior scleral staphyloma features reminiscent of human myopic retinopathy. Immunomorphological and ultrastructural analyses showed that increased eye lengthening was first observed by post-natal day 5 (P5) and that it was accompanied by a rapid decrease of the bipolar, photoreceptor and retinal ganglion cells, and eventually the optic nerve axons. It was followed by scleral thinning and collagen fiber disorganization, essentially in the posterior pole. We conclude that the function of LRP2 in the ocular tissues is necessary for normal eye growth and that the Lrp2-deficient eyes provide a unique tool to further study human HM. PMID:26107939

  17. Ion transport by pulmonary epithelia.

    PubMed

    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.

  18. 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

  19. Protective effect of plasmin in marginal donor lungs in an ex vivo lung perfusion model.

    PubMed

    Motoyama, Hideki; Chen, Fengshi; Ohsumi, Akihiro; Hijiya, Kyoko; Okita, Kenji; Nakajima, Daisuke; Sakamoto, Jin; Yamada, Tetsu; Sato, Masaaki; Aoyama, Akihiro; Bando, Toru; Date, Hiroshi

    2013-05-01

    Donor lung thrombi are considered an important etiology for primary graft dysfunction in lung transplantation. We hypothesized that thrombolysis before lung transplantation could alleviate ischemia-reperfusion injury. This study was designed to evaluate the effect of the fibrinolytic agent plasmin on lungs damaged by thrombi in an ex vivo lung perfusion (EVLP) system. Rats were divided into control, non-plasmin, and plasmin groups (n = 7 each). In the control and plasmin groups, cardiac arrest was induced by withdrawal of mechanical ventilation without heparinization. Ventilation was restarted 150 minutes after cardiac arrest. The lungs were flushed, and the heart and lungs were excised en bloc. The lungs were perfused in the EVLP system for 60 minutes, and plasmin or placebo was administered upon EVLP initiation. Fibrin/fibrinogen degradation products in the perfusate were significantly higher in the plasmin group than in the control and non-control groups (p < 0.001 for both). Plasmin administration significantly decreased pulmonary vascular resistance (plasmin vs non-plasmin, p = 0.011) and inhibited the exacerbation of dynamic compliance (plasmin vs non-plasmin, p = 0.003). Lung weight gain was less in the plasmin group than in the non-plasmin group (p = 0.04). Our results confirmed that plasmin administration in an EVLP model dissolved thrombi in the lungs, resulting in reconditioning of the lungs as assessed by various physiologic parameters. Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  20. Application of the proposed new ICRP lung model to bioassay

    SciTech Connect

    Johnson, J.R.; James, A.C.; Hill, R.L.

    1992-05-01

    The new lung model being proposed by ICRP for use in radiation protection dosimetry requires the calculation of doses to separate regions of the respiratory tract, multiplying these doses by factors proportional to the risk per unit dose to each region, and summing over all regions of the lung to give a ``weighted`` lung dose. This paper compares the doses that would be calculated form bioassay measurements using the new model with those calculated using the current model, which essentially uses total lung burden to estimate lung dose.

  1. Application of the proposed new ICRP lung model to bioassay

    SciTech Connect

    Johnson, J.R.; James, A.C.; Hill, R.L.

    1992-05-01

    The new lung model being proposed by ICRP for use in radiation protection dosimetry requires the calculation of doses to separate regions of the respiratory tract, multiplying these doses by factors proportional to the risk per unit dose to each region, and summing over all regions of the lung to give a weighted'' lung dose. This paper compares the doses that would be calculated form bioassay measurements using the new model with those calculated using the current model, which essentially uses total lung burden to estimate lung dose.

  2. Development of a Guinea Pig Lung Deposition Model

    DTIC Science & Technology

    2016-01-01

    6 3.4. MECHANISTIC MODEL OF PARTICLE DEPOSITION IN THE LUNG ................................. 7 4.0 SOFTWARE IMPLEMENTATION...4 Figure 2. Particle deposition in the lung of the guinea pig via endotracheal breathing...10 Figure 3. Deposition fraction of various size particles at different lung depths. ..................................... 11 Figure 4

  3. 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

  4. A mathematical model of lung parenchyma.

    PubMed

    Karakaplan, A D; Bieniek, M P; Skalak, R

    1980-05-01

    The geometry of the proposed model of the parenchyma of a mammalian lung reproduces a cluster of alveoli arranged around a lowest-level air duct. The alveolar walls are assumed to be nonlinear elastic membranes, whose properties are described in terms of a strain energy function which reflects the hardening character of the stress-strain curve. The effect of the surfactant is included in terms of a variable (area-dependent) surface tension. Analyses of various mechanical processes in the parenchyma are performed with the aid of the finite element method, with the geometric and physical nonlinearities of the problem taken into account.

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

    PubMed

    Arai, Daisuke; Hegab, Ahmed E; Soejima, Kenzo; Kuroda, Aoi; Ishioka, Kota; Yasuda, Hiroyuki; Naoki, Katsuhiko; Kagawa, Shizuko; Hamamoto, Junko; Yin, Yongjun; Ornitz, David M; Betsuyaku, Tomoko

    2015-03-01

    Fibroblast growth factor 9 (FGF9) 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 tumours. We showed that prolonged FGF9 over-expression 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 tumour cells harboured tumour-propagating cells that were able to form secondary tumours in recipient mice, regardless of FGF9 expression. However, the highest degree of tumour propagation was observed when unfractionated tumour cells were co-administered with autologous, tumour-associated mesenchymal cells. Although the initiation of lung adenocarcinomas was dependent on activation of the FGF9-FGF receptor 3 (FGFR3) signalling axis, maintenance and propagation of the tumour was independent of this signalling. Activation of an alternative FGF-FGFR axis and the interaction with tumour stromal cells is likely to be responsible for the development of this independence. This study demonstrates the complex role of FGF-FGFR signalling in the initiation, growth and propagation of lung cancer. Our findings suggest that analysing the expressions of FGF-FGFRs in human lung cancer will be a useful tool for guiding customized therapy.

  6. Dynamic epithelia of the developing vertebrate face.

    PubMed

    Choe, Chong Pyo; Crump, J Gage

    2015-06-01

    A segmental series of endoderm-derived pouch and ectoderm-derived cleft epithelia act as signaling centers in the developing face. Their precise morphogenesis is therefore essential for proper patterning of the vertebrate head. Intercellular adhesion and polarity are highly dynamic within developing facial epithelial cells, with signaling from the adjacent mesenchyme controlling both epithelial character and directional migration. Endodermal and ectodermal epithelia fuse to form the primary mouth and gill slits, which involves basement membrane dissolution, cell intercalations, and apoptosis, as well as undergo further morphogenesis to generate the middle ear cavity and glands of the neck. Recent studies of facial epithelia are revealing both core programs of epithelial morphogenesis and insights into the coordinated assembly of the vertebrate head.

  7. Differentiation of columnar epithelia: the hensin pathway.

    PubMed

    Vijayakumar, Soundarapandian; Takito, Jiro; Gao, XiaoBo; Schwartz, George J; Al-Awqati, Qais

    2006-12-01

    Epithelia, the most common variety of cells in complex organisms exist in many shapes. They are sheets of polarized cells that separate two compartments and selectively transport materials from one to the other. After acquiring these general characteristics, they differentiate to become specialized types such as squamous columnar or transitional epithelia. High density seeding converts a kidney-derived cell line from flat ;generic' epithelial cells to columnar cells. The cells acquire all the characteristics of differentiated columnar cells, including microvilli, and the capacity for apical endocytosis. The high seeding density induces the deposition of a new protein termed hensin and polymerization of hensin is the crucial event that dictates changes in epithelial phenotype. Hensin is widely expressed in most epithelia. Its deletion in mice leads to embryonic lethality at the time of generation of the first columnar epithelium, the visceral endoderm. Moreover many human cancers have deletions in the hensin gene, which indicates that it is a tumor suppressor.

  8. Hepatocyte growth factor/scatter factor effects on epithelia. Regulation of intercellular junctions in transformed and nontransformed cell lines, basolateral polarization of c-met receptor in transformed and natural intestinal epithelia, and induction of rapid wound repair in a transformed model epithelium.

    PubMed Central

    Nusrat, A; Parkos, C A; Bacarra, A E; Godowski, P J; Delp-Archer, C; Rosen, E M; Madara, J L

    1994-01-01

    Intestinal epithelial cells rest on a fibroblast sheath. Thus, factors produced by these fibroblasts may influence epithelial function in a paracrine fashion. We examined modulation of intestinal epithelial function by one such fibroblast product, scatter factor/hepatocyte growth factor (HGF/SF). This effect was studied in vitro by using model T84 intestinal epithelial cells. When applied to confluent T84 monolayers, HGF/SF attenuates transepithelial resistance to passive ion flow in a dose-dependent manner (maximum fall at 300 ng/ml, 28% control monolayer resistance, P < 0.001, ED50 of 1.2 nM), t1/2 of 20 h. This functional effect of HGF/SF and distribution of its receptor, c-met, are polarized to the basolateral membranes of T84 intestinal epithelial cells. HGF/SF effects on resistance are not attributable to altered transcellular resistance (opening of Cl- and/or basolateral K+ channels), cytotoxicity, or enhanced cell proliferation; they therefore represent specific regulation of paracellular tight junction resistance. Analysis with biochemically purified rodent HGF/SF and Madin-Darby canine kidney cells reveals that effects on paracellular tight junctions also occur in other nontransformed epithelia. Binding of HGF/SF to its receptor in T84 intestinal epithelial cells is accompanied by tyrosine phosphorylation of the receptor. Because loosening of intercellular junctions between cells could facilitate separation, spreading, and migration of epithelial cells during physiologic processes such as wound resealing, we determined the effects of HGF/SF on intestinal epithelial wound resealing using our previously published in vitro model (Nusrat, A., C. Delp, and J. L. Madara. 1992. J. Clin. Invest. 89:1501-1511). HGF/SF markedly enhanced wound closure (> 450% increase in rate, P < 0.001) by influencing the migratory and spreading response in not only cells adjoining the wound but also cells many positions removed from the wound. We thus speculate that HGF/SF may

  9. Irreversible Electroporation in a Swine Lung Model

    SciTech Connect

    Dupuy, Damian E.; Aswad, Bassam; Ng, Thomas

    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 2 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.

  10. Modeling of the lung nodules for detection in LDCT scans.

    PubMed

    Farag, Amal; Elhabian, Shireen; Graham, James; Farag, Aly; Elshazly, Salwa; Falk, Robert; Mahdi, Hani; Abdelmunim, Hossam; Al-Ghaafary, Sahar

    2010-01-01

    A novel approach is proposed for generating data driven models of the lung nodules appearing in low dose CT (LDCT) scans of the human chest. Four types of common lung nodules are analyzed using Active Appearance Model methods to create descriptive lung nodule models. The proposed approach is also applicable for automatic classification of nodules into pathologies given a descriptive database. This approach is a major step forward for early diagnosis of lung cancer. We show the performance of the new nodule models on clinical datasets which illustrates significant improvements in both sensitivity and specificity.

  11. Modeling Airflow Using Subject-Specific 4DCT-Based Deformable Volumetric Lung Models

    PubMed Central

    Ilegbusi, Olusegun J.; Li, Zhiliang; Seyfi, Behnaz; Min, Yugang; Meeks, Sanford; Kupelian, Patrick; Santhanam, Anand P.

    2012-01-01

    Lung radiotherapy is greatly benefitted when the tumor motion caused by breathing can be modeled. The aim of this paper is to present the importance of using anisotropic and subject-specific tissue elasticity for simulating the airflow inside the lungs. A computational-fluid-dynamics (CFD) based approach is presented to simulate airflow inside a subject-specific deformable lung for modeling lung tumor motion and the motion of the surrounding tissues during radiotherapy. A flow-structure interaction technique is employed that simultaneously models airflow and lung deformation. The lung is modeled as a poroelastic medium with subject-specific anisotropic poroelastic properties on a geometry, which was reconstructed from four-dimensional computed tomography (4DCT) scan datasets of humans with lung cancer. The results include the 3D anisotropic lung deformation for known airflow pattern inside the lungs. The effects of anisotropy are also presented on both the spatiotemporal volumetric lung displacement and the regional lung hysteresis. PMID:23365554

  12. Nanoparticle interaction with model lung surfactant monolayers

    PubMed Central

    Harishchandra, Rakesh Kumar; Saleem, Mohammed; Galla, Hans-Joachim

    2010-01-01

    One of the most important functions of the lung surfactant monolayer is to form the first line of defence against inhaled aerosols such as nanoparticles (NPs), which remains largely unexplored. We report here, for the first time, the interaction of polyorganosiloxane NPs (AmorSil20: 22 nm in diameter) with lipid monolayers characteristic of alveolar surfactant. To enable a better understanding, the current knowledge about an established model surface film that mimics the surface properties of the lung is reviewed and major results originating from our group are summarized. The pure lipid components dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol have been used to study the biophysical behaviour of their monolayer films spread at the air–water interface in the presence of NPs. Film balance measurements combined with video-enhanced fluorescence microscopy have been used to investigate the formation of domain structures and the changes in the surface pattern induced by NPs. We are able to show that NPs are incorporated into lipid monolayers with a clear preference for defect structures at the fluid–crystalline interface leading to a considerable monolayer expansion and fluidization. NPs remain at the air–water interface probably by coating themselves with lipids in a self-assembly process, thereby exhibiting hydrophobic surface properties. We also show that the domain structure in lipid layers containing surfactant protein C, which is potentially responsible for the proper functioning of surfactant material, is considerably affected by NPs. PMID:19846443

  13. A mouse model of orthotopic vascularized aerated lung transplantation.

    PubMed

    Okazaki, M; Krupnick, A S; Kornfeld, C G; Lai, J M; Ritter, J H; Richardson, S B; Huang, H J; Das, N A; Patterson, G A; Gelman, A E; Kreisel, D

    2007-06-01

    Outcomes after lung transplantation are markedly inferior to those after other solid organ transplants. A better understanding of cellular and molecular mechanisms contributing to lung graft injury will be critical to improve outcomes. Advances in this field have been hampered by the lack of a mouse model of lung transplantation. Here, we report a mouse model of vascularized aerated single lung transplantation utilizing cuff techniques. We show that syngeneic grafts have normal histological appearance with minimal infiltration of T lymphocytes. Allogeneic grafts show acute cellular rejection with infiltration of T lymphocytes and recipient-type antigen presenting cells. Our data show that we have developed a physiological model of lung transplantation in the mouse, which provides ample opportunity for the study of nonimmune and immune mechanisms that contribute to lung allograft injury.

  14. Persistent gene expression in mouse nasal epithelia following feline immunodeficiency virus-based vector gene transfer.

    PubMed

    Sinn, Patrick L; Burnight, Erin R; Hickey, Melissa A; Blissard, Gary W; McCray, Paul B

    2005-10-01

    Gene transfer development for treatment or prevention of cystic fibrosis lung disease has been limited by the inability of vectors to efficiently and persistently transduce airway epithelia. Influenza A is an enveloped virus with natural lung tropism; however, pseudotyping feline immunodeficiency virus (FIV)-based lentiviral vector with the hemagglutinin envelope protein proved unsuccessful. Conversely, pseudotyping FIV with the envelope protein from influenza D (Thogoto virus GP75) resulted in titers of 10(6) transducing units (TU)/ml and conferred apical entry into well-differentiated human airway epithelial cells. Baculovirus GP64 envelope glycoproteins share sequence identity with influenza D GP75 envelope glycoproteins. Pseudotyping FIV with GP64 from three species of baculovirus resulted in titers of 10(7) to 10(9) TU/ml. Of note, GP64 from Autographa californica multicapsid nucleopolyhedrovirus resulted in high-titer FIV preparations (approximately 10(9) TU/ml) and conferred apical entry into polarized primary cultures of human airway epithelia. Using a luciferase reporter gene and bioluminescence imaging, we observed persistent gene expression from in vivo gene transfer in the mouse nose with A. californica GP64-pseudotyped FIV (AcGP64-FIV). Longitudinal bioluminescence analysis documented persistent expression in nasal epithelia for approximately 1 year without significant decline. According to histological analysis using a LacZ reporter gene, olfactory and respiratory epithelial cells were transduced. In addition, methylcellulose-formulated AcGP64-FIV transduced mouse nasal epithelia with much greater efficiency than similarly formulated vesicular stomatitis virus glycoprotein-pseudotyped FIV. These data suggest that AcGP64-FIV efficiently transduces and persistently expresses a transgene in nasal epithelia in the absence of agents that disrupt the cellular tight junction integrity.

  15. 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

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

    PubMed

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

    2015-08-01

    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.

  17. 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

  18. Individualized Risk Prediction Model for Lung Cancer in Korean Men

    PubMed Central

    Park, Sohee; Nam, Byung-Ho; Yang, Hye-Ryung; Lee, Ji An; Lim, Hyunsun; Han, Jun Tae; Park, Il Su; Shin, Hai-Rim; Lee, Jin Soo

    2013-01-01

    Purpose Lung cancer is the leading cause of cancer deaths in Korea. The objective of the present study was to develop an individualized risk prediction model for lung cancer in Korean men using population-based cohort data. Methods From a population-based cohort study of 1,324,804 Korean men free of cancer at baseline, the individualized absolute risk of developing lung cancer was estimated using the Cox proportional hazards model. We checked the validity of the model using C statistics and the Hosmer–Lemeshow chi-square test on an external validation dataset. Results The risk prediction model for lung cancer in Korean men included smoking exposure, age at smoking initiation, body mass index, physical activity, and fasting glucose levels. The model showed excellent performance (C statistic = 0.871, 95% CI = 0.867–0.876). Smoking was significantly associated with the risk of lung cancer in Korean men, with a four-fold increased risk in current smokers consuming more than one pack a day relative to non-smokers. Age at smoking initiation was also a significant predictor for developing lung cancer; a younger age at initiation was associated with a higher risk of developing lung cancer. Conclusion This is the first study to provide an individualized risk prediction model for lung cancer in an Asian population with very good model performance. In addition to current smoking status, earlier exposure to smoking was a very important factor for developing lung cancer. Since most of the risk factors are modifiable, this model can be used to identify those who are at a higher risk and who can subsequently modify their lifestyle choices to lower their risk of lung cancer. PMID:23408946

  19. Spatial Variation in the Healthy Human Lung Microbiome and the Adapted Island Model of Lung Biogeography.

    PubMed

    Dickson, Robert P; Erb-Downward, John R; Freeman, Christine M; McCloskey, Lisa; Beck, James M; Huffnagle, Gary B; Curtis, Jeffrey L

    2015-06-01

    The lung microbiome is spatially heterogeneous in advanced airway diseases, but whether it varies spatially in health is unknown. We postulated that the primary determinant of lung microbiome constitution in health is the balance of immigration and elimination of communities from the upper respiratory tract (URT; "adapted island model of lung biogeography"), rather than differences in regional bacterial growth conditions. To determine if the lung microbiome is spatially varied in healthy adults. Bronchoscopy was performed on 15 healthy subjects. Specimens were sequentially collected in the lingula and right middle lobe (by bronchoalveolar lavage [BAL]), then in the right upper lobe, left upper lobe, and supraglottic space (by protected-specimen brush). Bacterial 16S ribosmal RNA-encoding genes were sequenced using MiSeq (Illumina, San Diego, CA). There were no significant differences between specimens collected by BAL and protected-specimen brush. Spatially separated intrapulmonary sites, when compared with each other, did not contain consistently distinct microbiota. On average, intrasubject variation was significantly less than intersubject variation (P = 0.00003). By multiple ecologic parameters (community richness, community composition, intersubject variability, and similarity to source community), right upper lobe microbiota more closely resembled those of the URT than did microbiota from more distal sites. As predicted by the adapted island model, community richness decreased with increasing distance from the source community of the URT (P < 0.05). In healthy lungs, spatial variation in microbiota within an individual is significantly less than variation across individuals. The lung microbiome in health is more influenced by microbial immigration and elimination (the adapted island model) than by the effects of local growth conditions on bacterial reproduction rates, which are more determinant in advanced lung diseases. BAL of a single lung segment is an

  20. Model Lung Surfactant Films: Why Composition Matters

    SciTech Connect

    Selladurai, Sahana L.; Miclette Lamarche, Renaud; Schmidt, Rolf; DeWolf, Christine E.

    2016-10-18

    Lung surfactant replacement therapies, Survanta and Infasurf, and two lipid-only systems both containing saturated and unsaturated phospholipids and one containing additional palmitic acid were used to study the impact of buffered saline on the surface activity, morphology, rheology, and structure of Langmuir monolayer model membranes. Isotherms and Brewster angle microscopy show that buffered saline subphases induce a film expansion, except when the cationic protein, SP-B, is present in sufficient quantities to already screen electrostatic repulsion, thus limiting the effect of changing pH and adding counterions. Grazing incidence X-ray diffraction results indicate an expansion not only of the liquid expanded phase but also an expansion of the lattice of the condensed phase. The film expansion corresponded in all cases with a significant reduction in the viscosity and elasticity of the films. The viscoelastic parameters are dominated by liquid expanded phase properties and do not appear to be dependent on the structure of the condensed phase domains in a phase separated film. The results highlight that the choice of subphase and film composition is important for meaningful interpretations of measurements using model systems.

  1. Lung Cancer Risk Prediction: Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial Models and Validation

    PubMed Central

    Pinsky, Paul F.; Caporaso, Neil E.; Kvale, Paul A.; Hocking, William G.; Church, Timothy R.; Riley, Thomas L.; Commins, John; Oken, Martin M.; Berg, Christine D.; Prorok, Philip C.

    2011-01-01

    Introduction Identification of individuals at high risk for lung cancer should be of value to individuals, patients, clinicians, and researchers. Existing prediction models have only modest capabilities to classify persons at risk accurately. Methods Prospective data from 70 962 control subjects in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) were used in models for the general population (model 1) and for a subcohort of ever-smokers (N = 38 254) (model 2). Both models included age, socioeconomic status (education), body mass index, family history of lung cancer, chronic obstructive pulmonary disease, recent chest x-ray, smoking status (never, former, or current), pack-years smoked, and smoking duration. Model 2 also included smoking quit-time (time in years since ever-smokers permanently quit smoking). External validation was performed with 44 223 PLCO intervention arm participants who completed a supplemental questionnaire and were subsequently followed. Known available risk factors were included in logistic regression models. Bootstrap optimism-corrected estimates of predictive performance were calculated (internal validation). Nonlinear relationships for age, pack-years smoked, smoking duration, and quit-time were modeled using restricted cubic splines. All reported P values are two-sided. Results During follow-up (median 9.2 years) of the control arm subjects, 1040 lung cancers occurred. During follow-up of the external validation sample (median 3.0 years), 213 lung cancers occurred. For models 1 and 2, bootstrap optimism-corrected receiver operator characteristic area under the curves were 0.857 and 0.805, and calibration slopes (model-predicted probabilities vs observed probabilities) were 0.987 and 0.979, respectively. In the external validation sample, models 1 and 2 had area under the curves of 0.841 and 0.784, respectively. These models had high discrimination in women, men, whites, and nonwhites. Conclusion The PLCO

  2. NNK-Induced Lung Tumors: A Review of Animal Model

    PubMed Central

    Zheng, Hua-Chuan; Takano, Yasuo

    2011-01-01

    The incidence of lung adenocarcinoma has been remarkably increasing in recent years due to the introduction of filter cigarettes and secondary-hand smoking because the people are more exposed to higher amounts of nitrogen oxides, especially 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK), which is widely applied in animal model of lung tumors. In NNK-induced lung tumors, genetic mutation, chromosome instability, gene methylation, and activation of oncogenes have been found so as to disrupt the expression profiles of some proteins or enzymes in various cellular signal pathways. Transgenic animal with specific alteration of lung cancer-related molecules have also been introduced to clarify the molecular mechanisms of NNK in the pathogenesis and development of lung tumors. Based on these animal models, many antioxidant ingredients and antitumor chemotherapeutic agents have been proved to suppress the NNK-induced lung carcinogenesis. In the future, it is necessary to delineate the most potent biomarkers of NNK-induced lung tumorigenesis, and to develop efficient methods to fight against NNK-associated lung cancer using animal models. PMID:21559252

  3. Optimizing a canine survival model of orthotopic lung transplantation.

    PubMed

    Farivar, A S; Yunusov, M Y; Chen, P; Leone, R J; Madtes, D K; Kuhr, C S; Spector, M R; Abrams, K; Hwang, B; Nash, R A; Mulligan, M S

    2006-06-01

    While acute models of orthotopic lung transplantation have been described in dogs, the technical considerations of developing a survival model in this species have not been elaborated. Herein, we describe optimization of a canine survival model of orthotopic lung transplantation. Protocols of orthotopic left lung transplantation and single lung ventilation were established in acute experiments (n=9). Four dogs, serving as controls, received autologous, orthotopic lung transplants. Allogeneic transplants were performed in 16 DLA-identical and 16 DLA-mismatched unrelated recipient dogs. Selective right lung ventilation was utilized in all animals. A Malecot tube was left in the pleural space connected to a Heimlich valve for up to 24 hours. To date, animals have been followed up to 24 months by chest radiography, pulmonary function tests, bronchoscopy with lavage, and open biopsies. Long-term survival was achieved in 34/36 animals. Two recipients died intraoperatively secondary to cardiac arrest. All animals were extubated on the operating table, and in all cases the chest tube was removed within 24 hours. Major complications included thrombosis of the pulmonary artery and subcritical stenosis of bronchial anastamosis. One recipient underwent successful treatment of a small bowel intussusception. We report our experience in developing a survival canine model of orthotopic single lung transplantation. While short-term survival following canine lung transplantation is achievable, we report particular considerations that facilitate animal comfort, early extubation, and lung reexpansion in the immediate postoperative period, further optimizing use of this species for experimental modeling of long-term complications after lung transplantation.

  4. 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.

  5. A lung segmental model of chronic Pseudomonas infection in sheep.

    PubMed

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

    2013-01-01

    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. 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 (>10(4) cfu/g). 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.

  6. Implications of the ICRP Task Group's proposed lung model for internal dose assessments in the mineral sands industry

    SciTech Connect

    James, A.C. ); Birchall, A. )

    1990-09-01

    The ICRP Task Group on Respiratory Tract Models for Radiological Projection is proposing a model to describe the deposition, clearance, retention and dosimetry of inhaled radionuclides for dose-intake calculations and interpretation of bioassay data. The deposition model takes into account new data on the regional deposition of aerosol particles in human lung and the inhalability of large particles. The clearance model treats clearance as competition between mechanical transport, which moves particles to the gastro-intestinal tract and lymph nodes, and the translocation of material to blood. This provides a realistic estimate of the amount of a given material (such as mineral sand) that is absorbed systemically, and its variation with aerosol size. The proposed dosimetry model takes into account the relative sensitivities of the various tissue components of the respiratory tract. A new treatment of dose received by epithelia in the tracheo-bronchiolar and extrathoracic regions is proposed. This paper outlines the novel features of the task group model, and then examines the impact that adoption of the model may have on the assessment of doses from occupational exposures to mineral sands and thoron progeny. 39 refs., 15 figs., 6 tabs.

  7. The ΔF508-CFTR mutation inhibits wild-type CFTR processing and function when co-expressed in human airway epithelia and in mouse nasal mucosa

    PubMed Central

    2012-01-01

    Background Rescue or correction of CFTR function in native epithelia is the ultimate goal of CF therapeutics development. Wild-type (WT) CFTR introduction and replacement is also of particular interest. Such therapies may be complicated by possible CFTR self-assembly into an oligomer or multimer. Results Surprisingly, functional CFTR assays in native airway epithelia showed that the most common CFTR mutant, ΔF508-CFTR (ΔF-CFTR), inhibits WT-CFTR when both forms are co-expressed. To examine more mechanistically, both forms of CFTR were transfected transiently in varying amounts into IB3-1 CF human airway epithelial cells and HEK-293 human embryonic kidney cells null for endogenous CFTR protein expression. Increasing amounts of ΔF-CFTR inhibited WT-CFTR protein processing and function in CF human airway epithelial cells but not in heterologous HEK-293 cells. Stably expressed ΔF-CFTR in clones of the non-CF human airway epithelial cell line, CALU-3, also showed reduction in cAMP-stimulated anion secretion and in WT-CFTR processing. An ultimate test of this dominant negative-like effect of ΔF-CFTR on WT-CFTR was the parallel study of two different CF mouse models: the ΔF-CFTR mouse and the bitransgenic CFTR mouse corrected in the gut but null in the lung and airways. WT/ΔF heterozygotes had an intermediate phenotype with regard to CFTR agonist responses in in vivo nasal potential difference (NPD) recordings and in Ussing chamber recordings of short-circuit current (ISC) in vitro on primary tracheal epithelial cells isolated from the same mice. In contrast, CFTR bitransgenic +/− heterozygotes had no difference in their responses versus +/+ wild-type mice. Conclusions Taken altogether, these data suggest that ΔF-CFTR and WT-CFTR co-assemble into an oligomeric macromolecular complex in native epithelia and share protein processing machinery and regulation at the level of the endoplasmic reticulum (ER). As a consequence, ΔF-CFTR slows WT-CFTR protein processing

  8. Animal models of beryllium-induced lung disease

    SciTech Connect

    Finch, G.L.; Hoover, M.D.; Hahn, F.F.

    1996-10-01

    The Inhalation Toxicology Research Institute (ITRI) is conducting research to improve the understanding of chronic beryllium disease (CBD) and beryllium-induced lung cancer. Initial animal studies examined beagle dogs that inhaled BeO calcined at either 500 or 1000{degrees}C. At similar lung burdens, the 500{degrees}C BeO induced more severe and extensive granulomatous pneumonia, lymphocytic infiltration into the lung, and positive Be-specific lymphocyte proliferative responses in vitro than the 1000{degrees}C BeO. However, the progressive nature of human CBD was not duplicated. More recently, Strains A/J and C3H/HeJ mice were exposed to Be metal by inhalation. This produced a marked granulomatous pneumonia, diffuse infiltrates, and multifocal aggregates of interstitial lymphocytes with a pronounced T helper component and pulmonary in situ lymphocyte proliferation. With respect to lung cancer, at a mean lung burden as low as 17 pg Be/g lung, inhaled Be metal induced benign and/or malignant lung tumors in over 50% of male and female F344 rats surviving {ge}1 year on study. Substantial tumor multiplicity was found, but K-ras and p53 gene mutations were virtually absent. In mice, however, a lung burden of approximately 60 {mu}g ({approximately}300 {mu}g Be/g lung) caused only a slight increase in crude lung tumor incidence and multiplicity over controls in strain A/J mice and no elevated incidence in strain C3H mice. Taken together, this research program constitutes a coordinated effort to understand beryllium-induced lung disease in experimental animal models. 47 refs., 1 fig., 3 tabs.

  9. 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

  10. 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

  11. 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

  12. Computational model of OCT in lung tissue

    NASA Astrophysics Data System (ADS)

    Reed, David C.; DiMarzio, Charles A.

    2010-02-01

    Lung research may have significant impact on human health. As two examples, recovery from collapse of the alveoli and the severe post surgery declines in forced vital capacity in patients under the effects of anesthesia are both poorly understood. Optical imaging is important to lung research for its inherently high resolution. Microscopy and color imaging are fundamentals of medicine, but interior lung tissue is usually viewed either endoscopically or ex vivo, stained slices. Techniques such as confocal microscopy and optical coherence tomography (OCT) have become increasingly popular in medical imaging because of their sectioning and depth penetration. Since OCT has the ability to achieve higher depth penetration than confocal it is more widely used in lung imaging, despite the difficulty of interpreting the images due to the poor numerical aperture (NA). To understand light propagation through the highly reflective and refractive surfaces of the lung, we developed a Finite-Difference Time Domain (FDTD) simulation. FDTD solves a discrete approximation to Maxwell's equations. Initial simulations have shown that structure up to 30 - 40μm below the surface is clearly visible. Deeper structures are hard to interpret, because of light scattering, compounded by speckle associated with coherent detection. Further simulations and experimental imaging may lead to improved collection and processing of images at deeper levels.

  13. Mooney-Rivlin biomechanical modeling of lung with Inhomogeneous material.

    PubMed

    Nasehi Tehrani, J; Wang, J

    2015-01-01

    In this study, the Mooney-Rivlin material with hyperelastic strain energy was proposed for biomechanical modeling of the lung. We modeled the lung as an inhomogeneous Mooney-Rivlin material with uncoupled deviatoric and volumetric behavior. The proposed method was evaluated on the lungs of eight lung cancer patients. For each patient, the lung was segmented from the 4D-CT images and tetrahedral volume mesh of the lung in phase 50% was created by using the adaptive mesh generation toolkit. The demons deformable registration algorithm was used to extract the displacement vector fields (DVFs). The Jacobian of the deformation gradient was calculated from DVFs, and the lung strain energy function was optimized to improve the tumor center of mass (TCM) motion simulation accuracy between respiratory phase 50% and 0%. The average TCM motion simulation error for the proposed strategy is 1.95 mm for eight patients. We observed 13% improvement in the TCM position prediction compared with the homogeneous Mooney-Rivlin modeling.

  14. Macrophage-specific RAM11 monoclonal antibody cross-reacts with basal cells of stratified squamous epithelia.

    PubMed

    Lis, Grzegorz J; Litwin, Jan A; Furgal-Borzych, Alicja; Zarzecka, Joanna; Cichocki, Tadeusz

    2007-01-01

    RAM11 is a mouse monoclonal anti-rabbit macrophage antibody recognizing connective tissue and vascular (atheromatous tissue) macrophages. This study demonstrates a cross-reaction of RAM11 with an unknown antigen in rabbit normal epithelial cells. Formalin-fixed, paraffin sections of the New Zealand White rabbit normal skin, oral mucosa, esophagus, small intestine and lung were immunostained with RAM11 antibody followed by goat anti-mouse Cy-3-conjugated antiglobulin. RAM11-positive immunofluorescence was observed in basal layer cells of stratified squamous epithelia (skin, oral mucosa, esophagus). No RAM11 immunostaining was found in any cells of simple (intestinal, bronchial) epithelia. These findings show that basal cells of stratified squamous keratinized and non-keratinized epithelia of the rabbit express an antigenic epitope which is common with that of macrophage antigen recognized by RAM11 monoclonal antibody.

  15. 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.

  16. Hematopoietic lineage skewing and intestinal epithelia degeneration in aged mice with telomerase RNA component deletion

    PubMed Central

    Chen, Jichun; Bryant, Mark A.; Dent, James J.; Sun, Yu; Desierto, Marie J.; Young, Neal S.

    2015-01-01

    A deletion of telomerase RNA component (Terc−/−) in C57BL/6 (B6) mice resulted in hematopoietic lineage skewing with increased neutrophils and CD11b+ myeloid cells and decreased red blood cells and CD45R+ B lymphocytes when animals reach ages older than 12 months. There was no decline in bone marrow (BM) c-Kit+Sca-1+Lin− (KSL) cells in old Terc−/− mice, and the lineage skewing phenomenon was not transferred when BM cells from old Terc−/− donors were transplanted into young B6 recipients. Necropsy and histological examinations found minimal to no change in the lung, spleen and liver but detected severe epithelia degeneration, ulceration and infection in small and large intestines, leading to enteritis, typhlitis and colitis in old Terc−/− mice. In a mouse model of dextran-sulfate-sodium-induced typhlitis and colitis, development of intestinal pathology was associated with increases in neutrophils and CD11b+ myeloid cells and a decrease in CD45R+ B cells, similar to those observed in old Terc−/− mice. Treatment of 11–13 month old Terc−/− mice with antibiotic trimethoprim-sulfa water reduced neutrophils and myeloid cells and increased B lymphocytes in the blood, indicating that mitigation of intestinal infection and inflammation could alleviate hematological abnormalities in old Terc−/− animals. PMID:26523501

  17. Hematopoietic lineage skewing and intestinal epithelia degeneration in aged mice with telomerase RNA component deletion.

    PubMed

    Chen, Jichun; Bryant, Mark A; Dent, James J; Sun, Yu; Desierto, Marie J; Young, Neal S

    2015-12-01

    A deletion of a telomerase RNA component (Terc(-/-)) in C57BL/6 (B6) mice resulted in hematopoietic lineage skewing with increased neutrophils and CD11b(+) myeloid cells and decreased red blood cells and CD45R(+) B lymphocytes when animals reach ages older than 12 months. There was no decline in bone marrow (BM) c-Kit(+)Sca-1(+)Lin(-) (KSL) cells in old Terc(-/-) mice, and the lineage skewing phenomenon was not transferred when BM cells from old Terc(-/-) donors were transplanted into young B6 recipients. Necropsy and histological examinations found minimal to no change in the lung, spleen and liver but detected severe epithelia degeneration, ulceration and infection in small and large intestines, leading to enteritis, typhlitis and colitis in old Terc(-/-) mice. In a mouse model of dextran-sulfate-sodium-induced typhlitis and colitis, development of intestinal pathology was associated with increases in neutrophils and CD11b(+) myeloid cells and a decrease in CD45R(+) B cells, similar to those observed in old Terc(-/-) mice. Treatment of 11-13 month old Terc(-/-) mice with antibiotic trimethoprim-sulfa water reduced neutrophils and myeloid cells and increased B lymphocytes in the blood, indicating that mitigation of intestinal infection and inflammation could alleviate hematological abnormalities in old Terc(-/-) animals.

  18. 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.

  19. 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

  20. 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.

  1. Human lung morphology models for particle deposition studies.

    PubMed

    Martonen, T B; Schroeter, J D; Hwang, D; Fleming, J S; Conway, J H

    2000-01-01

    Knowledge of human lung morphology is of paramount importance in calculating deposition patterns of inhaled particulate matter (PM) to be used in the definition of ambient air quality standards. Due to the inherently complex nature of the branching structure of the airway network, practical assumptions must be made for modeling purposes. The most commonly used mathematical models reported in the literature that describe PM deposition use Weibel's model A morphology. This assumes the airways of the lung to be a symmetric, dichotomously branching system. However, computer simulations of this model, when compared to scintigraphy images, have shown it to lack physiological realism (Martonen et al., 1994a). Therefore, a more physiologically realistic model of the lung is needed to improve the current PM dosimetry models. Herein, a morphological model is presented that is based on laboratory data from planar gamma camera and single-photon emission computed tomography (SPECT) images. Key elements of this model include: The parenchymal wall of the lung is defined in mathematical terms, the whole lung is divided into distinct left and right components, a set of branching angles is derived from experimental measurements, and the branching network is confined within the discrete left and right components (i.e., there is no overlapping of airways). In future work, this new, more physiologically realistic morphological model can be used to calculate PM deposition patterns for risk assessment protocols.

  2. Hypoxia in Models of Lung Cancer: Implications for Targeted Therapeutics

    PubMed Central

    Graves, Edward E.; Vilalta, Marta; Cecic, Ivana K.; Erler, Janine T.; Tran, Phuoc T.; Felsher, Dean; Sayles, Leanne; Sweet-Cordero, Alejandro; –Thu Le, Quynh; Giaccia, Amato J.

    2010-01-01

    Purpose In order to efficiently translate experimental methods from bench to bedside, it is imperative that laboratory models of cancer mimic human disease as closely as possible. In this study we sought to compare patterns of hypoxia in several standard and emerging mouse models of lung cancer in order to establish the appropriateness of each for evaluating the role of oxygen in lung cancer progression and therapeutic response. Experimental Design Subcutaneous and orthotopic human A549 lung carcinomas growing in nude mice as well as spontaneous K-ras or Myc-induced lung tumors grown in situ or subcutaneously were studied using fluorodeoxyglucose (FDG) and fluoroazomycin arabinoside (FAZA) positron emission tomography (PET), and post-mortem by immunohistochemical observation of the hypoxia marker pimonidazole. The response of these models to the hypoxia-activated cytotoxin PR-104 was also quantified by formation of γH2AX foci in vitro and in vivo. Finally, our findings were compared with oxygen electrode measurements of human lung cancers. Results Minimal FAZA and pimonidazole accumulation was seen in tumors growing within the lungs, while subcutaneous tumors showed substantial trapping of both hypoxia probes. These observations correlated with the response of these tumors to PR-104, and with the reduced incidence of hypoxia in human lung cancers relative to other solid tumor types. Conclusions These findings suggest that in situ models of lung cancer in mice may be more reflective of the human disease, and encourage judicious selection of preclinical tumor models for the study of hypoxia imaging and anti-hypoxic cell therapies. PMID:20858837

  3. Fluid transport phenomena in ocular epithelia.

    PubMed

    Candia, Oscar A; Alvarez, Lawrence J

    2008-03-01

    This article discusses three largely unrecognized aspects related to fluid movement in ocular tissues; namely, (a) the dynamic changes in water permeability observed in corneal and conjunctival epithelia under anisotonic conditions, (b) the indications that the fluid transport rate exhibited by the ciliary epithelium is insufficient to explain aqueous humor production, and (c) the evidence for fluid movement into and out of the lens during accommodation. We have studied each of these subjects in recent years and present an evaluation of our data within the context of the results of others who have also worked on electrolyte and fluid transport in ocular tissues. We propose that (1) the corneal and conjunctival epithelia, with apical aspects naturally exposed to variable tonicities, are capable of regulating their water permeabilities as part of the cell-volume regulatory process, (2) fluid may directly enter the anterior chamber of the eye across the anterior surface of the iris, thereby representing an additional entry pathway for aqueous humor production, and (3) changes in lens volume occur during accommodation, and such changes are best explained by a net influx and efflux of fluid.

  4. Mitotic indices of rat laryngeal epithelia.

    PubMed

    Lewis, D J

    1981-05-01

    The histology and mitotic indices of rat laryngeal epithelia were investigated. Five distinct types of epithelia were found: stratified squamous, squamoid (low squamous), respiratory and two cuboidal forms. Squamous epithelium was present mainly in the cranial portion of the larynx, whereas the respiratory type was mostly located in caudal regions. One type of cuboidal epithelium often formed intermediate zones between squamous and respiratory areas. Another form of cuboidal epithelium lined the ventral pouch, and the vocal folds were covered by a low squamous or squamoid type. The mitotic index for each type of epithelium was calculated using colchicine and was expressed as the percentage of total epithelial cells of that kind in mitosis. Mitotic indices for laryngeal epithelial types were: 5.6% in squamous epithelium; 2.4% in the squamoid epithelium of the vocal folds; 2.2% in the cuboidal epithelium in the ventrolateral region; 1.5% in the cuboidal epithelium of the ventral pouch, and 0.6% in respiratory epithelium, although in isolated ciliated areas in the lower epiglottis it was considerably higher (2.6%). There were no significant differences between rats examined on different occasions.

  5. Mitotic indices of rat laryngeal epithelia.

    PubMed Central

    Lewis, D J

    1981-01-01

    The histology and mitotic indices of rat laryngeal epithelia were investigated. Five distinct types of epithelia were found: stratified squamous, squamoid (low squamous), respiratory and two cuboidal forms. Squamous epithelium was present mainly in the cranial portion of the larynx, whereas the respiratory type was mostly located in caudal regions. One type of cuboidal epithelium often formed intermediate zones between squamous and respiratory areas. Another form of cuboidal epithelium lined the ventral pouch, and the vocal folds were covered by a low squamous or squamoid type. The mitotic index for each type of epithelium was calculated using colchicine and was expressed as the percentage of total epithelial cells of that kind in mitosis. Mitotic indices for laryngeal epithelial types were: 5.6% in squamous epithelium; 2.4% in the squamoid epithelium of the vocal folds; 2.2% in the cuboidal epithelium in the ventrolateral region; 1.5% in the cuboidal epithelium of the ventral pouch, and 0.6% in respiratory epithelium, although in isolated ciliated areas in the lower epiglottis it was considerably higher (2.6%). There were no significant differences between rats examined on different occasions. Images Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 PMID:7298492

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

    PubMed

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

    2012-05-01

    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 (CF ΔF508CFTR, nasal surface) epithelial cells: depolarization of mitochondrial (mito) membrane potential (Δψ(mito)) 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 Ca(2+) and ER-targeted GFP and oxidized contents into the cytosol). Effects began within 5 min and were complete in 1-2 h. 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 Δψ(mito) 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 Δψ(mito) and increases in Ca(cyto) 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. © 2012 Blackwell Publishing Ltd.

  7. 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

  8. Lessons from a canine model of compensatory lung growth.

    PubMed

    Hsia, Connie C W

    2004-01-01

    For over a century, canines have been used to study adaptation to surgical lung resection or pneumonectomy (PNX) that results in a quantifiable and reproducible loss of lung units. As reviewed by Schilling (1965), the first successful experimental pneumonectomies were performed in dogs and rabbits in 1881. By the early 1920s, it was appreciated that dogs can function normally with one remaining lung that increases in volume to fill the thoracic cavity (Andrus, 1923; Heuer and Andrus, 1922; Heuer and Dunn, 1920); these pioneering observations paved the way for surgeons to perform major lung resection in patients. Reports in the 1950s (Schilling et al., 1956) detail surprisingly well-preserved work performance in dogs following staged resection of up to 70% of lung mass. Since then, the bulk of the literature on post-PNX adaptation has shifted to rodents, especially for defining molecular mediators of compensatory lung growth. Because rodents are smaller and easier to handle, more animals can be studied over a shorter duration, resulting in time and cost savings. On the other hand, key aspects of lung anatomy, development, and time course of response in the rodent do not mimic those in the human subject, and few rodent studies have related structural adaptation to functional consequences. In larger mammals, anatomical lung development more closely resembles that in humans, and physiological function can be readily measured. Because dogs are natural athletes, functional limits of compensation can be characterized relatively easily by stressing oxygen transport at peak exercise. Thus, the canine model remains useful for relating structure to function, defining sources and limits of adaptation as well as evaluating therapeutic manipulation. This chapter summarizes key concepts of compensatory lung growth that have been consolidated from canine studies: (i) structure-function relationships during adaptation, (ii) dysanaptic (unequal) nature of compensation, and (iii

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

    PubMed Central

    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

  10. 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

  11. 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; pFEV1 = 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.

  12. A lung dosimetry model of vapor uptake and tissue disposition.

    PubMed

    Asgharian, B; Price, O T; Schroeter, J D; Kimbell, J S; Singal, M

    2012-02-01

    Inhaled vapors may be absorbed at the alveolar-capillary membrane and enter arterial blood flow to be carried to other organs of the body. Thus, the biological effects of inhaled vapors depend on vapor uptake in the lung and distribution to the rest of the body. A mechanistic model of vapor uptake in the human lung and surrounding tissues was developed for soluble and reactive vapors during a single breath. Lung uptake and tissue disposition of inhaled formaldehyde, acrolein, and acetaldehyde were simulated for different solubilities and reactivities. Formaldehyde, a highly reactive and soluble vapor, was estimated to be taken up by the tissues in the upper tracheobronchial airways with shallow penetration into the lung. Vapors with moderate solubility such as acrolein and acetaldehyde were estimated to penetrate deeper into the lung, reaching the alveolar region where absorbed vapors had a much higher probability of passing through the thin alveolar-capillary membrane to reach the blood. For all vapors, tissue concentration reached its maximum at the end of inhalation at the air-tissue interface. The depth of peak concentration moved within the tissue layer due to vapor desorption during exhalation. The proposed vapor uptake model offers a mechanistic approach for calculations of lung vapor uptake, air:tissue flux, and tissue concentration profiles within the respiratory tract that can be correlated to local biological response in the lung. In addition, the uptake model provides the necessary input for pharmacokinetic models of inhaled chemicals in the body, thus reducing the need for estimating requisite parameters.

  13. Alterations of lung microbiota in a mouse model of LPS-induced lung injury

    PubMed Central

    Meng, Fanyong; Meliton, Angelo; Afonyushkin, Taras; Ulanov, Alexander; Semenyuk, Ekaterina; Latif, Omar; Tesic, Vera; Birukova, Anna A.; Birukov, Konstantin G.

    2015-01-01

    Acute lung injury (ALI) and the more severe acute respiratory distress syndrome are common responses to a variety of infectious and noninfectious insults. We used a mouse model of ALI induced by intratracheal administration of sterile bacterial wall lipopolysaccharide (LPS) to investigate the changes in innate lung microbiota and study microbial community reaction to lung inflammation and barrier dysfunction induced by endotoxin insult. One group of C57BL/6J mice received LPS via intratracheal injection (n = 6), and another received sterile water (n = 7). Bronchoalveolar lavage (BAL) was performed at 72 h after treatment. Bacterial DNA was extracted and used for qPCR and 16S rRNA gene-tag (V3–V4) sequencing (Illumina). The bacterial load in BAL from ALI mice was increased fivefold (P = 0.03). The community complexity remained unchanged (Simpson index, P = 0.7); the Shannon diversity index indicated the increase of community evenness in response to ALI (P = 0.07). Principal coordinate analysis and analysis of similarity (ANOSIM) test (P = 0.005) revealed a significant difference between microbiota of control and ALI groups. Bacteria from families Xanthomonadaceae and Brucellaceae increased their abundance in the ALI group as determined by Metastats test (P < 0.02). In concordance with the 16s-tag data, Stenotrohomonas maltophilia (Xanthomonadaceae) and Ochrobactrum anthropi (Brucellaceae) were isolated from lungs of mice from both groups. Metabolic profiling of BAL detected the presence of bacterial substrates suitable for both isolates. Additionally, microbiota from LPS-treated mice intensified IL-6-induced lung inflammation in naive mice. We conclude that the morbid transformation of ALI microbiota was attributed to the set of inborn opportunistic pathogens thriving in the environment of inflamed lung, rather than the external infectious agents. PMID:25957290

  14. Alterations of lung microbiota in a mouse model of LPS-induced lung injury.

    PubMed

    Poroyko, Valeriy; Meng, Fanyong; Meliton, Angelo; Afonyushkin, Taras; Ulanov, Alexander; Semenyuk, Ekaterina; Latif, Omar; Tesic, Vera; Birukova, Anna A; Birukov, Konstantin G

    2015-07-01

    Acute lung injury (ALI) and the more severe acute respiratory distress syndrome are common responses to a variety of infectious and noninfectious insults. We used a mouse model of ALI induced by intratracheal administration of sterile bacterial wall lipopolysaccharide (LPS) to investigate the changes in innate lung microbiota and study microbial community reaction to lung inflammation and barrier dysfunction induced by endotoxin insult. One group of C57BL/6J mice received LPS via intratracheal injection (n = 6), and another received sterile water (n = 7). Bronchoalveolar lavage (BAL) was performed at 72 h after treatment. Bacterial DNA was extracted and used for qPCR and 16S rRNA gene-tag (V3-V4) sequencing (Illumina). The bacterial load in BAL from ALI mice was increased fivefold (P = 0.03). The community complexity remained unchanged (Simpson index, P = 0.7); the Shannon diversity index indicated the increase of community evenness in response to ALI (P = 0.07). Principal coordinate analysis and analysis of similarity (ANOSIM) test (P = 0.005) revealed a significant difference between microbiota of control and ALI groups. Bacteria from families Xanthomonadaceae and Brucellaceae increased their abundance in the ALI group as determined by Metastats test (P < 0.02). In concordance with the 16s-tag data, Stenotrohomonas maltophilia (Xanthomonadaceae) and Ochrobactrum anthropi (Brucellaceae) were isolated from lungs of mice from both groups. Metabolic profiling of BAL detected the presence of bacterial substrates suitable for both isolates. Additionally, microbiota from LPS-treated mice intensified IL-6-induced lung inflammation in naive mice. We conclude that the morbid transformation of ALI microbiota was attributed to the set of inborn opportunistic pathogens thriving in the environment of inflamed lung, rather than the external infectious agents.

  15. Novel Effects of Azithromycin on Tight Junction Proteins in Human Airway Epithelia

    PubMed Central

    Asgrimsson, Valthor; Gudjonsson, Thorarinn; Gudmundsson, Gudmundur Hrafn; Baldursson, Olafur

    2006-01-01

    The macrolide antibiotic azithromycin improves lung function and prognosis among patients with cystic fibrosis or diffuse panbronchiolitis, independently of bacterial eradication. Anti-inflammatory effects have been implicated, but data from in vivo studies are scarce, and the link between abnormal electrolyte content in airway surface liquid and bronchial infections remains uncertain. In the present study, we treated human airway epithelia on filter supports with azithromycin and monitored transepithelial electrical resistance. We found that azithromycin increased transepithelial electrical resistance of airway epithelia in a dose-dependent manner. Immunocytochemistry and Western blotting showed that addition of azithromycin changed the locations of proteins in cell cultures and induced processing of the tight junction proteins claudin-1 and claudin-4, occludin, and junctional adhesion molecule-A. These effects were reversible, and no effect was seen when cells were treated with penicillin or erythromycin. The data indicate that azithromycin increases the transepithelial electrical resistance of human airway epithelia by changing the processing of tight junction proteins. The results are novel and may help explain the beneficial effects of azithromycin in patients with cystic fibrosis, diffuse panbronchiolitis, and community-acquired pneumonia. PMID:16641453

  16. A biomechanical model of pendelluft induced lung injury.

    PubMed

    Alzahrany, Mohammed; Banerjee, Arindam

    2015-07-16

    Lung ventilation using high frequency oscillatory techniques have been documented to attain adequate gas exchange through various gas transport mechanisms. Among them, the pendelluft flow is considered one of the most crucial mechanisms. In this work, we computationally investigate the induction of abnormal mechanical stresses and a regionally trapped volume of gas due to pendelluft flow. Large eddy simulation was used to model the turbulence in an upper tracheobronchial lung geometry that was derived from CT scans. The pendelluft flow was captured by modeling physiological boundary conditions at the truncated level of the lung model that is sensitive to the coupled resistance and compliance of individual patients. The flow-volume and volume-pressure loops are characterized by irregular shapes and suggest abnormal regional lung ventilation. Incomplete loops were observed indicating gas trapping in these regions signifying a potential for local injury due to incomplete ventilation from a residual volume build-up at the end of the expiration phase. In addition, the gas exchange between units was observed to create a velocity gradient causing a region of high wall shear stress surrounding the carina ridges. The recurrence of the pendelluft flow could cause a rupture to the lung epithelium layer. The trapped gas and wall shear stress were observed to amplify with increasing compliance asymmetry and ventilator operating frequency. In general, despite the significant contribution of the pendelluft flow to the gas exchange augmentation there exists significant risks of localized lung injury, phenomena we describe as pendelluft induced lung injury or PILI. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. A Mechanistic Model for Predicting Lung Inflammogenicity of Oxide Nanoparticles.

    PubMed

    Burello, Enrico

    2017-10-01

    This study presents a mechanistic model for identifying oxide nanoparticles that induce a high level of neutrophils in the bronchoalveolar lavage fluid, an important marker for lung inflammogenicity. The model is based on 4 nanoparticles' physicochemical properties, ie, the reactivity, surface charge, wettability, and dissolution. First, I calculate these properties and show that theoretical values reproduce acceptably the experimental measurements. Then, I combine these properties with mechanistic knowledge to build a classification model for the prediction of acute invivo lung inflammogenicity, measured as the total number of polymorphonuclear neutrophils. The model uses reactivity and dissolution properties of nanoparticles as toxicological initiating events, whereas surface charge and wettability are characteristics involved in the interactions between the nanoparticles and the lung surfactant, eventually leading to increased cellular uptake and bioaccumulation. The model is validated on a set of 43 oxide nanoparticles tested invivo to confirm that acute lung inflammation can be described using this mechanistic framework. In addition, I also develop a linear regression model for insoluble nanoparticles to quantitatively predict the polymorphonuclear neutrophil count as a function of reactivity and surface charge. The proposed models are based on mechanistic knowledge and can support the development of adverse outcome pathways, risk assessment frameworks and safe design strategies at early stages of material's R&D. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  18. Protein tyrosine phosphatase SHP2 regulates TGF-β1 production in airway epithelia and asthmatic airway remodeling in mice

    PubMed Central

    Qin, X.-J.; Zhang, G.-S.; Zhang, X.; Qiu, Z.-W.; Wang, P.-L.; Li, Y.-W.; Li, W.; Xie, Q.-M.; Ke, Y.-H.; Lee, J. J.; Shen, H.-H.

    2014-01-01

    Background Transforming growth factor (TGF)-β1 produced in airway epithelia has been suggested as a contributor to the airway remodeling observed in asthma patients. The protein tyrosine phosphatase SHP2 is a demonstrable modulator of TGF-β1 production and thus a potential regulator of airway remodeling. Objectives To define the signal event by which SHP2 regulates asthmatic responses in airway epithelial cells by using a mouse model of experimental OVA-induced airway remodeling. Methods The airways of Shp2flox/flox mice were infected with recombinant adenovirus vectors expressing a Cre recombinase–green fluorescence protein (GFP) fusion protein as part of allergen provocation studies using mice sensitized with ovalbumin (OVA) and repeatedly challenged with OVA. Several endpoint pathologies were assessed, including airway hyper-responsiveness (AHR), lung inflammatory score, peribronchial collagen deposition, and α-smooth muscle actin (SMA) hyperplasia. In vitro studies using airway epithelial cells (BEAS-2B) were used to investigate the role of SHP2 in the regulation of pulmonary remodeling events, including the expression of collagen, α-SMA, and TGF-β1. Results Chronic OVA challenges in wild-type mice resulted in airway remodeling and lung dysfunction (e.g., increased inflammatory scores, collagen deposition (fibrosis), smooth muscle hyperplasia, and a significant increase in AHR). These endpoint pathology metrics were each significantly attenuated by conditional shp2 gene knockdown in airway epithelia. In vitro studies using BEAS-2B cells also demonstrated that the level of TGF-β1 production by these cells correlated with the extent of shp2 gene expression. Conclusions SHP2 activities in airway epithelial cells appear to modulate TGF-β1 production and, in turn, regulate allergic airway remodeling following allergen provocation. Clinical Implications Our findings identify SHP2 as a previously underappreciated contributor to the airway remodeling and lung

  19. Animal models in carotenoids research and lung cancer prevention.

    PubMed

    Kim, Jina; Kim, Yuri

    2011-10-01

    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.

  20. 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.

  1. Interdependent regional lung emptying during forced expiration: a transistor model.

    PubMed

    Solway, J; Fredberg, J J; Ingram, R H; Pedersen, O F; Drazen, J M

    1987-05-01

    We recognized similarities between isovolume pressure-flow curves of the lung and emitter-collector voltage-current characteristics of bipolar transistors, and used this analogy to model expiratory flow limitation in a two-generation branching network with parallel nonhomogeneity. In this model, each of two bronchi empty parenchymal compliances through a common trachea, and each branch includes resistances upstream and downstream of a flow-limiting site. Properties of each airway are specified independently, allowing simulation of differences between the tracheal and bronchial generations and between the parallel bronchial paths. Simulations of four types of parallel asymmetry were performed: unilateral peripheral bronchoconstriction; unilateral central bronchoconstriction; asymmetric redistribution of parenchymal compliance; and unilateral alteration of the bronchial area-transmural pressure characteristic. Our results indicate that multiple axial choke points can exist simultaneously in a symmetric lung when large airway opening-pleural pressure gradients exist; despite severe nonhomogeneity of regional lung emptying, flow interdependence among parallel branches tends to maintain a near normal configuration of the overall maximal expiratory flow-volume (MEFV) curve throughout a large fraction of the vital capacity; and sudden changes of slope of the MEFV curve ("knees" or "bumps") may reflect choking in one branch in a nonuniform lung, but need not be obvious even when severe heterogeneity of lung emptying exists.

  2. Development of a three-dimensional model of lung cancer using cultured transformed lung cells.

    PubMed

    Vertrees, Roger A; McCarthy, Maureen; Solley, Travis; Popov, Vselovod L; Roaten, John; Pauley, Matthew; Wen, Xiaodong; Goodwin, Thomas J

    2009-02-01

    Despite great strides in understanding cancer biology, the role cellular differentiation and three-dimensional (3-D) structural organization play in metastasis and malignancy remains unclear. Development of 3-D cultures may ultimately provide a model facilitating discovery and interpretation of more relevant information for the expression and role of antibodies in lung cellular pathobiology. The purpose was to develop traditional monolayer (ML) and 3-D cultures of a known transformed metastatic lung cell line and then determine similarities and differences between cultures in terms of differentiation, molecular marker expression and metastasis. A transformed lung cell line (BZR-T33) was initially transfected with green fluorescent protein (GFP) in ML culture. Nude mice were inoculated with BZR-T33 and observed for metastasis. BZR-T33 was grown as ML and 3-D cultures under identical conditions. Immunohistochemical comparison for degree of antibody expression between cultures and control tissue were studied. Electron microscopy (EM) for identification of ultra structures was done and compared between cultures. A 3-D co-culture containing GFP-transformed cells over an immortalized lung-cell line was developed. The GFP-transfected cell line formed tumors and metastasized in mice. EM identified significant mitochondrial and granular endoplasmic reticular pathology in ML not seen in 3-D. Degree of differentiation shows ultra structures and antibody expressions were more representative of control tissue in 3-D than ML. The co-culture experiment in 3-D demonstrates the ability of transformed cells to penetrate the sub-layer of immortalized cells. Development of 3-D cultures will provide a new and powerful tool to study lung biology and pathobiology.

  3. 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.

  4. 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)

  5. 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)

  6. Using Clinical Risk Models for Lung Nodule Classification.

    PubMed

    Deppen, Stephen A; Grogan, Eric L

    2015-01-01

    Evaluation and diagnosis of indeterminate pulmonary nodules is a significant and increasing burden on our health care system. The advent of lung cancer screening with low-dose computed tomography only exacerbates this problem, and more surgeons will be evaluating smaller and screening discovered nodules. Multiple calculators exist that can help the clinician diagnose lung cancer at the bedside. The Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) model helps to determine who needs lung cancer screening, and the McWilliams and Mayo models help to guide the primary care clinician or pulmonologist with diagnosis by estimating the probability of cancer in patients with indeterminate pulmonary nodules. The Thoracic Research Evaluation And Treatment (TREAT) model assists surgeons to determine who needs a surgical biopsy among patients referred for suspicious lesions. Additional work is needed to develop decision support tools that will facilitate the use of these models in clinical practice, to complement the clinician's judgment and enhance shared decision making with the patient at the bedside.

  7. 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…

  8. 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…

  9. Radiation-enhanced lung cancer progression in a transgenic mouse model of lung cancer is predictive of outcomes in human lung and breast cancer.

    PubMed

    Delgado, Oliver; Batten, Kimberly G; Richardson, James A; Xie, Xian-Jin; Gazdar, Adi F; Kaisani, Aadil A; Girard, Luc; Behrens, Carmen; Suraokar, Milind; Fasciani, Gail; Wright, Woodring E; Story, Michael D; Wistuba, Ignacio I; Minna, John D; Shay, Jerry W

    2014-03-15

    Carcinogenesis is an adaptive process between nascent tumor cells and their microenvironment, including the modification of inflammatory responses from antitumorigenic to protumorigenic. Radiation exposure can stimulate inflammatory responses that inhibit or promote carcinogenesis. The purpose of this study is to determine the impact of radiation exposure on lung cancer progression in vivo and assess the relevance of this knowledge to human carcinogenesis. K-ras(LA1) mice were irradiated with various doses and dose regimens and then monitored until death. Microarray analyses were performed using Illumina BeadChips on whole lung tissue 70 days after irradiation with a fractionated or acute dose of radiation and compared with age-matched unirradiated controls. Unique group classifiers were derived by comparative genomic analysis of three experimental cohorts. Survival analyses were performed using principal component analysis and k-means clustering on three lung adenocarcinoma, three breast adenocarcinoma, and two lung squamous carcinoma annotated microarray datasets. Radiation exposure accelerates lung cancer progression in the K-ras(LA1) lung cancer mouse model with dose fractionation being more permissive for cancer progression. A nonrandom inflammatory signature associated with this progression was elicited from whole lung tissue containing only benign lesions and predicts human lung and breast cancer patient survival across multiple datasets. Immunohistochemical analyses suggest that tumor cells drive predictive signature. These results demonstrate that radiation exposure can cooperate with benign lesions in a transgenic model of cancer by affecting inflammatory pathways, and that clinically relevant similarities exist between human lung and breast carcinogenesis. ©2014 AACR.

  10. Modeling Nanoparticle Transport and Distribution in Lung Vasculature

    NASA Astrophysics Data System (ADS)

    Liu, Yaling; Zheng, Junda

    2013-11-01

    The nanoparticle targeted delivery in vascular system involves interplay of transport, hydrodynamic force, and multivalent interactions with targeted biosurfaces. To estimate the percentage of NPs delivered to the targeted region, properties of the vascular environment must be considered, i.e., the vascular geometry and flow conditions. This paper describes a computational model for NP transport and distribution in a complex lung vasculature through combined NP Brownian dynamics and computational fluid dynamics approaches. MRI sliced lung vasculature images are transferred into vascular geometry, discretized into tetrahedral meshes, and used in blood velocity calculation and particle deposition simulation. A non-uniform NP distribution is observed on the vascular surface, with a high NP concentration in the bifurcation region. The simulation results show that NPs with different size have different distribution pattern in lung vasculature. This study provides a tool to predict NP distribution in a complex vascular network.

  11. 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.

  12. Procedures for the preparation and culture of 'reconstructed' rainbow trout branchial epithelia.

    PubMed

    Kelly, S P; Fletcher, M; Pärt, P; Wood, C M

    2000-01-01

    Techniques for the in vitro 'reconstruction' of freshwater rainbow trout branchial epithelia using the primary culture of gill cells on permeable polyethylene terephthalate cell culture filter supports are described. Representing models of the freshwater fish gill, epithelia grown by two separate techniques are composed of branchial pavement cells with or without the inclusion of mitochondria-rich (MR) cells. The generation of epithelia consisting of pavement cells only (via a method called single seeded inserts = SSI) involves an initial period of flask culture during which time MR cells, that appear unable to attach to the culture flask base, are excluded from the general cell populace. Alternately, the generation of a heterogeneous epithelia consisting of both pavement cells and MR cells (via a method called double seeded inserts = DSI) is facilitated by the direct seeding of cells into cell culture filter inserts. Critical to this second procedure is the repeat seeding of filter inserts over a two day period. Repeat seeding appears to allow MR cells to nest amongst the attached cell layer generated by the first day's seeding. The use of cell culture filter supports allows free access to both the apical and basolateral compartment of the epithelium and is ideal for experimental manipulation. Cells are grown under symmetrical conditions (apical media/basolateral media) and epithelium growth is measured as a function of transepithelial resistance (TER). When the epithelia exhibit a plateau in growth they can be subjected to asymmetrical conditions (freshwater apical/media basolateral) in order to assess gill cell function as in vivo.

  13. Turing mechanism underlying a branching model for lung morphogenesis

    PubMed Central

    Sun, Mingzhu

    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. PMID:28376090

  14. Risk Prediction Models for Lung Cancer: A Systematic Review.

    PubMed

    Gray, Eoin P; Teare, M Dawn; Stevens, John; Archer, Rachel

    2016-03-01

    Many lung cancer risk prediction models have been published but there has been no systematic review or comprehensive assessment of these models to assess how they could be used in screening. We performed a systematic review of lung cancer prediction models and identified 31 articles that related to 25 distinct models, of which 11 considered epidemiological factors only and did not require a clinical input. Another 11 articles focused on models that required a clinical assessment such as a blood test or scan, and 8 articles considered the 2-stage clonal expansion model. More of the epidemiological models had been externally validated than the more recent clinical assessment models. There was varying discrimination, the ability of a model to distinguish between cases and controls, with an area under the curve between 0.57 and 0.879 and calibration, the model's ability to assign an accurate probability to an individual. In our review we found that further validation studies need to be considered; especially for the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial 2012 Model Version (PLCOM2012) and Hoggart models, which recorded the best overall performance. Future studies will need to focus on prediction rules, such as optimal risk thresholds, for models for selective screening trials. Only 3 validation studies considered prediction rules when validating the models and overall the models were validated using varied tests in distinct populations, which made direct comparisons difficult. To improve this, multiple models need to be tested on the same data set with considerations for sensitivity, specificity, model accuracy, and positive predictive values at the optimal risk thresholds. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Incorporation of adenovirus in calcium phosphate precipitates enhances gene transfer to airway epithelia in vitro and in vivo.

    PubMed Central

    Fasbender, A; Lee, J H; Walters, R W; Moninger, T O; Zabner, J; Welsh, M J

    1998-01-01

    Adenovirus (Ad)-mediated gene transfer to airway epithelia is inefficient because the apical membrane lacks the receptor activity to bind adenovirus fiber protein. Calcium phosphate (CaPi) precipitates have been used to deliver plasmid DNA to cultured cell lines. However, such precipitates are not effective in many primary cultures or in vivo. Here we show that incorporating recombinant adenovirus into a CaPi coprecipitate markedly enhances transgene expression in cells that are resistant to adenovirus infection. Enhancement requires that the virus be contained in the precipitate and viral proteins are required to increase expression. Ad: CaPi coprecipitates increase gene transfer by increasing fiber-independent binding of virus to cells. With differentiated cystic fibrosis (CF) airway epithelia in vitro, a 20-min application of Ad:CaPi coprecipitates that encode CF transmembrane conductance regulator produced as much CF transmembrane conductance regulator Cl- current as a 24-h application of adenovirus alone. We found that Ad:CaPi coprecipitates also increased transgene expression in mouse lung in vivo; importantly, expression was particularly prominent in airway epithelia. These results suggest a new mechanism for gene transfer that may be applicable to a number of different gene transfer applications and could be of value in gene transfer to CF airway epithelia in vivo. PMID:9649572

  16. Suppression of lung inflammation in an LPS-induced acute lung injury model by the fruit hull of Gleditsia sinensis.

    PubMed

    Kim, Kyun Ha; Kwun, Min Jung; Han, Chang Woo; Ha, Ki-Tae; Choi, Jun-Yong; Joo, Myungsoo

    2014-10-15

    The fruit hull of Gleditsia sinensis (FGS) used in traditional Asian medicine was reported to have a preventive effect on lung inflammation in an acute lung injury (ALI) mouse model. Here, we explored FGS as a possible therapeutics against inflammatory lung diseases including ALI, and examined an underlying mechanism for the effect of FGS. The decoction of FGS in water was prepared and fingerprinted. Mice received an intra-tracheal (i.t.) FGS 2 h after an intra-peritoneal (i.p.) injection of lipopolysaccharide (LPS). The effect of FGS on lung inflammation was determined by chest imaging of NF-κB reporter mice, counting inflammatory cells in bronchoalveolar lavage fluid, analyzing lung histology, and performing semi-quantitative RT-PCR analysis of lung tissue. Impact of Nrf2 on FGS effect was assessed by comparing Nrf2 knockout (KO) and wild type (WT) mice that were treated similarly. Bioluminescence from the chest of the reporter mice was progressively increased to a peak at 16 h after an i.p. LPS treatment. FGS treatment 2 h after LPS reduced the bioluminescence and the expression of pro-inflammatory cytokine genes in the lung. While suppressing the infiltration of inflammatory cells to the lungs of WT mice, FGS post-treatment failed to reduce lung inflammation in Nrf2 KO mice. FGS activated Nrf2 and induced Nrf2-dependent gene expression in mouse lung. FGS post-treatment suppressed lung inflammation in an LPS-induced ALI mouse model, which was mediated at least in part by Nrf2. Our results suggest a therapeutic potential of FGS on inflammatory lung diseases.

  17. The mechanical behavior of a mammalian lung alveolar duct model.

    PubMed

    Denny, E; Schroter, R C

    1995-08-01

    A model for the mechanical properties of an alveolar duct is analyzed using the finite element method. Its geometry comprises an assemblage of truncated octahedral alveoli surrounding a longitudinal air duct. The amounts and distributions of elastin and collagen fiber bundles, modeled by separate stress-strain laws, are based upon published data for dogs. The surface tension of the air-liquid interface is modeled using an area-dependent relationship. Pressure-volume curves are computed that compare well with experimental data for both saline-filled and air-filled lungs. Pressure-volume curves of the separate elastin and collagen fiber contributions are similar in form to the behavior of saline-filled lungs treated with either elastase or collagenase. A comparison with our earlier model, based upon a single alveolus, shows the duct to have a behavior closer to reported experimental data.

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

    PubMed

    Burrowes, Kelly Suzanne; Doel, Tom; Brightling, Chris

    2014-11-28

    Asthma and chronic obstructive pulmonary disease (COPD) are characterized by airway obstruction and airflow imitation 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 currentstate

  19. Postnatal development of lung T lymphocytes in a porcine model.

    PubMed

    Balam-May, Angel J; Ramírez-Estudillo, Carmen; Lazo-Vázquez, Gloria; Vega-López, Marco A

    2014-10-01

    Despite the high prevalence of respiratory diseases in the world and the extensive information available on the mucosal immune system, research on the development of the lung immune system in humans is limited by technical and ethical considerations; therefore, we studied the postnatal development of T lymphocytes in lung lobes in a porcine model. Using less than 36-hour-old (NB), 1-week-weaned (5-week-old -AW-), 3-month-old (3M), and 4-year-old (4YR) healthy, nonvaccinated, specific pathogen free (SPF) Vietnamese miniature pigs, we studied the CD3+, CD4+, CD8+, TCR1 (gamma-delta T cells), and CD25+ (IL-2R-alpha) cell subpopulations in lung lobes parenchyma, bronchoalveolar lavage (BAL), peripheral blood mononuclear cells (PBMC), and cervical lymph nodes (LN) by flow cytometry. No differences among lung lobes were detected in any of the cell subpopulations tested. A low proportion of T cell subsets was detected in NB and 4YR groups in lung and BAL. Besides, the AW and 3M groups showed important changes in T cell subpopulations. These results suggest that in healthy animals the lung lobes behave as a homogeneous immune organ. T cells were detected in very low percentages at birth and in adult life, which may explain the high susceptibility to respiratory infections both early and later in life. Postweaning antigenic challenges and endocrine and sexual maturity at 3M had important effects on the development of the mucosal immune system. It was also evident that changes at mucosal sites were poorly correlated with PBMC and LN.

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

    PubMed Central

    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

    2014-01-01

    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 137Cs gamma rays, protons (acute, low-dose exposure mimicking the 1972 SPE), 600 MeV/u 56Fe ions, or 350 MeV/u 28Si 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 56Fe or 28Si 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. PMID:25526737

  1. 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.

  2. 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

  3. A comparative study of aerosol deposition in different lung models.

    PubMed

    Yu, C P; Diu, C K

    1982-01-01

    Theoretical calculations are made on total and regional deposition of inhaled particles in the human respiratory system based upon various current lung models. It is found that although total deposition does not vary appreciably from model to model, considerably large differences are present in regional deposition. Deposition profiles along the airways from different models also show very different patterns. These differences can be explained in terms of airway dimensions and the number of structures in different models. Extension to explain intersubject variability is also made.

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

    PubMed

    Pozin, N; Montesantos, S; Katz, I; Pichelin, M; Vignon-Clementel, I; Grandmont, C

    2017-02-22

    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 tracheo-bronchial 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 CT scans are considered. Realistic Dirichlet boundary conditions can be deduced from surface registration on CT 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.

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. Validation of the conceptual anatomical model of the lung airway.

    PubMed

    Fleming, John S; Sauret, Veronique; Conway, Joy H; Martonen, Ted B

    2004-01-01

    The conceptual anatomical model of the lung airway considers each lung volume divided into ten concentric shells. It specifies the volume of each airway generation in each shell, using Weibel morphometry. This study updates and validates the model and evaluates the errors obtained when using it to estimate inhaled aerosol deposition per generation from spatial imaging data. A comparison of different airway models describing the volume per generation, including data from CT images of a lung cast and a human subject, was performed. A revised version of the conceptual model was created, using the average volume per generation from these data. The new model was applied to derive the aerosol deposition per generation from 24 single photon emission computed tomography (SPECT) studies. Analysis errors were assessed by applying the same calculations but using airway models based on the minimum and maximum volumes per generation. The mean shell position of each generation in the average model was not significantly different from either CT model. However there were differences between the volumes per generation of the different models. The root mean square differences between bronchial airways deposition fraction (generations 2-8) obtained from the maximum and minimum models compared to the new average model was 0.66 percentage points (14%). For the conducting airways deposition fraction (generations 2-15) this was 1.66 percentage points (12%). The conceptual model is consistent with CT measurements of airway geometry. The errors resulting from using a generic airway model to interpret 3D radionuclide image data have been defined.

  10. Experimental Models of Transfusion-Related Acute Lung Injury (TRALI)

    PubMed Central

    Gilliss, Brian M.; Looney, Mark R.

    2010-01-01

    Transfusion-related acute lung injury (TRALI) is defined clinically as acute lung injury occurring within six hours of the transfusion of any blood product. It is the leading cause of transfusion-related death in the United States, but under-recognition and diagnostic uncertainty have limited clinical research to smaller case control studies. In this review we will discuss the contribution of experimental models to the understanding of TRALI pathophysiology and potential therapeutic approaches. Experimental models suggest that TRALI occurs when a host, with a primed immune system, is exposed to an activating agent such as anti-leukocyte antibody or a biologic response modifier such as lysophosphatidylcholines. Recent work has suggested a critical role for platelets in antibody-based experimental models and identified potential therapeutic strategies for TRALI. PMID:21134622

  11. A novel SCID mouse model for studying spontaneous metastasis of human lung cancer to human tissue.

    PubMed

    Teraoka, S; Kyoizumi, S; Seyama, T; Yamakido, M; Akiyama, M

    1995-05-01

    We established a novel severe combined immunodeficient (SCID) mouse model for the study of human lung cancer metastasis to human lung. Implantation of both human fetal and adult lung tissue into mammary fat pads of SCID mice showed a 100% rate of engraftment, but only fetal lung implants revealed normal morphology of human lung tissue. Using these chimeric mice, we analyzed human lung cancer metastasis to both mouse and human lungs by subcutaneous inoculation of human squamous cell carcinoma and adenocarcinoma cell lines into the mice. In 60 to 70% of SCID mice injected with human-lung squamous-cell carcinoma, RERF-LC-AI, cancer cells were found to have metastasized to both mouse lungs and human fetal lung implants but not to human adult lung implants 80 days after cancer inoculation. Furthermore, human-lung adenocarcinoma cells, RERF-LC-KJ, metastasized to the human lung implants within 90 days in about 40% of SCID mice, whereas there were no metastases to the lungs of the mice. These results demonstrate the potential of this model for the in vivo study of human lung cancer metastasis.

  12. Computational and bioengineered lungs as alternatives to whole animal, isolated organ, and cell-based lung models.

    PubMed

    Patel, Brijeshkumar; Gauvin, Robert; Absar, Shahriar; Gupta, Vivek; Gupta, Nilesh; Nahar, Kamrun; Khademhosseini, Ali; Ahsan, Fakhrul

    2012-11-01

    Development of lung models for testing a drug substance or delivery system has been an intensive area of research. However, a model that mimics physiological and anatomical features of human lungs is yet to be established. Although in vitro lung models, developed and fine-tuned over the past few decades, were instrumental for the development of many commercially available drugs, they are suboptimal in reproducing the physiological microenvironment and complex anatomy of human lungs. Similarly, intersubject variability and high costs have been major limitations of using animals in the development and discovery of drugs used in the treatment of respiratory disorders. To address the complexity and limitations associated with in vivo and in vitro models, attempts have been made to develop in silico and tissue-engineered lung models that allow incorporation of various mechanical and biological factors that are otherwise difficult to reproduce in conventional cell or organ-based systems. The in silico models utilize the information obtained from in vitro and in vivo models and apply computational algorithms to incorporate multiple physiological parameters that can affect drug deposition, distribution, and disposition upon administration via the lungs. Bioengineered lungs, on the other hand, exhibit significant promise due to recent advances in stem or progenitor cell technologies. However, bioengineered approaches have met with limited success in terms of development of various components of the human respiratory system. In this review, we summarize the approaches used and advancements made toward the development of in silico and tissue-engineered lung models and discuss potential challenges associated with the development and efficacy of these models.

  13. Analytical modelling of regional radiotherapy dose response of lung

    NASA Astrophysics Data System (ADS)

    Lee, Sangkyu; Stroian, Gabriela; Kopek, Neil; AlBahhar, Mahmood; Seuntjens, Jan; El Naqa, Issam

    2012-06-01

    Knowledge of the dose-response of radiation-induced lung disease (RILD) is necessary for optimization of radiotherapy (RT) treatment plans involving thoracic cavity irradiation. This study models the time-dependent relationship between local radiation dose and post-treatment lung tissue damage measured by computed tomography (CT) imaging. Fifty-eight follow-up diagnostic CT scans from 21 non-small-cell lung cancer patients were examined. The extent of RILD was segmented on the follow-up CT images based on the increase of physical density relative to the pre-treatment CT image. The segmented RILD was locally correlated with dose distribution calculated by analytical anisotropic algorithm and the Monte Carlo method to generate the corresponding dose-response curves. The Lyman-Kutcher-Burman (LKB) model was fit to the dose-response curves at six post-RT time periods, and temporal change in the LKB parameters was recorded. In this study, we observed significant correlation between the probability of lung tissue damage and the local dose for 96% of the follow-up studies. Dose-injury correlation at the first three months after RT was significantly different from later follow-up periods in terms of steepness and threshold dose as estimated from the LKB model. Dependence of dose response on superior-inferior tumour position was also observed. The time-dependent analytical modelling of RILD might provide better understanding of the long-term behaviour of the disease and could potentially be applied to improve inverse treatment planning optimization.

  14. Basolateral Cl- uptake mechanisms in Xenopus laevis lung epithelium.

    PubMed

    Berger, Jens; Hardt, Martin; Clauss, Wolfgang G; Fronius, Martin

    2010-07-01

    A thin liquid layer covers the lungs of air-breathing vertebrates. Active ion transport processes via the pulmonary epithelial cells regulate the maintenance of this layer. This study focuses on basolateral Cl(-) uptake mechanisms in native lungs of Xenopus laevis and the involvement of the Na(+)/K(+)/2 Cl(-) cotransporter (NKCC) and HCO(3)(-)/Cl(-) anion exchanger (AE), in particular. Western blot analysis and immunofluorescence staining revealed the expression of the NKCC protein in the Xenopus lung. Ussing chamber experiments demonstrated that the NKCC inhibitors (bumetanide and furosemide) were ineffective at blocking the cotransporter under basal conditions, as well as under pharmacologically stimulated Cl(-)-secreting conditions (forskolin and chlorzoxazone application). However, functional evidence for the NKCC was detected by generating a transepithelial Cl(-) gradient. Further, we were interested in the involvement of the HCO(3)(-)/Cl(-) anion exchanger to transepithelial ion transport processes. Basolateral application of DIDS, an inhibitor of the AE, resulted in a significantly decreased the short-circuit current (I(SC)). The effect of DIDS was diminished by acetazolamide and reduced by increased external HCO(3)(-) concentrations. Cl(-) secretion induced by forskolin was decreased by DIDS, but this effect was abolished in the presence of HCO(3)(-). These experiments indicate that the AE at least partially contributes to Cl(-) secretion. Taken together, our data show that in Xenopus lung epithelia, the AE, rather than the NKCC, is involved in basolateral Cl(-) uptake, which contrasts with the common model for Cl(-) secretion in pulmonary epithelia.

  15. Modeling the risk of radiation-induced lung fibrosis: Irradiated heart tissue is as important as irradiated lung.

    PubMed

    Cella, Laura; D'Avino, Vittoria; Palma, Giuseppe; Conson, Manuel; Liuzzi, Raffaele; Picardi, Marco; Pressello, Maria Cristina; Boboc, Genoveva Ionela; Battistini, Roberta; Donato, Vittorio; Pacelli, Roberto

    2015-10-01

    We used normal tissue complication probability (NTCP) modeling to explore the impact of heart irradiation on radiation-induced lung fibrosis (RILF). We retrospectively reviewed for RILF 148 consecutive Hodgkin lymphoma (HL) patients treated with sequential chemo-radiotherapy (CHT-RT). Left, right, total lung and heart dose-volume and dose-mass parameters along with clinical, disease and treatment-related characteristics were analyzed. NTCP modeling by multivariate logistic regression analysis using bootstrapping was performed. Models were evaluated by Spearman Rs coefficient and ROC area. At a median time of 13months, 18 out of 115 analyzable patients (15.6%) developed RILF after treatment. A three-variable predictive model resulted to be optimal for RILF. The two models most frequently selected by bootstrap included increasing age and mass of heart receiving >30Gy as common predictors, in combination with left lung V5 (Rs=0.35, AUC=0.78), or alternatively, the lungs near maximum dose D2% (Rs=0.38, AUC=0.80). CHT-RT may cause lung injury in a small, but significant fraction of HL patients. Our results suggest that aging along with both heart and lung irradiation plays a fundamental role in the risk of developing RILF. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. A Computational Model of Cellular Engraftment on Lung Scaffolds

    PubMed Central

    Pothen, Joshua J.; Rajendran, Vignesh; Wagner, Darcy; Weiss, Daniel J.; Smith, Bradford J.; Ma, Baoshun; Bates, Jason H.T.

    2016-01-01

    Abstract The possibility that stem cells might be used to regenerate tissue is now being investigated for a variety of organs, but these investigations are still essentially exploratory and have few predictive tools available to guide experimentation. We propose, in this study, that the field of lung tissue regeneration might be better served by predictive tools that treat stem cells as agents that obey certain rules of behavior governed by both their phenotype and their environment. Sufficient knowledge of these rules of behavior would then, in principle, allow lung tissue development to be simulated computationally. Toward this end, we developed a simple agent-based computational model to simulate geographic patterns of cells seeded onto a lung scaffold. Comparison of the simulated patterns to those observed experimentally supports the hypothesis that mesenchymal stem cells proliferate preferentially toward the scaffold boundary, whereas alveolar epithelial cells do not. This demonstrates that a computational model of this type has the potential to assist in the discovery of rules of cellular behavior. PMID:27843709

  17. Observations on a model of proliferative lung disease

    PubMed Central

    Strauss, B.; Caldwell, P. R. B.; Fritts, H. W.

    1970-01-01

    Intravenous injections of complete Freund's adjuvant, used by others to stimulate the reticuloendothelial system of small laboratory animals, produced granulomas resembling sarcoid in the lung of the dog. At the height of the disease, when granulomas occupied more than half of the alveolar tissues, transpulmonary arteriovenous (A-[unk]V) differences of lactate, pyruvate, and glucose were measured. When the diseased dogs breathed room air, the A-[unk]V differences of lactate and pyruvate were greater than normal; and when the dogs breathed an hypoxic mixture, the differences increased further. Hence the model affords the opportunity for studying the in vivo metabolism of diseased lungs. It may also prove useful for studying other aspects of granulomatous disease which cannot be easily approached in man. PMID:5432367

  18. Surface tension and the dodecahedron model for lung elasticity.

    PubMed

    Kimmel, E; Budiansky, B

    1990-05-01

    Macroscopic elastic moduli governing the incremental deformations of lung parenchyma are calculated on the basis of a model for an individual lung element in the shape of a regular dodecahedron. Elastic stiffness within the element is provided by pin-jointed tension members along the edges of the dodecahedron, surface tension is incorporated into its pentagonal faces, and the influence of transpulmonary pressure is simulated by an externally applied hydrostatic tension. The analysis is based on a variational statement of nonlinear structural mechanics, and the results show how the moduli depend on the effective inflation pressure, the constitutive behavior of the idealized truss members, and the surface-area dependent surface tension. The theory is discussed in the light of available experimental information. A more general analysis is needed to account for the effects of structural as well as surface-tension hysteresis.

  19. Vortical Structures in CT-based Breathing Lung Models

    NASA Astrophysics Data System (ADS)

    Choi, Jiwoong; Lee, Changhyun; Hoffman, Eric; Lin, Ching-Long

    2016-11-01

    The 1D-3D coupled computational fluid dynamics (CFD) lung model is applied to study vortical structures in the human airways during normal breathing cycles. During inhalation, small vortical structures form around the turbulent laryngeal jet and Taylor-Gőrtler-like vortices form near the curved walls in the supraglottal region and at airway bifurcations. On exhalation elongated vortical tubes are formed in the left main bronchus, whereas a relatively slower stream is observed in the right main bronchus. These structures result in helical motions in the trachea, producing long lasting high wall shear stress on the wall. The current study elucidates that the correct employment of image-based airway deformation and lung deflation information is crucial for capturing the physiologically consistent regional airflow structures. The pathophysiological implications of these structures in destruction of tracheal wall will be discussed.

  20. Radiation-enhanced Lung Cancer Progression in a Transgenic Mouse Model of Lung Cancer is Predictive of Outcomes in Human Lung and Breast Cancer

    PubMed Central

    Delgado, Oliver; Batten, Kimberly G.; Richardson, James A.; Xie, Xian-Jin; Gazdar, Adi F.; Kaisani, Aadil A.; Girard, Luc; Behrens, Carmen; Suraokar, Milind; Fasciani, Gail; Wright, Woodring E.; Story, Michael D.; Wistuba, Ignacio I.; Minna, John D.; Shay, Jerry W.

    2014-01-01

    Purpose Carcinogenesis is an adaptive process between nascent tumor cells and their microenvironment including the modification of inflammatory responses from anti-tumorigenic to pro-tumorigenic. Radiation exposure can stimulate inflammatory responses that inhibit or promote carcinogenesis. The purpose of this study is to determine the impact of radiation exposure on lung cancer progression in vivo and assess the relevance of this knowledge to human carcinogenesis. Experimental Design K-rasLA1 mice were irradiated with various doses and dose regimens and then monitored till death. Microarray analyses were performed using Illumina® BeadChips on whole lung tissue 70 days post-irradiation with a fractionated or acute dose of radiation and compared to age-matched unirradiated controls. Unique group classifiers were derived by comparative genomic analysis of three experimental cohorts. Survival analyses were performed using principal component analysis and k-means clustering on three lung adenocarcinoma, three breast adenocarcinoma, and two lung squamous carcinoma annotated microarray datasets. Results Radiation exposure accelerates lung cancer progression in the K-rasLA1 lung cancer mouse model with dose fractionation being more permissive for cancer progression. A non-random inflammatory signature associated with this progression was elicited from whole lung tissue containing only benign lesions and predicts human lung and breast cancer patient survival across multiple datasets. Immunohistochemical analyses suggest that tumor cells drive predictive signature. Conclusions These results demonstrate that radiation exposure can cooperate with benign lesions in a transgenic model of cancer by impacting inflammatory pathways, and that clinically relevant similarities exist between human lung and breast carcinogenesis. PMID:24486591

  1. Morphological impact of zinc oxide particles on the antibacterial activity and human epithelia toxicity.

    PubMed

    Čepin, Marjeta; Hribar, Gorazd; Caserman, Simon; Orel, Zorica Crnjak

    2015-01-01

    ZnO nanoparticles are utilized in an ever growing number of products and can, therefore, be readily encountered in our everyday life. Human beings' outermost tissues consist of different epithelia and are, therefore, the most exposed to materials from the environment. In this paper, Caco-2 and Calu-3 cell lines were used, having been previously broadly applied for in vitro modelling of intestinal and respiratory epithelia, respectively. The toxicity of synthesized micro-, submicro- and nanoparticulate ZnO on these epithelia was measured and compared to the efficacy of the same ZnO particles as antibacterial agents. An approximately four-fold excess in antibacterial activity of ZnO nanoparticles over ZnO granulate was observed. The results of this paper reveal a sharp distinction between toxic nanoparticulate ZnO and safe ZnO particles of larger sizes in intestinal and airway in vitro epithelial models. In contrast, ZnO of larger particle sizes had only modestly lower antibacterial activity, which can be compensated for with higher dosing. These results show that nanoparticulate ZnO requires critical in vivo assessment before application. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Ion-secreting epithelia: chloride cells in the head region of Fundulus heteroclitus.

    PubMed

    Karnaky, K J

    1980-03-01

    Transporting cells of ion-secreting epithelia are characterized by similar morphological patterns that include rich supplies of mitochondria, exotic patterns of surface amplification, and basolateral, plasma-membrane location of Na-K-ATPase, even though the direction of sodium transport across these epithelia is toward the apical side. Several new models for NaCl secretion propose that sodium, extruded into the intercellular space by Na-K-ATPase, reaches the apical side via the zonulae occludentes. Very recent freeze-fracture electron microscopy of avian salt gland and teleost chloride cells reveals that transporting cells are joined by simple, shallow zonulae occludentes. These observations lend morphological support to the concept that paracellular sodium ion permeation plays a central role in secretion. The chloride ion may traverse the epithelium via a transcellular route, entering the cell at the basolateral membrane by a chloride carrier linked to the cotransport of sodium down its electrochemical gradient into the cell. Finally, the chloride ion may exit the cell across the apical membrane by electrical forces. This review summarizes biochemical, morphological, and electrophysiological aspects of these new secretory models and the important contribution of a half century of research on teleost osmoregulatory mechanisms, including the chloride cell, to our understanding of sodium and chloride transport across secretory epithelia.

  3. Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture

    PubMed Central

    Koehler, Karl R.; Mikosz, Andrew M.; Molosh, Andrei I.; Patel, Dharmeshkumar; Hashino, Eri

    2013-01-01

    The inner ear contains sensory epithelia that detect head movements, gravity and sound. It is unclear how to derive these sensory epithelia from pluripotent stem cells, a process which will be critical for modeling inner ear disorders or developing cell-based therapies for profound hearing loss and balance disorders1,2. To date, attempts to derive inner ear mechanosensitive hair cells and sensory neurons have resulted in inefficient or incomplete phenotypic conversion of stem cells into inner ear-like cells3–7. A key insight lacking from these previous studies is the importance of the non-neural and pre-placodal ectoderm, two critical precursors during inner ear development8–11. Here we report the step-wise differentiation of inner ear sensory epithelia from mouse embryonic stem cells (ESCs) in three-dimensional culture12,13. We show that by recapitulating in vivo development with precise temporal control of BMP, TGFβ and FGF signaling, ESC aggregates transform sequentially into non-neural, pre-placodal and otic placode-like epithelia. Remarkably, in a self-organized process that mimics normal development, vesicles containing prosensory cells emerge from the presumptive otic placodes and give rise to hair cells bearing stereocilia bundles and a kinocilium. Moreover, these stem cell-derived hair cells exhibit functional properties of native mechanosensitive hair cells and form specialized synapses with sensory neurons that have also arisen from ESCs in the culture. Finally, we demonstrate how these vesicles are structurally and biochemically comparable to developing vestibular end organs. Our data thus establish a novel in vitro model of inner ear differentiation that can be used to gain deeper insight into inner ear development and disorder. PMID:23842490

  4. A simple model for predicting lung cancer occurrence in a lung cancer screening program: The Pittsburgh Predictor.

    PubMed

    Wilson, David O; Weissfeld, Joel

    2015-07-01

    A user-friendly method for assessing lung cancer risk may help standardize selection of current and former smokers for screening. We evaluated a simple 4-factor model, the Pittsburgh Predictor, against two well-known, but more complicated models for predicting lung cancer risk. Trained against outcomes observed in the National Lung Screening Trial (NLST), the Pittsburgh Predictor used four risk factors, duration of smoking, smoking status, smoking intensity, and age, to predict 6-year lung cancer incidence. After calibrating the Bach and PLCOM2012 models to outcomes observed in the low-dose computed tomography arm of the NLST, we compared model calibration, discrimination, and clinical usefulness (net benefit) in the NLST and Pittsburgh Lung Screening Study (PLuSS) populations. The Pittsburgh Predictor, Bach, and PLCOM2012 represented risk equally well, except for the tendency of PLCOM2012 to overestimate risk in subjects at highest risk. Relative to the Pittsburgh Predictor, Bach and PLCOM2012 increased the area under the receiver operator characteristic curve by 0.007-0.009 and 0.012-0.021 units, respectively, depending on study population. Across a clinically relevant span of 6-year lung cancer risk thresholds (0.01-0.05), Bach and PLCOM2012 increased net benefit by less than 0.1% in NLST and 0.3% in PLuSS. In exchange for a small reduction in prediction accuracy, a simpler lung cancer risk prediction model may facilitate standardized procedures for advising and selecting patients with respect to lung cancer screening. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  5. The beetle amnion and serosa functionally interact as apposed epithelia

    PubMed Central

    Hilbrant, Maarten; Horn, Thorsten; Koelzer, Stefan; Panfilio, Kristen A

    2016-01-01

    Unlike passive rupture of the human chorioamnion at birth, the insect extraembryonic (EE) tissues – the amnion and serosa – actively rupture and withdraw in late embryogenesis. Withdrawal is essential for development and has been a morphogenetic puzzle. Here, we use new fluorescent transgenic lines in the beetle Tribolium castaneum to show that the EE tissues dynamically form a basal-basal epithelial bilayer, contradicting the previous hypothesis of EE intercalation. We find that the EE tissues repeatedly detach and reattach throughout development and have distinct roles. Quantitative live imaging analyses show that the amnion initiates EE rupture in a specialized anterior-ventral cap. RNAi phenotypes demonstrate that the serosa contracts autonomously. Thus, apposition in a bilayer enables the amnion as 'initiator' to coordinate with the serosa as 'driver' to achieve withdrawal. This EE strategy may reflect evolutionary changes within the holometabolous insects and serves as a model to study interactions between developing epithelia. DOI: http://dx.doi.org/10.7554/eLife.13834.001 PMID:26824390

  6. 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

  7. Quantification of Lung Metastases from In Vivo Mouse Models.

    PubMed

    Chang, Joan; Erler, Janine T

    2016-01-01

    Cancer research has made significant progress in terms of understanding and targeting primary tumors; however, the challenge remains for the successful treatment of metastatic cancers. This highlights the importance to use in vivo models to study the metastatic process, as well as for preclinical testing of compounds that could inhibit metastasis. As a result, proper quantification of metastases from in vivo models is of the utmost significance. Here, we provide a detailed protocol for collecting and handling lung tissues from mice, and guidance for subsequent analysis of metastases, as well as interpretation of data.

  8. 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.

  9. 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.

  10. 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

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

    PubMed

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

    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.

  12. Identification of differentially expressed genes from multipotent epithelia at the onset of an asexual development

    PubMed Central

    Ricci, Lorenzo; Chaurasia, Ankita; Lapébie, Pascal; Dru, Philippe; Helm, Rebecca R.; Copley, Richard R.; Tiozzo, Stefano

    2016-01-01

    Organisms that have evolved alternative modes of reproduction, complementary to the sexual mode, are found across metazoans. The chordate Botryllus schlosseri is an emerging model for asexual development studies. Botryllus can rebuild its entire body from a portion of adult epithelia in a continuous and stereotyped process called blastogenesis. Anatomy and ontogenies of blastogenesis are well described, however molecular signatures triggering this developmental process are entirely unknown. We isolated tissues at the site of blastogenesis onset and from the same epithelia where this process is never triggered. We linearly amplified an ultra-low amount of mRNA (<10ng) and generated three transcriptome datasets. To provide a conservative landscape of transcripts differentially expressed between blastogenic vs. non-blastogenic epithelia we compared three different mapping and analysis strategies with a de novo assembled transcriptome and partially assembled genome as references, additionally a self-mapping strategy on the dataset. A subset of differentially expressed genes were analyzed and validated by in situ hybridization. The comparison of different analyses allowed us to isolate stringent sets of target genes, including transcripts with potential involvement in the onset of a non-embryonic developmental pathway. The results provide a good entry point to approach regenerative event in a basal chordate. PMID:27264734

  13. Rho signaling regulates pannexin 1-mediated ATP release from airway epithelia.

    PubMed

    Seminario-Vidal, Lucia; Okada, Seiko F; Sesma, Juliana I; Kreda, Silvia M; van Heusden, Catharina A; Zhu, Yunxiang; Jones, Lisa C; O'Neal, Wanda K; Penuela, Silvia; Laird, Dale W; Boucher, Richard C; Lazarowski, Eduardo R

    2011-07-29

    ATP released from airway epithelial cells promotes purinergic receptor-regulated mucociliary clearance activities necessary for innate lung defense. Cell swelling-induced membrane stretch/strain is a common stimulus that promotes airway epithelial ATP release, but the mechanisms transducing cell swelling into ATP release are incompletely understood. Using knockdown and knockout approaches, we tested the hypothesis that pannexin 1 mediates ATP release from hypotonically swollen airway epithelia and investigated mechanisms regulating this activity. Well differentiated primary cultures of human bronchial epithelial cells subjected to hypotonic challenge exhibited enhanced ATP release, which was paralleled by the uptake of the pannexin probe propidium iodide. Both responses were reduced by pannexin 1 inhibitors and by knocking down pannexin 1. Importantly, hypotonicity-evoked ATP release from freshly excised tracheas and dye uptake in primary tracheal epithelial cells were impaired in pannexin 1 knockout mice. Hypotonicity-promoted ATP release and dye uptake in primary well differentiated human bronchial epithelial cells was accompanied by RhoA activation and myosin light chain phosphorylation and was reduced by the RhoA dominant negative mutant RhoA(T19N) and Rho and myosin light chain kinase inhibitors. ATP release and Rho activation were reduced by highly selective inhibitors of transient receptor potential vanilloid 4 (TRPV4). Lastly, knocking down TRPV4 impaired hypotonicity-evoked airway epithelial ATP release. Our data suggest that TRPV4 and Rho transduce cell membrane stretch/strain into pannexin 1-mediated ATP release in airway epithelia.

  14. Rho Signaling Regulates Pannexin 1-mediated ATP Release from Airway Epithelia*

    PubMed Central

    Seminario-Vidal, Lucia; Okada, Seiko F.; Sesma, Juliana I.; Kreda, Silvia M.; van Heusden, Catharina A.; Zhu, Yunxiang; Jones, Lisa C.; O'Neal, Wanda K.; Penuela, Silvia; Laird, Dale W.; Boucher, Richard C.; Lazarowski, Eduardo R.

    2011-01-01

    ATP released from airway epithelial cells promotes purinergic receptor-regulated mucociliary clearance activities necessary for innate lung defense. Cell swelling-induced membrane stretch/strain is a common stimulus that promotes airway epithelial ATP release, but the mechanisms transducing cell swelling into ATP release are incompletely understood. Using knockdown and knockout approaches, we tested the hypothesis that pannexin 1 mediates ATP release from hypotonically swollen airway epithelia and investigated mechanisms regulating this activity. Well differentiated primary cultures of human bronchial epithelial cells subjected to hypotonic challenge exhibited enhanced ATP release, which was paralleled by the uptake of the pannexin probe propidium iodide. Both responses were reduced by pannexin 1 inhibitors and by knocking down pannexin 1. Importantly, hypotonicity-evoked ATP release from freshly excised tracheas and dye uptake in primary tracheal epithelial cells were impaired in pannexin 1 knockout mice. Hypotonicity-promoted ATP release and dye uptake in primary well differentiated human bronchial epithelial cells was accompanied by RhoA activation and myosin light chain phosphorylation and was reduced by the RhoA dominant negative mutant RhoA(T19N) and Rho and myosin light chain kinase inhibitors. ATP release and Rho activation were reduced by highly selective inhibitors of transient receptor potential vanilloid 4 (TRPV4). Lastly, knocking down TRPV4 impaired hypotonicity-evoked airway epithelial ATP release. Our data suggest that TRPV4 and Rho transduce cell membrane stretch/strain into pannexin 1-mediated ATP release in airway epithelia. PMID:21606493

  15. Abundant Production of Brain-Derived Neurotrophic Factor by Adult Visceral Epithelia

    PubMed Central

    Lommatzsch, Marek; Braun, Armin; Mannsfeldt, Anne; Botchkarev, Vladimir A.; Botchkareva, Natalia V.; Paus, Ralf; Fischer, Axel; Lewin, Gary R.; Renz, Harald

    1999-01-01

    Brain-derived neurotrophic factor (BDNF) plays a crucial role for the survival of visceral sensory neurons during development. However, the physiological sources and the function of BDNF in the adult viscera are poorly described. We have investigated the cellular sources and the potential role of BDNF in adult murine viscera. We found markedly different amounts of BDNF protein in different organs. Surprisingly, BDNF levels in the urinary bladder, lung, and colon were higher than those found in the brain or skin. In situ hybridization experiments revealed that BDNF mRNA was made by visceral epithelial cells, several types of smooth muscle, and neurons of the myenteric plexus. Epithelia that expressed BDNF lacked both the high- and low-affinity receptors for BDNF, trkB and p75NTR. In contrast, both receptors were present on neurons of the peripheral nervous system. Studies with BDNF−/−mice demonstrated that epithelial and smooth muscle cells developed normally in the absence of BDNF. These data provide evidence that visceral epithelia are a major source, but not a target, of BDNF in the adult viscera. The abundance of BDNF protein in certain internal organs suggests that this neurotrophin may regulate the function of adult visceral sensory and motor neurons. PMID:10514401

  16. Lung Cancer Signatures in Plasma Based on Proteome Profiling of Mouse Tumor Models

    PubMed Central

    Taguchi, Ayumu; Politi, Katerina; Pitteri, Sharon J.; Lockwood, William W.; Faça, Vitor M.; Kelly-Spratt, Karen; Wong, Chee-Hong; Zhang, Qing; Chin, Alice; Park, Kwon-Sik; Goodman, Gary; Gazdar, Adi F.; Sage, Julien; Dinulescu, Daniela M.; Kucherlapati, Raju; DePinho, Ronald A.; Kemp, Christopher J.; Varmus, Harold E.; Hanash, Samir M.

    2012-01-01

    SUMMARY We investigated the potential of in-depth quantitative proteomics to reveal plasma protein signatures that reflect lung tumor biology. We compared plasma protein profiles of four mouse models of lung cancer with profiles of models of pancreatic, ovarian, colon, prostate, and breast cancer and two models of inflammation. A protein signature for Titf1/Nkx2-1, a known lineage-survival oncogene in lung cancer, was found in plasmas of mouse models of lung adenocarcinoma. An EGFR signature was found in plasma of an EGFR mutant model, and a distinct plasma signature related to neuroendocrine development was uncovered in the small-cell lung cancer model. We demonstrate relevance to human lung cancer of the protein signatures identified on the basis of mouse models. PMID:21907921

  17. Experimental and Computational Models for Simulating Sound Propagation Within the Lungs

    PubMed Central

    Acikgoz, S.; Ozer, M. B.; Mansy, H. A.; Sandler, R. H.

    2008-01-01

    An acoustic boundary element model is used to simulate sound propagation in the lung parenchyma and surrounding chest wall. It is validated theoretically and numerically and then compared with experimental studies on lung-chest phantom models that simulate the lung pathology of pneumothorax. Studies quantify the effect of the simulated lung pathology on the resulting acoustic field measured at the phantom chest surface. This work is relevant to the development of advanced auscultatory techniques for lung, vascular, and cardiac sounds within the torso that utilize multiple noninvasive sensors to create acoustic images of the sound generation and transmission to identify certain pathologies. PMID:18568101

  18. A biomathematical model of particle clearance and retention in the lungs of coal miners.

    PubMed

    Kuempel, E D; O'Flaherty, E J; Stayner, L T; Smith, R J; Green, F H; Vallyathan, V

    2001-08-01

    To understand better the factors influencing the relationships among airborne particle exposure, lung burden, and fibrotic lung disease, we developed a biologically based kinetic model to predict the long-term retention of particles in the lungs of coal miners. This model includes alveolar, interstitial, and hilar lymph node compartments. The 131 miners in this study had worked in the Beckley, West Virginia, area and died during the 1960s. The data used to develop this model include exposure to respirable coal mine dust by intensity and duration within each job, lung and lymph node dust burdens at autopsy, pathological classification of fibrotic lung disease, and smoking history. Initial parameter estimates for this model were based on both human and animal data of particle deposition and clearance and on the biological and physical factors influencing these processes. Parameter estimation and model fit to the data were determined using least squares. Results show that the end-of-life lung dust burdens in these coal miners were substantially higher than expected from first-order clearance kinetics, yet lower than expected from the overloading of alveolar clearance predicted from rodent studies. The best-fitting and most parsimonious model includes processes for first-order alveolar-macrophage-mediated clearance and transfer of particles to the lung interstitium. These results are consistent with the particle retention patterns observed previously in the lungs of primates. The findings indicate that rodent models extrapolated to humans, without adjustment for the kinetic differences in particle clearance and retention, would be inadequate for predicting lung dust burdens in humans. Also, this human lung kinetic model predicts greater retained lung dust burdens from occupational exposure than predicted from current human models based on lower exposure data. This model is useful for risk assessment of particle-induced lung diseases, by estimating equivalent internal

  19. Application of a Neutral Community Model To Assess Structuring of the Human Lung Microbiome

    PubMed Central

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

    2015-01-01

    ABSTRACT  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. Importance  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. PMID:25604788

  20. Macrophages mediate lung inflammation in a mouse model of ischemic acute kidney injury

    PubMed Central

    Altmann, Christopher; Andres-Hernando, Ana; McMahan, Rachel H.; Ahuja, Nilesh; He, Zhibin; Rivard, Chris J.; Edelstein, Charles Louis; Barthel, Lea; Janssen, William J.

    2012-01-01

    Serum IL-6 is increased in acute kidney injury (AKI) and inhibition of IL-6 reduces AKI-mediated lung inflammation. We hypothesized that circulating monocytes produce IL-6 and that alveolar macrophages mediate lung inflammation after AKI via chemokine (CXCL1) production. To investigate systemic and alveolar macrophages in lung injury after AKI, sham operation or 22 min of renal pedicle clamping (AKI) was performed in three experimental settings: 1) systemic macrophage depletion via diphtheria toxin (DT) injection to CD11b-DTR transgenic mice, 2) DT injection to wild-type mice, and 3) alveolar macrophage depletion via intratracheal (IT) liposome-encapsulated clodronate (LEC) administration to wild-type mice. In mice with AKI and systemic macrophage depletion (CD11b-DTR transgenic administered DT) vs. vehicle-treated AKI, blood monocytes and lung interstitial macrophages were reduced, renal function was similar, serum IL-6 was increased, lung inflammation was improved, lung CXCL1 was reduced, and lung capillary leak was increased. In wild-type mice with AKI administered DT vs. vehicle, serum IL-6 was increased. In mice with AKI and alveolar macrophage depletion (IT-LEC) vs. AKI with normal alveolar macrophage content, blood monocytes and lung interstitial macrophages were similar, alveolar macrophages were reduced, renal function was similar, lung inflammation was improved, lung CXCL1 was reduced, and lung capillary leak was increased. In conclusion, administration of DT in AKI is proinflammatory, limiting the use of the DTR-transgenic model to study systemic effects of AKI. Mice with AKI and either systemic mononuclear phagocyte depletion or alveolar macrophage depletion had reduced lung inflammation and lung CXCL1, but increased lung capillary leak; thus, mononuclear phagocytes mediate lung inflammation, but they protect against lung capillary leak after ischemic AKI. Since macrophage activation and chemokine production are key events in the development of acute

  1. A model for predicting lung cancer response to therapy

    SciTech Connect

    Seibert, Rebecca M. . E-mail: rseiber1@utk.edu; Ramsey, Chester R.; Hines, J. Wesley; Kupelian, Patrick A.; Langen, Katja M.; Meeks, Sanford L.; Scaperoth, Daniel D.

    2007-02-01

    Purpose: Volumetric computed tomography (CT) images acquired by image-guided radiation therapy (IGRT) systems can be used to measure tumor response over the course of treatment. Predictive adaptive therapy is a novel treatment technique that uses volumetric IGRT data to actively predict the future tumor response to therapy during the first few weeks of IGRT treatment. The goal of this study was to develop and test a model for predicting lung tumor response during IGRT treatment using serial megavoltage CT (MVCT). Methods and Materials: Tumor responses were measured for 20 lung cancer lesions in 17 patients that were imaged and treated with helical tomotherapy with doses ranging from 2.0 to 2.5 Gy per fraction. Five patients were treated with concurrent chemotherapy, and 1 patient was treated with neoadjuvant chemotherapy. Tumor response to treatment was retrospectively measured by contouring 480 serial MVCT images acquired before treatment. A nonparametric, memory-based locally weight regression (LWR) model was developed for predicting tumor response using the retrospective tumor response data. This model predicts future tumor volumes and the associated confidence intervals based on limited observations during the first 2 weeks of treatment. The predictive accuracy of the model was tested using a leave-one-out cross-validation technique with the measured tumor responses. Results: The predictive algorithm was used to compare predicted verse-measured tumor volume response for all 20 lesions. The average error for the predictions of the final tumor volume was 12%, with the true volumes always bounded by the 95% confidence interval. The greatest model uncertainty occurred near the middle of the course of treatment, in which the tumor response relationships were more complex, the model has less information, and the predictors were more varied. The optimal days for measuring the tumor response on the MVCT images were on elapsed Days 1, 2, 5, 9, 11, 12, 17, and 18 during

  2. Modelling primary blast lung injury: current capability and future direction.

    PubMed

    Scott, Timothy; Hulse, E; Haque, M; Kirkman, E; Hardman, J; Mahoney, P

    2017-04-01

    Primary blast lung injury frequently complicates military conflict and terrorist attacks on civilian populations. The fact that it occurs in areas of conflict or unpredictable mass casualty events makes clinical study in human casualties implausible. Research in this field is therefore reliant on the use of some form of biological or non-biological surrogate model. This article briefly reviews the modelling work undertaken in this field until now and describes the rationale behind the generation of an in silico physiological model. 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/.

  3. Bayesian analysis of a disability model for lung cancer survival.

    PubMed

    Armero, C; Cabras, S; Castellanos, M E; Perra, S; Quirós, A; Oruezábal, M J; Sánchez-Rubio, J

    2016-02-01

    Bayesian reasoning, survival analysis and multi-state models are used to assess survival times for Stage IV non-small-cell lung cancer patients and the evolution of the disease over time. Bayesian estimation is done using minimum informative priors for the Weibull regression survival model, leading to an automatic inferential procedure. Markov chain Monte Carlo methods have been used for approximating posterior distributions and the Bayesian information criterion has been considered for covariate selection. In particular, the posterior distribution of the transition probabilities, resulting from the multi-state model, constitutes a very interesting tool which could be useful to help oncologists and patients make efficient and effective decisions. © The Author(s) 2012.

  4. Lung Cancer Pathological Image Analysis Using a Hidden Potts Model.

    PubMed

    Li, Qianyun; Yi, Faliu; Wang, Tao; Xiao, Guanghua; Liang, Faming

    2017-01-01

    Nowadays, many biological data are acquired via images. In this article, we study the pathological images scanned from 205 patients with lung cancer with the goal to find out the relationship between the survival time and the spatial distribution of different types of cells, including lymphocyte, stroma, and tumor cells. Toward this goal, we model the spatial distribution of different types of cells using a modified Potts model for which the parameters represent interactions between different types of cells and estimate the parameters of the Potts model using the double Metropolis-Hastings algorithm. The double Metropolis-Hastings algorithm allows us to simulate samples approximately from a distribution with an intractable normalizing constant. Our numerical results indicate that the spatial interaction between the lymphocyte and tumor cells is significantly associated with the patient's survival time, and it can be used together with the cell count information to predict the survival of the patients.

  5. Lung Cancer Pathological Image Analysis Using a Hidden Potts Model

    PubMed Central

    Li, Qianyun; Yi, Faliu; Wang, Tao; Xiao, Guanghua; Liang, Faming

    2017-01-01

    Nowadays, many biological data are acquired via images. In this article, we study the pathological images scanned from 205 patients with lung cancer with the goal to find out the relationship between the survival time and the spatial distribution of different types of cells, including lymphocyte, stroma, and tumor cells. Toward this goal, we model the spatial distribution of different types of cells using a modified Potts model for which the parameters represent interactions between different types of cells and estimate the parameters of the Potts model using the double Metropolis-Hastings algorithm. The double Metropolis-Hastings algorithm allows us to simulate samples approximately from a distribution with an intractable normalizing constant. Our numerical results indicate that the spatial interaction between the lymphocyte and tumor cells is significantly associated with the patient’s survival time, and it can be used together with the cell count information to predict the survival of the patients. PMID:28615918

  6. Mechanisms of regulating cell topology in proliferating epithelia: impact of division plane, mechanical forces, and cell memory.

    PubMed

    Li, Yingzi; Naveed, Hammad; Kachalo, Sema; Xu, Lisa X; Liang, Jie

    2012-01-01

    Regulation of cell growth and cell division has a fundamental role in tissue formation, organ development, and cancer progression. Remarkable similarities in the topological distributions were found in a variety of proliferating epithelia in both animals and plants. At the same time, there are species with significantly varied frequency of hexagonal cells. Moreover, local topology has been shown to be disturbed on the boundary between proliferating and quiescent cells, where cells have fewer sides than natural proliferating epithelia. The mechanisms of regulating these topological changes remain poorly understood. In this study, we use a mechanical model to examine the effects of orientation of division plane, differential proliferation, and mechanical forces on animal epithelial cells. We find that regardless of orientation of division plane, our model can reproduce the commonly observed topological distributions of cells in natural proliferating animal epithelia with the consideration of cell rearrangements. In addition, with different schemes of division plane, we are able to generate different frequency of hexagonal cells, which is consistent with experimental observations. In proliferating cells interfacing quiescent cells, our results show that differential proliferation alone is insufficient to reproduce the local changes in cell topology. Rather, increased tension on the boundary, in conjunction with differential proliferation, can reproduce the observed topological changes. We conclude that both division plane orientation and mechanical forces play important roles in cell topology in animal proliferating epithelia. Moreover, cell memory is also essential for generating specific topological distributions.

  7. Apical entry channels in calcium-transporting epithelia.

    PubMed

    Peng, Ji-Bin; Brown, Edward M; Hediger, Matthias A

    2003-08-01

    The identification of the apical calcium channels CaT1 and ECaC revealed the key molecular mechanisms underlying apical calcium entry in calcium-transporting epithelia. These channels are regulated directly or indirectly by vitamin D and dietary calcium and undergo feedback control by intracellular calcium, suggesting their rate-limiting roles in transcellular calcium transport.

  8. Evidence of inherent spontaneous polarization in the metazoan integument epithelia.

    PubMed Central

    Athenstaedt, H; Claussen, H

    1983-01-01

    The live integument epithelia of the metazoa have an inherent spontaneous polarization (an inherent permanent electric dipole moment) of corresponding direction perpendicular to the integument surface. The existence of the inherent polarization was proved by their temperature dependence, i.e., by the pyroelectric (PE) effect. Quantitative PE measurements were carried out on a number of integument epithelia of vertebrates (a) in vivo, (b) on fresh epidermis preparations, and (c) on dead, air-dried epidermis specimens of the same species. The demonstrated spontaneous polarization is not dependent on the living state and not caused by a potential difference between the outer and inner integument surface. Dead, dry epidermis samples (potential difference less than 0.01 mV) as well as dead, dry integument appendages (bristles, hairs), and dead cuticles (of arthropoda, annelida, nematoda) showed an inherent dipole moment of the same orientation as the live epidermis. The findings reveal a relationship between the direction (vector) of inherent spontaneous polarization and that of growth (morphogenesis) in the animal epidermis, their appendages, and cuticles. We conclude (a) that the inherent spontaneous polarization is present in live individual epithelial cells of the metazoan integument, and (b) that this physical property is related to the structural and functional cell polarity of integument epithelia and possibly of other epithelia. Images FIGURE 10 PMID:6838974

  9. Improving the channeler ant model for lung CT analysis

    NASA Astrophysics Data System (ADS)

    Cerello, Piergiorgio; Lopez Torres, Ernesto; Fiorina, Elisa; Oppedisano, Chiara; Peroni, Cristiana; Arteche Diaz, Raul; Bellotti, Roberto; Bosco, Paolo; Camarlinghi, Niccolo; Massafra, Andrea

    2011-03-01

    The Channeler Ant Model (CAM) is an algorithm based on virtual ant colonies, conceived for the segmentation of complex structures with different shapes and intensity in a 3D environment. It exploits the natural capabilities of virtual ant colonies to modify the environment and communicate with each other by pheromone deposition. When applied to lung CTs, the CAM can be turned into a Computer Aided Detection (CAD) method for the identification of pulmonary nodules and the support to radiologists in the identification of early-stage pathological objects. The CAM has been validated with the segmentation of 3D artificial objects and it has already been successfully applied to the lung nodules detection in Computed Tomography images within the ANODE09 challenge. The model improvements for the segmentation of nodules attached to the pleura and to the vessel tree are discussed, as well as a method to enhance the detection of low-intensity nodules. The results on five datasets annotated with different criteria show that the analytical modules (i.e. up to the filtering stage) provide a sensitivity in the 80 - 90% range with a number of FP/scan of the order of 20. The classification module, although not yet optimised, keeps the sensitivity in the 70 - 85% range at about 10 FP/scan, in spite of the fact that the annotation criteria for the training and the validation samples are different.

  10. Exosomal miRs in Lung Cancer: A Mathematical Model

    PubMed Central

    Lai, Xiulan; Friedman, Avner

    2016-01-01

    Lung cancer, primarily non-small-cell lung cancer (NSCLC), is the leading cause of cancer deaths in the United States and worldwide. While early detection significantly improves five-year survival, there are no reliable diagnostic tools for early detection. Several exosomal microRNAs (miRs) are overexpressed in NSCLC, and have been suggested as potential biomarkers for early detection. The present paper develops a mathematical model for early stage of NSCLC with emphasis on the role of the three highest overexpressed miRs, namely miR-21, miR-205 and miR-155. Simulations of the model provide quantitative relationships between the tumor volume and the total mass of each of the above miRs in the tumor. Because of the positive correlation between these miRs in the tumor tissue and in the blood, the results of the paper may be viewed as a first step toward establishing a combination of miRs 21, 205, 155 and possibly other miRs as serum biomarkers for early detection of NSCLC. PMID:28002496

  11. 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

  12. Electroporation-mediated delivery of genes in rodent models of lung contusion.

    PubMed

    Machado-Aranda, David; Raghavendran, Krishnan

    2014-01-01

    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.

  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. 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.

  15. 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.

  16. 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.

  17. 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

  18. Fibroblastic foci, covered with alveolar epithelia exhibiting epithelial-mesenchymal transition, destroy alveolar septa by disrupting blood flow in idiopathic pulmonary fibrosis.

    PubMed

    Yamaguchi, Miki; Hirai, Sachie; Tanaka, Yusuke; Sumi, Toshiyuki; Miyajima, Masahiro; Mishina, Taijiro; Yamada, Gen; Otsuka, Mitsuo; Hasegawa, Tadashi; Kojima, Takashi; Niki, Toshiro; Watanabe, Atsushi; Takahashi, Hiroki; Sakuma, Yuji

    2017-03-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown cause. IPF has a distinct histopathological pattern of usual interstitial pneumonia in which fibroblastic foci (FF) represent the leading edge of fibrotic destruction of the lung. Currently there are three major hypotheses for how FF are generated: (1) from resident fibroblasts, (2) from bone marrow-derived progenitors of fibroblasts, and (3) from alveolar epithelial cells that have undergone epithelial-mesenchymal transition (EMT). We found that FF dissociated capillary vessels from the alveolar epithelia, the basement membranes of which are fused in normal physiological conditions, and pushed the capillaries and elastic fibers down ~100 μm below the alveolar epithelia. Furthermore, the alveolar epithelial cells covering the FF exhibited a partial EMT phenotype. In addition, normal human alveolar epithelial cells in vitro underwent dynamic EMT in response to transforming growth factor-β signaling within 72 h. Because it seems that resident fibroblasts or bone marrow-derived cells cannot easily infiltrate and form FF between the alveolar epithelia and capillaries in tight contact with each other, FF are more likely to be derived from the epithelial-to-mesenchymal transitioned alveolar epithelia located over them. Moreover, histology and immunohistochemistry suggested that the FF formed in the lung parenchyma disrupt blood flow to the alveolar septa, thus destroying them. Consequently, collapse of the alveolar septa is likely to be the first step toward honeycombing in the lung during late stage IPF. On the basis of these findings, inhibition of transforming growth factor-β signaling, which can suppress EMT of the alveolar epithelial cells in vitro, is a potential strategy for treating IPF.

  19. Rat models of asthma and chronic obstructive lung disease.

    PubMed

    Martin, James G; Tamaoka, Meiyo

    2006-01-01

    The rat has been extensively used to model asthma and somewhat less extensively to model chronic obstructive pulmonary disease (COPD). The features of asthma that have been successfully modeled include allergen-induced airway constriction, eosinophilic inflammation and allergen-induced airway hyperresponsiveness. T-cell involvement has been directly demonstrated using adoptive transfer techniques. Both CD4+ and CD8+ T cells are activated in response to allergen challenge in the sensitized rat and express Thelper2 cytokines (IL-4, IL-5 and IL-13). Repeated allergen exposure causes airway remodeling. Dry gas hyperpnea challenge also evokes increases in lung resistance, allowing exercise-induced asthma to be modeled. COPD is modeled using elastase-induced parenchymal injury to mimic emphysema. Cigarette smoke-induced airspace enlargement occurs but requires months of cigarette exposure. Inflammation and fibrosis of peripheral airways is an important aspect of COPD that is less well modeled. Novel approaches to the treatment of COPD have been reported including treatments aimed at parenchymal regeneration.

  20. 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.

  1. 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).

  2. 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...

  3. 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...

  4. 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...

  5. 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...

  6. Autophagy and Macropinocytosis: Keeping an Eye on the Corneal/Limbal Epithelia

    PubMed Central

    Peng, Han; Park, Jong Kook; Lavker, Robert M.

    2017-01-01

    Autophagy and macropinocytosis are processes that are vital for cellular homeostasis, and help cells respond to stress and take up large amounts of material, respectively. The limbal and corneal epithelia have the machinery necessary to carry out both processes; however, autophagy and macropinocytosis are relatively understudied in these two epithelia. In this Perspectives, we describe the basic principles behind macropinocytosis and autophagy, discuss how these two processes are regulated in the limbal and corneal epithelia, consider how these two processes impact on the physiology of limbal and corneal epithelia, and elaborate on areas of future research in autophagy and macropinocytosis as related to the limbal/corneal epithelia. PMID:28118670

  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. Biology Based Lung Cancer Model for Chronic Low Radon Exposures

    SciTech Connect

    Truta-Popa, Lucia-Adina; Hofmann, Werner; Fakir, Hatim; Cosma, Constantin

    2008-08-07

    Low dose effects of alpha particles at the tissue level are characterized by the interaction of single alpha particles, affecting only a small fraction of the cells within that tissue. Alpha particle intersections of bronchial target cells during a given exposure period were simulated by an initiation-promotion model, formulated in terms of cellular hits within the cycle time of the cell (dose-rate) and then integrated over the whole exposure period (dose). For a given average number of cellular hits during the lifetime of bronchial cells, the actual number of single and multiple hits was selected from a Poisson distribution. While oncogenic transformation is interpreted as the primary initiation step, stimulated mitosis by killing adjacent cells is assumed to be the primary radiological promotion event. Analytical initiation and promotion functions were derived from experimental in vitro data on oncogenic transformation and cellular survival.To investigate the shape of the lung cancer risk function at chronic, low level exposures in more detail, additional biological factors describing the tissue response and operating specifically at low doses were incorporated into the initiation-promotion model. These mechanisms modifying the initial response at the cellular level were: adaptive response, genomic instability, induction of apoptosis by surrounding cells, and detrimental as well as protective bystander mechanisms. To quantify the effects of these mechanisms as functions of dose, analytical functions were derived from the experimental evidence presently available. Predictions of lung cancer risk, including these mechanisms, exhibit a distinct sublinear dose-response relationship at low exposures, particularly for very low exposure rates.

  9. Biology Based Lung Cancer Model for Chronic Low Radon Exposures

    NASA Astrophysics Data System (ADS)

    TruÅ£ǎ-Popa, Lucia-Adina; Hofmann, Werner; Fakir, Hatim; Cosma, Constantin

    2008-08-01

    Low dose effects of alpha particles at the tissue level are characterized by the interaction of single alpha particles, affecting only a small fraction of the cells within that tissue. Alpha particle intersections of bronchial target cells during a given exposure period were simulated by an initiation-promotion model, formulated in terms of cellular hits within the cycle time of the cell (dose-rate) and then integrated over the whole exposure period (dose). For a given average number of cellular hits during the lifetime of bronchial cells, the actual number of single and multiple hits was selected from a Poisson distribution. While oncogenic transformation is interpreted as the primary initiation step, stimulated mitosis by killing adjacent cells is assumed to be the primary radiological promotion event. Analytical initiation and promotion functions were derived from experimental in vitro data on oncogenic transformation and cellular survival. To investigate the shape of the lung cancer risk function at chronic, low level exposures in more detail, additional biological factors describing the tissue response and operating specifically at low doses were incorporated into the initiation-promotion model. These mechanisms modifying the initial response at the cellular level were: adaptive response, genomic instability, induction of apoptosis by surrounding cells, and detrimental as well as protective bystander mechanisms. To quantify the effects of these mechanisms as functions of dose, analytical functions were derived from the experimental evidence presently available. Predictions of lung cancer risk, including these mechanisms, exhibit a distinct sublinear dose-response relationship at low exposures, particularly for very low exposure rates.

  10. 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.

  11. Time dependence of recruitment and derecruitment in the lung: a theoretical model.

    PubMed

    Bates, Jason H T; Irvin, Charles G

    2002-08-01

    Recruitment and derecruitment (R/D) of air spaces within the lung is greatly enhanced in lung injury and is thought to be responsible for exacerbating injury during mechanical ventilation. There is evidence to suggest that R/D is a time-dependent phenomenon. We have developed a computer model of the lung consisting of a parallel arrangement of airways and alveolar units. Each airway has a critical pressure (Pcrit) above which it tends to open and below which it tends to close but at a rate determined by how far pressure is from Pcrit. With an appropriate distribution of Pcrit and R/D velocity characteristics, the model able to produce realistic first and second pressure-volume curves of a lung inflated from an initially degassed state. The model also predicts that lung elastance will increase transiently after a deep inflation to a degree that increases as lung volume decreases and as the lung becomes injured. We conclude that our model captures the time-dependent mechanical behavior of the lung due to gradual R/D of lung units.

  12. From holoprosencephaly to osteopathology: role of multifunctional endocytic receptors in absorptive epithelia.

    PubMed

    Müller, Dominik; Nykjaer, Anders; Willnow, Thomas E

    2003-01-01

    Megalin and cubilin are two multifunctional endocytic receptors expressed in many absorptive epithelia including the yolk sac, the renal proximal tubules, and the intestine. In these tissues, the receptors act in concert to mediate the cellular uptake of a variety of lipoproteins and vitamin/ carrier complexes. Recent studies in animal models and in patients suffering from receptor gene defects have highlighted the crucial role played by the receptors in systemic lipid and vitamin homeostasis, and the severe defects that result from receptor dysfunction. Here, we will review the molecular mechanisms that underlie normal receptor activity and that cause disease in the receptor-deficient organism.

  13. A novel mechanical lung model of pulmonary diseases to assist with teaching and training

    PubMed Central

    Chase, J Geoffrey; Yuta, Toshinori; Mulligan, Kerry J; Shaw, Geoffrey M; Horn, Beverley

    2006-01-01

    Background A design concept of low-cost, simple, fully mechanical model of a mechanically ventilated, passively breathing lung is developed. An example model is built to simulate a patient under mechanical ventilation with accurate volumes and compliances, while connected directly to a ventilator. Methods The lung is modelled with multiple units, represented by rubber bellows, with adjustable weights placed on bellows to simulate compartments of different superimposed pressure and compliance, as well as different levels of lung disease, such as Acute Respiratory Distress Syndrome (ARDS). The model was directly connected to a ventilator and the resulting pressure volume curves recorded. Results The model effectively captures the fundamental lung dynamics for a variety of conditions, and showed the effects of different ventilator settings. It was particularly effective at showing the impact of Positive End Expiratory Pressure (PEEP) therapy on lung recruitment to improve oxygenation, a particulary difficult dynamic to capture. Conclusion Application of PEEP therapy is difficult to teach and demonstrate clearly. Therefore, the model provide opportunity to train, teach, and aid further understanding of lung mechanics and the treatment of lung diseases in critical care, such as ARDS and asthma. Finally, the model's pure mechanical nature and accurate lung volumes mean that all results are both clearly visible and thus intuitively simple to grasp. PMID:16919173

  14. The effect of artificial neural network model combined with six tumor markers in auxiliary diagnosis of lung cancer.

    PubMed

    Feng, Feifei; Wu, Yiming; Wu, Yongjun; Nie, Guangjin; Ni, Ran

    2012-10-01

    To evaluate the diagnosis potential of artificial neural network (ANN) model combined with six tumor markers in auxiliary diagnosis of lung cancer, to differentiate lung cancer from lung benign disease, normal control, and gastrointestinal cancers. Serum carcino-embryonic antigen (CEA), gastrin, neurone specific enolase (NSE), sialic acid (SA), Cu/Zn, Ca were measured through different experimental procedures in 117 lung cancer patients, 93 lung benign disease patients, 111 normal control, 47 gastric cancer patients, 50 patients with colon cancer and 50 esophagus cancer patients, 19 parameters of basic information were surveyed among lung cancer, lung benign disease and normal control, then developed and evaluated ANN models to distinguish lung cancer. Using the ANN model with the six serum tumor markers and 19 parameters to distinguish lung cancer from benign lung disease and healthy people, the sensitivity was 98.3%, the specificity was 99.5% and the accuracy was 96.9%. Another three ANN models with the six serum tumor markers were employed to differentiate lung cancer from three gastrointestinal cancers, the sensitivity, specificity and accuracy of distinguishing lung cancer from gastric cancer by the ANN model of lung cancer-gastric cancer were 100%, 83.3% and 93.5%, respectively; The sensitivity, specificity and accuracy of discriminating lung cancer by lung cancer-colon cancer ANN model were 90.0%, 90.0%, and 90.0%; And which were 86.7%, 84.6%, and 86.0%, respectively, by lung cancer-esophagus cancer ANN model. ANN model built with the six serum tumor markers could distinguish lung cancer, not only from lung benign disease and normal people, but also from three common gastrointestinal cancers. And our evidence indicates the ANN model maybe is an excellent and intelligent system to discriminate lung cancer.

  15. The NEU1-selective sialidase inhibitor, C9-butyl-amide-DANA, blocks sialidase activity and NEU1-mediated bioactivities in human lung in vitro and murine lung in vivo.

    PubMed

    Hyun, Sang W; Liu, Anguo; Liu, Zhenguo; Cross, Alan S; Verceles, Avelino C; Magesh, Sadagopan; Kommagalla, Yadagiri; Kona, Chandrababunaidu; Ando, Hiromune; Luzina, Irina G; Atamas, Sergei P; Piepenbrink, Kurt H; Sundberg, Eric J; Guang, Wei; Ishida, Hideharu; Lillehoj, Erik P; Goldblum, Simeon E

    2016-08-01

    Neuraminidase-1 (NEU1) is the predominant sialidase expressed in human airway epithelia and lung microvascular endothelia where it mediates multiple biological processes. We tested whether the NEU1-selective sialidase inhibitor, C9-butyl-amide-2-deoxy-2,3-dehydro-N-acetylneuraminic acid (C9-BA-DANA), inhibits one or more established NEU1-mediated bioactivities in human lung cells. We established the IC50 values of C9-BA-DANA for total sialidase activity in human airway epithelia, lung microvascular endothelia and lung fibroblasts to be 3.74 µM, 13.0 µM and 4.82 µM, respectively. In human airway epithelia, C9-BA-DANA dose-dependently inhibited flagellin-induced, NEU1-mediated mucin-1 ectodomain desialylation, adhesiveness for Pseudomonas aeruginosa and shedding. In lung microvascular endothelia, C9-BA-DANA reversed NEU1-driven restraint of cell migration into a wound and disruption of capillary-like tube formation. NEU1 and its chaperone/transport protein, protective protein/cathepsin A (PPCA), were differentially expressed in these same cells. Normalized NEU1 protein expression correlated with total sialidase activity whereas PPCA expression did not. In contrast to eukaryotic sialidases, C9-BA-DANA exerted far less inhibitory activity for three selected bacterial neuraminidases (IC50 > 800 µM). Structural modeling of the four human sialidases and three bacterial neuraminidases revealed a loop between the seventh and eighth strands of the β-propeller fold, that in NEU1, was substantially shorter than that seen in the six other enzymes. Predicted steric hindrance between this loop and C9-BA-DANA could explain its selectivity for NEU1. Finally, pretreatment of mice with C9-BA-DANA completely protected against flagellin-induced increases in lung sialidase activity. Our combined data indicate that C9-BA-DANA inhibits endogenous and ectopically expressed sialidase activity and established NEU1-mediated bioactivities in human airway epithelia, lung microvascular

  16. A computational model of the topographic distribution of ventilation in healthy human lungs

    PubMed Central

    Swan, Annalisa J; Clark, Alys R; Tawhai, Merryn H

    2012-01-01

    The topographic distribution of ventilation in the lungs is determined by the interaction of several factors, including lung shape, airway tree geometry, posture, and tissue deformation. Inter-species differences in lung structure-function and technical difficulty in obtaining high resolution imaging of the upright human lung mean that it is not straightforward to experimentally determine the contribution of each of these factors to ventilation distribution. We present a mathematical model for predicting the topological distribution of inhaled air in the upright healthy human lung, based on anatomically-structured model geometries and biophysical equations for model function. Gravitational deformation of the lung tissue is predicted using a continuum model. Air flow is simulated in anatomically-based conducting airways coupled to geometrically simplified terminal acinar units with varying volume-dependent compliances. The predicted ventilation distribution is hence governed by local tissue density and elastic recoil pressure, airway resistance and acinar compliance. Results suggest that there is significant spatial variation in intrinsic tissue properties in the lungs. The model confirms experimental evidence that in the healthy lungs tissue compliance has a far greater effect than airway resistance on the spatial distribution of ventilation, and hence a realistic description of tissue deformation is essential in models of ventilation. PMID:22326472

  17. Stereotactic Body Radiation Therapy Delivery in a Genetically Engineered Mouse Model of Lung Cancer

    PubMed Central

    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

    2016-01-01

    Purpose 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. Methods and Materials 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. Results 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. Conclusions 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. PMID:27681749

  18. 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.

  19. Identification and behavior of label-retaining cells in epithelia

    SciTech Connect

    Bickenbach, J.R.

    1982-01-01

    A subpopulation of stem cells has been demonstrated in several renewing tissues. Such cells have a slow cell cycle and provide differentiating cells during normal turnover and during regeneration of the tissue following damage. The presence of slowly-cycling cells in epithelia from regions of skin and oral mucosa was examined by labeling 10-day-old mice and 5-day-old hamsters with tritiated thymidine (/sup 3/H-TdR) and observing the rate at which label was diluted from the basal cells. Label was rapidly diluted by cell division in most cells but a small percentage of basal cells (label-retaining cells, LRCS) was found to retain label for up to ninety days. Electron microscopic autoradiography and ..beta..-glucuronidase histochemistry with autoradiography were used to distinguish slowly-cycling keratinocytes from Langerhans cells. Such findings of slowly-cycling keratinocytes in epithelia with the ability to proliferate in culture and with a direct relationship to patterns of tissue architecture suggest that LRCs in epithelia correspond to stem cells described in other continuously renewing tissues.

  20. Modeling and incorporating cardiac-induced lung tissue motion in a breathing motion model

    PubMed Central

    White, Benjamin M.; Santhanam, Anand; Thomas, David; Min, Yugang; Lamb, James M.; Neylon, Jack; Jani, Shyam; Gaudio, Sergio; Srinivasan, Subashini; Ennis, Daniel; Low, Daniel A.

    2014-01-01

    Purpose: The purpose of this work is to develop a cardiac-induced lung motion model to be integrated into an existing breathing motion model. Methods: The authors’ proposed cardiac-induced lung motion model represents the lung tissue's specific response to the subject's cardiac cycle. The model is mathematically defined as a product of a converging polynomial function h of the cardiac phase (c) and the maximum displacement \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} \\smash{\\mathord{\\buildrel{\\lower3pt\\hbox{\\scriptscriptstyle\\rightharpoonup}}\\over \\gamma } ( {\\mathord{\\buildrel{\\lower3pt\\hbox{\\scriptscriptstyle\\rightharpoonup}}\\over X} _0 } )}\\end{document}γ⇀(X⇀0) of each voxel (\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} \\smash{\\mathord{\\buildrel{\\lower3pt\\hbox{\\scriptscriptstyle\\rightharpoonup}}\\over X} _0 }\\end{document}X⇀0) among all the cardiac phases. The function h(c) was estimated from cardiac-gated MR imaging of ten healthy volunteers using an Akaike Information Criteria optimization algorithm. For each volunteer, a total of 24 short-axis and 18 radial planar views were acquired on a 1.5 T MR scanner during a series of 12–15 s breath-hold maneuvers. Each view contained 30 temporal frames of equal time-duration beginning with the end-diastolic cardiac phase. The frames in each of the planar views were resampled to create a set of three-dimensional (3D) anatomical volumes representing thoracic anatomy at different cardiac phases. A 3D multiresolution optical flow deformable image registration algorithm was used to quantify the difference

  1. 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

  2. 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.

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

    SciTech Connect

    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. - 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.

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

    NASA Astrophysics Data System (ADS)

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

    2015-11-01

    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, 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.

  5. Human lung cancer cells grown in an ex vivo 3D lung model produce matrix metalloproteinases not produced in 2D culture.

    PubMed

    Mishra, Dhruva K; Sakamoto, Jason H; Thrall, Michael J; Baird, Brandi N; Blackmon, Shanda H; Ferrari, Mauro; Kurie, Jonathan M; Kim, Min P

    2012-01-01

    We compared the growth of human lung cancer cells in an ex vivo three-dimensional (3D) lung model and 2D culture to determine which better mimics lung cancer growth in patients. A549 cells were grown in an ex vivo 3D lung model and in 2D culture for 15 days. We measured the size and formation of tumor nodules and counted the cells after 15 days. We also stained the tissue/cells for Ki-67, and Caspase-3. We measured matrix metalloproteinase (MMP) levels in the conditioned media and in blood plasma from patients with adenocarcinoma of the lung. Organized tumor nodules with intact vascular space formed in the ex vivo 3D lung model but not in 2D culture. Proliferation and apoptosis were greater in the ex vivo 3D lung model compared to the 2D culture. After 15 days, there were significantly more cells in the 2D culture than the 3D model. MMP-1, MMP-9, and MMP-10 production were significantly greater in the ex vivo 3D lung model. There was no production of MMP-9 in the 2D culture. The patient samples contained MMP-1, MMP-2, MMP-9, and MMP-10. The human lung cancer cells grown on ex vivo 3D model form perfusable nodules that grow over time. It also produced MMPs that were not produced in 2D culture but seen in human lung cancer patients. The ex vivo 3D lung model may more closely mimic the biology of human lung cancer development than the 2D culture.

  6. A simple, closed-form, mathematical model for gas exchange in microchannel artificial lungs.

    PubMed

    Potkay, Joseph A

    2013-06-01

    Microfabrication techniques are attractive for constructing artificial lungs due to the ability to create features similar in size to those in the natural lung. However, a simple and intuitive mathematical model capable of accurately predicting the gas exchange performance of microchannel artificial lungs does not currently exist. Such a model is critical to understanding and optimizing these devices. Here, we describe a simple, closed-form mathematical model for gas exchange in microchannel artificial lungs and qualify it through application to experimental data from several research groups. We utilize lumped parameters and several assumptions to obtain a closed-form set of equations that describe gas exchange. This work is intended to augment computational models by providing a more intuitive, albeit potentially less accurate, understanding of the operation and trade-offs inherent in microchannel artificial lung devices.

  7. 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.

  8. Lung Cancer Stem Cell: New Insights on Experimental Models and Preclinical Data

    PubMed Central

    Rivera, Caroline; Rivera, Sofia; Loriot, Yohann; Vozenin, Marie-Catherine; Deutsch, Eric

    2011-01-01

    Lung cancer remains the leading cause of cancer death. Understanding lung tumors physiopathology should provide opportunity to prevent tumor development or/and improve their therapeutic management. Cancer stem cell (CSC) theory refers to a subpopulation of cancer cells, also named tumor-initiating cells, that can drive cancer development. Cells presenting these characteristics have been identified and isolated from lung cancer. Exploring cell markers and signaling pathways specific to lung CSCs may lead to progress in therapy and improve the prognosis of patients with lung cancer. Continuous efforts in developing in vitro and in vivo models may yield reliable tools to better understand CSC abilities and to test new therapeutic targets. Preclinical data on putative CSC targets are emerging by now. These preliminary studies are critical for the next generation of lung cancer therapies. PMID:21209720

  9. A comparison of fixation methods on lung morphology in a murine model of emphysema.

    PubMed

    Braber, S; Verheijden, K A T; Henricks, P A J; Kraneveld, A D; Folkerts, G

    2010-12-01

    Emphysema is characterized by enlargement of the alveoli, which is the most important parameter to assess the presence and severity of this disease. Alveolar enlargement is primarily defined on morphological criteria; therefore, characterization of this disease with morphological parameters is a prerequisite to study the pathogenesis. For this purpose, different methods of lung fixation were evaluated in a murine model of LPS-induced lung emphysema. Five different methods of lung fixation were evaluated: intratracheal instillation of fixatives, in situ fixation, fixed-volume fixation, vascular whole body perfusion, and vacuum inflation. In addition, the effects of three different fixatives (10% formalin, Carnoy's, and agarose/10% formalin solution) and two embedding methods (paraffin and plastic) were investigated on the murine lung morphology. Mice received intranasal administration of LPS to induce alveolar wall destruction. Quantification of air space enlargement was determined by mean linear intercept analysis, and the histological sections were analyzed for the most optimal fixation method. Additionally, routine immunohistological staining was performed on lung tissue of PBS-treated mice. Intratracheal instillation of formalin or agarose/formalin solution, in situ fixation, and fixed-volume fixation provided a normal lung architecture, in contrast to the lungs fixed via whole body perfusion and vacuum inflation. Formalin-fixed lungs resulted in the most optimal lung morphology for lung emphysema analysis when embedded in paraffin, while for Carnoy's fixed lungs, plastic embedding was preferred. The histological findings, the mean linear intercept measurement, and the immunohistochemistry data demonstrated that fixation by intratracheal instillation of 10% formalin or in situ fixation with 10% formalin are the two most optimal methods to fix lungs for alveolar enlargement analysis to study lung emphysema.

  10. Inhaled nitric oxide aggravates phosgene model of acute lung injury.

    PubMed

    Li, Wen-Li; Hai, Chun-Xu; Pauluhn, Jürgen

    2011-11-01

    The principal acute mode of action of inhaled phosgene gas is related to an increase alveolar fluid exudation under pathologic conditions. This paper considers some aspects in modeling phosgene-induced acute lung injury (ALI) in an acute rat bioassay and whether edema formation can be modulated by inhaled nitric oxide (iNO). Protein analysis in bronchoalveolar lavage (BAL) fluid is amongst the most sensitive method to quantify the phosgene-induced non-cardiogenic, pulmonary high-permeability edema following acute inhalation exposure. Maximum concentrations in BAL-protein occur within one day postexposure, typically within a latency period up to about 15 h as a consequence of an increasingly exhausted lymphatic drainage. An almost similar sensitivity was given by the functional endpoint 'enhanced pause (Penh)' when measured by non-invasive whole-body barometric plethysmography over a time period of 20 h. The magnitude of edema formation follows a concentration x time (C¹xt) relationship, although animal model-specific deviations may occur at very short exposure durations (1-20 min) due to a rodent-specific, reflexively induced transient decreased ventilation. This has to be accounted for when simulating accidental exposure scenarios to study the mechanisms involved in pharmacological modulation of fluid transport in this type of ALI. Therefore, a special focus has to be given to the dosimetry of inhaled phosgene, otherwise any change in effect magnitude, as a result of under-dosing of phosgene, may be misconceived as promising therapy. This study demonstrates that accidental exposures can be modeled best in rats by exposure durations of at least 20-30 min. Lung function measurements (Penh) show that pathophysiological effects appear to occur concomitant with the exposure to phosgene; however, its full clinical manifestation requires a gross imbalance of pulmonary fluid clearance. When applying this concept, post-phosgene exposure iNO at 1.5 ppm × 6 h or

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

    PubMed Central

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

    2008-01-01

    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. PMID:18593661

  12. A rat model for isolated bilateral lung contusion from blunt chest trauma.

    PubMed

    Raghavendran, Krishnan; Davidson, Bruce A; Helinski, Jadwiga D; Marschke, Cristi J; Manderscheid, Patricia; Woytash, James A; Notter, Robert H; Knight, Paul R

    2005-11-01

    Lung contusion affects 17%-25% of adult blunt trauma patients, and is the leading cause of death from blunt thoracic injury. A small animal model for isolated bilateral lung contusion has not been developed. We induced lung contusion in anesthetized rats by dropping a 0.3-kg weight onto a precordial protective shield to direct the impact force away from the heart and toward the lungs. Lung injury was characterized as a function of chest impact energy (1.8-2.7 J) by measurements of arterial oxygenation, bronchoalveolar lavage (BAL) albumin and cytology, pressure-volume mechanics, and histopathology. Histology confirmed bilateral lung contusion without substantial cardiac muscle trauma. Rats receiving 2.7 J of chest impact energy had 33% mortality that exceeded prospectively defined limits for sublethal injury. Hypoxemia in rats with maximal sublethal injury (2.45 J) met criteria for acute lung injury at < or =24 h, improving by 48 h. BAL albumin levels were highest at < or =24 h, and remained elevated along with increased BAL leukocytes and decreased lung volumes at 48 h. We concluded that an impact energy of 2.45 J induces isolated, bilateral lung contusion and provides a useful model for future mechanistic pathophysiological assessments.

  13. Modeling the nuclear magnetic resonance behavior of lung: from electrical engineering to critical care medicine.

    PubMed

    Cutillo, A G; Ailion, D C

    1999-01-01

    The present article reviews the basic principles of a new approach to the characterization of pulmonary disease. This approach is based on the unique nuclear magnetic resonance (NMR) properties of the lung and combines experimental measurements (using specially developed NMR techniques) with theoretical simulations. The NMR signal from inflated lungs decays very rapidly compared with the signal from completely collapsed (airless) lungs. This phenomenon is due to the presence of internal magnetic field inhomogeneity produced by the alveolar air-tissue interface (because air and water have different magnetic susceptibilities). The air-tissue interface effects can be detected and quantified by magnetic resonance imaging (MRI) techniques using temporally symmetric and asymmetric spin-echo sequences. Theoretical models developed to explain the internal (tissue-induced) magnetic field inhomogeneity in aerated lungs predict the NMR lung behavior as a function of various technical and physiological factors (e.g., the level of lung inflation) and simulate the effects of various lung disorders (in particular, pulmonary edema) on this behavior. Good agreement has been observed between the predictions obtained from the mathematical models and the results of experimental NMR measurements in normal and diseased lungs. Our theoretical and experimental data have important pathophysiological and clinical implications, especially with respect to the characterization of acute lung disease (e.g., pulmonary edema) and the management of critically ill patients.

  14. Endocytic reawakening of motility in jammed epithelia

    NASA Astrophysics Data System (ADS)

    Malinverno, Chiara; Corallino, Salvatore; Giavazzi, Fabio; Bergert, Martin; Li, Qingsen; Leoni, Marco; Disanza, Andrea; Frittoli, Emanuela; Oldani, Amanda; Martini, Emanuele; Lendenmann, Tobias; Deflorian, Gianluca; Beznoussenko, Galina V.; Poulikakos, Dimos; Ong, Kok Haur; Uroz, Marina; Trepat, Xavier; Parazzoli, Dario; Maiuri, Paolo; Yu, Weimiao; Ferrari, Aldo; Cerbino, Roberto; Scita, Giorgio

    2017-05-01

    Dynamics of epithelial monolayers has recently been interpreted in terms of a jamming or rigidity transition. How cells control such phase transitions is, however, unknown. Here we show that RAB5A, a key endocytic protein, is sufficient to induce large-scale, coordinated motility over tens of cells, and ballistic motion in otherwise kinetically arrested monolayers. This is linked to increased traction forces and to the extension of cell protrusions, which align with local velocity. Molecularly, impairing endocytosis, macropinocytosis or increasing fluid efflux abrogates RAB5A-induced collective motility. A simple model based on mechanical junctional tension and an active cell reorientation mechanism for the velocity of self-propelled cells identifies regimes of monolayer dynamics that explain endocytic reawakening of locomotion in terms of a combination of large-scale directed migration and local unjamming. These changes in multicellular dynamics enable collectives to migrate under physical constraints and may be exploited by tumours for interstitial dissemination.

  15. Endocytic reawakening of motility in jammed epithelia.

    PubMed

    Malinverno, Chiara; Corallino, Salvatore; Giavazzi, Fabio; Bergert, Martin; Li, Qingsen; Leoni, Marco; Disanza, Andrea; Frittoli, Emanuela; Oldani, Amanda; Martini, Emanuele; Lendenmann, Tobias; Deflorian, Gianluca; Beznoussenko, Galina V; Poulikakos, Dimos; Ong, Kok Haur; Uroz, Marina; Trepat, Xavier; Parazzoli, Dario; Maiuri, Paolo; Yu, Weimiao; Ferrari, Aldo; Cerbino, Roberto; Scita, Giorgio

    2017-01-30

    Dynamics of epithelial monolayers has recently been interpreted in terms of a jamming or rigidity transition. How cells control such phase transitions is, however, unknown. Here we show that RAB5A, a key endocytic protein, is sufficient to induce large-scale, coordinated motility over tens of cells, and ballistic motion in otherwise kinetically arrested monolayers. This is linked to increased traction forces and to the extension of cell protrusions, which align with local velocity. Molecularly, impairing endocytosis, macropinocytosis or increasing fluid efflux abrogates RAB5A-induced collective motility. A simple model based on mechanical junctional tension and an active cell reorientation mechanism for the velocity of self-propelled cells identifies regimes of monolayer dynamics that explain endocytic reawakening of locomotion in terms of a combination of large-scale directed migration and local unjamming. These changes in multicellular dynamics enable collectives to migrate under physical constraints and may be exploited by tumours for interstitial dissemination.

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

    SciTech Connect

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

    2013-07-01

    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 C{sub 1} 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.

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

    NASA Astrophysics Data System (ADS)

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

    2013-07-01

    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.

  18. Cultured corneal epithelia for ocular surface disease.

    PubMed Central

    Schwab, I R

    1999-01-01

    PURPOSE: To evaluate the potential efficacy for autologous and allogeneic expanded corneal epithelial cell transplants derived from harvested limbal corneal epithelial stem cells cultured in vitro for the management of ocular surface disease. METHODS: Human Subjects. Of the 19 human subjects included, 18 (20 procedures) underwent in vitro cultured corneal epithelial cell transplants using various carriers for the epithelial cells to determine the most efficacious approach. Sixteen patients (18 procedures on 17 eyes) received autologous transplants, and 2 patients (1 procedure each) received allogeneic sibling grafts. The presumed corneal epithelial stem cells from 1 patient did not grow in vitro. The carriers for the expanded corneal epithelial cells included corneal stroma, type 1 collagen (Vitrogen), soft contact lenses, collagen shields, and amniotic membrane for the autologous grafts and only amniotic membrane for the allogeneic sibling grafts. Histologic confirmation was reviewed on selected donor grafts. Amniotic membrane as carrier. Further studies were made to determine whether amniotic membrane might be the best carrier for the expanding corneal epithelial cells. Seventeen different combinations of tryspinization, sonication, scraping, and washing were studied to find the simplest, most effective method for removing the amniotic epithelium while still preserving the histologic appearance of the basement membrane of the amnion. Presumed corneal epithelial stem cells were harvested and expanded in vitro and applied to the amniotic membrane to create a composite graft. Thus, the composite graft consisted of the amniotic membrane from which the original epithelium had been removed without significant histologic damage to the basement membrane, and the expanded corneal epithelial stem cells, which had been applied to and had successfully adhered to the denuded amniotic membrane. Animal model. Twelve rabbits had the ocular surface of 1 eye damaged in a standard

  19. 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.

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

    PubMed Central

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

    2011-01-01

    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 physiological 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, NNK. Tumors that develop in this model have mutations in K-ras, which is a 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 of 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 to those of NRT, suggesting that nicotine has a dose threshold, below which it has no appreciable effect. These studies are consistent with epidemiological data showing that NRT does not enhance lung cancer risk in former smokers. PMID:22027685

  1. Dry Lung as a Physical Model in Studies of Aerosol Deposition.

    PubMed

    Morozov, Victor N; Kanev, Igor L

    2015-10-01

    A new physical model was developed to evaluate the deposition of micro- and nanoaerosol particles (NAPs) into the lungs as a function of size and charges. The model was manufactured of a dry, inflated swine lung produced by Nasco company (Fort Atkinson, WI). The dry lung was cut into two lobes and a conductive tube was glued into the bronchial tube. The upper 1-2-mm-thick layer of the lung lobe was removed with a razor blade to expose the alveoli. The lobe was further enclosed into a plastic bag and placed within a metalized plastic box. The probability of aerosol deposition was calculated by comparing the size distribution of NAPs passed through the lung with that of control, where aerosol passed through a box bypassing the lung. Using this new lung model, it was demonstrated that charged NAPs are deposited inside the lung substantially more efficiently than neutral ones. It was also demonstrated that deposition of neutral NAPs well fits prediction of the Multiple-Path Particle Dosimetry (MPPD) model developed by the Applied Research Associates, Inc. (ARA).

  2. 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...

  3. Two mathematical models for predicting dispersion of particles in the human lung.

    PubMed

    Ganser, G H; Christie, I; McCawley, M A

    2007-02-01

    The dispersion of particles in the human lung is modeled as a series of virtual mixing tanks. Using the experimental results of Scherer et al. (1975, J. Appl. Physiol., 38(4), pp. 719-723) for a five-generation glass lung model, it is shown that each generation of the glass lung behaves like an independent virtual mixing tank. The corresponding resident time distribution is shown to have a variance approximately equal to the square of the average time a particle spends in the generation. By assuming that each generation of the human lung behaves as an independent virtual mixing tank, the realistic lung data provided by Weibel (1963, Morphometry of the Human Lung, Spinger-Verlag, New York) are used to validate this assumption in two ways. First, the half-width of the exhaled particle concentration profile is obtained. Second, a system of differential equations, with the concentration of particles in each mixing tank as its solution, is derived and solved numerically. This gives the exhaled concentration profile. Both techniques yield similar results to each other, and both give excellent agreement with the experimental data. The virtual mixing tank approach allows the complex mixing that occurs in the branching pathways of the lung to be more simply modeled. The model, thereby derived, is simple to change and could lead to enhancements in the understanding of the underlying processes contributing to the ventilation of the lung in health and disease.

  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. Lung Protective Ventilation (ARDSNet) versus APRV: Ventilatory Management in a Combined Model of Acute Lung and Brain Injury

    PubMed Central

    Davies, Stephen W.; Leonard, Kenji L.; Falls, Randall K.; Mageau, Ronald P.; Efird, Jimmy T.; Hollowell, Joseph P.; Trainor, Wayne E.; Kanaan, Hilal A.; Hickner, Robert C.; Sawyer, Robert G.; Poulin, Nathaniel R.; Waibel, Brett H.; Toschlog, Eric A.

    2014-01-01

    Background Concomitant lung/brain traumatic injury, results in significant morbidity and mortality. Lung protective ventilation (ARDSNet) has become the standard for managing acute respiratory distress syndrome (ARDS); however, the resulting permissive hypercapnea may compound traumatic brain injury (TBI). Airway pressure release ventilation (APRV) offers an alternative strategy for management of this patient population. APRV was hypothesized to retard the progression of acute lung/brain injury to a greater degree than ARDSNet in a swine model. Methods Yorkshire swine were randomized to ARDSNet, APRV, or sham. Ventilatory settings and pulmonary parameters, vitals, blood gases, quantitative histopathology, and cerebral microdialysis were compared between groups using chi-square, Fisher’s exact, Student’s t-test, Wilcoxon rank-sum, and mixed effects repeated measures modeling. Results 22 swine (17 male, 5 female), weighing 25±6.0kg, were randomized to APRV (n=9), ARDSNet (n=12), or sham (n=1). PaO2/FiO2 (P/F) ratio dropped significantly while intracranial pressure increased significantly for all three groups immediately following lung and brain injury. Over time, peak inspiratory pressure, mean airway pressure, and P/F ratio significantly increased, while total respiratory rate significantly decreased within the APRV group compared to the ARDSNet group. Histopathology did not show significant differences between groups in overall brain or lung tissue injury; however, cerebral microdialysis trends suggested increased ischemia within the APRV group compared to ARDSNet over time. Conclusion Previous studies have not evaluated the effects of APRV in this population. While our macroscopic parameters and histopathology did not observe a significant difference between groups, microdialysis data suggest a trend toward increased cerebral ischemia associated with APRV over time. Additional and future studies should focus on extending the time interval for observation to

  6. The Implantable Pediatric Artificial Lung: Interim Report on the Development of an End-Stage Lung Failure Model

    PubMed Central

    Alghanem, Fares; Davis, Ryan P.; Bryner, Benjamin S.; Hoffman, Hayley R.; Trahanas, John; Cornell, Marie; Rojas-Peña, Alvaro; Bartlett, Robert H.; Hirschl, Ronald B.

    2015-01-01

    An implantable pediatric artificial lung (PAL) may serve as a bridge to lung transplantation for children with end-stage lung failure (ESLF); however, an animal model of pediatric lung failure is needed to evaluate a PAL’s efficacy before it can enter clinical trials. The objective of this study was to assess ligation of the right pulmonary artery (rPA) as a model for pediatric ESLF. Seven 20-30kg lambs underwent rPA ligation and were recovered and monitored for up to 4 days. Intraoperatively, rPA ligation significantly increased physiologic deadspace fraction (Vd/Vt: baseline=48.6±5.7%, rPA ligation=60.1±5.2%, p=0.012), mean pulmonary arterial pressure (mPPA: baseline=17.4±2.2mmHg, rPA ligation=28.5±5.2mmHg, p<0.001), and arterial partial pressure of carbon dioxide (PaCO2: baseline=40.4±9.3mmHg, rPA ligation=57.3±12.7mmHg, p=0.026). Of the 7 lambs, 3 were unable to be weaned from mechanical ventilation post-operatively, 3 were successfully weaned but suffered cardiorespiratory failure within 4 days, and 1 survived all 4 days. All 4 animals that were successfully weaned from mechanical ventilation had persistent pulmonary hypertension (mPPA=28.6±2.2mmHg) and remained tachypneic (respiratory rate=63±21min−1). Three of the 4 recovered lambs required supplemental oxygen. We conclude that rPA ligation creates the physiologic derangements commonly seen in pediatric end-stage lung failure and may be suitable for testing and implanting a PAL. PMID:25905495

  7. Sevoflurane anesthetic preconditioning protects the lung endothelial glycocalyx from ischemia reperfusion injury in an experimental lung autotransplant model.

    PubMed

    Casanova, Javier; Simon, Carlos; Vara, Elena; Sanchez, Guillermo; Rancan, Lisa; Abubakra, Selma; Calvo, Alberto; Gonzalez, Francisco Jose; Garutti, Ignacio

    2016-10-01

    The glycocalyx is a glycoprotein-polysaccaride layer covering the endothelium luminal surface, and plays a key regulatory role in several endothelial functions. Lung ischemia reperfusion (IR) is a clinical entity that occurs in everyday thoracic surgery and causes glycocalix destruction and a florid local and systemic immune response. Moreover, sevoflurane is able to modulate the inflammatory response triggered by IR lung injury. In this study, we evaluated the protective effects of sevoflurane on the pulmonary endothelial glycocalyx in an in-vivo lung autotransplant model in pigs. Sixteen Large White pigs underwent pneumonectomy plus lung autotransplant. They were divided into two groups depending on the hypnotic agent received (propofol or anesthetic preconditioning with sevoflurane). Glycocalyx components (syndecan-1 and heparan sulphate), cathepsin B, chemokines (MCP-1, MIP-1, and MIP-2) and adhesion molecules (VCAM and ICAM-1) were measured at four different timepoints using porcine-specific enzyme-linked immunosorbent assay (ELISA) kits. There were no differences between groups in weight or in surgical and one-lung ventilation time. Greater glycocalyx destruction and higher chemokine and adhesion molecule expression were observed in the group that did not receive sevoflurane. Heparan sulphate and serum syndecan levels were higher in the propofol group (P < 0.0001) after reperfusion, as was cathepsin B activity (P < 0.015). MCP-1, MIP-1, MIP-2, VCAM, and ICAM-1 levels were also higher in the propofol group (P < 0.006). Sevoflurane preconditioning protects pulmonary glycocalyx and reduces expression of leukocyte chemokines in an in-vivo model of pulmonary IR.

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. Validation of a model for flow-dependent carbon dioxide exchange in artificial lungs.

    PubMed

    Hout, M S; Hattler, B G; Federspiel, W J

    2000-02-01

    The exchange rate of CO2 in artificial lungs depends on the sweep gas flow rate. Control of the amount of CO2 removed by an artificial lung requires quantitative knowledge of the flow dependence. A simple model of the dependence of CO2 exchange on sweep gas flow rate in artificial lungs has been previously presented (1). For a given partial pressure of CO2 in the blood phase, sweep gas flow rate, and CO2 exchange rate, the model indicates how close the CO2 exchange rate is to the maximum level attainable by the artificial lung. The focus of this study was to validate the model experimentally by testing 2 commercial artificial lungs in an in vitro test loop. The CO2 exchange rate for each artificial lung was measured over a range of sweep gas flow rates. Linear regression was used to fit the data to the model and estimate the maximum possible CO2 exchange rate and the average water-side PCO2 (PCO2w). The difference between the measured and regressed values of PCO2w was used as an indicator of the ability of the model to quantitatively predict the dependence of CO2 exchange on gas flow rate. This difference was less than 5% for each experiment, indicating that the model can be used to guide control of CO2 exchange rates in artificial lungs.

  13. Modeling gas phase nitric oxide release in lung epithelial cells

    PubMed Central

    Jiang, Jingjing; George, Steven C.

    2012-01-01

    Nitric oxide (NO) is present in exhaled breath and is generally considered to be a noninvasive marker of airway inflammation, and is thus of particular relevance to monitoring asthma. NO is produced when l-arginine is converted to l-citrulline by NO synthase (NOS); however, l-arginine is also the substrate for arginase and both enzymes are upregulated in asthma. Recent reports have speculated that enhanced expression of one or both enzymes could lead to a limitation in substrate availability, and hence impact downstream targets or markers such as exhaled NO. The non-linear nature and vastly different kinetics of the enzymes make predictions difficult, particularly over the wide range of enzyme activity between baseline and inflammation. In this study, we developed a steady state model of l-arginine transmembrane transport, NO production, diffusion, and gas phase NO release from lung epithelial cells. We validated our model with experimental results of gas phase NO release and intracellular l-arginine concentration in A549 cells, and then performed a sensitivity analysis to determine relative impact of each enzyme on NO production. Our model predicts intracellular l-arginine and gas phase NO release over a wide range of initial extracellular l-arginine concentrations following stimulation with cytomix (10 ng/ml TNF-α, IL-1β, and INF-γ). Relative sensitivity analysis demonstrates that enhanced arginase activity has little impact on l-arginine bioavailability for NOS. In addition, NOS activity is the dominant parameter which impacts gas phase NO release. PMID:21550413

  14. Predictive radiogenomics modeling of EGFR mutation status in lung cancer

    PubMed Central

    Gevaert, Olivier; Echegaray, Sebastian; Khuong, Amanda; Hoang, Chuong D.; Shrager, Joseph B.; Jensen, Kirstin C.; Berry, Gerald J.; Guo, H. Henry; Lau, Charles; Plevritis, Sylvia K.; Rubin, Daniel L.; Napel, Sandy; Leung, Ann N.

    2017-01-01

    Molecular analysis of the mutation status for EGFR and KRAS are now routine in the management of non-small cell lung cancer. Radiogenomics, the linking of medical images with the genomic properties of human tumors, provides exciting opportunities for non-invasive diagnostics and prognostics. We investigated whether EGFR and KRAS mutation status can be predicted using imaging data. To accomplish this, we studied 186 cases of NSCLC with preoperative thin-slice CT scans. A thoracic radiologist annotated 89 semantic image features of each patient’s tumor. Next, we built a decision tree to predict the presence of EGFR and KRAS mutations. We found a statistically significant model for predicting EGFR but not for KRAS mutations. The test set area under the ROC curve for predicting EGFR mutation status was 0.89. The final decision tree used four variables: emphysema, airway abnormality, the percentage of ground glass component and the type of tumor margin. The presence of either of the first two features predicts a wild type status for EGFR while the presence of any ground glass component indicates EGFR mutations. These results show the potential of quantitative imaging to predict molecular properties in a non-invasive manner, as CT imaging is more readily available than biopsies. PMID:28139704

  15. Dynamics of Surfactant Liquid Plugs at Bifurcating Lung Airway Models

    NASA Astrophysics Data System (ADS)

    Tavana, Hossein

    2013-11-01

    A surfactant liquid plug forms in the trachea during surfactant replacement therapy (SRT) of premature babies. Under air pressure, the plug propagates downstream and continuously divides into smaller daughter plugs at continuously branching lung airways. Propagating plugs deposit a thin film on airway walls to reduce surface tension and facilitate breathing. The effectiveness of SRT greatly depends on the final distribution of instilled surfactant within airways. To understand this process, we investigate dynamics of splitting of surfactant plugs in engineered bifurcating airway models. A liquid plug is instilled in the parent tube to propagate and split at the bifurcation. A split ratio, R, is defined as the ratio of daughter plug lengths in the top and bottom daughter airway tubes and studied as a function of the 3D orientation of airways and different flow conditions. For a given Capillary number (Ca), orienting airways farther away from a horizontal position reduced R due to the flow of a larger volume into the gravitationally favored daughter airway. At each orientation, R increased with 0.0005 < Ca < 0.05. This effect diminished by decrease in airways diameter. This approach will help elucidate surfactant distribution in airways and develop effective SRT strategies.

  16. 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.

  17. Mitigation of chlorine gas lung injury in rats by postexposure administration of sodium nitrite

    PubMed Central

    Yadav, Amit K.; Doran, Stephen F.; Samal, Andrey A.; Sharma, Ruchita; Vedagiri, Kokilavani; Postlethwait, Edward M.; Squadrito, Giuseppe L.; Fanucchi, Michelle V.; Roberts, L. Jackson; Patel, Rakesh P.

    2011-01-01

    Nitrite (NO2−) has been shown to limit injury to the heart, liver, and kidneys in various models of ischemia-reperfusion injury. Potential protective effects of systemic NO2− in limiting lung injury or enhancing repair have not been documented. We assessed the efficacy and mechanisms by which postexposure intraperitoneal injections of NO2− mitigate chlorine (Cl2)-induced lung injury in rats. Rats were exposed to Cl2 (400 ppm) for 30 min and returned to room air. NO2− (1 mg/kg) or saline was administered intraperitoneally at 10 min and 2, 4, and 6 h after exposure. Rats were killed at 6 or 24 h. Injury to airway and alveolar epithelia was assessed by quantitative morphology, protein concentrations, number of cells in bronchoalveolar lavage (BAL), and wet-to-dry lung weight ratio. Lipid peroxidation was assessed by measurement of lung F2-isoprostanes. Rats developed severe, but transient, hypoxemia. A significant increase of protein concentration, neutrophil numbers, airway epithelia in the BAL, and lung wet-to-dry weight ratio was evident at 6 h after Cl2 exposure. Quantitative morphology revealed extensive lung injury in the upper airways. Airway epithelial cells stained positive for terminal deoxynucleotidyl-mediated dUTP nick end labeling (TUNEL), but not caspase-3. Administration of NO2− resulted in lower BAL protein levels, significant reduction in the intensity of the TUNEL-positive cells, and normal lung wet-to-dry weight ratios. F2-isoprostane levels increased at 6 and 24 h after Cl2 exposure in NO2−- and saline-injected rats. This is the first demonstration that systemic NO2− administration mitigates airway and epithelial injury. PMID:21148791

  18. Differential Effect of Soy Isoflavones in Enhancing High Intensity Radiotherapy and Protecting Lung Tissue in a Pre-Clinical Model of Lung Carcinoma

    PubMed Central

    Hillman, Gilda G.; Singh-Gupta, Vinita; Hoogstra, David J.; Abernathy, Lisa; Rakowski, Joseph; Yunker, Christopher K.; Rothstein, Shoshana E.; Sarkar, Fazlul H.; Gadgeel, Shirish; Konski, Andre A.; Lonardo, Fulvio; Joiner, Michael C.

    2013-01-01

    Background Radiotherapy of locally-advanced non-small cell lung cancer is limited by radiation-induced pneumonitis and fibrosis. We have further investigated the role of soy isoflavones to improve the effect of a high intensity radiation and reduce lung damage in a pre-clinical lung tumor model. Methods Human A549 NSCLC cells were injected i.v. in nude mice to generate a large tumor burden in the lungs. Mice were treated with lung irradiation at 10 Gy and with oral soy. The therapy effect on the tumor cells and surrounding lung tissue was analyzed on lung sections stained with H&E, Ki-67 and Masson’s Trichrome. Pneumonitis and vascular damage were evaluated by measurements of alveolar septa and immunofluorescent staining of vessel walls. Results Combined soy and radiation caused a significantly stronger inhibition of tumor progression compared to each modality alone in contrast to large invasive tumor nodules seen in control mice. At the same time, soy reduced radiation injury in lung tissue by decreasing pneumonitis, fibrosis and protecting alveolar septa, bronchioles and vessels. Conclusions These studies demonstrate a differential effect of soy isoflavones on augmenting tumor destruction induced by radiation while radioprotecting normal lung tissue and support using soy to alleviate radiotoxicity in lung cancer. PMID:24021346

  19. Fluid and electrolyte transport by cultured human airway epithelia.

    PubMed Central

    Smith, J J; Welsh, M J

    1993-01-01

    An understanding of the fluid and electrolyte transport properties of any epithelium requires knowledge of the direction, rate, and regulation of fluid transport and the composition of the fluid. Although human airway epithelial likely play a key role in controlling the quantity and composition of the respiratory tract fluid, evidence for such a role is not available. To obtain such knowledge, we measured fluid and electrolyte transport by cultured human nasal epithelia. Under basal conditions we found that epithelia absorbed Na+ and fluid; both processes were inhibited by addition of amiloride to the mucosal surface. These data suggest that active Na+ absorption is responsible for fluid absorption. Interestingly, Na+ absorption was not accompanied by the net absorption of Cl-; some other anion accompanied Na+. The combination of cAMP agonists and mucosal amiloride stimulated the secretion of NaCl-rich fluid. But surprisingly, the response to cAMP agonists in the absence of amiloride showed substantial intersubject variability: cAMP stimulated fluid secretion across some epithelia, for others, cAMP stimulated fluid absorption. The explanation for the differences in response is uncertain, but we speculate that the magnitude of apical membrane Na+ conductance may modulate the direction of fluid transport in response to cAMP. We also found that airway epithelial secrete H+ and absorb K+ under basal conditions; both processes were inhibited by cAMP agonists. Because the H+/K(+)-ATPase inhibitor, SCH 28080, inhibited K+ absorption, an apical membrane H+/K(+)-ATPase may be at least partly responsible for K+ and H+ transport. However, H+/K+ exchange could not entirely account for the luminal acidification. The finding that cAMP agonists inhibited luminal acidification may be explained by the recent finding that cAMP increases apical HCO3- conductance. These results provide new insights into how the intact airway epithelium may modify the composition of the respiratory

  20. p21 suppresses inflammation and tumorigenesis on pRB-deficient stratified epithelia

    PubMed Central

    Garín, Marina; Ruiz, Sergio; Santos, Mirentxu; Lorz, Corina; García-Escudero, Ramón; Martínez-Fernández, Mónica; Bravo, Ana; Fernández-Capetillo, Oscar; Segrelles, Carmen; Paramio, Jesús M

    2016-01-01

    The retinoblastoma gene product (pRb) controls proliferation and differentiation processes in stratified epithelia. Importantly, an in contrast to other tissues, Rb deficiency does not lead to spontaneous skin tumor formation. As the cyclin dependent kinase inhibitor p21 regulates proliferation and differentiation in the absence of pRb, we analyzed the consequences of deleting p21 in pRb-ablated stratified epithelia (hereafter pRbΔEpi;p21-/-). These mice display an enhancement of the phenotypic abnormalities observed in pRbΔEpi animals, indicating that p21 partially compensates pRb absence. Remarkably, pRbΔEpi;p21-/- mice show an acute skin inflammatory phenotype and develop spontaneous epithelial tumors, particularly affecting tongue and oral tissues. Biochemical analyses and transcriptome studies reveal changes affecting multiple pathways, including DNA damage and p53-dependent signaling responses. Comparative metagenomic analyses, together with the histopathological profiles, indicate that these mice constitute a faithful model for human head and neck squamous cell carcinomas. Collectively, our findings demonstrate that p21, in conjunction with pRb, plays a central role in regulating multiple epithelial processes and orchestrating specific tumor suppressor functions. PMID:24121270

  1. Topological Progression in Proliferating Epithelia Is Driven by a Unique Variation in Polygon Distribution

    PubMed Central

    Sánchez-Gutiérrez, Daniel; Sáez, Aurora; Pascual, Alberto; Escudero, Luis M.

    2013-01-01

    Morphogenesis is consequence of lots of small coordinated variations that occur during development. In proliferating stages, tissue growth is coupled to changes in shape and organization. A number of studies have analyzed the topological properties of proliferating epithelia using the Drosophila wing disc as a model. These works are based in the existence of a fixed distribution of these epithelial cells according to their number of sides. Cell division, cell rearrangements or a combination of both mechanisms have been proposed to be responsible for this polygonal assembling. Here, we have used different system biology methods to compare images from two close proliferative stages that present high morphological similarity. This approach enables us to search for traces of epithelial organization. First, we show that geometrical and network characteristics of individual cells are mainly dependent on their number of sides. Second, we find a significant divergence between the distribution of polygons in epithelia from mid-third instar larva versus early prepupa. We show that this alteration propagates into changes in epithelial organization. Remarkably, only the variation in polygon distribution driven by morphogenesis leads to progression in epithelial organization. In addition, we identify the relevant features that characterize these rearrangements. Our results reveal signs of epithelial homogenization during the growing phase, before the planar cell polarity pathway leads to the hexagonal packing of the epithelium during pupal stages. PMID:24223910

  2. Aurora Kinases Phosphorylate Lgl to Induce Mitotic Spindle Orientation in Drosophila Epithelia

    PubMed Central

    Bell, Graham P.; Fletcher, Georgina C.; Brain, Ruth; Thompson, Barry J.

    2015-01-01

    Summary The Lethal giant larvae (Lgl) protein was discovered in Drosophila as a tumor suppressor in both neural stem cells (neuroblasts) and epithelia. In neuroblasts, Lgl relocalizes to the cytoplasm at mitosis, an event attributed to phosphorylation by mitotically activated aPKC kinase and thought to promote asymmetric cell division. Here we show that Lgl also relocalizes to the cytoplasm at mitosis in epithelial cells, which divide symmetrically. The Aurora A and B kinases directly phosphorylate Lgl to promote its mitotic relocalization, whereas aPKC kinase activity is required only for polarization of Lgl. A form of Lgl that is a substrate for aPKC, but not Aurora kinases, can restore cell polarity in lgl mutants but reveals defects in mitotic spindle orientation in epithelia. We propose that removal of Lgl from the plasma membrane at mitosis allows Pins/LGN to bind Dlg and thus orient the spindle in the plane of the epithelium. Our findings suggest a revised model for Lgl regulation and function in both symmetric and asymmetric cell divisions. PMID:25484300

  3. Changes in lung permeability correlate with lung histology in a chronic exposure model.

    PubMed

    Hays, A M; Parliman, G; Pfaff, J K; Lantz, R C; Tinajero, J; Tollinger, B; Hall, J N; Witten, M L

    1995-01-01

    In a simulated military flight-line exposure protocol, the effects of JP-8 jet fuel exposure on lung epithelial permeability were evaluated in male Fischer 344 rats (F344). Exposures were nose-only and for one hour daily. Groups were exposed for 7, 28, and 56 days. A protocol for administering a low dose (500mg/m3/hr) and a high dose (813-1094mg/m3/hr) of JP-8 jet fuel was used. Longitudinal sham-exposure groups (no jet fuel) for 7, 28, and 56 days were included in the protocol. Lung epithelial permeability was measured by clearance of technetium-labeled diethylenetriamine pentaacetate (99mTcDTPA, molecular weight = 492 daltons, physical half-life = 6.02 hours). The percent clearance of 99mTcDTPA per minute was calculated. Alveolar epithelial clearance for JP-8-exposed rats was dependent on both exposure concentration and duration. It was noted that at low-dose exposure concentrations alveolar epithelial clearance of 99mTcDTPA returned to low levels (LD56 = 1.09% per min; LC56 = 0.98% per min), suggesting recovery as evidenced by microscopic exam. The corresponding 56-day high-dose group (n = 10) had a significantly higher (p < 0.05) value of 2.25% per minute. The 28-day low-dose (n = 15) and high-dose (n = 20) groups had clearance values that were significantly increased from their longitudinal control group (n = 17). The alveolar epithelial permeability values were 2.51, 1.95, and 1.20, respectively. The seven-day longitudinal control, low-dose, and high-dose groups had alveolar permeability values of 1.57, 2.16, and 2.07, respectively. The lung histology correlated with the clearance values. Electron micrographs showed that all groups had interstitial edema resulting from endothelial damage. There was apparent thickening of the alveolar septa, and alveolar macrophages were activated in all groups. Lung permeability data, as determined by 99mTcDTPA alveolar clearance, indicated that lung injuries peaked at 28 days of jet fuel exposure, and this finding

  4. Longitudinal micro-CT provides biomarkers of lung disease that can be used to assess the effect of therapy in preclinical mouse models, and reveal compensatory changes in lung volume.

    PubMed

    Vande Velde, Greetje; Poelmans, Jennifer; De Langhe, Ellen; Hillen, Amy; Vanoirbeek, Jeroen; Himmelreich, Uwe; Lories, Rik J

    2016-01-01

    In vivo lung micro-computed tomography (micro-CT) is being increasingly embraced in pulmonary research because it provides longitudinal information on dynamic disease processes in a field in which ex vivo assessment of experimental disease models is still the gold standard. To optimize the quantitative monitoring of progression and therapy of lung diseases, we evaluated longitudinal changes in four different micro-CT-derived biomarkers [aerated lung volume, lung tissue (including lesions) volume, total lung volume and mean lung density], describing normal development, lung infections, inflammation, fibrosis and therapy. Free-breathing mice underwent micro-CT before and repeatedly after induction of lung disease (bleomycin-induced fibrosis, invasive pulmonary aspergillosis, pulmonary cryptococcosis) and therapy (imatinib). The four lung biomarkers were quantified. After the last time point, we performed pulmonary function tests and isolated the lungs for histology. None of the biomarkers remained stable during longitudinal follow-up of adult healthy mouse lungs, implying that biomarkers should be compared with age-matched controls upon intervention. Early inflammation and progressive fibrosis led to a substantial increase in total lung volume, which affects the interpretation of aerated lung volume, tissue volume and mean lung density measures. Upon treatment of fibrotic lung disease, the improvement in aerated lung volume and function was not accompanied by a normalization of the increased total lung volume. Significantly enlarged lungs were also present in models of rapidly and slowly progressing lung infections. The data suggest that total lung volume changes could partly reflect a compensatory mechanism that occurs during disease progression in mice. Our findings underscore the importance of quantifying total lung volume in addition to aerated lung or lesion volumes to accurately document growth and potential compensatory mechanisms in mouse models of lung

  5. Human Organotypic Lung Tumor Models: Suitable For Preclinical 18F-FDG PET-Imaging

    PubMed Central

    Fecher, David; Hofmann, Elisabeth; Buck, Andreas; Bundschuh, Ralph; Nietzer, Sarah; Dandekar, Gudrun; Walles, Thorsten; Walles, Heike; Lückerath, Katharina; Steinke, Maria

    2016-01-01

    Development of predictable in vitro tumor models is a challenging task due to the enormous complexity of tumors in vivo. The closer the resemblance of these models to human tumor characteristics, the more suitable they are for drug-development and –testing. In the present study, we generated a complex 3D lung tumor test system based on acellular rat lungs. A decellularization protocol was established preserving the architecture, important ECM components and the basement membrane of the lung. Human lung tumor cells cultured on the scaffold formed cluster and exhibited an up-regulation of the carcinoma-associated marker mucin1 as well as a reduced proliferation rate compared to respective 2D culture. Additionally, employing functional imaging with 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) these tumor cell cluster could be detected and tracked over time. This approach allowed monitoring of a targeted tyrosine kinase inhibitor treatment in the in vitro lung tumor model non-destructively. Surprisingly, FDG-PET assessment of single tumor cell cluster on the same scaffold exhibited differences in their response to therapy, indicating heterogeneity in the lung tumor model. In conclusion, our complex lung tumor test system features important characteristics of tumors and its microenvironment and allows monitoring of tumor growth and -metabolism in combination with functional imaging. In longitudinal studies, new therapeutic approaches and their long-term effects can be evaluated to adapt treatment regimes in future. PMID:27501455

  6. Interaction of epithelium with mesenchyme affects global features of lung architecture: a computer model of development.

    PubMed

    Tebockhorst, Seth; Lee, Dongyoub; Wexler, Anthony S; Oldham, Michael J

    2007-01-01

    Lung airway morphogenesis is simulated in a simplified diffusing environment that simulates the mesenchyme to explore the role of morphogens in airway architecture development. Simple rules govern local branching morphogenesis. Morphogen gradients are modeled by four pairs of sources and their diffusion through the mesenchyme. Sensitivity to lobar architecture and mesenchymal morphogen are explored. Even if the model accurately represents observed patterns of local development, it could not produce realistic global patterns of lung architecture if interaction with its environment was not taken into account, implying that reciprocal interaction between airway growth and morphogens in the mesenchyme plays a critical role in producing realistic global features of lung architecture.

  7. Asymmetric dimethylarginine potentiates lung inflammation in a mouse model of allergic asthma

    PubMed Central

    Klein, Elizabeth; Weigel, Jason; Buford, Mary C.; Holian, Andrij

    2010-01-01

    Nitric oxide (NO), formed by nitric oxide synthase (NOS), is an important mediator of lung inflammation in allergic asthma. Asymmetric dimethylarginine (ADMA), a competitive endogenous inhibitor of NOS, is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Elevated ADMA has been shown to affect lung function in mice, and by inhibiting NOS it alters NO and reactive oxygen species production in mouse lung epithelial cells. However, the effects of altered ADMA levels during lung inflammation have not been explored. A model of allergen-induced airway inflammation was utilized in combination with the modulation of endogenous circulating ADMA levels in mice. Airway inflammation was assessed by quantifying inflammatory cell infiltrates in lung lavage and by histology. Lung DDAH expression was assessed by quantitative PCR and immunohistochemistry. Nitrite levels were determined in lung lavage fluid as a measure of NO production. iNOS expression was determined by immunohistochemistry, immunofluorescence, Western blot, and quantitative PCR. NF-κB binding activity was assessed by a transcription factor binding assay. Allergen-induced lung inflammation was potentiated in mice with elevated circulating ADMA and was reduced in mice overexpressing DDAH. Elevated ADMA reduced nitrite levels in lung lavage fluid in both allergen-challenged and control animals. ADMA increased iNOS expression in airway epithelial cells in vivo following allergen challenge and in vitro in stimulated mouse lung epithelial cells. ADMA also increased NF-κB binding activity in airway epithelial cells in vitro. These data support that ADMA may play a role in inflammatory airway diseases such as asthma through modulation of iNOS expression in lung epithelial cells. PMID:20889675

  8. A simple classification model for hospital mortality in patients with acute lung injury managed with lung protective ventilation.

    PubMed

    Brown, Lisa M; Calfee, Carolyn S; Matthay, Michael A; Brower, Roy G; Thompson, B Taylor; Checkley, William

    2011-12-01

    Despite improvements in the care of critically ill patients, hospital mortality rate for acute lung injury remains high at approximately 40%. We developed a classification rule to stratify mechanically ventilated patients with acute lung injury according to hospital mortality and compared this rule with the Acute Physiology and Chronic Health Evaluation III prediction. We used data of 2,022 participants in Acute Respiratory Distress Syndrome Network trials to build a classification rule based on 54 variables collected before randomization. We used a classification tree approach to stratify patients according to hospital mortality using a training subset of 1800 participants and estimated expected prediction errors using tenfold crossvalidation. We validated our classification tree using a subset of 222 participants not included in model building and calculated areas under the receiver operating characteristic curves. We identified combinations of age (>63 yrs), blood urea nitrogen (>15 mg/dL), shock, respiratory rate (>21 breaths/min), and minute ventilation (>13.9 L/min) as important predictors of hospital mortality at 90 days. The classification tree had a similar expected prediction error in the training set (28% vs. 26%; p = .18) and areas under the receiver operating characteristic curve in the validation set (0.71 vs. 0.73; p = .71) as did a model based on Acute Physiology and Chronic Health Evaluation III. Our tree-based classification rule performed similarly to Acute Physiology and Chronic Health Evaluation III in stratifying patients according to hospital mortality, is simpler to use, contains risk factors that may be specific to acute lung injury, and identified minute ventilation as a potential novel predictor of death in patients with acute lung injury.

  9. The Implantable Pediatric Artificial Lung: Interim Report on the Development of an End-Stage Lung Failure Model.

    PubMed

    Alghanem, Fares; Davis, Ryan P; Bryner, Benjamin S; Hoffman, Hayley R; Trahanas, John; Cornell, Marie S; Rojas-Peña, Alvaro; Bartlett, Robert H; Hirschl, Ronald B

    2015-01-01

    An implantable pediatric artificial lung (PAL) may serve as a bridge to lung transplantation for children with end-stage lung failure (ESLF); however, an animal model of pediatric lung failure is needed to evaluate the efficacy of PAL before it can enter clinical trials. The objective of this study was to assess ligation of the right pulmonary artery (rPA) as a model for pediatric ESLF. Seven lambs weighing 20-30 kg underwent rPA ligation and were recovered and monitored for up to 4 days. Intraoperatively, rPA ligation significantly increased physiologic dead space fraction (Vd/Vt; baseline = 48.6 ± 5.7%, rPA ligation = 60.1 ± 5.2%, p = 0.012), mean pulmonary arterial pressure (mPPA; baseline = 17.4 ± 2.2 mm Hg, rPA ligation = 28.5 ± 5.2 mm Hg, p < 0.001), and arterial partial pressure of carbon dioxide (baseline = 40.4 ± 9.3 mm Hg, rPA ligation = 57.3 ± 12.7 mm Hg, p = 0.026). Of the seven lambs, three were unable to be weaned from mechanical ventilation postoperatively, three were successfully weaned but suffered cardiorespiratory failure within 4 days, and one survived all 4 days. All four animals that were successfully weaned from mechanical ventilation had persistent pulmonary hypertension (mPPA = 28.6 ± 2.2 mm Hg) and remained tachypneic (respiratory rate = 63 ± 21 min). Three of the four recovered lambs required supplemental oxygen. We conclude that rPA ligation creates the physiologic derangements commonly seen in pediatric ESLF and may be suitable for testing and implanting a PAL.

  10. Lung Impedance Contributions to the Total Impedance based on a FDM Model and Lead Field Theory.

    PubMed

    Patterson, Robert; Yang, Fei

    2005-01-01

    Predicting tissue resistivity is of significance in medical diagnosis due to the fact that disease induces related tissue resistivity change. Studies have shown that the lung and tissues tumors reflect significant impedance change with disease states. It is hypothesized that the impedance measurement with the largest contribution from the organ of interest will result in less error. In this paper, we determined the percentage contribution of the lung impedance to the total impedance for five different external electrode configurations using a high resolution finite difference model (FDM) of the thorax along with lead field theory. The electrode combinations showed a contribution by the lungs of approximately 20% of the total impedance. Many configurations showed contributions of 15%. The results also showed that each lung could be isolated from the opposite lung.

  11. A Peptide to Reduce Pulmonary Edema in a Rat Model of Lung Transplantation

    PubMed Central

    Finsterwalder, Richard; Friedl, Heinz P.; Rauscher, Sabine; Gröger, Marion; Kocher, Alfred; Wagner, Christine; Wagner, Stephan N.; Fischer, Gottfried; Schultz, Marcus J.; Wiedemann, Dominik; Petzelbauer, Peter

    2015-01-01

    Background Despite significant advances in organ preservation, surgical techniques and perioperative care, primary graft dysfunction is a serious medical problem in transplantation medicine in general and a specific problem in patients undergoing lung transplantation. As a result, patients develop lung edema, causing reduced tissue oxygenation capacity, reduced lung compliance and increased requirements for mechanical ventilatory support. Yet, there is no effective strategy available to protect the grafted organ from stress reactions induced by ischemia/reperfusion and by the surgical procedure itself. Methods We assessed the effect of a cingulin-derived peptide, XIB13 or a random peptide in an established rat model of allogeneic lung transplantation. Donor lungs and recipients received therapeutic peptide at the time of transplantation and outcome was analyzed 100min and 28 days post grafting. Results XIB13 improved blood oxygenation and reduced vascular leak 100min post grafting. Even after 28 days, lung edema was significantly reduced by XIB13 and lungs had reduced fibrotic or necrotic zones. Moreover, the induction of an allogeneic T cell response was delayed indicating a reduced antigen exchange between the donor and the host. Conclusions In summary, we provide a new tool to strengthen endothelial barrier function thereby improving outcomes in lung transplantation. PMID:26536466

  12. 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.

  13. 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.

  14. Experimental chronic kidney disease attenuates ischemia-reperfusion injury in an ex vivo rat lung model

    PubMed Central

    Huang, Kun-Lun; Lan, Chou-Chin; Hsu, Yu-Juei; Wu, Geng-Chin; Peng, Chia-Hui

    2017-01-01

    Lung ischemia reperfusion injury (LIRI) is one of important complications following lung transplant and cardiopulmonary bypass. Although patients on hemodialysis are still excluded as lung transplant donors because of the possible effects of renal failure on the lungs, increased organ demand has led us to evaluate the influence of chronic kidney disease (CKD) on LIRI. A CKD model was induced by feeding Sprague-Dawley rats an adenine-rich (0.75%) diet for 2, 4 and 6 weeks, and an isolated rat lung in situ model was used to evaluate ischemia reperfusion (IR)-induced acute lung injury. The clinicopathological parameters of LIRI, including pulmonary edema, lipid peroxidation, histopathological changes, immunohistochemistry changes, chemokine CXCL1, inducible nitric oxide synthase (iNOS), proinflammatory and anti-inflammatory cytokines, heat shock protein expression, and nuclear factor-κB (NF-κB) activation were determined. Our results indicated that adenine-fed rats developed CKD as characterized by increased blood urea nitrogen and creatinine levels and the deposition of crystals in the renal tubules and interstitium. IR induced a significant increase in the pulmonary arterial pressure, lung edema, lung injury scores, the expression of CXCL1 mRNA, iNOS level, and protein concentration of the bronchial alveolar lavage fluid (BALF). The tumor necrosis factor-α levels in the BALF and perfusate; the interleukin-10 level in the perfusate; and the malondialdehyde levels in the lung tissue and perfusate were also significantly increased by LIRI. Counterintuitively, adenine-induced CKD significantly attenuated the severity of lung injury induced by IR. CKD rats exhibited increased heat shock protein 70 expression and decreased activation of NF-κB signaling. In conclusion, adenine-induced CKD attenuated LIRI by inhibiting the NF-κB pathway. PMID:28291795

  15. Slit-Robo Repulsive Signaling Extrudes Tumorigenic Cells from Epithelia.

    PubMed

    Vaughen, John; Igaki, Tatsushi

    2016-12-19

    Cells dynamically interact throughout animal development to coordinate growth and deter disease. For example, cell-cell competition weeds out aberrant cells to enforce homeostasis. In Drosophila, tumorigenic cells mutant for the cell polarity gene scribble (scrib) are actively eliminated from epithelia when surrounded by wild-type cells. While scrib cell elimination depends critically on JNK signaling, JNK-dependent cell death cannot sufficiently explain scrib cell extirpation. Thus, how JNK executed cell elimination remained elusive. Here, we show that repulsive Slit-Robo2-Ena signaling exerts an extrusive force downstream of JNK to eliminate scrib cells from epithelia by disrupting E-cadherin. While loss of Slit-Robo2-Ena in scrib cells potentiates scrib tumor formation within the epithelium, Robo2-Ena hyperactivation surprisingly triggers luminal scrib tumor growth following excess extrusion. This extrusive signaling is amplified by a positive feedback loop between Slit-Robo2-Ena and JNK. Our observations provide a potential causal mechanism for Slit-Robo dysregulation in numerous human cancers.

  16. Taurine levels and localisation in the stratified squamous epithelia.

    PubMed

    Lobo, M V; Alonso, F J; Latorre, A; Martín del Río, R

    2001-04-01

    The content and distribution of the amino acid taurine in squamous epithelia were studied using high-performance liquid chromatography and immunohistochemical methods. Quantitative analysis demonstrated that taurine was highly concentrated in the epidermis (5.49 mumol/g fresh tissue in the hairless skin of the hind footpad of the rat), although the values in the isolated stratum corneum were extremely low (< 0.073 mumol/g in the horny layer of the same skin area). No other analysed amino acid (such as glutamate, glutamine, glycine or alanine) showed this specific pattern of distribution. The immunohistochemical study revealed that in the dog and rat epidermis, taurine was present in the keratinocytes of the granular and upper spinous layers. The basal layer, lower spinous layer and stratum corneum were immunonegative. A similar immunostaining pattern was found in the epithelia of the different organs studied: the mouth, tongue and oesophagus of the dog and rat, the rat forestomach and the rat corneal epithelium. Other cell types, such as sebaceous and muscle cells, were immunolabelled. The existence of a circulating pool of taurine in the epidermis (via taurine release from keratinocytes before they reach the horny layer and its uptake by nearby cells) and its possible roles in these cells are discussed.

  17. Dynamics of Bacterial Community Composition in the Malaria Mosquito's Epithelia.

    PubMed

    Tchioffo, Majoline T; Boissière, Anne; Abate, Luc; Nsango, Sandrine E; Bayibéki, Albert N; Awono-Ambéné, Parfait H; Christen, Richard; Gimonneau, Geoffrey; Morlais, Isabelle

    2015-01-01

    The Anopheles midgut hosts diverse bacterial communities and represents a complex ecosystem. Several evidences indicate that mosquito midgut microbiota interferes with malaria parasite transmission. However, the bacterial composition of salivary glands and ovaries, two other biologically important tissues, has not been described so far. In this study, we investigated the dynamics of the bacterial communities in the mosquito tissues from emerging mosquitoes until 8 days after a blood meal containing Plasmodium falciparum gametocytes and described the temporal colonization of the mosquito epithelia. Bacterial communities were identified in the midgut, ovaries, and salivary glands of individual mosquitoes using pyrosequencing of the 16S rRNA gene. We found that the mosquito epithelia share a core microbiota, but some bacteria taxa were more associated with one or another tissue at a particular time point. The bacterial composition in the tissues of emerging mosquitoes varied according to the breeding site, indicating that some bacteria are acquired from the environment. Our results revealed temporal variations in the bacterial community structure, possibly as a result of the mosquito physiological changes. The abundance of Serratia significantly correlated with P. falciparum infection both in the midgut and salivary glands of malaria challenged mosquitoes, which suggests that interactions occur between microbes and parasites. These bacteria may represent promising targets for vector control strategies. Overall, this study points out the importance of characterizing bacterial communities in malaria mosquito vectors.

  18. Dynamics of Bacterial Community Composition in the Malaria Mosquito's Epithelia

    PubMed Central

    Tchioffo, Majoline T.; Boissière, Anne; Abate, Luc; Nsango, Sandrine E.; Bayibéki, Albert N.; Awono-Ambéné, Parfait H.; Christen, Richard; Gimonneau, Geoffrey; Morlais, Isabelle

    2016-01-01

    The Anopheles midgut hosts diverse bacterial communities and represents a complex ecosystem. Several evidences indicate that mosquito midgut microbiota interferes with malaria parasite transmission. However, the bacterial composition of salivary glands and ovaries, two other biologically important tissues, has not been described so far. In this study, we investigated the dynamics of the bacterial communities in the mosquito tissues from emerging mosquitoes until 8 days after a blood meal containing Plasmodium falciparum gametocytes and described the temporal colonization of the mosquito epithelia. Bacterial communities were identified in the midgut, ovaries, and salivary glands of individual mosquitoes using pyrosequencing of the 16S rRNA gene. We found that the mosquito epithelia share a core microbiota, but some bacteria taxa were more associated with one or another tissue at a particular time point. The bacterial composition in the tissues of emerging mosquitoes varied according to the breeding site, indicating that some bacteria are acquired from the environment. Our results revealed temporal variations in the bacterial community structure, possibly as a result of the mosquito physiological changes. The abundance of Serratia significantly correlated with P. falciparum infection both in the midgut and salivary glands of malaria challenged mosquitoes, which suggests that interactions occur between microbes and parasites. These bacteria may represent promising targets for vector control strategies. Overall, this study points out the importance of characterizing bacterial communities in malaria mosquito vectors. PMID:26779155

  19. Lung Surfactant Protein A (SP-A) Interactions with Model Lung Surfactant Lipids and an SP-B Fragment

    PubMed Central

    2011-01-01

    Surfactant protein A (SP-A) is the most abundant protein component of lung surfactant, a complex mixture of proteins and lipids. SP-A performs host defense activities and modulates the biophysical properties of surfactant in concerted action with surfactant protein B (SP-B). Current models of lung surfactant mechanism generally assume SP-A functions in its octadecameric form. However, one of the findings of this study is that when SP-A is bound to detergent and lipid micelles that mimic lung surfactant phospholipids, it exists predominantly as smaller oligomers, in sharp contrast to the much larger forms observed when alone in water. These investigations were carried out in sodium dodecyl sulfate (SDS), dodecylphosphocholine (DPC), lysomyristoylphosphatidylcholine (LMPC), lysomyristoylphosphatidylglycerol (LMPG), and mixed LMPC + LMPG micelles, using solution and diffusion nuclear magnetic resonance (NMR) spectroscopy. We have also probed SP-A’s interaction with Mini-B, a biologically active synthetic fragment of SP-B, in the presence of micelles. Despite variations in Mini-B’s own interactions with micelles of different compositions, SP-A is found to interact with Mini-B in all micelle systems and perhaps to undergo a further structural rearrangement upon interacting with Mini-B. The degree of SP-A–Mini-B interaction appears to be dependent on the type of lipid headgroup and is likely mediated through the micelles, rather than direct binding. PMID:21553841

  20. Lung surfactant protein A (SP-A) interactions with model lung surfactant lipids and an SP-B fragment.

    PubMed

    Sarker, Muzaddid; Jackman, Donna; Booth, Valerie

    2011-06-07

    Surfactant protein A (SP-A) is the most abundant protein component of lung surfactant, a complex mixture of proteins and lipids. SP-A performs host defense activities and modulates the biophysical properties of surfactant in concerted action with surfactant protein B (SP-B). Current models of lung surfactant mechanism generally assume SP-A functions in its octadecameric form. However, one of the findings of this study is that when SP-A is bound to detergent and lipid micelles that mimic lung surfactant phospholipids, it exists predominantly as smaller oligomers, in sharp contrast to the much larger forms observed when alone in water. These investigations were carried out in sodium dodecyl sulfate (SDS), dodecylphosphocholine (DPC), lysomyristoylphosphatidylcholine (LMPC), lysomyristoylphosphatidylglycerol (LMPG), and mixed LMPC + LMPG micelles, using solution and diffusion nuclear magnetic resonance (NMR) spectroscopy. We have also probed SP-A's interaction with Mini-B, a biologically active synthetic fragment of SP-B, in the presence of micelles. Despite variations in Mini-B's own interactions with micelles of different compositions, SP-A is found to interact with Mini-B in all micelle systems and perhaps to undergo a further structural rearrangement upon interacting with Mini-B. The degree of SP-A-Mini-B interaction appears to be dependent on the type of lipid headgroup and is likely mediated through the micelles, rather than direct binding.

  1. Validation of a model of lung cancer risk prediction among smokers.

    PubMed

    Cronin, Kathleen A; Gail, Mitchell H; Zou, Zhaohui; Bach, Peter B; Virtamo, Jarmo; Albanes, Demetrius

    2006-05-03

    The Bach model was developed to predict the absolute 10-year risk of developing lung cancer among smokers by use of participants in the Carotene and Retinol Efficacy Trial of lung cancer prevention. We assessed the validity of the Bach model among 6239 smokers from the placebo arm of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. The expected numbers of lung cancer cases and deaths without lung cancer were calculated from the Bach model and compared with the observed numbers of corresponding events over 10 years. We found that the risk model slightly underestimated the observed lung cancer risk (number of lung cancers expected/number observed = 0.89, 95% confidence interval [CI] = 0.80 to 0.99) over 10 years. The competing risk portion of the model substantially underestimated risk of non-lung cancer mortality (number of non-lung cancer deaths expected/number observed = 0.61, 95% CI = 0.57 to 0.64) over 10 years. The age-specific concordance indices for 10-year predictions were 0.77 (95% CI = 0.70 to 0.84), 0.59 (95% CI = 0.53 to 0.65), 0.62 (95% CI = 0.57 to 0.67), and 0.57 (95% CI = 0.49 to 0.67) for the age groups 50-54, 55-59, 60-64, and 65-69 years, respectively. Periodic radiographic screening in the ATBC Study may explain why slightly more cancers were observed than expected from the Bach model.

  2. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2017-03-01

    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.

  4. Towards an Ecology of the Lung: New Conceptual Models of Pulmonary Microbiology and Pneumonia Pathogenesis

    PubMed Central

    Dickson, Robert P.; Erb-Downward, John R.; Huffnagle, Gary B.

    2014-01-01

    Summary Pneumonia is a major cause of morbidity and mortality for which no new methods of treatment have entered clinical practice since the discovery of antibiotics. Innovations in the techniques of culture-independent microbial identification have shown that the lungs, previously deemed sterile in the absence of infection, contain diverse and dynamic communities of microbes. In this Personal View, we argue that these observations have shown the inadequacy of traditional conceptual models of lung microbiology and the pathogenesis of pneumonia, hampering progress in research and practice. We propose three new conceptual models to replace the traditional models of lung microbiology: an adapted island model of lung biogeography, the effect of environmental gradients on lung microbiota, and pneumonia as an emergent phenomenon propelled by unexplored positive feedback loops. We argue that the ecosystem of lung microbiota has all of the features of a complex adaptive system: diverse entities interacting with each other within a common space, showing interdependent actions and possessing the capacity to adapt to changes in conditions. Complex adaptive systems are fundamentally different in behaviour from the simple, linear systems typified by the traditional model of pneumonia pathogenesis, and need distinct analytical approaches. PMID:24621685

  5. Stigma among patients with lung cancer: A patient-reported measurement model

    PubMed Central

    Hamann, Heidi A.; Ostroff, Jamie S.; Marks, Emily G.; Gerber, David E.; Schiller, Joan H.; Craddock Lee, Simon J.

    2014-01-01

    Objective Although stigma may have negative psychosocial and behavioral outcomes for patients with lung cancer, its measurement has been limited. A conceptual model of lung cancer stigma and a patient-reported outcome (PRO) measure is needed to mitigate these sequelae. This study identified key stigma-related themes to provide a blueprint for item development through thematic analysis of semi-structured interviews and focus groups with lung cancer patients. Methods Participants were recruited from two outpatient oncology clinics and included: a) 42 lung cancer patients who participated in individual interviews and, b) 5 focus groups (inclusive of 23 new lung cancer patients). Never smokers, long-term quitters, recent quitters, and current smokers participated. Individual interviews facilitated theme development and a conceptual model of lung cancer stigma, whereas subsequent focus groups provided feedback on the conceptual model. Qualitative data analyses included iterative coding and validation with existing theory. Results Two main thematic elements emerged from interviews with lung cancer patients: perceived (felt) stigma and internalized (self) stigma. Discussions of perceived stigma were pervasive, while internalized stigma was more commonly endorsed among current and recently quit smokers. Participants also discussed maladaptive (e.g., decreased disclosure) and adaptive (e.g., increased advocacy) stigma-related consequences. Conclusions Results indicate widespread acknowledgment of perceived stigma among lung cancer patients, but varying degrees of internalized stigma and associated consequences. Next steps for PRO measure development are item consolidation, item development, expert input, and cognitive interviews before field testing and psychometric analysis. Future work should address stigma-related consequences and interventions for reducing lung cancer stigma. PMID:24123664

  6. Stigma among patients with lung cancer: a patient-reported measurement model.

    PubMed

    Hamann, Heidi A; Ostroff, Jamie S; Marks, Emily G; Gerber, David E; Schiller, Joan H; Lee, Simon J Craddock

    2014-01-01

    Although stigma may have negative psychosocial and behavioral outcomes for patients with lung cancer, its measurement has been limited. A conceptual model of lung cancer stigma and a patient-reported outcome measure are needed to mitigate these sequelae. This study identified key stigma-related themes to provide a blueprint for item development through a thematic analysis of semi-structured interviews and focus groups with lung cancer patients. Participants were recruited from two outpatient oncology clinics and included (i) 42 lung cancer patients who participated in individual interviews and (ii) 5 focus groups (inclusive of 23 new lung cancer patients). Never smokers, long-term quitters, recent quitters, and current smokers participated. Individual interviews facilitated theme development and a conceptual model of lung cancer stigma, whereas subsequent focus groups provided feedback on the conceptual model. Qualitative data analyses included iterative coding and validation with existing theory. Two main thematic elements emerged from interviews with lung cancer patients: perceived (felt) stigma and internalized (self) stigma. Discussions of perceived stigma were pervasive, whereas those of internalized stigma were more commonly endorsed among current and recently quit smokers. Participants also discussed maladaptive (e.g., decreased disclosure) and adaptive (e.g., increased advocacy) stigma-related consequences. Results indicate widespread acknowledgment of perceived stigma among lung cancer patients but varying degrees of internalized stigma and associated consequences. Next steps for patient-reported outcome measure development are item consolidation, item development, expert input, and cognitive interviews before field testing and psychometric analysis. Future work should address stigma-related consequences and interventions for reducing lung cancer stigma. Copyright © 2013 John Wiley & Sons, Ltd.

  7. c-ANCA-induced neutrophil-mediated lung injury: a model of acute Wegener's granulomatosis.

    PubMed

    Hattar, K; Oppermann, S; Ankele, C; Weissmann, N; Schermuly, R T; Bohle, R M; Moritz, R; Krögel, B; Seeger, W; Grimminger, F; Sibelius, U; Grandel, U

    2010-07-01

    Anti-neutrophil cytoplasmic antibodies (c-ANCA) targeting proteinase 3 (PR3) are implicated in the pathogenesis of Wegener's granulomatosis (WG). Fulminant disease can present as acute lung injury (ALI). In this study, a model of ALI in WG was developed using isolated rat lungs. Isolated human polymorphonuclear leukocytes (PMNs) were primed with tumour necrosis factor (TNF) to induce surface expression of PR3. Co-perfusion of TNF-primed neutrophils and monoclonal anti-PR3 antibodies induced a massive weight gain in isolated lungs. This effect was not observed when control immunoglobulin G was co-perfused with TNF-primed PMNs. The c-ANCA-induced oedema formation was paralleled by an increase in the capillary filtration coefficient as a marker of increased pulmonary endothelial permeability. In contrast, pulmonary artery pressure was not affected. In the presence of the oxygen radical scavenger superoxide dismutase and a NADPH oxidase inhibitor, c-ANCA-induced lung oedema could be prevented. Inhibition of neutrophil elastase was equally effective in preventing c-ANCA-induced lung injury. In conclusion, anti-PR3 antibodies induced neutrophil mediated, elastase- and oxygen radical-dependent ALI in the isolated lung. This experimental model supports the hypothesis of a pathogenic role for c-ANCA in WG and offers the possibility of the development of therapeutic strategies for the treatment of lung injury in fulminant WG.

  8. Therapeutic Efficacy of Esomeprazole in Cotton Smoke-Induced Lung Injury Model

    PubMed Central

    Nelson, Christina; Lee, Jameisha; Ko, Kang; Sikora, Andrew G.; Bonnen, Mark D.; Enkhbaatar, Perenlei; Ghebre, Yohannes T.

    2017-01-01

    Proton pump inhibitors (PPIs) are well-known antacid drugs developed to treat gastric disorders. Emerging studies demonstrate that PPIs possess biological activities that extend beyond inhibition of H+/K+ ATPase (proton pumps) expressed in parietal cells of the stomach. Some of the extra-gastric activities of PPIs include modulation of epithelial, endothelial, and immune cell functions. Recently, we reported that PPIs suppress the expression of several proinflammatory and profibrotic molecules, as well as enhance antioxidant mechanisms in order to favorably regulate lung inflammation and fibrosis in an animal model of bleomycin-induced lung injury. In addition, several retrospective clinical studies report that the use of PPIs is associated with beneficial outcomes in chronic lung diseases including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Based on these preclinical and clinical observations, we hypothesized that PPIs ameliorate smoke-induced lung injury. Accordingly, we evaluated the pharmacological efficacy of the PPI esomeprazole in a mouse model of cotton smoke-induced lung injury. The animals were exposed to cotton smoke for 3-weeks in the presence or absence of esomeprazole treatment. We found that therapeutic administration of esomeprazole significantly inhibited the progression of fibrosis throughout the lungs of the animals in this group compared to controls. In addition, esomeprazole also reduced circulating markers of inflammation and fibrosis. Overall, our work extends the emerging anti-inflammatory and antifibrotic potential of PPIs and their role in modulation of chronic lung diseases. PMID:28184197

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

    PubMed

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

    2015-08-14

    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.

  10. 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

  11. 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

  12. Development of a Three-Dimensional Bioengineering Technology to Generate Lung Tissue for Personalized Disease Modeling.

    PubMed

    Wilkinson, Dan C; Alva-Ornelas, Jackelyn A; Sucre, Jennifer M S; Vijayaraj, Preethi; Durra, Abdo; Richardson, Wade; Jonas, Steven J; Paul, Manash K; Karumbayaram, Saravanan; Dunn, Bruce; Gomperts, Brigitte N

    2017-02-01

    Stem cell technologies, especially patient-specific, induced stem cell pluripotency and directed differentiation, hold great promise for changing the landscape of medical therapies. Proper exploitation of these methods may lead to personalized organ transplants, but to regenerate organs, it is necessary to develop methods for assembling differentiated cells into functional, organ-level tissues. The generation of three-dimensional human tissue models also holds potential for medical advances in disease modeling, as full organ functionality may not be necessary to recapitulate disease pathophysiology. This is specifically true of lung diseases where animal models often do not recapitulate human disease. Here, we present a method for the generation of self-assembled human lung tissue and its potential for disease modeling and drug discovery for lung diseases characterized by progressive and irreversible scarring such as idiopathic pulmonary fibrosis (IPF). Tissue formation occurs because of the overlapping processes of cellular adhesion to multiple alveolar sac templates, bioreactor rotation, and cellular contraction. Addition of transforming growth factor-β1 to single cell-type mesenchymal organoids resulted in morphologic scarring typical of that seen in IPF but not in two-dimensional IPF fibroblast cultures. Furthermore, this lung organoid may be modified to contain multiple lung cell types assembled into the correct anatomical location, thereby allowing cell-cell contact and recapitulating the lung microenvironment. Our bottom-up approach for synthesizing patient-specific lung tissue in a scalable system allows for the development of relevant human lung disease models with the potential for high throughput drug screening to identify targeted therapies. Stem Cells Translational Medicine 2017;6:622-633.

  13. Development of a Three-Dimensional Bioengineering Technology to Generate Lung Tissue for Personalized Disease Modeling.

    PubMed

    Wilkinson, Dan C; Alva-Ornelas, Jackelyn A; Sucre, Jennifer M S; Vijayaraj, Preethi; Durra, Abdo; Richardson, Wade; Jonas, Steven J; Paul, Manash K; Karumbayaram, Saravanan; Dunn, Bruce; Gomperts, Brigitte N

    2016-09-15

    : Stem cell technologies, especially patient-specific, induced stem cell pluripotency and directed differentiation, hold great promise for changing the landscape of medical therapies. Proper exploitation of these methods may lead to personalized organ transplants, but to regenerate organs, it is necessary to develop methods for assembling differentiated cells into functional, organ-level tissues. The generation of three-dimensional human tissue models also holds potential for medical advances in disease modeling, as full organ functionality may not be necessary to recapitulate disease pathophysiology. This is specifically true of lung diseases where animal models often do not recapitulate human disease. Here, we present a method for the generation of self-assembled human lung tissue and its potential for disease modeling and drug discovery for lung diseases characterized by progressive and irreversible scarring such as idiopathic pulmonary fibrosis (IPF). Tissue formation occurs because of the overlapping processes of cellular adhesion to multiple alveolar sac templates, bioreactor rotation, and cellular contraction. Addition of transforming growth factor-β1 to single cell-type mesenchymal organoids resulted in morphologic scarring typical of that seen in IPF but not in two-dimensional IPF fibroblast cultures. Furthermore, this lung organoid may be modified to contain multiple lung cell types assembled into the correct anatomical location, thereby allowing cell-cell contact and recapitulating the lung microenvironment. Our bottom-up approach for synthesizing patient-specific lung tissue in a scalable system allows for the development of relevant human lung disease models with the potential for high throughput drug screening to identify targeted therapies.

  14. 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

  15. 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

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

    PubMed

    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.

  17. 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

  18. Evaluation and application of 3D lung warping and registration model using HRCT images

    NASA Astrophysics Data System (ADS)

    Fan, Li; Chen, Chang W.; Reinhardt, Joseph M.; Hoffman, Eric A.

    2001-05-01

    Image-based study of structure-function relationships is a challenging problem in that the structure or region of interest may vary in position and shape on images captured over time. Such variation may be caused by the change in body posture or the motion of breathing and heart beating. Therefore, the structure or region of interest should be registered before any further regional study can be carried out. In this paper, we propose a novel approach to study the structure-function relationship of ventilation using a previously developed 3D lung warping and registration model. First, we evaluate the effectiveness of the lung warping and registration model using a set of criteria, including apparent lung motion patterns and ground truths. Then, we study the ventilation by integrating the warping model with air content calibration. The warping model is applied to three CT lung data sets, obtained under volume control of FRC, 40% and 75% vital capacity (VC). Dense displacement fields are obtained to represent deformation between different lung volume steps. For any specific region of interest, we first register it between images over time using the dense displacement, and then estimate the corresponding regional inspired air content. Assessments include change of regional volume during inspiration, change of regional air content, and the distribution of regional ventilation. This is the first time that 3D warping of lung images is applied to assess clinically significant pulmonary functions.

  19. Mineral-fluid interaction in the lungs: insights from reaction-path modeling.

    PubMed

    Wood, Scott A; Taunton, Anne E; Normand, Charles; Gunter, Mickey E

    2006-11-01

    Thermodynamic modeling, in conjunction with available kinetic information, has been employed to investigate the fate of chrysotile and tremolite in the human lung. In particular, we focus on mineral-fluid reactions using techniques borrowed from geochemistry, including calculation of saturation indices, activity-ratio phase diagrams, and reaction-path modeling. Saturation index calculations show that fresh lung fluid is undersaturated with respect to both tremolite and chrysotile and these minerals should dissolve, in accordance with conclusions from previous work described in the literature. Modeling of reaction paths in both closed and open systems confirms previous suggestions that chrysotile dissolves faster than tremolite in lung fluid, which offers an explanation for the apparent increase in tremolite/chrysotile ratios in lungs of miners and millers over time. However, examination of activity-ratio phase diagrams and reaction-path model calculations raises the possibility not only that minerals dissolve congruently in lung fluid, but that secondary minerals such as talc or various Ca-Mg carbonates might potentially form in lung fluid as asbestiform minerals dissolve.

  20. Tobacco carcinogen NNK-induced lung cancer animal models and associated carcinogenic mechanisms.

    PubMed

    Ge, Guang-Zhe; Xu, Tian-Rui; Chen, Ceshi

    2015-07-01

    Tobacco usage is a major risk factor in the development, progression, and outcomes for lung cancer. Of the carcinogens associated with lung cancer, tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is among the most potent ones. The oncogenic mechanisms of NNK are not entirely understood, hindering the development of effective strategies for preventing and treating smoking-associated lung cancers. Here, we introduce the NNK-induced lung cancer animal models in different species and its potential mechanisms. Finally, we summarize several chemopreventive agents developed from these animal models. © The Author 2015. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

  1. Toward in vivo lung's tissue incompressibility characterization for tumor motion modeling in radiation therapy

    SciTech Connect

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

    2013-05-15

    Purpose: A novel technique is proposed to characterize lung tissue incompressibility variation during respiration. Estimating lung tissue incompressibility parameter variations resulting from air content variation throughout respiration is critical for computer assisted tumor motion tracking. Continuous tumor motion is a major challenge in lung cancer radiotherapy, especially with external beam radiotherapy. If not accounted for, this motion may lead to areas of radiation overdosage for normal tissue. Given the unavailability of imaging modality that can be used effectively for real-time lung tumor tracking, computer assisted approach based on tissue deformation estimation can be a good alternative. This approach involves lung biomechanical model where its fidelity depends on input tissue properties. This investigation shows that considering variable tissue incompressibility parameter is very important for predicting tumor motion accurately, hence improving the lung radiotherapy outcome. Methods: First, an in silico lung phantom study was conducted to demonstrate the importance of employing variable Poisson's ratio for tumor motion predication. After it was established that modeling this variability is critical for accurate tumor motion prediction, an optimization based technique was developed to estimate lung tissue Poisson's ratio as a function of respiration cycle time. In this technique, the Poisson's ratio and lung pressure value were varied systematically until optimal values were obtained, leading to maximum similarity between acquired and simulated 4D CT lung images. This technique was applied in an ex vivo porcine lung study where simulated images were constructed using the end exhale CT image and deformation fields obtained from the lung's FE modeling of each respiration time increment. To model the tissue, linear elastic and Marlow hyperelastic material models in conjunction with variable Poisson's ratio were used. Results: The phantom study showed that

  2. Role of GADD45a in murine models of radiation- and bleomycin-induced lung injury

    PubMed Central

    Mathew, Biji; Takekoshi, Daisuke; Sammani, Saad; Epshtein, Yulia; Sharma, Rajesh; Smith, Brett D.; Mitra, Sumegha; Desai, Ankit A.; Weichselbaum, Ralph R.; Garcia, Joe G. N.

    2015-01-01

    We previously reported protective effects of GADD45a (growth arrest and DNA damage-inducible gene 45 alpha) in murine ventilator-induced lung injury (VILI) via effects on Akt-mediated endothelial cell signaling. In the present study we investigated the role of GADD45a in separate murine models of radiation- and bleomycin-induced lung injury. Initial studies of wild-type mice subjected to single-dose thoracic radiation (10 Gy) confirmed a significant increase in lung GADD45a expression within 24 h and persistent at 6 wk. Mice deficient in GADD45a (GADD45a−/−) demonstrated increased susceptibility to radiation-induced lung injury (RILI, 10 Gy) evidenced by increased bronchoalveolar lavage (BAL) fluid total cell counts, protein and albumin levels, and levels of inflammatory cytokines compared with RILI-challenged wild-type animals at 2 and 4 wk. Furthermore, GADD45a−/− mice had decreased total and phosphorylated lung Akt levels both at baseline and 6 wk after RILI challenge relative to wild-type mice while increased RILI susceptibility was observed in both Akt+/− mice and mice treated with an Akt inhibitor beginning 1 wk prior to irradiation. Additionally, overexpression of a constitutively active Akt1 transgene reversed RILI-susceptibility in GADD45a−/− mice. In separate studies, lung fibrotic changes 2 wk after treatment with bleomycin (0.25 U/kg IT) was significantly increased in GADD45a−/− mice compared with wild-type mice assessed by lung collagen content and histology. These data implicate GADD45a as an important modulator of lung inflammatory responses across different injury models and highlight GADD45a-mediated signaling as a novel target in inflammatory lung injury clinically. PMID:26498248

  3. 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.

  4. Early recognition of lung cancer by integrin targeted imaging in K-ras mouse model.

    PubMed

    Ermolayev, Vladimir; Mohajerani, Pouyan; Ale, Angelique; Sarantopoulos, Athanasios; Aichler, Michaela; Kayser, Gian; Walch, Axel; Ntziachristos, Vasilis

    2015-09-01

    Non-small cell lung cancer is characterized by slow progression and high heterogeneity of tumors. Integrins play an important role in lung cancer development and metastasis and were suggested as a tumor marker; however their role in anticancer therapy remains controversial. In this work, we demonstrate the potential of integrin-targeted imaging to recognize early lesions in transgenic mouse model of lung cancer based on spontaneous introduction of mutated human gene bearing K-ras mutation. We conducted ex vivo and fluorescence molecular tomography-X-ray computed tomography (FMT-XCT) in vivo imaging and analysis for specific targeting of early lung lesions and tumors in rodent preclinical model for lung cancer. The lesions and tumors were characterized by histology, immunofluorescence and immunohistochemistry using a panel of cancer markers. Ex vivo, the integrin-targeted fluorescent signal significantly differed between wild type lung tissue and K-ras pulmonary lesions (PL) at all ages studied. The panel of immunofluorescence experiments demonstrated that PL, which only partially show cancer cell features were detected by αvβ3-integrin targeted imaging. Human patient material analysis confirmed the specificity of target localization in different lung cancer types. Most importantly, small tumors in the lungs of 4-week-old animals could be noninvasively detected in vivo on the fluorescence channel of FMT-XCT. Our findings demonstrated αvβ3-integrin targeted fluorescent imaging to specifically detect premalignant pleural lesions in K-ras mice. Integrin targeted imaging may find application areas in preclinical research and clinical practice, such as early lung cancer diagnostics, intraoperative assistance or therapy monitoring.

  5. Role of GADD45a in murine models of radiation- and bleomycin-induced lung injury.

    PubMed

    Mathew, Biji; Takekoshi, Daisuke; Sammani, Saad; Epshtein, Yulia; Sharma, Rajesh; Smith, Brett D; Mitra, Sumegha; Desai, Ankit A; Weichselbaum, Ralph R; Garcia, Joe G N; Jacobson, Jeffrey R

    2015-12-15

    We previously reported protective effects of GADD45a (growth arrest and DNA damage-inducible gene 45 alpha) in murine ventilator-induced lung injury (VILI) via effects on Akt-mediated endothelial cell signaling. In the present study we investigated the role of GADD45a in separate murine models of radiation- and bleomycin-induced lung injury. Initial studies of wild-type mice subjected to single-dose thoracic radiation (10 Gy) confirmed a significant increase in lung GADD45a expression within 24 h and persistent at 6 wk. Mice deficient in GADD45a (GADD45a(-/-)) demonstrated increased susceptibility to radiation-induced lung injury (RILI, 10 Gy) evidenced by increased bronchoalveolar lavage (BAL) fluid total cell counts, protein and albumin levels, and levels of inflammatory cytokines compared with RILI-challenged wild-type animals at 2 and 4 wk. Furthermore, GADD45a(-/-) mice had decreased total and phosphorylated lung Akt levels both at baseline and 6 wk after RILI challenge relative to wild-type mice while increased RILI susceptibility was observed in both Akt(+/-) mice and mice treated with an Akt inhibitor beginning 1 wk prior to irradiation. Additionally, overexpression of a constitutively active Akt1 transgene reversed RILI-susceptibility in GADD45a(-/-) mice. In separate studies, lung fibrotic changes 2 wk after treatment with bleomycin (0.25 U/kg IT) was significantly increased in GADD45a(-/-) mice compared with wild-type mice assessed by lung collagen content and histology. These data implicate GADD45a as an important modulator of lung inflammatory responses across different injury models and highlight GADD45a-mediated signaling as a novel target in inflammatory lung injury clinically.

  6. Exhaled flow monitoring can detect bronchial flap-valve obstruction in a mechanical lung model.

    PubMed

    Breen, P H; Serina, E R; Barker, S J

    1995-08-01

    Flap-valve obstruction to expiratory flow (V) in a major bronchus can result from inspissated secretions, blood, or foreign body. During inhalation, increasing airway caliber preserves inspired V past the obstruction; during exhalation, decreasing airway diameter causes airflow obstruction and even frank gas trapping. We reasoned that the resultant sequential, biphasic exhalation of the lungs would be best detected by measuring exhaled V versus time. Accordingly, we designed an airway obstruction element in a mechanical lung model to examine flap-valve bronchial obstruction. A mechanical lung simulator was ventilated with a pressure-limited flow generator, where f = 10/min, tidal volume = 850 mL, and respiratory compliance = 40 mL/cm H2O. Airway V (pneumotachometer) and pressure (P) were digitally sampled for 1 min. Then, the circumference of the diaphragm in a respiratory one-way valve was trimmed to generate unidirectional resistance to expiratory V. Measurement sequences were repeated after this flap-valve was interposed in the right "main-stem bronchus." Integration of airway V versus time generated changes in lung volume. During flap-valve obstruction of the right bronchus, the V-time plot revealed preservation of peak expired flow from the normal lung, followed by retarded and decreased flow from the obstructed right lung. Gas trapping of the obstructed lung occurred during conditions of decreased expiratory time and increased expiratory resistance. Airway P could not differentiate between bronchial and tracheal flap-valve obstruction because P decreased abruptly in both conditions. The flow-volume loop displayed less distinctive changes than the flow-time plot, in part because the flow-volume loop was data (flow) plotted against its time integral (volume), with loss of temporal data. In this mechanical lung model, we conclude that bronchial flap-valve obstruction was best detected by the flow-time plot, which could measure the sequential emptying of the

  7. Protective roles of Cordyceps on lung fibrosis in cellular and rat models.

    PubMed

    Chen, Mengli; Cheung, Florence W K; Chan, Ming Hung; Hui, Pak Kwan; Ip, Siu-Po; Ling, Yick Hin; Che, Chun-Tao; Liu, Wing Keung

    2012-09-28

    Cordyceps sinensis is a fungus used in traditional Chinese medicine as a tonic to soothe the lung for the treatment of fatigue and respiratory diseases. Idiopathic pulmonary fibrosis is a chronic, irreversible and debilitating lung disease showing fibroblast/myofibroblast expansion and excessive deposition of extracellular matrix in the interstitium leading to breathing difficulty. Our previous observation revealed a partial relief of lung fibrosis in patients suffering from severe acute respiratory syndrome (SARS). We hypothesize that Cordyceps has beneficial effects on lung fibrosis and the objective of this study is to explore the target(s) of Cordyceps in the relief of lung fibrosis in animal and cell models and to gain insight into its underlying mechanisms. A rat model of bleomycin (BLM)-induced lung fibrosis and a fibrotic cell model with transforming growth factor beta-1 induction were employed in the studies. Reduction of infiltration of inflammatory cells, deposition of fibroblastic loci and collagen, formation of reactive oxygen species, and production of cytokines, as well as recovery from imbalance of MMP-9/TIMP-1, were observed in fibrotic rats after treatment with Cordyceps in preventive (from the day of BLM administration) and therapeutic (from 14 days after BLM) regimens. In a fibrotic cell model with transforming growth factor beta-1 induction, the human lung epithelial A549 acquired a mesenchymal phenotype and an increase of vimentin expression with a concomitant decrease of E-cadherin. This epithelial-mesenchymal transition could be partially reverted by cordycepin, a major component of Cordyceps. The findings provide an insight into the preventive and therapeutic potentials of Cordyceps for the treatment of lung fibrosis. Copyright © 2012. Published by Elsevier Ireland Ltd.

  8. Modeling of lung's electrical impedance using fractional calculus for analysis of heat generation during RF-ablation.

    PubMed

    Yamazaki, Nozomu; Kobayashi, Yo; Kikuchi, Hayato; Isobe, Yosuke; Lu, XiaoWei; Miyashita, Tomoyuki; Fujie, Masakatsu G

    2014-01-01

    Recently, Radio Frequency Ablation (RFA) is becoming a popular therapy for various cancers such as liver, breast, or lung cancer. RFA is one kinds of thermal therapy. However, it has been often reported about excessive ablation or non-ablation due to difficult control of ablation energy. In order to solve these difficulties, we have been proposed robotized RF-ablation system for precise cancer treatment. We have been tried to control heat energy by control of electromagnetic-wave frequency. In this paper, we reported about relation among electrical impedance of lung, lung's internal air volumes, and heat energy by use of electromagnetic-wave. In case of RFA for lung cancer, heat energy depends on electrical impedance and lung's internal air volumes. Electrical impedance has the dependence of electromagnetic-wave frequency and the dependence of lung's internal air volumes. Therefore, firstly we considered about fractional calculus model between lung's internal air volumes and electrical impedance. Secondly, we measured electric impedance frequency characteristic of lung with change of lung's internal air volumes. The measured and modeled results showed that use of fractional calculus realized high accurate model for electrical impedance of lung. And, from the results of numerical analysis of heat energy, it is supposed that control of electromagnetic-wave frequency has a small effectiveness for lung tissue ablation even if lung includes abundant air.

  9. Development and Validation of a Lung Cancer Risk Prediction Model for African-Americans

    PubMed Central

    Etzel, Carol J.; Kachroo, Sumesh; Liu, Mei; D'Amelio, Anthony; Dong, Qiong; Cote, Michele L.; Wenzlaff, Angela S.; Hong, Waun Ki; Greisinger, Anthony J.; Schwartz, Ann G.; Spitz, Margaret R.

    2009-01-01

    Because existing risk prediction models for lung cancer were developed in white populations, they may not be appropriate for predicting risk among African-Americans. Therefore, a need exists to construct and validate a risk prediction model for lung cancer that is specific to African-Americans. We analyzed data from 491 African-Americans with lung cancer and 497 matched African-American controls to identify specific risks and incorporate them into a multivariable risk model for lung cancer and estimate the 5-year absolute risk of lung cancer. We performed internal and external validations of the risk model using data on additional cases and controls from the same ongoing multiracial/ethnic lung cancer case-control study from which the model-building data were obtained as well as data from two different lung cancer studies in metropolitan Detroit, respectively. We also compared our African-American model with our previously developed risk prediction model for whites. The final risk model included smoking-related variables [smoking status, pack-years smoked, age at smoking cessation (former smokers), and number of years since smoking cessation (former smokers)], self- reported physician diagnoses of chronic obstructive pulmonary disease or hay fever, and exposures to asbestos or wood dusts. Our risk prediction model for African-Americans exhibited good discrimination [75% (95% confidence interval, 0.67−0.82)] for our internal data and moderate discrimination [63% (95% confidence interval, 0.57−0.69)] for the external data group, which is an improvement over the Spitz model for white subjects. Existing lung cancer prediction models may not be appropriate for predicting risk for African-Americans because (a) they were developed using white populations, (b) level of risk is different for risk factors that African-American share with whites, and (c) unique group-specific risk factors exist for African-Americans. This study developed and validated a risk prediction

  10. Endosomal processing limits gene transfer to polarized airway epithelia by adeno-associated virus

    PubMed Central

    Duan, Dongsheng; Yue, Yongping; Yan, Ziying; Yang, Jusan; Engelhardt, John F.

    2000-01-01

    The restriction of viral receptors and coreceptors to the basolateral surface of airway epithelial cells has been blamed for the inefficient transfer of viral vectors to the apical surface of this tissue. We now report, however, that differentiated human airway epithelia internalize rAAV type-2 virus efficiently from their apical surfaces, despite the absence of known adeno-associated virus–2 (AAV-2) receptors or coreceptors at these sites. The dramatically lower transduction efficiency of rAAV infection from the apical surface of airway cells appears to result instead from differences in endosomal processing and nuclear trafficking of apically or basolaterally internalized virions. AAV capsid proteins are ubiquitinated after endocytosis, and gene transfer can be significantly enhanced by proteasome or ubiquitin ligase inhibitors. Tripeptide proteasome inhibitors increased persistent rAAV gene delivery from the apical surface >200-fold, to a level nearly equivalent to that achieved with basolateral infection. In vivo application of proteasome inhibitor in mouse lung augmented rAAV gene transfer from undetectable levels to a mean of 10.4 ± 1.6% of the epithelial cells in large bronchioles. Proteasome inhibitors also increased rAAV-2–mediated gene transfer to the liver tenfold, but they did not affect transduction of skeletal or cardiac muscle. These findings suggest that tissue-specific ubiquitination of viral capsid proteins interferes with rAAV-2 transduction and provides new approaches to circumvent this barrier for gene therapy of diseases such as cystic fibrosis. PMID:10841516

  11. 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.

  12. Establishment of a Reverse Genetics System for Studying Human Bocavirus in Human Airway Epithelia

    PubMed Central

    Cheng, Fang; Luo, Yong; Shen, Weiran; Lei-Butters, Diana C. M.; Chen, Aaron Yun; Li, Yi; Tang, Liang; Söderlund-Venermo, Maria; Engelhardt, John F.; Qiu, Jianming

    2012-01-01

    Human bocavirus 1 (HBoV1) has been identified as one of the etiological agents of wheezing in young children with acute respiratory-tract infections. In this study, we have obtained the sequence of a full-length HBoV1 genome (including both termini) using viral DNA extracted from a nasopharyngeal aspirate of an infected patient, cloned the full-length HBoV1 genome, and demonstrated DNA replication, encapsidation of the ssDNA genome, and release of the HBoV1 virions from human embryonic kidney 293 cells. The HBoV1 virions generated from this cell line-based production system exhibits a typical icosahedral structure of approximately 26 nm in diameter, and is capable of productively infecting polarized primary human airway epithelia (HAE) from the apical surface. Infected HAE showed hallmarks of lung airway-tract injury, including disruption of the tight junction barrier, loss of cilia and epithelial cell hypertrophy. Notably, polarized HAE cultured from an immortalized airway epithelial cell line, CuFi-8 (originally derived from a cystic fibrosis patient), also supported productive infection of HBoV1. Thus, we have established a reverse genetics system and generated the first cell line-based culture system for the study of HBoV1 infection, which will significantly advance the study of HBoV1 replication and pathogenesis. PMID:22956907

  13. Prostaglandin E2 mediates proliferation and chloride secretion in ADPKD cystic renal epithelia

    PubMed Central

    Liu, Yu; Rajagopal, Madhumitha; Lee, Kim; Battini, Lorenzo; Flores, Daniel; Gusella, G. Luca; Pao, Alan C.

    2012-01-01

    Prostaglandin E2 (PGE2) contributes to cystogenesis in genetically nonorthologous models of autosomal dominant polycystic kidney disease (ADPKD). However, it remains unknown whether PGE2 induces the classic features of cystic epithelia in genetically orthologous models of ADPKD. We hypothesized that, in ADPKD epithelia, PGE2 induces proliferation and chloride (Cl−) secretion, two archetypal phenotypic features of ADPKD. To test this hypothesis, proliferation and Cl− secretion were measured in renal epithelial cells deficient in polycystin-1 (PC-1). PC-1-deficient cells increased in cell number (proliferated) faster than PC-1-replete cells, and this proliferative advantage was abrogated by cyclooxygenase inhibition, indicating a role for PGE2 in cell proliferation. Exogenous administration of PGE2 increased proliferation of PC-1-deficient cells by 38.8 ± 5.2% (P < 0.05) but inhibited the growth of PC-1-replete control cells by 49.4 ± 1.9% (P < 0.05). Next, we tested whether PGE2-specific E prostanoid (EP) receptor agonists induce intracellular cAMP and downstream β-catenin activation. PGE2 and EP4 receptor agonism (TCS 2510) increased intracellular cAMP concentration and the abundance of active β-catenin in PC-1-deficient cells, suggesting a mechanism for PGE2-mediated proliferation. Consistent with this hypothesis, antagonizing EP4 receptors reverted the growth advantage of PC-1-deficient cells, implicating a central role for the EP4 receptor in proliferation. To test whether PGE2-dependent Cl− secretion is also enhanced in PC-1-deficient cells, we used an Ussing chamber to measure short-circuit current (Isc). Addition of PGE2 induced a fivefold higher increase in Isc in PC-1-deficient cells compared with PC-1-replete cells. This PGE2-induced increase in Isc in PC-1-deficient cells was blocked by CFTR-172 and flufenamic acid, indicating that PGE2 activates CFTR and calcium-activated Cl− channels. In conclusion, PGE2 activates aberrant signaling pathways

  14. MAGNETIC RESONANCE ELASTOGRAPHY OF HUMAN LUNG PARENCHYMA: TECHNICAL DEVELOPMENT, THEORETICAL MODELING AND IN VIVO VALIDATION

    PubMed Central

    Mariappan, Yogesh K; Glaser, Kevin J; Hubmayr, Rolf D; Manduca, Armando; Ehman, Richard L; McGee, Kiaran P

    2011-01-01

    Purpose To develop a novel MR-based method for visualizing the elastic properties of human lung parenchyma in vivo and to evaluate the ability of this method to resolve differences in parenchymal stiffness at different respiration states in healthy volunteers. Materials and Methods A spin-echo MR Elastography (MRE) pulse sequence was developed to provide both high shear wave motion sensitivity and short TE for improved visualization of lung parenchyma. The improved motion sensitivity of this approach was modeled and tested with phantom experiments. In vivo testing was then performed on ten healthy volunteers at the respiratory states of residual volume (RV) and total lung capacity (TLC). Results Shear wave propagation was visualized within the lungs of all volunteers and was processed to provide parenchymal shear stiffness maps of all ten subjects. Density corrected stiffness values at TLC (1.83 ± 0.22 kPa) were higher than those at the RV (1.14 ± 0.14 kPa) with the difference being statistically significant (p<0.0001). Conclusion 1H-based MR Elastography can noninvasively measure the shear stiffness of human lung parenchyma in vivo and can quantitate the change in shear stiffness due to respiration. The values obtained were consistent with previously reported in vitro assessments of cadaver lungs. Further work is required to increase the flexibility of the current acquisition and to investigate the clinical potential of lung MRE. PMID:21591003

  15. 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.

  16. 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.

  17. Model-based risk assessment for motion effects in 3D radiotherapy of lung tumors

    NASA Astrophysics Data System (ADS)

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

    2012-02-01

    Although 4D CT imaging becomes available in an increasing number of radiotherapy facilities, 3D imaging and planning is still standard in current clinical practice. In particular for lung tumors, respiratory motion is a known source of uncertainty and should be accounted for during radiotherapy planning - which is difficult by using only a 3D planning CT. In this contribution, we propose applying a statistical lung motion model to predict patients' motion patterns and to estimate dosimetric motion effects in lung tumor radiotherapy if only 3D images are available. Being generated based on 4D CT images of patients with unimpaired lung motion, the model tends to overestimate lung tumor motion. It therefore promises conservative risk assessment regarding tumor dose coverage. This is exemplarily evaluated using treatment plans of lung tumor patients with different tumor motion patterns and for two treatment modalities (conventional 3D conformal radiotherapy and step-&- shoot intensity modulated radiotherapy). For the test cases, 4D CT images are available. Thus, also a standard registration-based 4D dose calculation is performed, which serves as reference to judge plausibility of the modelbased 4D dose calculation. It will be shown that, if combined with an additional simple patient-specific breathing surrogate measurement (here: spirometry), the model-based dose calculation provides reasonable risk assessment of respiratory motion effects.

  18. Glucocorticoid Clearance and Metabolite Profiling in an In Vitro Human Airway Epithelium Lung Model.

    PubMed

    Rivera-Burgos, Dinelia; Sarkar, Ujjal; Lever, Amanda R; Avram, Michael J; Coppeta, Jonathan R; Wishnok, John S; Borenstein, Jeffrey T; Tannenbaum, Steven R

    2016-02-01

    The emergence of microphysiologic epithelial lung models using human cells in a physiologically relevant microenvironment has the potential to be a powerful tool for preclinical drug development and to improve predictive power regarding in vivo drug clearance. In this study, an in vitro model of the airway comprising human primary lung epithelial cells cultured in a microfluidic platform was used to establish a physiologic state and to observe metabolic changes as a function of glucocorticoid exposure. Evaluation of mucus production rate and barrier function, along with lung-specific markers, demonstrated that the lungs maintained a differentiated phenotype. Initial concentrations of 100 nM hydrocortisone (HC) and 30 nM cortisone (C) were used to evaluate drug clearance and metabolite production. Measurements made using ultra-high-performance liquid chromatography and high-mass-accuracy mass spectrometry indicated that HC metabolism resulted in the production of C and dihydrocortisone (diHC). When the airway model was exposed to C, diHC was identified; however, no conversion to HC was observed. Multicompartmental modeling was used to characterize the lung bioreactor data, and pharmacokinetic parameters, including elimination clearance and elimination half-life, were estimated. Polymerse chain reaction data confirmed overexpression of 11-β hydroxysteroid dehydrogenase 2 (11βHSD2) over 11βHSD1, which is biologically relevant to human lung. Faster metabolism was observed relative to a static model on elevated rates of C and diHC formation. Overall, our results demonstrate that this lung airway model has been successfully developed and could interact with other human tissues in vitro to better predict in vivo drug behavior.

  19. Glucocorticoid Clearance and Metabolite Profiling in an In Vitro Human Airway Epithelium Lung Model

    PubMed Central

    Rivera-Burgos, Dinelia; Sarkar, Ujjal; Lever, Amanda R.; Avram, Michael J.; Coppeta, Jonathan R.; Wishnok, John S.; Borenstein, Jeffrey T.

    2016-01-01

    The emergence of microphysiologic epithelial lung models using human cells in a physiologically relevant microenvironment has the potential to be a powerful tool for preclinical drug development and to improve predictive power regarding in vivo drug clearance. In this study, an in vitro model of the airway comprising human primary lung epithelial cells cultured in a microfluidic platform was used to establish a physiologic state and to observe metabolic changes as a function of glucocorticoid exposure. Evaluation of mucus production rate and barrier function, along with lung-specific markers, demonstrated that the lungs maintained a differentiated phenotype. Initial concentrations of 100 nM hydrocortisone (HC) and 30 nM cortisone (C) were used to evaluate drug clearance and metabolite production. Measurements made using ultra-high-performance liquid chromatography and high-mass-accuracy mass spectrometry indicated that HC metabolism resulted in the production of C and dihydrocortisone (diHC). When the airway model was exposed to C, diHC was identified; however, no conversion to HC was observed. Multicompartmental modeling was used to characterize the lung bioreactor data, and pharmacokinetic parameters, including elimination clearance and elimination half-life, were estimated. Polymerse chain reaction data confirmed overexpression of 11-β hydroxysteroid dehydrogenase 2 (11βHSD2) over 11βHSD1, which is biologically relevant to human lung. Faster metabolism was observed relative to a static model on elevated rates of C and diHC formation. Overall, our results demonstrate that this lung airway model has been successfully developed and could interact with other human tissues in vitro to better predict in vivo drug behavior. PMID:26586376

  20. Boundary element model for simulating sound propagation and source localization within the lungs.

    PubMed

    Ozer, M B; Acikgoz, S; Royston, T J; Mansy, H A; Sandler, R H

    2007-07-01

    An acoustic boundary element (BE) model is used to simulate sound propagation in the lung parenchyma. It is computationally validated and then compared with experimental studies on lung phantom models. Parametric studies quantify the effect of different model parameters on the resulting acoustic field within the lung phantoms. The BE model is then coupled with a source localization algorithm to predict the position of an acoustic source within the phantom. Experimental studies validate the BE-based source localization algorithm and show that the same algorithm does not perform as well if the BE simulation is replaced with a free field assumption that neglects reflections and standing wave patterns created within the finite-size lung phantom. The BE model and source localization procedure are then applied to actual lung geometry taken from the National Library of Medicine's Visible Human Project. These numerical studies are in agreement with the studies on simpler geometry in that use of a BE model in place of the free field assumption alters the predicted acoustic field and source localization results. This work is relevant to the development of advanced auscultatory techniques that utilize multiple noninvasive sensors to construct acoustic images of sound generation and transmission to identify pathologies.

  1. Novel Mouse Model of Chronic Pseudomonas aeruginosa Lung Infection Mimicking Cystic Fibrosis

    PubMed Central

    Hoffmann, Nadine; Rasmussen, Thomas Bovbjerg; Jensen, PeterØstrup; Stub, Charlotte; Hentzer, Morten; Molin, Søren; Ciofu, Oana; Givskov, Michael; Johansen, Helle Krogh; Høiby, Niels

    2005-01-01

    Pseudomonas aeruginosa causes a chronic infection in the lungs of cystic fibrosis (CF) patients by establishing an alginate-containing biofilm. The infection has been studied in several animal models; however, most of the models required artificial embedding of the bacteria. We present here a new pulmonary mouse model without artificial embedding. The model is based on a stable mucoid CF sputum isolate (NH57388A) with hyperproduction of alginate due to a deletion in mucA and functional N-acylhomoserine lactone (AHL)-based quorum-sensing systems. Chronic lung infection could be established in both CF mice (CftrtmlUnc−/−) and BALB/c mice, as reflected by the detection of a high number of P. aeruginosa organisms in the lung homogenates at 7 days postinfection and alginate biofilms, surrounded by polymorphonuclear leukocytes in the alveoli. In comparison, both an AHL-producing nonmucoid revertant (NH57388C) from the mucoid isolate (NH57388A) and a nonmucoid isolate (NH57388B) deficient in AHL were almost cleared from the lungs of the mice. This model, in which P. aeruginosa is protected against the defense system of the lung by alginate, is similar to the clinical situation. Therefore, the mouse model provides an improved method for evaluating the interaction between mucoid P. aeruginosa, the host, and antibacterial therapy. PMID:15784597

  2. Adhesion GPCRs Govern Polarity of Epithelia and Cell Migration.

    PubMed

    Strutt, David; Schnabel, Ralf; Fiedler, Franziska; Prömel, Simone

    2016-01-01

    In multicellular organisms cells spatially arrange in a highly coordinated manner to form tissues and organs, which is essential for the function of an organism. The component cells and resulting structures are often polarised in one or more axes, and how such polarity is established and maintained correctly has been one of the major biological questions for many decades. Research progress has shown that many adhesion GPCRs (aGPCRs) are involved in several types of polarity. Members of the two evolutionarily oldest groups, Flamingo/Celsr and Latrophilins, are key molecules in planar cell polarity of epithelia or the propagation of cellular polarity in the early embryo, respectively. Other adhesion GPCRs play essential roles in cell migration, indicating that this receptor class includes essential molecules for the control of various levels of cellular organisation.

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

    PubMed

    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.

  4. 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

  5. Competitive Adsorption: A Physical Model for Lung Surfactant Inactivation

    PubMed Central

    Fernsler, Jonathan G.; Zasadzinski, Joseph A.

    2009-01-01

    Charged, surface-active serum proteins can severely reduce or eliminate the adsorption of lung surfactant from the subphase to the alveolar air-liquid interface via a kinetically controlled competitive adsorption process. The decreased surfactant concentration at the interface leads to higher surface tensions during the compression of the interface during breathing. The correspondence between the factors governing colloid stability and competitive adsorption is validated via a new method of measuring surfactant and serum protein adsorption rates to the air-water interface using quantitative Brewster Angle Microscopy (BAM). Competitive adsorption from a 10 mg/mL albumin subphase prevents the adsorption of lung surfactant from even high subphase concentrations due to the fast diffusion of the water-soluble proteins to the interface. The formation of an albumin film causes an electrostatic and steric barrier to subsequent surfactant adsorption, which can destroy the necessary properties of functional lung surfactant: low surface tension during compression and rapid respreading after film collapse. Surfactant inactivation is at least partially due to decreased surfactant adsorption; such decreased adsorption due to the presence of serum proteins may play a role in the development and severity of Acute Respiratory Distress Syndrome. PMID:19534502

  6. A numerical study of gas transport in human lung models

    NASA Astrophysics Data System (ADS)

    Lin, Ching-Long; Hoffman, Eric A.

    2005-04-01

    Stable Xenon (Xe) gas has been used as an imaging agent for decades in its radioactive form, is chemically inert, and has been used as a ventilation tracer in its non radioactive form during computerized tomography (CT) imaging. Magnetic resonance imaging (MRI) using hyperpolarized Helium (He) gas and Xe has also emerged as a powerful tool to study regional lung structure and function. However, the present state of knowledge regarding intra-bronchial Xe and He transport properties is incomplete. As the use of these gases rapidly advances, it has become critically important to understand the nature of their transport properties and to, in the process, better understand the role of gas density in general in determining regional distribution of respiratory gases. In this paper, we applied the custom developed characteristic-Galerkin finite element method, which solves the three-dimensional (3D) incompressible variable-density Navier-Stokes equations, to study the transport of Xe and He in the CT-based human lung geometries, especially emulating the washin and washout processes. The realistic lung geometries are segmented and reconstructed from CT images as part of an effort to build a normative atlas (NIH HL-064368) documenting airway geometry over 4 decades of age in healthy and disease-state adult humans. The simulation results show that the gas transport process depends on the gas density and the body posture. The implications of these results on the difference between washin and washout time constants are discussed.

  7. Open Tracheostomy Gastric Acid Aspiration Murine Model of Acute Lung Injury Results in Maximal Acute Nonlethal Lung Injury.

    PubMed

    Alluri, Ravi; Kutscher, Hilliard L; Mullan, Barbara A; Davidson, Bruce A; Knight, Paul R

    2017-02-26

    Acid pneumonitis is a major cause of sterile acute lung injury (ALI) in humans. Acid pneumonitis spans the clinical spectrum from asymptomatic to acute respiratory distress syndrome (ARDS), characterized by neutrophilic alveolitis, and injury to both alveolar epithelium and vascular endothelium. Clinically, ARDS is defined by acute onset of hypoxemia, bilateral patchy pulmonary infiltrates and non-cardiogenic pulmonary edema. Human studies have provided us with valuable information about the physiological and inflammatory changes in the lung caused by ARDS, which has led to various hypotheses about the underling mechanisms. Unfortunately, difficulties determining the etiology of ARDS, as well as a wide range of pathophysiology have resulted in a lack of critical information that could be useful in developing therapeutic strategies. Translational animal models are valuable when their pathogenesis and pathophysiology accurately reproduce a concept proven in both in vitro and clinical settings. Although large animal models (e.g., sheep) share characteristics of the anatomy of human trachea-bronchial tree, murine models provide a host of other advantages including: low cost; short reproductive cycle lending itself to greater data acquisition; a well understood immunologic system; and a well characterized genome leading to the availability of a variety of gene deletion and transgenic strains. A robust model of low pH induced ARDS requires a murine ALI that targets mainly the alveolar epithelium, secondarily the vascular endothelium, as well as the small airways leading to the alveoli. Furthermore, a reproducible injury with wide differences between different injurious and non-injurious insults is important. The murine gastric acid aspiration model presented here using hydrochloric acid employs an open tracheostomy and recreates a pathogenic scenario that reproduces the low pH pneumonitis injury in humans. Additionally, this model can be used to examine interaction of a

  8. Longitudinal multistage model for lung cancer incidence, mortality, and CT detected indolent and aggressive cancers

    PubMed Central

    Hazelton, William D.; Goodman, Gary; Rom, William N.; Tockman, Melvyn; Thornquist, Mark; Moolgavkar, Suresh; Weissfeld, Joel L.; Feng, Ziding

    2012-01-01

    It is currently not known whether most lung cancers detected by computerized tomography (CT) screening are aggressive and likely to be fatal if left untreated, or if a sizable fraction are indolent and unlikely to cause death during the natural lifetime of the individual. We developed a longitudinal biologically-based model of the relationship between individual smoking histories and the probability for lung cancer incidence, CT screen detection, lung cancer mortality, and other-cause mortality. The longitudinal model relates these different outcomes to an underlying lung cancer disease pathway and an effective other-cause mortality pathway, which are both influenced by the individual smoking history. The longitudinal analysis provides additional information over that available if these outcomes were analyzed separately, including testing if the number of CT detected and histologically-confirmed lung cancers is consistent with the expected number of lung cancers “in the pipeline”. We assume indolent nodules undergo Gompertz growth and are detectable by CT, but do not grow large enough to contribute significantly to symptom-based lung cancer incidence or mortality. Likelihood-based model calibration was done jointly to data from 6,878 heavy smokers without asbestos exposure in the control (placebo) arm of the Carotene and Retinol Efficacy Trial (CARET); and to 3,642 heavy smokers with comparable smoking histories in the Pittsburgh Lung Screening Study (PLuSS), a single-arm prospective trial of low-dose spiral CT screening for diagnosis of lung cancer. Model calibration was checked using data from two other single-arm prospective CT screening trials, the New York University Lung Cancer Biomarker Center (NYU) (n=1,021), and Moffitt Cancer Center (Moffitt) cohorts (n=677). In the PLuSS cohort, we estimate that at the end of year 2, after the baseline and first annual CT exam, that 33.0 (26.9, 36.9)% of diagnosed lung cancers among females and 7.0 (4.9, 11.7)% among

  9. Patient specific respiratory motion modeling using a limited number of 3D lung CT images.

    PubMed

    Cui, Xueli; Gao, Xin; Xia, Wei; Liu, Yangchuan; Liang, Zhiyuan

    2014-01-01

    To build a patient specific respiratory motion model with a low dose, a novel method was proposed that uses a limited number of 3D lung CT volumes with an external respiratory signal. 4D lung CT volumes were acquired for patients with in vitro labeling on the upper abdominal surface. Meanwhile, 3D coordinates of in vitro labeling were measured as external respiratory signals. A sequential correspondence between the 4D lung CT and the external respiratory signal was built using the distance correlation method, and a 3D displacement for every registration control point in the CT volumes with respect to time can be obtained by the 4D lung CT deformable registration. A temporal fitting was performed for every registration control point displacements and an external respiratory signal in the anterior-posterior direction respectively to draw their fitting curves. Finally, a linear regression was used to fit the corresponding samples of the control point displacement fitting curves and the external respiratory signal fitting curve to finish the pulmonary respiration modeling. Compared to a B-spline-based method using the respiratory signal phase, the proposed method is highly advantageous as it offers comparable modeling accuracy and target modeling error (TME); while at the same time, the proposed method requires 70% less 3D lung CTs. When using a similar amount of 3D lung CT data, the mean of the proposed method's TME is smaller than the mean of the PCA (principle component analysis)-based methods' TMEs. The results indicate that the proposed method is successful in striking a balance between modeling accuracy and number of 3D lung CT volumes.

  10. Lung nodule segmentation and recognition using SVM classifier and active contour modeling: a complete intelligent system.

    PubMed

    Keshani, Mohsen; Azimifar, Zohreh; Tajeripour, Farshad; Boostani, Reza

    2013-05-01

    In this paper, a novel method for lung nodule detection, segmentation and recognition using computed tomography (CT) images is presented. Our contribution consists of several steps. First, the lung area is segmented by active contour modeling followed by some masking techniques to transfer non-isolated nodules into isolated ones. Then, nodules are detected by the support vector machine (SVM) classifier using efficient 2D stochastic and 3D anatomical features. Contours of detected nodules are then extracted by active contour modeling. In this step all solid and cavitary nodules are accurately segmented. Finally, lung tissues are classified into four classes: namely lung wall, parenchyma, bronchioles and nodules. This classification helps us to distinguish a nodule connected to the lung wall and/or bronchioles (attached nodule) from the one covered by parenchyma (solitary nodule). At the end, performance of our proposed method is examined and compared with other efficient methods through experiments using clinical CT images and two groups of public datasets from Lung Image Database Consortium (LIDC) and ANODE09. Solid, non-solid and cavitary nodules are detected with an overall detection rate of 89%; the number of false positive is 7.3/scan and the location of all detected nodules are recognized correctly.

  11. 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.

  12. RAGE/NF-κB signaling mediates lipopolysaccharide induced acute lung injury in neonate rat model.

    PubMed

    Li, Yuhong; Wu, Rong; Tian, Yian; Yu, Min; Tang, Yun; Cheng, Huaipin; Tian, Zhaofang

    2015-01-01

    Lipopolysaccharide (LPS) is known to induce acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Accumulating data suggest the crucial role of RAGE in the pathogenesis of ALI/ARDS. However, the mechanism by which RAGE mediates inflammatory lung injury in the neonates remains elusive. In this study we established LPS-induced ALI model in neonate rats, and investigated the role of RAGE/NF-κB signaling in mediating ALI. We found that RAGE antibody or bortezomib reduced LPS-induced histopathological abnormalities in the lung and lung damage score. RAGE antibody or bortezomib also reduced TNF-α level in both serum and BALF of the rats. Furthermore, RAGE antibody or bortezomib significantly reduced LPS-induced upregulation of RAGE and NF-κB expression in the lung. In conclusion, we established ALI model in neonate rats to demonstrate that LPS induced inflammatory lung injury via RAGE/NF-κB signaling. Interference with RAGE/NF-κB signaling is a potential approach to prevent and treat sepsis-related ALI/ARDS.

  13. 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.

  14. Insulin-like growth factor-I gene expression in three models of accelerated lung growth.

    PubMed

    Nobuhara, K K; DiFiore, J W; Ibla, J C; Siddiqui, A M; Ferretti, M L; Fauza, D O; Schnitzer, J J; Wilson, J M

    1998-07-01

    We have learned previously that in utero tracheal ligation reverses the structural and physiological effects of surgically created congenital diaphragmatic hernia. In addition, we have discovered that postnatal lung growth similarly can be accelerated using liquid-based airway distension with perfluorocarbon. Another model of accelerated lung growth is that of compensatory growth seen after neonatal pneumonectomy. In all of these models, growth has occurred because of an increase in alveolar number rather than enlargement of preexisting alveoli. However, the molecular mechanisms underlying these processes remain unknown. The purpose of this study was to determine if gene expression could be altered by changes in physical forces in the prenatal and postnatal lung. The three models of accelerated lung growth studied were the following: (1) The prenatal group, consisted of fetal lambs (n = 12) that underwent the surgical creation of a left diaphragmatic hernia at 90 days' gestation. Six of these animals also underwent simultaneous tracheal ligation. (2) The PFC group consisted of five neonatal animals that underwent isolation of the superior segment of the right upper lobe, with intrabronchial distension with perfluorocarbon to 7 to 10 mm Hg pressure for a 3-week period. (3) The postpneumonectomy group consisted of four neonatal animals that underwent left pneumonectomy. In the fetal study, lungs were retrieved at term (130 days), and in the postnatal study, lungs were retrieved 3 weeks after initial intervention. In all cases, RNA was extracted from snap-frozen lung samples and Northern blot analysis performed. Insulinlike growth factor-I, insulinlike growth factor-II, and vascular endothelial growth factor gene expression were analyzed by densitometry. Insulinlike growth factor-I gene expression was found to be decreased in association with experimental diaphragmatic hernia (P = .005), but restored to normal with tracheal ligation. Insulinlike growth factor-I gene

  15. Is tail vein injection a relevant breast cancer lung metastasis model?

    PubMed Central

    Rashid, Omar M.; Nagahashi, Masayuki; Ramachandran, Suburamaniam; Dumur, Catherine I.; Schaum, Julia C.; Yamada, Akimitsu; Aoyagi, Tomoyoshi; Milstien, Sheldon; Spiegel, Sarah

    2013-01-01

    Background Two most commonly used animal models for studying breast cancer lung metastasis are: lung metastasis after orthotopic implantation of cells into the mammary gland, and lung implantations produced after tail vein (TV) injection of cells. Tail vein injection can produce lung lesions faster, but little has been studied regarding the differences between these tumors, thus, we examined their morphology and gene expression profiles. Methods Syngeneic murine mammary adenocarcinoma, 4T1-luc2 cells, were implanted either subcutaneously (Sq), orthotopically (OS), or injected via TV in Balb/c mice. Genome-wide microarray analyses of cultured 4T1 cells, Sq tumor, OS tumor, lung metastases after OS (LMet), and lung tumors after TV (TVt) were performed 10 days after implantation. Results Bioluminescence analysis demonstrated different morphology of metastases between LMet and TVt, confirmed by histology. Gene expression profile of cells were significantly different from tumors, OS, Sq, TVt or LMet (10,350 probe sets; FDR≤1%; P<0.0001). Sq tumors were significantly different than OS tumors (700 probe sets; FDR≤15%; P<0.01), and both tumor types (Sq and OS) were significantly different than LMet (1,247 probe sets; >1.5-fold-change; P<0.01), with no significant difference between TVt and LMet. Conclusions There were significant differences between the gene profiles of cells in culture and OS versus LMet, but there were no differences between LMet versus TVt. Therefore, the lung tumor generated by TVt can be considered genetically similar to those produced after OS, and thus TVt is a relevant model for breast cancer lung metastasis. PMID:23991292

  16. Modeling accumulations of particles in lung during chronic inhalation exposures that lead to impaired clearance

    SciTech Connect

    Wolff, R.K.; Griffith, W.C. Jr.; Cuddihy, R.G.; Snipes, M.B.; Henderson, R.F.; Mauderly, J.L.; McClellan, R.O. )

    1989-01-01

    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, 2 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.

  17. Lung arginase expression and activity is increased in cystic fibrosis mouse models.

    PubMed

    Jaecklin, Thomas; Duerr, Julia; Huang, Hailu; Rafii, Mahroukh; Bear, Christine E; Ratjen, Felix; Pencharz, Paul; Kavanagh, Brian P; Mall, Marcus A; Grasemann, Hartmut

    2014-08-01

    The activity of arginase is increased in airway secretions of patients with cystic fibrosis (CF). Downstream products of arginase activity may contribute to CF lung disease. We hypothesized that pulmonary arginase expression and activity would be increased in mouse models of CF and disproportionally increased in CF mice with Pseudomonas aeruginosa pneumonia. Expression of arginase isoforms in lung tissue was quantified with reverse transcriptase-PCR in naive cystic fibrosis transmembrane conductance regulator (Cftr)-deficient mice and β-epithelial sodium channel-overexpressing [β-ENaC-transgenic (Tg)] mice. An isolated lung stable isotope perfusion model was used to measure arginase activity in Cftr-deficient mice before and after intratracheal instillation of Pseudomonas aeruginosa. The expression of arginase-2 in lung was increased in adult Cftr-deficient animals and in newborn β-ENaC-Tg. Arginase-1 lung expression was normal in Cftr-deficient and in newborn β-ENaC-Tg mice, but was increased in β-ENaC-Tg mice at age 1, 3, and 6 wk. Arginase activity was significantly higher in lung (5.0 ± 0.7 vs. 3.2 ± 0.3 nmol·(-1)·h(-1), P = 0.016) and airways (204.6 ± 49.8 vs. 79.3 ± 17.2 nmol·(-1)·h(-1), P = 0.045) of naive Cftr-deficient mice compared with sex-matched wild-type littermate controls. Infection with Pseudomonas aeruginosa resulted in a far greater increase in lung arginase activity in Cftr-deficient mice (10-fold) than in wild-type controls (6-fold) (P = 0.01). This is the first ex vivo characterization of arginase expression and activity in CF mouse lung and airways. Our data show that pulmonary arginase expression and activity is increased in CF mice, especially with Pseudomonas aeruginosa infections.

  18. Angiogenesis inhibition using an oncolytic herpes simplex virus expressing endostatin in a murine lung cancer model.

    PubMed

    Goodwin, Jonathan M; Schmitt, Anthony D; McGinn, Christopher M; Fuchs, Bryan C; Kuruppu, Darshini; Tanabe, Kenneth K; Lanuti, Michael

    2012-03-01

    Herpes-mediated viral oncolysis alone is not sufficient to completely eradicate tumors. In this study we used a replication conditional, endostatin-expressing herpes simplex virus-1 mutant (HSV-Endo) in a murine lung cancer model. We hypothesized that the anti-angiogenic action of endostatin would improve upon the oncolytic effect of HSV-1. HSV-Endo was evaluated in a pulmonary metastases and orthotopic flank model, where there was significantly less tumor burden and reduced microvessel density compared to a control virus. Endostatin expression appears to improve the anti-tumor effect of HSV-1 in a lung cancer model.

  19. A novel dual ex vivo lung perfusion technique improves immediate outcomes in an experimental model of lung transplantation.

    PubMed

    Tanaka, Y; Noda, K; Isse, K; Tobita, K; Maniwa, Y; Bhama, J K; D'Cunha, J; Bermudez, C A; Luketich, J D; Shigemura, N

    2015-05-01

    The lungs are dually perfused by the pulmonary artery and the bronchial arteries. This study aimed to test the feasibility of dual-perfusion techniques with the bronchial artery circulation and pulmonary artery circulation synchronously perfused using ex vivo lung perfusion (EVLP) and evaluate the effects of dual-perfusion on posttransplant lung graft function. Using rat heart-lung blocks, we developed a dual-perfusion EVLP circuit (dual-EVLP), and compared cellular metabolism, expression of inflammatory mediators, and posttransplant graft function in lung allografts maintained with dual-EVLP, standard-EVLP, or cold static preservation. The microvasculature in lung grafts after transplant was objectively evaluated using microcomputed tomography angiography. Lung grafts subjected to dual-EVLP exhibited significantly better lung graft function with reduced proinflammatory profiles and more mitochondrial biogenesis, leading to better posttransplant function and compliance, as compared with standard-EVLP or static cold preservation. Interestingly, lung grafts maintained on dual-EVLP exhibited remarkably increased microvasculature and perfusion as compared with lungs maintained on standard-EVLP. Our results suggest that lung grafts can be perfused and preserved using dual-perfusion EVLP techniques that contribute to better graft function by reducing proinflammatory profiles and activating mitochondrial respiration. Dual-EVLP also yields better posttransplant graft function through increased microvasculature and better perfusion of the lung grafts after transplantation. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

  20. Modeling of deposition and clearance of inhaled Ni compounds in the human lung.

    PubMed

    Hsieh, T H; Yu, C P; Oberdörster, G

    1999-08-01

    By extrapolation from the rat study, a mathematical model of deposition, clearance, and retention kinetics for inhaled Ni compounds (high-temperature (green) NiO, Ni(3)S(2), and NiSO(4). 6H(2)O) in the alveolar region of the human lung has been developed. For human deposition, an updated version of an earlier model (C. P. Yu and C. K. Diu, 1982, Am. Ind. Hyg. Assoc. J.) was used in this study. Because of the profound differences in physiological and ventilation conditions between humans and rats, humans were found to have a higher alveolar deposition fraction than rats when exposed to the same Ni compounds. However, when normalized to the lung weight, the deposition rate per gram of lung in humans is much smaller than in rats. In the development of a clearance model, a single-compartment model in the lung was used and a general assumption was made that the clearance of the insoluble and moderately soluble nickel compounds (high-temperature (green) NiO and Ni(3)S(2), respectively) depends highly on the volume of retained particles in the lungs. As for the highly soluble nickel compound (NiSO(4). 6H(2)O), the clearance rate coefficient was assumed to depend on the retained particle mass and total alveolar surface. These clearance rate coefficients were extrapolated from the rat data. The retention half-times for high temperature (green) NiO and Ni(3)S(2) particles in humans were found to be much longer than in rats, whereas the retention half-time for NiSO(4). 6H(2)O particles was about the same for both species. The lung burden results in humans for various exposure conditions are predicted and the equivalent exposure concentrations for humans which lead to the same lung burdens found in rats were calculated. Copyright 1999 Academic Press.

  1. Quantification by SIFT-MS of acetaldehyde released by lung cells in a 3D model.

    PubMed

    Rutter, Abigail V; Chippendale, Thomas W E; Yang, Ying; Španěl, Patrik; Smith, David; Sulé-Suso, Josep

    2013-01-07

    Our previous studies have shown that both lung cancer cells and non-malignant lung cells release acetaldehyde in vitro. However, data from other laboratories have produced conflicting results. Furthermore, all these studies have been carried out in 2D models which are less physiological cell growth systems when compared to 3D models. Therefore, we have carried out further work on the release of acetaldehyde by lung cells in 3D collagen hydrogels. Lung cancer cells CALU-1 and non-malignant lung cells NL20 were seeded in these hydrogels at different cell concentrations and the release of acetaldehyde was measured with the Selected Ion Flow Tube Mass Spectrometry (SIFT-MS) technique. The data obtained showed that the amount of acetaldehyde released by both cell types grown in a 3D model is higher when compared to that of the same cells grown in 2D models. More importantly, acetaldehyde from the headspace of lung cancer cells could be measured even at a low cell concentration (10(5) cells per hydrogel). The differential of acetaldehyde release could be, depending on the cell concentration, more than 3 fold higher for cancer cells when compared to non-malignant lung cells. This pilot study is the first to study acetaldehyde emission from albeit only two cell types cultured in 3D scaffolds. Clearly, from such limited data the behaviour of other cell types and of tumour cells in vivo cannot be predicted with confidence. Nevertheless, this work represents another step in the search for volatile biomarkers of tumour cells, the ultimate goal of which is to exploit volatile compounds in exhaled breath and other biological fluids as biomarkers of tumours in vivo.

  2. 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

    2016-10-20

    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.

  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. Developing Novel Therapeutic Approaches in Small Cell Lung Carcinoma Using Genetically Engineered Mouse Models and Human Circulating Tumor Cells

    DTIC Science & Technology

    2015-10-01

    Using Genetically Engineered Mouse Models and Human Circulating Tumor Cells PRINCIPAL INVESTIGATOR: Jeffrey Engelman MD PhD CONTRACTING...SUBTITLE Developiing Novel Therapeutic Approaches in Small Cell Lung 5a. CONTRACT NUMBER Carcinoma Using Genetically Engineered Mouse Models and 5b...biomarkers. 15. SUBJECT TERMS Small cell lung cancer (SCLC), Genetically engineered mouse model (GEMM), BH3 mimetic, TORC inhibitor, Apoptosis

  5. A Method for Lung Boundary Correction Using Split Bregman Method and Geometric Active Contour Model

    PubMed Central

    Zhang, Jianxun; Liang, Rui

    2015-01-01

    In order to get the extracted lung region from CT images more accurately, a model that contains lung region extraction and edge boundary correction is proposed. Firstly, a new edge detection function is presented with the help of the classic structure tensor theory. Secondly, the initial lung mask is automatically extracted by an improved active contour model which combines the global intensity information, local intensity information, the new edge information, and an adaptive weight. It is worth noting that the objective function of the improved model is converted to a convex model, which makes the proposed model get the global minimum. Then, the central airway was excluded according to the spatial context messages and the position relationship between every segmented region and the rib. Thirdly, a mesh and the fractal theory are used to detect the boundary that surrounds the juxtapleural nodule. Finally, the geometric active contour model is employed to correct the detected boundary and reinclude juxtapleural nodules. We also evaluated the performance of the proposed segmentation and correction model by comparing with their popular counterparts. Efficient computing capability and robustness property prove that our model can correct the lung boundary reliably and reproducibly. PMID:26089976

  6. A Method for Lung Boundary Correction Using Split Bregman Method and Geometric Active Contour Model.

    PubMed

    Feng, Changli; Zhang, Jianxun; Liang, Rui

    2015-01-01

    In order to get the extracted lung region from CT images more accurately, a model that contains lung region extraction and edge boundary correction is proposed. Firstly, a new edge detection function is presented with the help of the classic structure tensor theory. Secondly, the initial lung mask is automatically extracted by an improved active contour model which combines the global intensity information, local intensity information, the new edge information, and an adaptive weight. It is worth noting that the objective function of the improved model is converted to a convex model, which makes the proposed model get the global minimum. Then, the central airway was excluded according to the spatial context messages and the position relationship between every segmented region and the rib. Thirdly, a mesh and the fractal theory are used to detect the boundary that surrounds the juxtapleural nodule. Finally, the geometric active contour model is employed to correct the detected boundary and reinclude juxtapleural nodules. We also evaluated the performance of the proposed segmentation and correction model by comparing with their popular counterparts. Efficient computing capability and robustness property prove that our model can correct the lung boundary reliably and reproducibly.

  7. Mechanism of Reduced Lung Injury by High Frequency Nasal Ventilation in a Preterm Lamb Model of Neonatal Chronic Lung Disease

    PubMed Central

    Rehan, Virender K.; Fong, Jeanette; Lee, Robert; Sakurai, Reiko; Wang, Zheng-Ming; Dahl, Mar Janna; Lane, Robert H.; Albertine, Kurt H.; Torday, John S.

    2011-01-01

    The mechanism underlying the potentially beneficial effects of the “gentler” modes of ventilation on chronic lung disease (CLD) of the premature infant is not known. We have previously demonstrated that alveolar Parathyroid Hormone-related Protein-Peroxisome Proliferator-Activated Receptorγ (PTHrP-PPARγ) signaling is critically important in alveolar formation, and this signaling pathway is disrupted in hyperoxia- and/or volutrauma-induced neonatal rat lung injury. Whether the same paradigm is also applicable to CLD, resulting from prolonged intermittent mandatory ventilation (IMV), and whether differential effects of the mode of ventilation on the PTHrP-PPARγ signaling pathway explain the potential benefits of the “gentler” modes of ventilation are not known. Using a well-established preterm lamb model of neonatal CLD, we tested the hypothesis that ventilatory support using high-frequency nasal ventilation (HFNV) promotes alveolar PTHrP-PPARγ signaling, whereas IMV inhibits it. Preterm lambs managed by HFNV or IMV for 21 days following preterm delivery at 132-day gestation were studied by Western hybridization and immunofluorescence labeling for key markers of alveolar homeostasis and injury/repair. In lambs managed by IMV, the abundance of key homeostatic alveolar epithelial-mesenchymal markers was reduced, whereas it was significantly increased in the HFNV group, providing a potential molecular mechanism by which “gentler” modes of ventilation reduce neonatal CLD. PMID:21814155

  8. Modeling lung motion using consistent image registration in four-dimensional computed tomography for radiation therapy

    NASA Astrophysics Data System (ADS)

    Lu, Wei; Song, Joo Hyun; Christensen, Gary E.; Parikh, Parag J.; Bradley, Jeffrey D.; Low, Daniel A.

    2006-03-01

    Respiratory motion is a significant source of error in conformal radiation therapy for the thorax and upper abdomen. Four-dimensional computed tomography (4D CT) has been proposed to reduce the uncertainty caused by internal respiratory organ motion. A 4D CT dataset is retrospectively reconstructed at various stages of a respiratory cycle. An important tool for 4D treatment planning is deformable image registration. An inverse consistent image registration is used to model lung motion from one respiratory stage to another during a breathing cycle. This diffeomorphic registration jointly estimates the forward and reverse transformations providing more accurate correspondence between two images. Registration results and modeled motions in the lung are shown for three example respiratory stages. The results demonstrate that the consistent image registration satisfactorily models the large motions in the lung, providing a useful tool for 4D planning and delivering.

  9. Characterization of Wild-Type and ΔF508 Cystic Fibrosis Transmembrane Regulator in Human Respiratory Epithelia

    PubMed Central

    Kreda, Silvia M.; Mall, Marcus; Mengos, April; Rochelle, Lori; Yankaskas, James; Riordan, John R.; Boucher, Richard C.

    2005-01-01

    Previous studies in native tissues have produced conflicting data on the localization and metabolic fate of WT and ΔF508 cystic fibrosis transmembrane regulator (CFTR) in the lung. Combining immunocytochemical and biochemical studies utilizing new high-affinity CFTR mAbs with ion transport assays, we examined both 1) the cell type and region specific expression of CFTR in normal airways and 2) the metabolic fate of ΔF508 CFTR and associated ERM proteins in the cystic fibrosis lung. Studies of lungs from a large number of normal subjects revealed that WT CFTR protein localized to the apical membrane of ciliated cells within the superficial epithelium and gland ducts. In contrast, other cell types in the superficial, gland acinar, and alveolar epithelia expressed little WT CFTR protein. No ΔF508 CFTR mature protein or function could be detected in airway specimens freshly excised from a large number of ΔF508 homozygous subjects, despite an intact ERM complex. In sum, our data demonstrate that WT CFTR is predominantly expressed in ciliated cells, and ΔF508 CFTR pathogenesis in native tissues, like heterologous cells, reflects loss of normal protein processing. PMID:15716351

  10. Effects of anesthetic regimes on inflammatory responses in a rat model of acute lung injury

    PubMed Central

    Fortis, Spyridon; Spieth, Peter M.; Lu, Wei-Yang; Parotto, Matteo; Haitsma, Jack J; Slutsky, Arthur S.; Zhong, Nanshan; Mazer, C. David; Zhang, Haibo

    2016-01-01

    Background Gamma amino butyric acid (GABA) is the major inhibitory neurotransmitter through activation of GABA receptors. Volatile anesthetics activate type A (GABAA) receptors resulting in inhibition of synaptic transmission. Lung epithelial cells have been recently found to express GABAA receptors that exert anti-inflammatory properties. We hypothesized that the volatile anesthetic sevoflurane (SEVO) attenuates lung inflammation through activation of lung epithelial GABAA receptors. Methods Sprague-Dawley rats were anesthetized with SEVO or ketamine/xylazine (KX). Acute lung inflammation was induced by intratracheal instillation of endotoxin, followed by mechanical ventilation for 4 h at a tidal volume of 15 mL/kg without positive end-expiratory pressure (two-hit lung injury model). To examine the specific effects of GABA, healthy human bronchial epithelial cells (BEAS-2B) were challenged with endotoxin in the presence and absence of GABA with and without addition of the GABAA receptor antagonist picrotoxin. Results Anesthesia with SEVO improved oxygenation and reduced pulmonary cytokine responses compared to KX. This phenomenon was associated with increased expression of the π subunit of GABAA receptors and glutamic acid decarboxylase (GAD). The endotoxin-induced cytokine release from BEAS-2B cells was attenuated by the treatment with GABA, which was reversed by the administration of picrotoxin. Conclusion Anesthesia with SEVO suppresses pulmonary inflammation thus protects the lung from the two-hit injury. The anti-inflammatory effect of SEVO is likely due to activation of pulmonary GABAA signaling pathways. PMID:22711173

  11. 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.

  12. The role of pneumolysin in mediating lung damage in a lethal pneumococcal pneumonia murine model

    PubMed Central

    García-Suárez, María del Mar; Flórez, Noelia; Astudillo, Aurora; Vázquez, Fernando; Villaverde, Roberto; Fabrizio, Kevin; Pirofski, Liise-Anne; Méndez, Francisco J

    2007-01-01

    Background Intranasal inoculation of Streptococcus pneumoniae D39 serotype 2 causes fatal pneumonia in mice. The cytotoxic and inflammatory properties of pneumolysin (PLY) have been implicated in the pathogenesis of pneumococcal pneumonia. Methods To examine the role of PLY in this experimental model we performed ELISA assays for PLY quantification. The distribution patterns of PLY and apoptosis were established by immunohistochemical detection of PLY, caspase-9 activity and TUNEL assay on tissue sections from mice lungs at various times, and the results were quantified with image analysis. Inflammatory and apoptotic cells were also quantified on lung tissue sections from antibody treated mice. Results In bronchoalveolar lavages (BAL), total PLY was found at sublytic concentrations which were located in alveolar macrophages and leukocytes. The bronchoalveolar epithelium was PLY-positive, while the vascular endothelium was not PLY reactive. The pattern and extension of cellular apoptosis was similar. Anti-PLY antibody treatment decreased the lung damage and the number of apoptotic and inflammatory cells in lung tissues. Conclusion The data strongly suggest that in vivo lung injury could be due to the pro-apoptotic and pro-inflammatory activity of PLY, rather than its cytotoxic activity. PLY at sublytic concentrations induces lethal inflammation in lung tissues and is involved in host cell apoptosis, whose effects are important to pathogen survival. PMID:17257395

  13. Sealing Effect of Cross-Linked Gelatin Glue in the Rat Lung Air Leak Model.

    PubMed

    Kawai, Norikazu; Suzuki, Shuko; Naito, Hiroshi; Kushibe, Keiji; Tojo, Takashi; Ikada, Yoshito; Taniguchi, Shigeki

    2016-07-01

    Air leak is a common problem in pulmonary surgical procedures. In this study, we evaluated the efficacy and safety of gelatin glue (cross-linked with glutaraldehyde) in a rat model of lung air leak. A model of pulmonary fistula was created in the rat lung with the use of a needle. The fistula was then sealed with either gelatin glue (group A), fibrin glue (group B), or fibrin glue with a polyglycolic acid sheet (group C). The seal breaking pressures were measured for each group, and the results were compared. To assess the biocompatibility of the gelatin glue, a model of lung damage was created with incision, and the gelatin glue was applied to seal the wound. Histologic analysis was then performed on the lung tissue. The seal breaking pressure in group A (47.88 ± 6.69 mm Hg) was significantly higher than that in group B (24.67 ± 3.24 mm Hg, p = 0.0302) or group C (28.67 ± 3.55 mm Hg, p = 0.0406). Histologically, the gelatin glue adhered firmly to the lung surface, and only localized tissue inflammation was observed. The sealing effect of gelatin glue was superior to that of fibrin glue, with or without a polyglycolic acid sheet. In addition, the gelatin glue only caused mild inflammation of the lung and was absorbed without any adverse foreign body response. These findings suggest that gelatin glue may be a therapeutically effective biomaterial for sealing lung wounds and restoring respiratory function. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  14. Modeling lung deformation: A combined deformable image registration method with spatially varying Young's modulus estimates

    PubMed Central

    Li, Min; Castillo, Edward; Zheng, Xiao-Lin; Luo, Hong-Yan; Castillo, Richard; Wu, Yi; Guerrero, Thomas

    2013-01-01

    Purpose: Respiratory motion introduces uncertainties in tumor location and lung deformation, which often results in difficulties calculating dose distributions in thoracic radiation therapy. Deformable image registration (DIR) has ability to describe respiratory-induced lung deformation, with which the radiotherapy techniques can deliver high dose to tumors while reducing radiation in surrounding normal tissue. The authors' goal is to propose a DIR method to overcome two main challenges of the previous biomechanical model for lung deformation, i.e., the requirement of precise boundary conditions and the lack of elasticity distribution. Methods: As opposed to typical methods in biomechanical modeling, the authors' method assumes that lung tissue is inhomogeneous. The authors thus propose a DIR method combining a varying intensity flow (VF) block-matching algorithm with the finite element method (FEM) for lung deformation from end-expiratory phase to end-inspiratory phase. Specifically, the lung deformation is formulated as a stress–strain problem, for which the boundary conditions are obtained from the VF block-matching algorithm and the element specific Young's modulus distribution is estimated by solving an optimization problem with a quasi-Newton method. The authors measure the spatial accuracy of their nonuniform model as well as a standard uniform model by applying both methods to four-dimensional computed tomography images of six patients. The spatial errors produced by the registrations are computed using large numbers (>1000) of expert-determined landmark point pairs. Results: In right-left, anterior–posterior, and superior–inferior directions, the mean errors (standard deviation) produced by the standard uniform FEM model are 1.42(1.42), 1.06(1.05), and 1.98(2.10) mm whereas the authors' proposed nonuniform model reduces these errors to 0.59(0.61), 0.52(0.51), and 0.78(0.89) mm. The overall 3D mean errors are 3.05(2.36) and 1.30(0.97) mm for the

  15. Boron uptake measurements in a rat model for Boron Neutron Capture Therapy of lung tumours.

    PubMed

    Bortolussi, S; Bakeine, J G; Ballarini, F; Bruschi, P; Gadan, M A; Protti, N; Stella, S; Clerici, A; Ferrari, C; Cansolino, L; Zonta, C; Zonta, A; Nano, R; Altieri, S

    2011-02-01

    Lung carcinoma is the leading cause of cancer mortality in the Western countries. Despite the introduction over the last few years of new therapeutic agents, survival from lung cancer has shown no discernible improvement in the last 20 years. For these reasons any efforts to find and validate new effective therapeutic procedures for lung cancer are very timely. The selective boron uptake in the tumour with respect to healthy tissues makes Boron Neutron Capture Therapy a potentially advantageous option in the treatment of tumours that affect whole vital organs, and that are surgically inoperable. To study the possibility of applying BNCT to the treatment of diffuse pulmonary tumours, an animal model for boron uptake measurements in lung metastases was developed. Both healthy and tumour-bearing rats were infused with Boronophenylalanine (BPA) and sacrificed at different time intervals after drug administration. The lungs were extracted, and prepared for boron analysis by neutron autoradiography and α-spectroscopy. The boron concentrations in tumour and normal lung were plotted as a function of the time elapsed after BPA administration. The concentration in tumour is almost constant within the error bars for all the time intervals of the experiment (1-8 h), while the curve in normal lung decreases after 4 h from BPA infusion. At 4 h, the ratio of boron concentration in tumour to boron concentration in healthy lung is higher than 3, and it stays above this level up to 8 h. Also the images of boron distribution in the samples, obtained by neutron autoradiography, show a selective absorption in the metastases. Copyright © 2010 Elsevier Ltd. All rights reserved.

  16. 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.

  17. 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

  18. Thixotropic solutions enhance viral-mediated gene transfer to airway epithelia.

    PubMed

    Seiler, Michael P; Luner, Paul; Moninger, Thomas O; Karp, Philip H; Keshavjee, Shaf; Zabner, Joseph

    2002-08-01

    Adenovirus-mediated gene transfer to airway epithelia is inefficient in part because its receptor is absent on the apical surface of the airways. Targeting adenovirus to other receptors, increasing the viral concentration, and even prolonging the incubation time with adenovirus vectors can partially overcome the lack of receptors and facilitate gene transfer. Unfortunately, mucociliary clearance would prevent prolonged incubation time in vivo. Thixotropic solutions (TS) are gels that upon a vigorous shearing force reversibly become liquid. We hypothesized that formulating recombinant adenoviruses in TS would decrease virus clearance and thus enhance gene transfer to the airway epithelia. We found that clearance of virus-sized fluorescent beads by human airway epithelia in vitro and by monkey trachea in vivo were markedly decreased when the beads were formulated in TS compared with phosphate-buffered saline (PBS). Adenovirus formulated in TS significantly increased adenovirus-mediated gene transfer of a reporter gene in human airway epithelia in vitro and in murine airway epithelia in vivo. Furthermore, an adenovirus encoding the cystic fibrosis transmembrane regulator (CFTR) gene (AdCFTR) formulated in TS was more efficient in correcting the chloride transport defect in cystic fibrosis airway epithelia than AdCFTR formulated in PBS. These data indicate a novel strategy to augment the efficiency of gene transfer to the airways that may be applicable to a number of different gene transfer vectors and could be of value in gene transfer to cystic fibrosis (CF) airway epithelia in vivo.

  19. Lung dosimetry and risk assessment of nanoparticles: Evaluating and extending current models in rats and humans

    SciTech Connect

    Kuempel, E.D.; Tran, C.L.; Castranova, V.; Bailer, A.J.

    2006-09-15

    Risk assessment of occupational exposure to nanomaterials is needed. Human data are limited, but quantitative data are available from rodent studies. To use these data in risk assessment, a scientifically reasonable approach for extrapolating the rodent data to humans is required. One approach is allometric adjustment for species differences in the relationship between airborne exposure and internal dose. Another approach is lung dosimetry modeling, which provides a biologically-based, mechanistic method to extrapolate doses from animals to humans. However, current mass-based lung dosimetry models may not fully account for differences in the clearance and translocation of nanoparticles. In this article, key steps in quantitative risk assessment are illustrated, using dose-response data in rats chronically exposed to either fine or ultrafine titanium dioxide (TiO{sub 2}), carbon black (CB), or diesel exhaust particulate (DEP). The rat-based estimates of the working lifetime airborne concentrations associated with 0.1% excess risk of lung cancer are approximately 0.07 to 0.3 mg/m{sup 3} for ultrafine TiO{sub 2}, CB, or DEP, and 0.7 to 1.3 mg/m{sup 3} for fine TiO{sub 2}. Comparison of observed versus model-predicted lung burdens in rats shows that the dosimetry models predict reasonably well the retained mass lung burdens of fine or ultrafine poorly soluble particles in rats exposed by chronic inhalation. Additional model validation is needed for nanoparticles of varying characteristics, as well as extension of these models to include particle translocation to organs beyond the lungs. Such analyses would provide improved prediction of nanoparticle dose for risk assessment.

  20. Method of Isolated Ex Vivo Lung Perfusion in a Rat Model: Lessons Learned from Developing a Rat EVLP Program

    PubMed Central

    Nelson, Kevin; Bobba, Christopher; Eren, Emre; Spata, Tyler; Tadres, Malak; Hayes,, Don; Black, Sylvester M.

    2015-01-01

    The number of acceptable donor lungs available for lung transplantation is severely limited due to poor quality. Ex-Vivo Lung Perfusion (EVLP) has allowed lung transplantation in humans to become more readily available by enabling the ability to assess organs and expand the donor pool. As this technology expands and improves, the ability to potentially evaluate and improve the quality of substandard lungs prior to transplant is a critical need. In order to more rigorously evaluate these approaches, a reproducible animal model needs to be established that would allow for testing of improved techniques and management of the donated lungs as well as to the lung-transplant recipient. In addition, an EVLP animal model of associated pathologies, e.g., ventilation induced lung injury (VILI), would provide a novel method to evaluate treatments for these pathologies. Here, we describe the development of a rat EVLP lung program and refinements to this method that allow for a reproducible model for future expansion. We also describe the application of this EVLP system to model VILI in rat lungs. The goal is to provide the research community with key information and “pearls of wisdom”/techniques that arose from trial and error and are critical to establishing an EVLP system that is robust and reproducible. PMID:25741794

  1. Predictive Accuracy of the PanCan Lung Cancer Risk Prediction Model -External Validation based on CT from the Danish Lung Cancer Screening Trial.

    PubMed

    Winkler Wille, Mathilde M; van Riel, Sarah J; Saghir, Zaigham; Dirksen, Asger; Pedersen, Jesper Holst; Jacobs, Colin; Thomsen, Laura Hohwü; Scholten, Ernst Th; Skovgaard, Lene T; van Ginneken, Bram

    2015-10-01

    Lung cancer risk models should be externally validated to test generalizability and clinical usefulness. The Danish Lung Cancer Screening Trial (DLCST) is a population-based prospective cohort study, used to assess the discriminative performances of the PanCan models. From the DLCST database, 1,152 nodules from 718 participants were included. Parsimonious and full PanCan risk prediction models were applied to DLCST data, and also coefficients of the model were recalculated using DLCST data. Receiver operating characteristics (ROC) curves and area under the curve (AUC) were used to evaluate risk discrimination. AUCs of 0.826-0.870 were found for DLCST data based on PanCan risk prediction models. In the DLCST, age and family history were significant predictors (p = 0.001 and p = 0.013). Female sex was not confirmed to be associated with higher risk of lung cancer; in fact opposing effects of sex were observed in the two cohorts. Thus, female sex appeared to lower the risk (p = 0.047 and p = 0.040) in the DLCST. High risk discrimination was validated in the DLCST cohort, mainly determined by nodule size. Age and family history of lung cancer were significant predictors and could be included in the parsimonious model. Sex appears to be a less useful predictor. • High accuracy in logistic modelling for lung cancer risk stratification of nodules. • Lung cancer risk prediction is primarily based on size of pulmonary nodules. • Nodule spiculation, age and family history of lung cancer are significant predictors. • Sex does not appear to be a useful risk predictor.

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

    NASA Astrophysics Data System (ADS)

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

    2010-09-01

    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.

  3. Prognostic model for brain metastases from lung adenocarcinoma identified with epidermal growth factor receptor mutation status.

    PubMed

    Li, Hongwei; Wang, Weili; Jia, Haixia; Lian, Jianhong; Cao, Jianzhong; Zhang, Xiaqin; Song, Xing; Jia, Sufang; Li, Zhengran; Cao, Xing; Zhou, Wei; Han, Songye; Yang, Weihua; Xi, Yanfen; Lian, Shenming

    2017-09-01

    Several indices have been developed to predict survival of brain metastases (BM) based on prognostic factors. However, such models were designed for general brain metastases from different kinds of cancers, and prognostic factors vary between cancers and histological subtypes. Recently, studies have indicated that epidermal growth factor receptor (EGFR) mutation status may be a potential prognostic biological factor in BM from lung adenocarcinoma. Thus, we sought to define the role of EGFR mutation in prognoses and introduce a prognostic model specific for BM from lung adenocarcinoma. Data of 256 patients with BM from lung adenocarcinoma identified with EGFR mutations were collected. Independent prognostic factors were confirmed using a Cox regression model. The new prognostic model was developed based on the results of multivariable analyses. The score of each factor was calculated by six-month survival. Prognostic groups were divided into low, medium, and high risk based on the total scores. The prediction ability of the new model was compared to the three existing models. EGFR mutation and Karnofsky performance status were independent prognostic factors and were thus integrated into the new prognostic model. The new model was superior to the three other scoring systems regarding the prediction of three, six, and 12-month survival by pairwise comparison of the area under the curve. Our proposed prognostic model specific for BM from lung adenocarcinoma incorporating EGFR mutation status was valid in predicting patient survival. Further verification is warranted, with prospective testing using large sample sizes. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

  4. Rationale for hypertonic saline therapy for cystic fibrosis lung disease.

    PubMed

    Tarran, Robert; Donaldson, Scott; Boucher, Richard C

    2007-06-01

    Cystic fibrosis (CF) is caused by alterations in the CF transmembrane conductance regulator ( CFTCR) gene. More than 1400 mutations in the CFTCR gene have been described, but the most common mutation (noted in 70% of CF chromosomes) is DeltaF508. Alterations in the CFTCR gene result in deranged sodium and chloride ion transport channels. This leads to failure of airway epithelia to hydrate their surfaces normally, particularly in response to infectious or toxic insults. Additional effects include mucus adhesion to airway surface, chronic inflammation, and infections. The concept that airway surface dehydration can cause CF-like lung disease is supported by in vitro data and in vivo animal models. Rehydrating airway surfaces may reduce or prevent lung injury and damage. Short- and longer term studies have shown that inhalation of hypertonic saline is well tolerated and improves lung function, reduces exacerbations, and improves quality of life in CF patients. This review discusses the importance of airway epithelial sodium and chloride channels in the pathogenesis of CF, and strategies (particularly the use of inhaled hypertonic saline) to reverse or minimize lung inflammation and injury in this disease.

  5. Development of a small animal model to simulate clinical stereotactic body radiotherapy-induced central and peripheral lung injuries

    PubMed Central

    Hong, Zhen-Yu; Eun, Sung Ho; Park, Kwangwoo; Choi, Won Hoon; Lee, Jung Il; Lee, Eun-Jung; Lee, Ji Min; Story, Michael D.; Cho, Jaeho

    2014-01-01

    Given the tremendous potential of stereotactic body radiotherapy (SBRT), investigations of the underlying radiobiology associated with SBRT-induced normal tissue injury are of paramount importance. This study was designed to develop an animal model that simulates centrally and peripherally located clinical SBRT-induced lung injuries. A 90-Gy irradiation dose was focally delivered to the central and peripheral areas of the left mouse lung with an image-guided small-animal irradiation system. At 1, 2 and 4 weeks after irradiation, micro-computed tomography (micro-CT) images of the lung were taken. Lung function measurements were performed with the Flexivent® system (SCIREQ©, Montreal, Canada). For the histopathological analysis, the lungs were fixed by perfusing with formalin, and paraffin sections were stained with hematoxylin and eosin and Masson's Trichrome. Gross inspection clearly indicated local lung injury confined to the central and peripheral areas of the left lung. Typical histopathological alterations corresponding to clinical manifestations were observed. The micro-CT analysis results appeared to correlate with the histopathological findings. Mouse lung tissue damping increased dramatically at central settings, compared with that at the control or peripheral settings. An animal model to simulate clinical SBRT-induced central and peripheral lung injuries was developed and validated with histopathological, radiological and functional analyses. This model increases our understanding of SBRT-induced central and peripheral lung injuries and will help to improve radiation therapy in the future. PMID:24556815

  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. Superior Suppressive Capacity of Skin Tregs Compared with Lung Tregs in a Model of Epicutaneous Priming.

    PubMed

    Mahapatra, Subhashree; Albrecht, Melanie; Baru, Abdul M; Sparwasser, Tim; Herrick, Christina; Dittrich, Anna M

    2015-10-01

    We have previously shown that T helper type 2 (Th2)-polarized airway inflammation can facilitate priming to new antigens in the lungs, which we called "collateral priming". To investigate whether allergic skin inflammation can also facilitate priming toward new antigens, we developed an allergic skin inflammation model based on an allergic lung inflammation model. Mice were sensitized intraperitoneally toward the primary antigen, ovalbumin. Challenge was subsequently performed intranasally or epicutaneously with ovalbumin and a secondary antigen, keyhole limpet hemocyanin (KLH). Re-challenge consisted of local application of either antigen alone. Analysis of KLH-specific antibody responses, KLH-specific cytokines, and local inflammation demonstrated tolerance induction toward the secondary antigen in the skin, whereas in the lung priming had occurred. Flow-cytometric analysis revealed increased numbers of regulatory T cells (Tregs), increased cytotoxic T lymphocyte antigen-4 (CTLA-4) expression, and an enhanced suppressive capacity of Tregs from skin-draining lymph nodes when compared with Tregs from the lung-draining lymph nodes. Furthermore, depletion of Tregs resulted in restoration of collateral priming in the skin. These results demonstrate crucial local differences between the Treg function in the skin and lung to repetitive antigen exposure, which can decisively influence the immune response toward new antigens.

  8. Effect of air pollution on lung cancer: A poisson regression model based on vital statistics

    SciTech Connect

    Tango, Toshiro

    1994-11-01

    This article describes a Poisson regression model for time trends of mortality to detect the long-term effects of common levels of air pollution on lung cancer, in which the adjustment for cigarette smoking is not always necessary. The main hypothesis to be tested in the model is that if the long-term and common-level air pollution had an effect on lung cancer, the death rate from lung cancer could be expected to increase gradually at a higher rate in the region with relatively high levels of air pollution than in the region with low levels, and that this trend would not be expected for other control diseases in which cigarette smoking is a risk factor. Using this approach, we analyzed the trend of mortality in females aged 40 to 79, from lung cancer and two control diseases, ischemic heart disease and cerebrovascular disease, based on vital statistics in 23 wards of the Tokyo metropolitan area for 1972 to 1988. Ward-specific mean levels per day of SO{sub 2} and NO{sub 2} from 1974 through 1976 estimated by Makino (1978) were used as the ward-specific exposure measure of air pollution. No data on tobacco consumption in each ward is available. Our analysis supported the existence of long-term effects of air pollution on lung cancer. 14 refs., 5 figs., 2 tabs.

  9. The Role of Neutrophil Myeloperoxidase in Models of Lung Tumor Development

    PubMed Central

    Rymaszewski, Amy L.; Tate, Everett; Yimbesalu, Joannes P.; Gelman, Andrew E.; Jarzembowski, Jason A.; Zhang, Hao; Pritchard, Kirkwood A.; Vikis, Haris G.

    2014-01-01

    Chronic inflammation plays a key tumor-promoting role in lung cancer. Our previous studies in mice demonstrated that neutrophils are critical mediators of tumor promotion in methylcholanthrene (MCA)-initiated, butylated hydroxytoluene (BHT)-promoted lung carcinogenesis. In the present study we investigated the role of neutrophil myeloperoxidase (MPO) activity in this inflammation promoted model. Increased levels of MPO protein and activity were present in the lungs of mice administered BHT. Treatment of mice with N-acetyl lysyltyrosylcysteine amide (KYC), a novel tripeptide inhibitor of MPO, during the inflammatory stage reduced tumor burden. In a separate tumor model, KYC treatment of a Lewis Lung Carcinoma (LLC) tumor graft in mice had no effect on tumor growth, however, mice genetically deficient in MPO had significantly reduced LLC tumor growth. Our observations suggest that MPO catalytic activity is critical during the early stages of tumor development. However, during the later stages of tumor progression, MPO expression independent of catalytic activity appears to be required. Our studies advocate for the use of MPO inhibitors in a lung cancer prevention setting. PMID:24821130

  10. 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.

  11. Disease-specific gene expression profiling in multiple models of lung disease.

    PubMed

    Lewis, Christina C; Yang, Jean Yee Hwa; Huang, Xiaozhu; Banerjee, Suman K; Blackburn, Michael R; Baluk, Peter; McDonald, Donald M; Blackwell, Timothy S; Nagabhushanam, Vijaya; Peters, Wendy; Voehringer, David; Erle, David J

    2008-02-15

    Microarray technology is widely employed for studying the molecular mechanisms underlying complex diseases. However, analyses of individual diseases or models of diseases frequently yield extensive lists of differentially expressed genes with uncertain relationships to disease pathogenesis. To compare gene expression changes in a heterogeneous set of lung disease models in order to identify common gene expression changes seen in diverse forms of lung pathology, as well as relatively small subsets of genes likely to be involved in specific pathophysiological processes. We profiled lung gene expression in 12 mouse models of infection, allergy, and lung injury. A linear model was used to estimate transcript expression changes for each model, and hierarchical clustering was used to compare expression patterns between models. Selected expression changes were verified by quantitative polymerase chain reaction. A total of 24 transcripts, including many involved in inflammation and immune activation, were differentially expressed in a substantial majority (9 or more) of the models. Expression patterns distinguished three groups of models: (1) bacterial infection (n = 5), with changes in 89 transcripts, including many related to nuclear factor-kappaB signaling, cytokines, chemokines, and their receptors; (2) bleomycin-induced diseases (n = 2), with changes in 53 transcripts, including many related to matrix remodeling and Wnt signaling; and (3) T helper cell type 2 (allergic) inflammation (n = 5), with changes in 26 transcripts, including many encoding epithelial secreted molecules, ion channels, and transporters. This multimodel dataset highlights novel genes likely involved in various pathophysiological processes and will be a valuable resource for the investigation of molecular mechanisms underlying lung disease pathogenesis.

  12. Computational fluid dynamics simulations of particle deposition in large-scale, multigenerational lung models.

    PubMed

    Walters, D Keith; Luke, William H

    2011-01-01

    Computational fluid dynamics (CFD) has emerged as a useful tool for the prediction of airflow and particle transport within the human lung airway. Several published studies have demonstrated the use of Eulerian finite-volume CFD simulations coupled with Lagrangian particle tracking methods to determine local and regional particle deposition rates in small subsections of the bronchopulmonary tree. However, the simulation of particle transport and deposition in large-scale models encompassing more than a few generations is less common, due in part to the sheer size and complexity of the human lung airway. Highly resolved, fully coupled flowfield solution and particle tracking in the entire lung, for example, is currently an intractable problem and will remain so for the foreseeable future. This paper adopts a previously reported methodology for simulating large-scale regions of the lung airway (Walters, D. K., and Luke, W. H., 2010, "A Method for Three-Dimensional Navier-Stokes Simulations of Large-Scale Regions of the Human Lung Airway," ASME J. Fluids Eng., 132(5), p. 051101), which was shown to produce results similar to fully resolved geometries using approximate, reduced geometry models. The methodology is extended here to particle transport and deposition simulations. Lagrangian particle tracking simulations are performed in combination with Eulerian simulations of the airflow in an idealized representation of the human lung airway tree. Results using the reduced models are compared with those using the fully resolved models for an eight-generation region of the conducting zone. The agreement between fully resolved and reduced geometry simulations indicates that the new method can provide an accurate alternative for large-scale CFD simulations while potentially reducing the computational cost of these simulations by several orders of magnitude.

  13. Comparing Benefits from Many Possible Computed Tomography Lung Cancer Screening Programs: Extrapolating from the National Lung Screening Trial Using Comparative Modeling

    PubMed Central

    McMahon, Pamela M.; Meza, Rafael; Plevritis, Sylvia K.; Black, William C.; Tammemagi, C. Martin; Erdogan, Ayca; ten Haaf, Kevin; Hazelton, William; Holford, Theodore R.; Jeon, Jihyoun; Clarke, Lauren; Kong, Chung Yin; Choi, Sung Eun; Munshi, Vidit N.; Han, Summer S.; van Rosmalen, Joost; Pinsky, Paul F.; Moolgavkar, Suresh

    2014-01-01

    Background The National Lung Screening Trial (NLST) demonstrated that in current and former smokers aged 55 to 74 years, with at least 30 pack-years of cigarette smoking history and who had quit smoking no more than 15 years ago, 3 annual computed tomography (CT) screens reduced lung cancer-specific mortality by 20% relative to 3 annual chest X-ray screens. We compared the benefits achievable with 576 lung cancer screening programs that varied CT screen number and frequency, ages of screening, and eligibility based on smoking. Methods and Findings We used five independent microsimulation models with lung cancer natural history parameters previously calibrated to the NLST to simulate life histories of the US cohort born in 1950 under all 576 programs. ‘Efficient’ (within model) programs prevented the greatest number of lung cancer deaths, compared to no screening, for a given number of CT screens. Among 120 ‘consensus efficient’ (identified as efficient across models) programs, the average starting age was 55 years, the stopping age was 80 or 85 years, the average minimum pack-years was 27, and the maximum years since quitting was 20. Among consensus efficient programs, 11% to 40% of the cohort was screened, and 153 to 846 lung cancer deaths were averted per 100,000 people. In all models, annual screening based on age and smoking eligibility in NLST was not efficient; continuing screening to age 80 or 85 years was more efficient. Conclusions Consensus results from five models identified a set of efficient screening programs that include annual CT lung cancer screening using criteria like NLST eligibility but extended to older ages. Guidelines for screening should also consider harms of screening and individual patient characteristics. PMID:24979231

  14. A whole new ball game: Stem cell-derived epithelia in the study of host-microbe interactions.

    PubMed

    Leslie, Jhansi L; Young, Vincent B

    2016-02-01

    Recent advances in developmental and stem cell biology have resulted in techniques that enable the generation and maintenance of complex epithelium in vitro. While these models have been utilized to study host development and disease, a renewed appreciation of host-microbe interactions has sparked interest in employing these new techniques to study microbes at the epithelial interface. Here we review the current advances in host-microbe interactions that have resulted from experiments using these complex epithelia. Furthermore we highlight aspects of these techniques that warrant further development to facilitate the study of host-microbe interactions. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo.

    PubMed Central

    Unemori, E N; Pickford, L B; Salles, A L; Piercy, C E; Grove, B H; Erikson, M E; Amento, E P

    1996-01-01

    Pulmonary fibrosis is the common end stage of a number of pneumopathies. In this study, we examined the ability of the human cytokine, relaxin, to block extracellular matrix deposition by human lung fibroblasts in vitro, and to inhibit lung fibrosis in a bleomycin-induced murine model. In vitro, relaxin (1-100 ng/ml) inhibited the transforming growth factor-beta-mediated over-expression of interstitial collagen types I and III by human lung fibroblasts by up to 45% in a dose-dependent manner. Relaxin did not affect basal levels of collagen expression in the absence of TGF-beta-induced stimulation. Relaxin also blocked transforming growth factor-beta-induced upregulation of fibronectin by 80% at the highest relaxin dose tested (100 ng/ml). The expression of matrix metalloproteinase-1, or procollagenase, was stimulated in a biphasic, dose-dependent manner by relaxin. In vivo, relaxin, at a steady state circulating concentration of approximately 50 ng/ml, inhibited bleomycin-mediated alveolar thickening compared with the vehicle only control group (P < 0.05). Relaxin also restored bleomycin-induced collagen accumulation, as measured by lung hydroxyproline content, to normal levels (P < 0.05). In summary, relaxin induced a matrix degradative phenotype in human lung fibroblasts in vitro and inhibited bleomycin-induced fibrosis in a murine model in vivo. These data indicate that relaxin may be efficacious in the treatment of pathologies characterized by lung fibrosis. PMID:8981919

  16. Development of a dynamic model for the lung lobes and airway tree in the NCAT phantom

    NASA Astrophysics Data System (ADS)

    Garrity, J. M.; Segars, W. P.; Knisley, S. B.; Tsui, B. M. W.

    2003-06-01

    The four-dimensional (4-D) NCAT phantom was developed to realistically model human anatomy based on the visible human data and cardiac and respiratory motions based on 4-D tagged magnetic resonance imaging and respiratory-gated CT data from normal human subjects. Currently, the 4-D NCAT phantom does not include the airway tree or its motion within the lungs. Also, each lung is defined with a single surface; the individual lobes are not distinguished. The authors further the development of the phantom by creating dynamic models for the individual lung lobes and for the airway tree in each lobe. NURBS surfaces for the lobes and an initial airway tree model (/spl sim/ 4 generations) were created through manual segmentation of the visible human data. A mathematical algorithm with physiological constraints was used to extend the original airway model to fill each lobe. For each parent airway branch inside a lobe, the algorithm extends the airway tree by creating two daughter branches modeled with cylindrical tubes. Parameters for the cylindrical tubes such as diameter, length, and angle are constrained based on flow parameters and available lung space.

  17. 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

  18. Brush cells of rodent gallbladder and stomach epithelia express neurofilaments.

    PubMed

    Luciano, Liliana; Groos, Stephanie; Reale, Enrico

    2003-02-01

    It has been suggested that brush cells (BCs), a distinct type of cell occurring in various epithelia of the respiratory and gastrointestinal tracts, may function as receptor cells. The major characteristics of BCs are a prominent brush border and an unusually highly ordered arrangement of cytoskeletal elements (F-actin, microtubules, and intermediate filaments). In this study we aimed to characterize the nature of the intermediate filaments in BCs by light and electron microscopic immunostaining. Gallbladder and stomach specimens from mice and rats, respectively, were fixed in various solutions, embedded either in paraffin or epoxy resin, and processed for immunodetection. Commercially available, well-characterized antibodies against neurofilaments, peripherin, and cytokeratin peptide 18 were used. The polyclonal antiserum cocktail to neurofilaments was applied as a supplement in a double-labeling procedure with anti-actin and anti-cytokeratin 18 antibodies. The results demonstrate that the BCs of both organs express two types of intermediate filaments, i.e., neurofilaments and cytokeratin 18 filaments, and that these have a compartmentalized distribution in the cytoplasm. BCs do not express peripherin. The immunodetection of intermediate filaments distinctive for mature neurons in BCs supports their putative receptor function. The co-expression of neurofilaments and cytokeratins is shown for the first time in healthy tissues.

  19. 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

  20. 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.

  1. Epigenetic Analysis of Laser Capture Microdissected Fetal Epithelia1

    PubMed Central

    Seelan, Ratnam S.; Warner, Dennis R.; Mukhopadhyay, Partha M.; Andres, Sarah A.; Smolenkova, Irina A.; Wittliff, James L.; Pisano, M. Michele; Greene, Robert M.

    2013-01-01

    Laser capture microdissection (LCM) is a superior method for non-destructive collection of specific cell populations from tissue sections. While DNA, RNA and protein have been analyzed from LCM-procured samples, epigenetic analyses, particularly of fetal, highly hydrated tissue, have not been attempted. A standardized protocol with quality assurance measures was established to procure cells by LCM of the medial edge epithelia (MEE) of the fetal palatal processes for isolation of intact microRNA for expression analyses and genomic DNA for CpG methylation analyses. MicroRNA preparations, obtained using the RNAqueous® Micro kit (Life Technologies), exhibited better yields and higher quality than those obtained using the Arcturus® PicoPure® RNA Isolation kit (Life Technologies). The approach was validated using real-time PCR to determine expression of selected microRNAs (miR-99a and miR-200b) and pyrosequencing to determine CpG methylation status of selected genes (Aph1a and Dkk4) in the MEE. These studies describe an optimized approach for employing LCM of epithelial cells from fresh frozen fetal tissue that enables quantitative analyses of miRNA expression levels and CpG methylation. PMID:23911529

  2. Field Population-based blocking treatment of esophageal epithelia dysplasia

    PubMed Central

    Hou, Jun; Lin, Pei-Zhong; Chen, Zhi-Feng; Ding, Zhen-Wei; Li, Shao-Sheng; Men, Fan-Shu; Guo, Li-Ping; He, Yu-Tong; Qiao, Chui-Yun; Guo, Chui-Lan; Duan, Jian-Ping; Wen, Deng-Gui

    2002-01-01

    AIM: To confirm the value of blocking treatment by zenshengping (ZSP), a Chinese herb composite, and Riboflavin for esophageal epithelia dysplasia cases screened out in high risk area in northern china by exfoliative balloon cytology (EBC), so to reduce the incidence rate of esophageal cancer (EC). METHODS: Esophageal epithelium dysplasia cases including mind esophageal epithelium dysplasia (MEED), stage one severe esophageal epithelium dysplasia (SEED I), and stage two severe esophageal epithelium dysplasia (SEED II) were screened out from people aged 40 years and older in the high risk area of Chixian. These cases were randomly divided into a treatment and control group. Subjects in the treatment and control groups took ZSP, riboflavin, and placebo daily for three years. EC cases registered by cancer registry and identified by EBC re-screening in the treatment and control groups were used to calculate incidence and blocking rates to demonstrate the effects of blocking medication. RESULTS: It was found that 31.92% and 24.15% of people aged 40 years and older in Cixian could been diagnosed as MEED and SEED cases. The severity of dysplasia increased with age. ZSP had blocked EC occurrence by 47.79% after 3 year medication among the SEED cases. CONCLUSION: ZSP can block the development from SEED I and SEED II to EC by 47.79%. Efforts should be made to screen and treat dysplasia cases in people aged 40 years and older in high risk areas to reduce the mortality figures. PMID:12046061

  3. Vacuolar-type proton pumps in insect epithelia

    PubMed Central

    Wieczorek, Helmut; Beyenbach, Klaus W.; Huss, Markus; Vitavska, Olga

    2009-01-01

    Summary Active transepithelial cation transport in insects was initially discovered in Malpighian tubules, and was subsequently also found in other epithelia such as salivary glands, labial glands, midgut and sensory sensilla. Today it appears to be established that the cation pump is a two-component system of a H+-transporting V-ATPase and a cation/nH+ antiporter. After tracing the discovery of the V-ATPase as the energizer of K+/nH+ antiport in the larval midgut of the tobacco hornworm Manduca sexta we show that research on the tobacco hornworm V-ATPase delivered important findings that emerged to be of general significance for our knowledge of V-ATPases, which are ubiquitous and highly conserved proton pumps. We then discuss the V-ATPase in Malpighian tubules of the fruitfly Drosophila melanogaster where the potential of post-genomic biology has been impressively illustrated. Finally we review an integrated physiological approach in Malpighian tubules of the yellow fever mosquito Aedes aegypti which shows that the V-ATPase delivers the energy for both transcellular and paracellular ion transport. PMID:19448071

  4. Lung-On-A-Chip Technologies for Disease Modeling and Drug Development

    PubMed Central

    Konar, Dipasri; Devarasetty, Mahesh; Yildiz, Didem V.; Atala, Anthony; Murphy, Sean V.

    2016-01-01

    Animal and two-dimensional cell culture models have had a profound impact on not only lung research but also medical research at large, despite inherent flaws and differences when compared with in vivo and clinical observations. Three-dimensional (3D) tissue models are a natural progression and extension of existing techniques that seek to plug the gaps and mitigate the drawbacks of two-dimensional and animal technologies. In this review, we describe the transition of historic models to contemporary 3D cell and organoid models, the varieties of current 3D cell and tissue culture modalities, the common methods for imaging these models, and finally, the applications of these models and imaging techniques to lung research. PMID:27127414

  5. Comparison of actual tidal volume in neonatal lung model volume control ventilation using three ventilators.

    PubMed

    Toyama, H; Endo, Y; Ejima, Y; Matsubara, M; Kurosawa, S

    2011-07-01

    In neonates, small changes in tidal volumes (V(T)) may lead to complications. Previous studies have shown a significant difference between ventilator-measured tidal volume and tidal volume delivered (actual V(T)). We evaluated the accuracy of three different ventilators to deliver small V(T) during volume-controlled ventilation. We tested Servo 300, 840 ventilator and Evita 4 Neoflow ventilators with lung models simulating normal and injured neonatal lung compliance models. Gas volume delivered from the ventilator into the test circuit (V(TV)) and actual V(T) to the test lung were measured using Ventrak respiration monitors at set V(T) (30 ml). The gas volume increase of the breathing circuit was then calculated. Tidal volumes of the SV300 and PB840 in both lung models were similar to the set V(T) and the actual tidal volumes in the injured model (20.7 ml and 19.8 ml, respectively) were significantly less than that in the normal model (27.4 ml and 23.4 ml). PB840 with circuit compliance compensation could not improve the actual V(T). V(TV) of the EV4N in the normal and the injured models (37.8 ml and 46.6 ml) were markedly increased compared with set V(T), and actual V(T) were similar to set V(T) in the normal and injured model (30.2 ml and 31.9 ml, respectively). EV4N measuring V(T) close to the lung could match actual V(T) to almost the same value as the set V(T) however the gas volume of the breathing circuit was increased. If an accurate value for the patient's actual V(T) is needed, this V(T) must be measured by a sensor located between the Y-piece and the tracheal tube.

  6. N-acetylcysteine attenuates lung injury in a rodent model of fracture.

    PubMed

    Timlin, Marcus; Condron, Claire; Toomey, Deirdre; Power, Colm; Thornes, Brian; Kearns, Stephen; Street, John; Murray, Paraic; Bouchier-Hayes, David

    2004-02-01

    Neutrophil-mediated lung injury is a cause of significant morbidity and mortality in patients with multiple injuries. We have shown previously that fracture hematoma can activate neutrophils and is thus a putative mediator of the systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS) and multiple organ failure (MOF) in those patients with severe skeletal trauma. Our aim was to establish a rodent model of fracture which caused lung injury and subsequently to administer a drug following fracture to attenuate the lung injury. The drug we chose was N-acetylcysteine, a potent antioxidant. Adult Sprague-Dawley rats were assigned to 4 groups: (1) general anesthetic only, (2) general anesthetic with bilateral femur fractures and nailing, (3) general anesthetic and N-acetylcysteine, (4) general anesthetic with bilateral femur fractures and nailing and N-acetylcysteine after the injury (n = 6 in each group). The dose of N-acetylcysteine was 0.5 mg/kg which was given intraperitoneally after injury to the treated groups. The rats were killed 24 hours after injury and some parameters of lung injury were evaluated--i.e., bronchoalveolar lavage (BAL), lung tissue myeloperoxidase levels (MPO) and wet/dry ratios of lung tissue. The results were analyzed, using one-way analysis of variance. Bilateral femur fracture produced a significant lung injury, measured by increases in MPO (25-43 microg/g tissue) and BAL protein (460-605 microg/mL). This effect was attenuated by treatment with N-acetylcysteine (MPO 43-9 microg/mL, BAL protein 605-198 microg/mL). N-acetyl cysteine, if given after skeletal trauma, is of potential therapeutic benefit, in preventing SIRS, ARDS and MOF.

  7. 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

  8. 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...

  9. Mouse lung infection model to assess Rhodococcus equi virulence and vaccine protection.

    PubMed

    González-Iglesias, Patricia; Scortti, Mariela; MacArthur, Iain; Hapeshi, Alexia; Rodriguez, Héctor; Prescott, John F; Vazquez-Boland, José A

    2014-08-06

    The pathogenic actinomycete Rhodococcus equi causes severe purulent lung infections in foals and immunocompromised people. Although relatively unsusceptible to R. equi, mice are widely used for in vivo studies with this pathogen. The most commonly employed mouse model is based on systemic (intravenous) infection and determination of R. equi burdens in spleen and liver. Here, we investigated the murine lung for experimental infection studies with R. equi. Using a 10(7)CFU intranasal challenge in BALB/c mice, virulent R. equi consistently survived in quantifiable numbers up to 10 days in the lungs whereas virulence-deficient R. equi bacteria were rapidly cleared. An internally controlled virulence assay was developed in which the test R. equi strains are co-inoculated and monitored in the same mouse. Isogenic R. equi bacteria lacking either the plasmid vapA gene or the entire virulence plasmid were compared using this competitive assay. Both strains showed no significant differences in in vivo fitness in the lung, indicating that the single loss of the virulence factor VapA was sufficient to account for the full attenuation seen in the absence of the virulence plasmid. To test the adequacy of the lung infection model for monitoring R. equi vaccine efficacy, BALB/c mice were immunized with live R. equi and challenged intranasally. Vaccination conferred protection against acute pulmonary challenge with virulent R. equi. Our data indicate that the murine lung infection model provides a useful tool for both R. equi virulence and vaccine studies. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. 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

  11. 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.

  12. Nanoparticle mass transfer from lung airways to systemic regions--Part II: Multi-compartmental modeling.

    PubMed

    Kolanjiyil, Arun V; Kleinstreuer, Clement

    2013-12-01

    This is the second article of a two-part paper, combining high-resolution computer simulation results of inhaled nanoparticle deposition in a human airway model (Kolanjiyil and Kleinstreuer, 2013, "Nanoparticle Mass Transfer From Lung Airways to Systemic Regions--Part I: Whole-Lung Aerosol Dynamics," ASME J. Biomech. Eng., 135(12), p. 121003) with a new multicompartmental model for insoluble nanoparticle barrier mass transfer into systemic regions. Specifically, it allows for the prediction of temporal nanoparticle accumulation in the blood and lymphatic systems and in organs. The multicompartmental model parameters were determined from experimental retention and clearance data in rat lungs and then the validated model was applied to humans based on pharmacokinetic cross-species extrapolation. This hybrid simulator is a computationally efficient tool to predict the nanoparticle kinetics in the human body. The study provides critical insight into nanomaterial deposition and distribution from the lungs to systemic regions. The quantitative results are useful in diverse fields such as toxicology for exposure-risk analysis of ubiquitous nanomaterial and pharmacology for nanodrug development and targeting.

  13. Supernatant of stored platelets causes lung inflammation and coagulopathy in a novel in vivo transfusion model.

    PubMed

    Vlaar, Alexander P J; Hofstra, Jorrit J; Kulik, Wim; van Lenthe, Henk; Nieuwland, Rienk; Schultz, Marcus J; Levi, Marcel M; Roelofs, Joris J T H; Tool, Anton T J; de Korte, Dirk; Juffermans, Nicole P

    2010-08-26

    Transfusion-related acute lung injury is suggested to be a "2-hit" event resulting from priming and activation of pulmonary neutrophils. Activation may result from infusion of lysophosphatidylcholines (LysoPCs), which accumulate during storage of blood products. In the present study, we developed a syngeneic in vivo transfusion model to test whether storage of platelet concentrates (PLTs) results in lung injury in healthy rats as well as in a "2-hit" model using lipopolysaccharide-pretreated rats. In addition, the effect of washing of platelets was studied. In healthy rats, transfusion of aged PLTs caused mild lung inflammation. In LPS-pretreated rats, transfusion of aged PLTs, but not fresh PLTs, augmented pulmonary systemic coagulopathy. When PLTs components were transfused separately, supernatant of aged PLTs, but not washed aged platelets, induced pulmonary injury in the "2-hit" model. Supernatants of aged PLTs contained increased concentrations of LysoPCs compared with fresh PLTs, which enhanced neutrophil priming activity in vitro. We conclude that transfusion of aged PLTs induces lung inflammation in healthy rats. In a "2-hit" model, aged PLTs contribute to pulmonary and systemic coagulopathy, which may be mediated by LysoPCs, which accumulate in the supernatant of PLTs during storage.

  14. Development of a nursing model for life adjustment in patients with lung cancer in Japan.

    PubMed

    Horii, Naoko; Maekawa, Atsuko

    2013-09-01

    The aim of this study was to obtain basic data about the support for life adjustment in lung cancer patients in Japan. We identified factors that affect life adjustment in people with lung cancer, developed a model for life adjustment support of lung cancer patients, and investigated its validity. A survey was conducted using self-completed questionnaires, and responses were received by 203 individuals. Analysis of the responses revealed that life adjustment was regulated by six factors associated with positive self-evaluation: stress dissipation, fighting spirit, helplessness/hopelessness, full discussion with doctor about treatment, clarity of thought, and support network size. A model search with covariance structure analysis was conducted. The resulting model was revealed to have a goodness-of-fit index of 0.963, an adjusted goodness-of-fit index of 0.930, a comparative fit index of 0.974, and a root mean square error of approximation of 0.040. The findings suggest that improvements in quality of life can be expected by combining a positive self-evaluation in lung cancer patients and interventions to raise self-adjustment ability with the use of this Model, although it requires further testing. © 2013 Wiley Publishing Asia Pty Ltd.

  15. 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.

  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. Presentation of a model-based data mining to predict lung cancer.

    PubMed

    Shahhoseini, Reza; Ghazvini, Ali; Esmaeilpour, Mansour; Pourtaghi, Gholamhossein; Tofighi, Shahram

    2015-01-01

    The data related to patients often have very useful information that can help us to resolve a lot of problems and difficulties in different areas. This study was performed to present a model-based data mining to predict lung cancer in 2014. In this exploratory and modeling study, information was collected by two methods library and field methods. All gathered variables were in the format of form of data transferring from those affected by pulmonary problems (303 records) as well as 26 fields including clinical and environmental variables. The validity of form of data transferring was obtained via consensus and meeting group method using purposive sampling through several meetings among members of research group and lung group. The methodology used was based on classification and prediction method of data mining as well as the method of supervision with algorithms of classification and regression tree using Clementine 12 software. For clinical variables, model's precision was high in three parts of training, test and validation. For environmental variables, maximum precision of model in training part relevant to C&R algorithm was equal to 76%, in test part relevant to Neural Net algorithm was equal to 61%, and in validation part relevant to Neural Net algorithm was equal to 57%. In clinical variables, C5.0, CHAID, C & R models were stable and suitable for detection of lung cancer. In addition, in environmental variables, C & R model was stable and suitable for detection of lung cancer. Variables such as pulmonary nodules, effusion of plural fluid, diameter of pulmonary nodules, and place of pulmonary nodules are very important variables that have the greatest impact on detection of lung cancer.

  18. 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

  19. Optimal determination of respiratory airflow patterns using a nonlinear multicompartment model for a lung mechanics system.

    PubMed

    Li, Hancao; Haddad, Wassim M

    2012-01-01

    We develop optimal respiratory airflow patterns using a nonlinear multicompartment model for a lung mechanics system. Specifically, we use classical calculus of variations minimization techniques to derive an optimal airflow pattern for inspiratory and expiratory breathing cycles. The physiological interpretation of the optimality criteria used involves the minimization of work of breathing and lung volume acceleration for the inspiratory phase, and the minimization of the elastic potential energy and rapid airflow rate changes for the expiratory phase. Finally, we numerically integrate the resulting nonlinear two-point boundary value problems to determine the optimal airflow patterns over the inspiratory and expiratory breathing cycles.

  20. Optimal Determination of Respiratory Airflow Patterns Using a Nonlinear Multicompartment Model for a Lung Mechanics System

    PubMed Central

    Li, Hancao; Haddad, Wassim M.

    2012-01-01

    We develop optimal respiratory airflow patterns using a nonlinear multicompartment model for a lung mechanics system. Specifically, we use classical calculus of variations minimization techniques to derive an optimal airflow pattern for inspiratory and expiratory breathing cycles. The physiological interpretation of the optimality criteria used involves the minimization of work of breathing and lung volume acceleration for the inspiratory phase, and the minimization of the elastic potential energy and rapid airflow rate changes for the expiratory phase. Finally, we numerically integrate the resulting nonlinear two-point boundary value problems to determine the optimal airflow patterns over the inspiratory and expiratory breathing cycles. PMID:22719793

  1. 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

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

    PubMed

    Bragulla, Hermann H; Homberger, Dominique G

    2009-04-01

    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 different

  3. Stable isotope resolved metabolomics of lung cancer in a SCID mouse model.

    PubMed

    Fan, Teresa W-M; Lane, Andrew N; Higashi, Richard M; Yan, Jun

    2011-06-01

    We have determined the time course of [U-(13)C]-glucose utilization and transformations in SCID mice via bolus injection of the tracer in the tail vein. Incorporation of (13)C into metabolites extracted from mouse blood plasma and several tissues (lung, heart, brain, liver, kidney, and skeletal muscle) were profiled by NMR and GC-MS, which helped ascertain optimal sampling times for different target tissues. We found that the time for overall optimal (13)C incorporation into tissue was 15-20 min but with substantial differences in (13)C labeling patterns of various organs that reflected their specific metabolism. Using this stable isotope resolved metabolomics (SIRM) approach, we have compared the (13)C metabolite profile of the lungs in the same mouse with or without an orthotopic lung tumor xenograft established from human PC14PE6 lung adenocarcinoma cells. The (13)C metabolite profile shows considerable differences in [U-(13)C]-glucose transformations between the two lung tissues, demonstrating the feasibility of applying SIRM to investigate metabolic networks of human cancer xenograft in the mouse model.

  4. 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

  5. Retention and clearance of inhaled ceramic fibres in rat lungs and development of a dissolution model.

    PubMed

    Yamato, H; Hori, H; Tanaka, I; Higashi, T; Morimoto, Y; Kido, M

    1994-04-01

    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.

  6. Aminophylline treatment in meconium-induced acute lung injury in a rabbit model.

    PubMed

    Mokra, D; Mokry, J; Tatarkova, Z; Redfors, B; Petraskova, M; Calkovska, A

    2007-11-01

    Administration of methylxanthines may diminish meconium-induced acute lung injury. Meconium-instilled rabbits intravenously received aminophylline (2.0 mg/kg) at two doses 0.5 h and 2.5 h after meconium instillation or were left without treatment, and were oxygen-ventilated for additional 5 h. At the end of experiment, lungs and trachea were excised. Within 5 h after the first dose of treatment, aminophylline significantly improved gas exchange and decreased right-to-left pulmonary shunts, central venous pressure, and ventilatory pressures. Moreover, aminophylline reduced meconium-induced lung edema formation, airway hyperreactivity to histamine, count of neutrophils in bronchoalveolar lavage fluid associated with higher total white blood cells and neutrophils in the blood, and diminished oxidative modifications of proteins and lipids in lung tissue compared with the non-treated meconium-instilled group. In a rabbit model of the meconium aspiration syndrome, aminophylline treatment enhanced pulmonary functions and alleviated oxidative injury and changes in airway reactivity related to lung inflammation.

  7. CpG-ODN increases the release of VEGF in a mouse model of lung carcinoma.

    PubMed

    Sorrentino, Rosalinda; Morello, Silvana; Giordano, Maria Grazia; Arra, Claudio; Maiolino, Piera; Adcock, Ian M; Pinto, Aldo

    2011-06-15

    Vascular endothelial-derived growth factor (VEGF) plays a fundamental role in the formation of new vessels within the tumour mass. Increasing evidence has highlighted the involvement of Toll-like receptors (TLRs) in cancer. Of interest, TLR9 is over-expressed in human lung carcinoma tissues. The aim of our study was to determine whether TLR9 activation could alter VEGF release in a mouse model of lung carcinoma. Lewis lung carcinoma cells were intravenously (i.v.) inoculated and 10 days later, tumour-bearing mice were treated with CpG-ODN (CpG, a TLR9 ligand) or PBS. CpG administration enhanced VEGF release, which was associated with increased tumour lesions in the lung. CpG induced high levels of IL-6 expression and activation of STAT3 in tumour-bearing mice. Moreover, CpG induced VEGF release from primary fibroblasts and endothelial cells, which correlated with IL-6 and TGFβ production. This may explain the large influx of fibroblasts and the production of basic fibroblast growth factor (bFGF) in the tumour mass. The administration of a monoclonal antibody against VEGF A arrested tumour progression and induced a Th1-like response in CpG-treated tumour-bearing mice. In conclusion, our study demonstrates that the combination of CpG with anti-VEGF monoclonal antibody could be of potential therapeutic in lung carcinoma.

  8. Comparison of two lung clearance models based on the dissolution rates of oxidized depleted uranium

    SciTech Connect

    Crist, K.C.

    1984-10-01

    An in-vitro dissolution study was conducted on two respirable oxidized depleted uranium samples. The dissolution rates generated from this study were then utilized in the International Commission on Radiological Protection Task Group lung clearance model and a lung clearance model proposed by Cuddihy. Predictions from both models based on the dissolution rates of the amount of oxidized depleted uranium that would be cleared to blood from the pulmonary region following an inhalation exposure were compared. It was found that the predictions made by both models differed considerably. The difference between the predictions was attributed to the differences in the way each model perceives the clearance from the pulmonary region. 33 references, 11 figures, 9 tables.

  9. 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.

  10. Analysis of regional compliance in a porcine model of acute lung injury.

    PubMed

    Czaplik, Michael; Biener, Ingeborg; Dembinski, Rolf; Pelosi, Paolo; Soodt, Thomas; Schroeder, Wolfgang; Leonhardt, Steffen; Marx, Gernot; Rossaint, Rolf; Bickenbach, Johannes

    2012-10-15

    Lung protective ventilation in acute lung injury (ALI) focuses on using low tidal volumes and adequate levels of positive end-expiratory pressure (PEEP). Identifying optimal pressure is difficult because pressure-volume (PV) relations differ regionally. Precise analysis demands local measurements of pressures and related alveolar morphologies. In a porcine model of surfactant depletion (n=24), we combined measuring static pressures with endoscopic microscopy and electrical impedance tomography (EIT) to examine regional PV loops and morphologic heterogeneities between healthy (control group; CON) and ALI lungs ventilated with low (LVT) or high tidal volumes (HVT). Quantification included indices for microscopy (Volume Air Index (VAI), Heterogeneity and Circularity Index), EIT analysis and calculation of regional compliances due to generated PV loops. We found that: (1) VAI decreased in lower lobe after ALI, (2) electrical impedance decreased in dorsal regions and (3) PV loops differed regionally. Further studies should prove the potentials of these techniques on individual respiratory settings and clinical outcome.

  11. [A nonlinear multi-compartment lung model for optimization of breathing airflow pattern].

    PubMed

    Cai, Yongming; Gu, Lingyan; Chen, Fuhua

    2015-02-01

    It is difficult to select the appropriate ventilation mode in clinical mechanical ventilation. This paper presents a nonlinear multi-compartment lung model to solve the difficulty. The purpose is to optimize respiratory airflow patterns and get the minimum of the work of inspiratory phrase and lung volume acceleration, minimum of the elastic potential energy and rapidity of airflow rate changes of expiratory phrase. Sigmoidal function is used to smooth the respiratory function of nonlinear equations. The equations are established to solve nonlinear boundary conditions BVP, and finally the problem was solved with gradient descent method. Experimental results showed that lung volume and the rate of airflow after optimization had good sensitivity and convergence speed. The results provide a theoretical basis for the development of multivariable controller monitoring critically ill mechanically ventilated patients.

  12. A model of the lung structure and its validation.

    PubMed

    Fung, Y C

    1988-05-01

    As a framework to describe the structure of the lung, a theory is presented under the assumptions that all alveoli are initially equal and space filling, are ventilated as uniformly as possible, and obey the laws of elasticity. A combination of the tetrakaidecahedron (14-hedron) and the order-2 14-hedron formed by 14 14-hedra surrounding a central one that is perforated for ventilation meets the requirements. Alveolar ductal tree is formed by these order-2 polyhedra. Equilibrium and elasticity require the alveolar mouths to be curved and convex toward the alveolar wall. Perforation of additional walls causes a variety of alveolar shapes. The predicted shapes of the alveoli, the shapes of alveolar mouths, the lengths of sacs and ducts, the statistics of the dihedral angles, stars, corners, lines, dots, and vertices compare well with available morphometric data. The vascular and bronchial trees are joined at the alveolar level: each arteriole supplies 0.75 and each venule drains 0.72 order-2 polyhedra.

  13. High flow nasal heliox improves work of breathing and attenuates lung injury in a newborn porcine lung injury model.

    PubMed

    Jassar, R K; Vellanki, H; Zhu, Yan; Hesek, A M; Wang, J; Rodriguez, E; Wolfson, M R; Shaffer, T H

    2015-01-01

    High flow nasal cannula (HFNC) has been shown to improve ventilation and oxygenation and reduce work of breathing in newborns with respiratory distress. Heliox, decreases resistance to airflow, reduces the work of breathing, facilitates the distribution of inspired gas, and has been shown to attenuate lung inflammation during the treatment of acute lung injury. Heliox delivered by HFNC will decrease resistive load, decrease work of breathing, improve ventilation and attenuate lung inflammation during spontaneous breathing following acute lung injury in the newborn pig. Spontaneously breathing neonatal pigs received Nitrox or Heliox by HFNC and studied over 4 hrs following oleic acid injury. Gas exchange, pulmonary mechanics and systemic inflammation were measured serially. Lung inflammation biomarkers were assessed at termination. Heliox breathing animals demonstrated lower work of breathing reflected by lower tracheal pressure, phase angle and phase relationship. Ventilation efficiency index was greater compared to Nitrox. Heliox group showed less lung inflammation reflected by lower tissue interleukin-6 and 8. High flow nasal Heliox decreased respiratory load, reduced resistive work of breathing indices and attenuated lung inflammatory profile while ventilation was supported at less pressure effort in the presence of acute lung injury.

  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. Effect of Long-Term Antiorthostatic Suspension in a Murine Model of Acute Lung Injury

    PubMed Central

    Jang, Tae Young; Jung, Ah-Yeoun; Kim, Young Hyo

    2016-01-01

    Objectives Antiorthostatic suspension (AOS) is ground-based model of simulated microgravity. There is still no study about the effect of long-term microgravity on the clinical course of acute lung injury. We evaluated the effect of simulated microgravity using AOS in a murine model of acute lung injury by lipopolysaccharide (LPS). Methods Thirty BALB/c mice were used. During 4 weeks, mice were equally allocated to control (free movement), restraint (tail suspended, but hindlimbs not unloaded), and AOS group (hindlimb unloaded). After then, mice got intranasal challenge with LPS (20 mg/kg, 50 μL). We measured: weight gain before and after AOS, the number of inflammatory cells and titers of cytokines (interleukin [IL]-1β, IL-6, IL-10, tumor necrosis factor-α, and interferon-γ) in bronchoalveolar lavage (BAL) fluid, titer of myeloperoxidase (MPO) in serum and lung homogenate, and histopathologic examination of lung tissue. Results AOS group had significant weight loss compared to control and restraint group (P<0.001). AOS group also showed significantly decreased lymphocytes (P=0.023) compared to control group. In AOS group, titer for IL-1β in BAL fluid was significantly lower than restraint group (P=0.049). Titer for serum MPO was significantly decreased in AOS group compared to restraint group (P=0.004). However, there was no significant difference of MPO titers in lung tissue between groups. Histopathologic examination of lung tissue revealed no significant difference in the degree of pulmonary infiltration between restraint and AOS group. Conclusion In spite of modest anti-inflammatory effect, prolonged AOS caused no significant change in LPS-induced pulmonary inflammation. PMID:27334509

  16. Improved therapeutic effectiveness by combining liposomal honokiol with cisplatin in lung cancer model.

    PubMed

    Jiang, Qi-qi; Fan, Lin-yu; Yang, Guang-li; Guo, Wen-Hao; Hou, Wen-li; Chen, Li-juan; Wei, Yu-quan

    2008-08-16

    Honokiol is a major bioactive compound extracted from Magnolia. The present study was designed to determine whether liposomal honokiol has the antitumor activity against human lung cancer as well as potentiates the antitumor activity of cisplatin in A549 lung cancer xenograft model, if so, to examine the possible mechanism in the phenomenon. human A549 lung cancer-bearing nude mice were treated with liposomal honokiol, liposomal honokiol plus DDP or with control groups. Apoptotic cells and vessels were evaluated by fluorescent in situ TUNEL assay and by immunohistochemistry with an antibody reactive to CD31 respectively. The present study showed that liposomal honokiol alone resulted in effective suppression of the tumor growth, and that the combined treatment with honokiol plus DDP had the enhanced inhibition of the tumor growth and resulted in a significant increase in life span. The more apparent apoptotic cells in the tumors treated with honokiol plus DDP was found in fluorescent in situ TUNEL assay, compared with the treatment with control groups. In addition, the combination of honokiol and DDP apparently reduced the number of vessels by immunolabeling of CD31 in the tissue sections, compared with control groups. In summary, our data suggest that honokiol alone had the antitumor activity against human lung cancer in A549 lung cancer xenograft model, and that the combination of honokiol with DDP can enhance the antitumor activity, and that the enhanced antitumor efficacy in vivo may in part result from the increased induction of the apoptosis and the enhanced inhibition of angiogenesis in the combined treatment. The present findings may be of importance to the further exploration of the potential application of the honokiol alone or the combined approach in the treatment of lung carcinoma.

  17. Improved therapeutic effectiveness by combining liposomal honokiol with cisplatin in lung cancer model

    PubMed Central

    Jiang, Qi-qi; Fan, Lin-yu; Yang, Guang-li; Guo, Wen-Hao; Hou, Wen-li; Chen, Li-juan; Wei, Yu-quan

    2008-01-01

    Background Honokiol is a major bioactive compound extracted from Magnolia. The present study was designed to determine whether liposomal honokiol has the antitumor activity against human lung cancer as well as potentiates the antitumor activity of cisplatin in A549 lung cancer xenograft model, if so, to examine the possible mechanism in the phenomenon. Methods human A549 lung cancer-bearing nude mice were treated with liposomal honokiol, liposomal honokiol plus DDP or with control groups. Apoptotic cells and vessels were evaluated by fluorescent in situ TUNEL assay and by immunohistochemistry with an antibody reactive to CD31 respectively. Results The present study showed that liposomal honokiol alone resulted in effective suppression of the tumor growth, and that the combined treatment with honokiol plus DDP had the enhanced inhibition of the tumor growth and resulted in a significant increase in life span. The more apparent apoptotic cells in the tumors treated with honokiol plus DDP was found in fluorescent in situ TUNEL assay, compared with the treatment with control groups. In addition, the combination of honokiol and DDP apparently reduced the number of vessels by immunolabeling of CD31 in the tissue sections, compared with control groups. Conclusion In summary, our data suggest that honokiol alone had the antitumor activity against human lung cancer in A549 lung cancer xenograft model, and that the combination of honokiol with DDP can enhance the antitumor activity, and that the enhanced antitumor efficacy in vivo may in part result from the increased induction of the apoptosis and the enhanced inhibition of angiogenesis in the combined treatment. The present findings may be of importance to the further exploration of the potential application of the honokiol alone or the combined approach in the treatment of lung carcinoma. PMID:18706101

  18. Lung Pathologies in a Chronic Inflammation Mouse Model Are Independent of Eosinophil Degranulation.

    PubMed

    Jacobsen, Elizabeth A; Ochkur, Sergei I; Doyle, Alfred D; LeSuer, William E; Li, Wen; Protheroe, Cheryl A; Colbert, Dana; Zellner, Katie R; Shen, HuaHao H; Irvin, Charles G; Lee, James J; Lee, Nancy A

    2017-05-15

    The release of eosinophil granule proteins in the lungs of patients with asthma has been dogmatically linked with lung remodeling and airway hyperresponsiveness. However, the demonstrated inability of established mouse models to display the eosinophil degranulation occurring in human subjects has prevented a definitive in vivo test of this hypothesis. To demonstrate in vivo causative links between induced pulmonary histopathologies/lung dysfunction and eosinophil degranulation. A transgenic mouse model of chronic T-helper cell type 2-driven inflammation overexpressing IL-5 from T cells and human eotaxin 2 in the lung (I5/hE2) was used to test the hypothesis that chronic histopathologies and the development of airway hyperresponsiveness occur as a consequence of extensive eosinophil degranulation in the lung parenchyma. Studies targeting specific inflammatory pathways in I5/hE2 mice surprisingly showed that eosinophil-dependent immunoregulative events and not the release of individual secondary granule proteins are the central contributors to T-helper cell type 2-induced pulmonary remodeling and lung dysfunction. Specifically, our studies highlighted a significant role for eosinophil-dependent IL-13 expression. In contrast, extensive degranulation leading to the release of major basic protein-1 or eosinophil peroxidase was not causatively linked to many of the induced pulmonary histopathologies. However, these studies did define a previously unappreciated link between the release of eosinophil peroxidase (but not major basic protein-1) and observed levels of induced airway mucin. These data suggest that improvements observed in patients with asthma responding to therapeutic strategies ablating eosinophils may occur as a consequence of targeting immunoregulatory mechanisms and not by simply eliminating the destructive activities of these purportedly end-stage effector cells.

  19. The influence of human respiratory epithelia on Pseudomonas aeruginosa gene expression.

    PubMed

    Chugani, Sudha; Greenberg, E P

    2007-01-01

    The opportunistic pathogen Pseudomonas aeruginosa can cause acute or chronic infections in humans. Little is known about the initial adaptation of P. aeruginosa to host tissues and the factors that determine whether a P. aeruginosa-epithelial cell interaction will manifest as an acute or a chronic infection. To gain insights into the initial phases of P. aeruginosa infections and to identify P. aeruginosa genes regulated in response to respiratory epithelia, we exposed P. aeruginosa to cultured primary differentiated human airway epithelia. We used a P. aeruginosa strain that causes acute damage to the epithelia and a mutant with defects in Type III secretion and in rhamnolipid synthesis. The mutant did not cause rapid damage to epithelia as did the wildtype. We compared the transcriptomes of the P. aeruginosa wildtype and the mutant to each other and to P. aeruginosa grown under other conditions, and we discovered overlapping sets of differentially expressed genes in the wildtype and mutant exposed to epithelia. A recent study reported that exposure of P. aeruginosa to epithelia is characterized by a repression of the bacterial iron-responsive genes. These findings were suggestive of ample iron availability during infection. In contrast, we found that P. aeruginosa shows an iron-starvation response upon exposure to epithelial cells. This observation highlights the importance of the iron starvation response in both acute and chronic infections and suggests opportunities for therapy.

  20. 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

  1. 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.

  2. Lung cancer mortality trends in Chile and six-year projections using Bayesian dynamic linear models.

    PubMed

    Torres-Avilés, Francisco; Moraga, Tomás; Núñez, Loreto; Icaza, Gloria

    2015-09-01

    The objectives were to analyze lung cancer mortality trends in Chile from 1990 to 2009, and to project the rates six years forward. Lung cancer mortality data were obtained from the Chilean Ministry of Health. To obtain mortality rates, population projections were used, based on the 2002 National Census. Rates were adjusted using the world standard population as reference. Bayesian dynamic linear models were fitted to estimate trends from 1990 to 2009 and to obtain projections for 2010-2015. During the period under study, there was a 19.9% reduction in the lung cancer mortality rate in men. In women, there was increase of 28.4%. The second-order model showed a better fit for men, and the first-order model a better fit for women. Between 2010 and 2015 the downward trend continued in men, while a trend to stabilization was projected for lung cancer mortality in women in Chile. This analytical approach could be useful implement surveillance systems for chronic non-communicable disease and to evaluate preventive strategies.

  3. Incorporation of a genetic factor into an epidemiologic model for prediction of individual risk of lung cancer: the Liverpool Lung Project.

    PubMed

    Raji, Olaide Y; Agbaje, Olorunsola F; Duffy, Stephen W; Cassidy, Adrian; Field, John K

    2010-05-01

    The Liverpool Lung Project (LLP) has previously developed a risk model for prediction of 5-year absolute risk of lung cancer based on five epidemiologic risk factors. SEZ6L, a Met430IIe polymorphic variant found on 22q12.2 region, has been previously linked with an increased risk of lung cancer in a case-control population. In this article, we quantify the improvement in risk prediction with addition of SEZ6L to the LLP risk model. Data from 388 LLP subjects genotyped for SEZ6L single-nucleotide polymorphism (SNP) were combined with epidemiologic risk factors. Multivariable conditional logistic regression was used to predict 5-year absolute risk of lung cancer with and without this SNP. The improvement in the model associated with the SEZ6L SNP was assessed through pairwise comparison of the area under the receiver operating characteristic curve and the net reclassification improvements (NRI). The extended model showed better calibration compared with the baseline model. There was a statistically significant modest increase in the area under the receiver operating characteristic curve when SEZ6L was added into the baseline model. The NRI also revealed a statistically significant improvement of around 12% for the extended model; this improvement was better for subjects classified into the two intermediate-risk categories by the baseline model (NRI, 27%). Our results suggest that the addition of SEZ6L improved the performance of the LLP risk model, particularly for subjects whose initial absolute risks were unable to discriminate into "low-risk" or "high-risk" group. This work shows an approach to incorporate genetic biomarkers in risk models for predicting an individual's lung cancer risk.

  4. Fast-track development of an in vitro 3D lung/immune cell model to study Aspergillus infections.

    PubMed

    Chandorkar, P; Posch, W; Zaderer, V; Blatzer, M; Steger, M; Ammann, C G; Binder, U; Hermann, M; Hörtnagl, P; Lass-Flörl, C; Wilflingseder, D

    2017-09-14