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Sample records for lung clearance models

  1. Model of mucociliary clearance in cystic fibrosis lungs.

    PubMed

    Kurbatova, P; Bessonov, N; Volpert, V; Tiddens, H A W M; Cornu, C; Nony, P; Caudri, D

    2015-05-01

    Mucus clearance is a primary innate defense mechanism in the human airways. Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CF is characterized by dehydration of airway surface liquid and impaired mucociliary clearance. As a result, microorganisms are not efficiently removed from the airways, and patients experience chronic pulmonary infections and inflammation. We propose a new physiologically based mathematical model of muco-ciliary transport consisting of the two major components of the mucociliary clearance system: (i) periciliary liquid layer (PCL) and (ii) mucus layer. We study mucus clearance under normal conditions and in CF patients. Restoring impaired clearance of airway secretions in one of the major goals of therapy in patients with CF. We consider the action of the aerosolized and inhaled medication dornase alfa, which reduces the viscosity of cystic fibrosis mucus, by selectively cleaving the long DNA strands it contains. The results of the model simulations stress the potential relevance of the location of the drug deposition in the central or peripheral airways. Mucus clearance was increased in case the drug was primarily deposited peripherally, i.e. in the small airways. PMID:25746843

  2. 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

  3. 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.

  4. 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. PMID:26586376

  5. Hyperglycemia impedes lung bacterial clearance in a murine model of cystic fibrosis-related diabetes

    PubMed Central

    Hunt, William R.; Zughaier, Susu M.; Guentert, Dana E.; Shenep, Melissa A.; Koval, Michael; McCarty, Nael A.

    2013-01-01

    Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity associated with cystic fibrosis (CF), impacting more than half of patients over age 30. CFRD is clinically significant, portending accelerated decline in lung function, more frequent pulmonary exacerbations, and increased mortality. Despite the profound morbidity associated with CFRD, little is known about the underlying CFRD-related pulmonary pathology. Our aim was to develop a murine model of CFRD to explore the hypothesis that elevated glucose in CFRD is associated with reduced lung bacterial clearance. A diabetic phenotype was induced in gut-corrected CF transmembrane conductance regulator (CFTR) knockout mice (CFKO) and their CFTR-expressing wild-type littermates (WT) utilizing streptozotocin. Mice were subsequently challenged with an intratracheal inoculation of Pseudomonas aeruginosa (PAO1) (75 μl of 1–5 × 106 cfu/ml) for 18 h. Bronchoalveolar lavage fluid was collected for glucose concentration and cell counts. A portion of the lung was homogenized and cultured as a measure of the remaining viable PAO1 inoculum. Diabetic mice had increased airway glucose compared with nondiabetic mice. The ability to clear bacteria from the lung was significantly reduced in diabetic WT mice and control CFKO mice. Critically, bacterial clearance by diabetic CFKO mice was significantly more diminished compared with nondiabetic CFKO mice, despite an even more robust recruitment of neutrophils to the airways. This finding that CFRD mice boast an exaggerated, but less effective, inflammatory cell response to intratracheal PAO1 challenge presents a novel and useful murine model to help identify therapeutic strategies that promote bacterial clearance in CFRD. PMID:24097557

  6. Hyperglycemia impedes lung bacterial clearance in a murine model of cystic fibrosis-related diabetes.

    PubMed

    Hunt, William R; Zughaier, Susu M; Guentert, Dana E; Shenep, Melissa A; Koval, Michael; McCarty, Nael A; Hansen, Jason M

    2014-01-01

    Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity associated with cystic fibrosis (CF), impacting more than half of patients over age 30. CFRD is clinically significant, portending accelerated decline in lung function, more frequent pulmonary exacerbations, and increased mortality. Despite the profound morbidity associated with CFRD, little is known about the underlying CFRD-related pulmonary pathology. Our aim was to develop a murine model of CFRD to explore the hypothesis that elevated glucose in CFRD is associated with reduced lung bacterial clearance. A diabetic phenotype was induced in gut-corrected CF transmembrane conductance regulator (CFTR) knockout mice (CFKO) and their CFTR-expressing wild-type littermates (WT) utilizing streptozotocin. Mice were subsequently challenged with an intratracheal inoculation of Pseudomonas aeruginosa (PAO1) (75 μl of 1-5 × 10(6) cfu/ml) for 18 h. Bronchoalveolar lavage fluid was collected for glucose concentration and cell counts. A portion of the lung was homogenized and cultured as a measure of the remaining viable PAO1 inoculum. Diabetic mice had increased airway glucose compared with nondiabetic mice. The ability to clear bacteria from the lung was significantly reduced in diabetic WT mice and control CFKO mice. Critically, bacterial clearance by diabetic CFKO mice was significantly more diminished compared with nondiabetic CFKO mice, despite an even more robust recruitment of neutrophils to the airways. This finding that CFRD mice boast an exaggerated, but less effective, inflammatory cell response to intratracheal PAO1 challenge presents a novel and useful murine model to help identify therapeutic strategies that promote bacterial clearance in CFRD. PMID:24097557

  7. Continuum-kinetic-microscopic model of lung clearance due to core-annular fluid entrainment

    NASA Astrophysics Data System (ADS)

    Mitran, Sorin

    2013-07-01

    The human lung is protected against aspirated infectious and toxic agents by a thin liquid layer lining the interior of the airways. This airway surface liquid is a bilayer composed of a viscoelastic mucus layer supported by a fluid film known as the periciliary liquid. The viscoelastic behavior of the mucus layer is principally due to long-chain polymers known as mucins. The airway surface liquid is cleared from the lung by ciliary transport, surface tension gradients, and airflow shear forces. This work presents a multiscale model of the effect of airflow shear forces, as exerted by tidal breathing and cough, upon clearance. The composition of the mucus layer is complex and variable in time. To avoid the restrictions imposed by adopting a viscoelastic flow model of limited validity, a multiscale computational model is introduced in which the continuum-level properties of the airway surface liquid are determined by microscopic simulation of long-chain polymers. A bridge between microscopic and continuum levels is constructed through a kinetic-level probability density function describing polymer chain configurations. The overall multiscale framework is especially suited to biological problems due to the flexibility afforded in specifying microscopic constituents, and examining the effects of various constituents upon overall mucus transport at the continuum scale.

  8. Continuum-kinetic-microscopic model of lung clearance due to core-annular fluid entrainment

    PubMed Central

    Mitran, Sorin

    2013-01-01

    The human lung is protected against aspirated infectious and toxic agents by a thin liquid layer lining the interior of the airways. This airway surface liquid is a bilayer composed of a viscoelastic mucus layer supported by a fluid film known as the periciliary liquid. The viscoelastic behavior of the mucus layer is principally due to long-chain polymers known as mucins. The airway surface liquid is cleared from the lung by ciliary transport, surface tension gradients, and airflow shear forces. This work presents a multiscale model of the effect of airflow shear forces, as exerted by tidal breathing and cough, upon clearance. The composition of the mucus layer is complex and variable in time. To avoid the restrictions imposed by adopting a viscoelastic flow model of limited validity, a multiscale computational model is introduced in which the continuum-level properties of the airway surface liquid are determined by microscopic simulation of long-chain polymers. A bridge between microscopic and continuum levels is constructed through a kinetic-level probability density function describing polymer chain configurations. The overall multiscale framework is especially suited to biological problems due to the flexibility afforded in specifying microscopic constituents, and examining the effects of various constituents upon overall mucus transport at the continuum scale. PMID:23729842

  9. Mucosal immunisation with novel Streptococcus pneumoniae protein antigens enhances bacterial clearance in an acute mouse lung infection model.

    PubMed

    Jomaa, Maha; Kyd, Jennelle M; Cripps, Allan W

    2005-04-01

    Streptococcus pneumoniae contains many proteins that have not been evaluated as potential protective vaccine antigens. In this study we isolated proteins from a serotype 3 strain of S. pneumoniae for use in mouse immunisation studies. Separation of the protein mix was achieved by SDS-PAGE electrophoresis followed by electro-elution to isolate individual proteins. This procedure successfully separated 21 fractions from which six proteins were selected based on purity and quantity and were initially denoted by their molecular masses: 14-, 34-, 38-, 48-, 57- and 75-kDa. The immunogenicity of these proteins was investigated in a mucosal immunisation model in mice involving a primary inoculation to the intestinal Peyer's patches followed by an intra-tracheal boost two weeks later. The immune response was assessed by enhancement of pulmonary clearance of infection, recruitment of phagocytes to the lungs and induction of an antibody response. Two of the proteins, the 14-kDa identified as a L7/L12 ribosomal protein, and the 34-kDa identified as glyceraldehyde-3-phosphate dehydrogenase resulted in up to 99% and 94%, respectively, enhanced clearance of infection within 5 h following pulmonary challenge with S. pneumoniae. This study has shown that novel pneumococcal proteins have the potential to be vaccine candidates to enhance clearance of an acute mucosal S. pneumoniae infection. PMID:15780579

  10. Lung Edema Clearance: Relevance to Patients with Lung Injury

    PubMed Central

    Azzam, Zaher S.; Sznajder, Jacob I.

    2015-01-01

    Pulmonary edema clearance is necessary for patients with lung injury to recover and survive. The mechanisms regulating edema clearance from the lungs are distinct from the factors contributing edema formation during injury. Edema clearance is effected via vectorial transport of Na+ out of the airspaces which generates an osmotic gradient causing water to follow the gradient out of the cells. This Na+ transport across the alveolar epithelium is mostly effected via apical Na+ and chloride channels and basolateral Na,K-ATPase. The Na,K-ATPase pumps Na+ out of the cell and K+ into the cell against their respective gradients in an ATP-consuming reaction. Two mechanisms contribute to the regulation of the Na,K-ATPase activity:recruitment of its subunits from intracellular compartments into the basolateral membrane, and transcriptional/translational regulation. Na,K-ATPase activity and edema clearance are increased by catecholamines, aldosterone, vasopressin, overexpression of the pump genes, and others. During lung injury, mechanisms regulating edema clearance are inhibited by yet unclear pathways. Better understanding of the mechanisms that regulate pulmonary edema clearance may lead to therapeutic interventions that counterbalance the inhibition of edema clearance during lung injury and improve the lungs’ ability to clear fluid, which is crucial for patient survival. PMID:26241220

  11. Modulation of lung liquid clearance by isoproterenol in rat lungs.

    PubMed

    Saldías, F; Lecuona, E; Friedman, E; Barnard, M L; Ridge, K M; Sznajder, J I

    1998-05-01

    beta-Adrenergic agonists have been reported to increase lung liquid clearance by stimulating active Na+ transport across the alveolar epithelium. We studied mechanisms by which beta-adrenergic isoproterenol (Iso) increases lung liquid clearance in isolated perfused fluid-filled rat lungs. Iso perfused through the pulmonary circulation at concentrations of 10(-4) to 10(-8) M increased lung liquid clearance compared with that of control lungs (P < 0.01). The increase in lung liquid clearance was inhibited by the beta-antagonist propranolol (10(-5) M), the Na(+)-channel blocker amiloride (10(-4) M), and the antagonist of Na-K-ATPase, ouabain (5 x 10(-4) M). Colchicine, which inhibits cell microtubular transport of ion-transporting proteins to the plasma membrane, blocked the stimulatory effects of Iso on active Na+ transport, whereas the isomer lumicolchicine, which does not affect cell microtubular transport, did not inhibit Na+ transport. In parallel with these changes, the Na-K-ATPase alpha 1-subunit protein abundance and activity increased in alveolar type II cells stimulated by 10(-6) M Iso. Colchicine blocked the stimulatory effect of Iso and the recruitment of Na-K-ATPase alpha 1-protein to the basolateral membrane of alveolar type II cells. Accordingly, Iso increased active Na+ transport and lung liquid clearance by stimulation of beta-adrenergic receptors and probably by upregulation of apical Na+ channels and basolateral Na-K-ATPase mechanisms. Recruitment from intracellular pools and microtubular transport of Na+ pumps to the plasma membrane participate in beta-adrenergic stimulation of lung liquid clearance in rat lungs. PMID:9612284

  12. Effects of lung volume on clearance of solutes from the air spaces of lungs

    SciTech Connect

    Peterson, B.T.; James, H.L.; McLarty, J.W.

    1988-03-01

    Several investigators have shown that the clearance rate of aerosolized 99mTc-labeled diethylenetriamine pentaacetate (DTPA, mol wt = 492, radius = 0.6 nm) from the air spaces of the lungs of humans and experimental animals increases with lung volume. To further investigate this phenomenon we performed a compartmental analysis of the 2-h clearance of DTPA from the lungs of anesthetized sheep using a new method to more accurately correct for the effects of DTPA recirculation. This analysis showed that the DTPA clearance in eight sheep ventilated with zero end-expired pressure was best described by a one-compartment model with a clearance rate of 0.42 +/- 0.15%/min. Ventilating eight sheep with an end-expired pressure of 10 cmH/sub 2/O throughout the study increased the end-expired volume 0.4 +/- 0.1 liter BTPS and created a clearance curve that was best described by a two-compartment model. In these sheep 56 +/- 16% of the DTPA cleared from the lungs at a rate of 7.9 +/- 2.9%/min. The remainder cleared at a rate similar to that measured in the sheep ventilated with zero end-expired pressure (0.35 +/- 0.18%/min). Additional control and lung inflation experiments were performed using /sup 99m/Tc-labeled human serum albumin (mol wt = 66,000, radius = 3.6 nm). In six control sheep ventilated with zero end-expired pressure the albumin clearance was best described by a one-compartment model with a clearance rate of 0.06 +/- 0.02%/min. The clearance rate in six sheep with increased lung volume was slightly larger (0.09 +/- 0.02, P less than 0.05) but was well described by a one-compartment model.

  13. ESR measurement of radical clearance in lung of whole mouse

    SciTech Connect

    Takeshita, K.; Utsumi, H.; Hamada, A. )

    1991-06-14

    Clearance of the nitroxide radicals, hydroxy-TEMPO and carboxy-PROxYL, in whole-mouse lung was directly measured by in vivo ESR. After injecting a nitroxide radical, distribution of the nitroxide radical all over the lung was confirmed by ESR imaging. The ESR signal of hydroxy-TEMPO was reduced in the lung and the clearance obeyed first-order kinetics, whereas the signal of carboxy-PROxYL remained constant. Comparison of the clearance rates of live and dead mice indicated the presence of 2 different clearance systems in the lung: loss of its paramagnetism in the lung, and transfer from alveolar to the blood circulation system.

  14. Radioaerosol lung clearance in patients with active pulmonary sarcoidosis

    SciTech Connect

    Jacobs, M.P.; Baughman, R.P.; Hughes, J.; Fernandez-Ulloa, M.

    1985-05-01

    Pulmonary radioaerosol clearance rate of /sup 99m/Tc diethylenetriamine pentacetate (DTPA) in 14 patients with untreated sarcoidosis was compared with /sup 67/Ga lung scan and increased lymphocytes in the bronchoalveolar lavage (BAL) fluid. Nine healthy nonsmoking subjects had a mean DTPA clearance rate of 1.18%/min (range, 0.54 to 1.60%/min). Eight of 14 patients with sarcoidosis had clearance rates greater than 1.60%/min. Of those 8 patients with abnormal DTPA clearance, 4 had positive gallium scans, 4 had more than 17% lymphocytes in the BAL fluid, and 3 had both tests positive. To study the cause of abnormal DTPA clearance, 23 subjects (including 3 normal controls, all 14 patients with sarcoidosis, and 6 patients with localized disease on chest roentgenogram) underwent both DTPA clearance studies and BAL for quantitation of the amount of albumin in lung fluid. There was a positive correlation between the rate of DTPA clearance and the albumin concentration in lung fluid (r = 0.87, p less than 0.01).

  15. Radioaerosol clearance to monitor effects of ozone on lung permeability

    SciTech Connect

    Webb, D.A.; Utell, M.J.; Bauer, M.A.; Banko, T.M.; Waldman, D.L.; Morrow, P.E.; Hyde, R.W.

    1985-05-01

    The Tc-99m DTPA aerosol clearance procedure was used to investigate the effects of low level ozone inhalation on lung permeability. Total and regional lung clearance was determined by scintillation camera imaging of 15 adult subjects presenting no history of lung disease using a radioaerosol with an aerodynamic diameter 0.5 ..mu..m(sigmag=1.50). Pulmonary function measurements and the radioaerosol procedure were conducted in each patient on at least two separate occasions. FVC, FEVl and airway resistance was measured pre and post monitored breathing of room air (30 min) and a subsequent aerosol clearance procedure was conducted as a baseline study; the same procedures were repeated after three or more days with 0.5 ppm ozone substituted for room air. The major observations from the clearance studies and the pulmonary function tests include: 1) no significant changes were detected between the baseline and ozone pulmonary function tests, 2) ROI analyses of the 30 min clearance data show no significant changes in the average Tc-99m DTPA clearance between the baseline room air (t1/2=85+-30 min) and ozone (t1/2=83+-24min) inhalation studies, and, 3) despite consistent average clearance rates, 7/15 subjects showed large changes in clearance (..delta..=24-72 min) and functional mapping showed major shifts in distribution in 5/15 subjects after ozone inhalation. The apparent high sensitivity, yet somewhat disparate observations, support the need of further investigation of factors influencing radioaerosol for the study of lung epithelial permeability.

  16. Stimulation of the dopamine 1 receptor increases lung edema clearance.

    PubMed

    Barnard, M L; Ridge, K M; Saldias, F; Friedman, E; Gare, M; Guerrero, C; Lecuona, E; Bertorello, A M; Katz, A I; Sznajder, J I

    1999-09-01

    We previously reported that lung edema clearance was stimulated by dopamine (DA). The purpose of this study was to determine whether the DA-mediated stimulation of edema clearance occurs via an adrenergic or dopaminergic regulation of alveolar epithelial Na, K-ATPase. When isolated perfused rat lungs were coinstilled with DA and SCH 23390 (a specific D(1) receptor antagonist), there was a dose-dependent attenuation of the stimulatory effects of DA. Coinstillation with S-sulpiride (a specific D(2) receptor antagonist) or propranolol (a beta-adrenergic antagonist) did not alter DA-stimulated clearance. Similarly, the specific dopaminergic D(1) agonist fenoldopam increased lung edema clearance, but quinpirole (a specific dopaminergic D(2) agonist) did not. (125)I-SCH 23982 binding studies suggested that D(1) receptors are expressed on alveolar type II (ATII) cells with an apparent dissociation constant (K(d)) of 4.4 nM and binding maximum (Bmax) 9.8 pmol/mg. Consistent with these results, the D(1) receptor messenger RNA (mRNA) and protein were detected in ATII cells by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. These data demonstrate a novel mechanism involving the activation of dopaminergic D(1) receptors which mediates DA-stimulated edema removal from rat lungs. PMID:10471628

  17. Modifications of lung clearance mechanisms by acute influenza A infection

    SciTech Connect

    Levandowski, R.A.; Gerrity, T.R.; Garrard, C.S.

    1985-10-01

    Four volunteers with naturally acquired, culture-proved influenza A infection inhaled a radiolabeled aerosol to permit investigation of lung mucociliary clearance mechanisms during and after symptomatic illness. Mucus transport in the trachea was undetectable when monitored with an external multidetector probe within 48 hours of the onset of the illness, but was found at a normal velocity by 1 week in three of the four subjects. In two volunteers who coughed 23 to 48 times during the 4.5-hour observation period, whole lung clearance was as fast within the first 48 hours of illness as during health 3 months later in spite of the absence of measurable tracheal mucus transport. Conversely, in spite of the return 1 week later of mucus transport at velocities expected in the trachea, whole lung clearance for the 4.5-hour period was slowed in two volunteers who coughed less than once an hour. The data offer evidence that cough is important in maintaining lung clearance for at least several days after symptomatic influenza A infection when other mechanisms that depend on ciliary function are severely deficient.

  18. Lung inflammation does not affect the clearance kinetics of lipid nanocapsules following pulmonary administration.

    PubMed

    Patel, Aateka; Woods, A; Riffo-Vasquez, Yanira; Babin-Morgan, Anna; Jones, Marie-Christine; Jones, Stuart; Sunassee, Kavitha; Clark, Stephen; T M de Rosales, Rafael; Page, Clive; Spina, Domenico; Forbes, Ben; Dailey, Lea Ann

    2016-08-10

    Lipid nanocapsules (LNCs) are semi-rigid spherical capsules with a triglyceride core that present a promising formulation option for the pulmonary delivery of drugs with poor aqueous solubility. Whilst the biodistribution of LNCs of different size has been studied following intravenous administration, the fate of LNCs following pulmonary delivery has not been reported. We investigated quantitatively whether lung inflammation affects the clearance of 50nm lipid nanocapsules, or is exacerbated by their pulmonary administration. Studies were conducted in mice with lipopolysaccharide-induced lung inflammation compared to healthy controls. Particle deposition and nanocapsule clearance kinetics were measured by single photon emission computed tomography/computed tomography (SPECT/CT) imaging over 48 h. A significantly lower lung dose of (111)In-LNC50 was achieved in the lipopolysaccharide (LPS)-treated animals compared with healthy controls (p<0.001). When normalised to the delivered lung dose, the clearance kinetics of (111)In-LNC50 from the lungs fit a first order model with an elimination half-life of 10.5±0.9h (R(2)=0.995) and 10.6±0.3h (R(2)=1.000) for healthy and inflamed lungs respectively (n=3). In contrast, (111)In-diethylene triamine pentaacetic acid (DTPA), a small hydrophilic molecule, was cleared rapidly from the lungs with the majority of the dose absorbed within 20min of administration. Biodistribution to lungs, stomach-intestine, liver, trachea-throat and blood at the end of the imaging period was unaltered by lung inflammation. This study demonstrated that lung clearance and whole body distribution of lipid nanocapsules were unaffected by the presence of acute lung inflammation. PMID:27180635

  19. Smoking produced mucus and clearance of particulates in the lung

    SciTech Connect

    Sterling, T.D.; Poland, T.M.

    1992-12-31

    Some studies of miners have shown a lesser relative lung-cancer risk for smokers than for nonsmokers. For example, experiments by Cross and associates with dogs have shown an apparent protective effect of cigarette smoke against radon-daughter and dust exposure. One reason for these changes may be the thickened mucus layer in the tracheobronchial region of smokers. Physiological changes in the lung due to smoking may decrease the effects of radioactive particles in cancers in the bronchial region by apparently promoting faster clearance, in that region, of radioactive particles and by decreasing the radiation dose through reduced penetration to the sensitive basal epithelial cells. Because of the short half-life of radon daughters, even if there is possible tobacco-related delay of particle clearance from the alveolar region it cannot affect radon clearance. Therefore, the possible mitigating effect of tobacco on radon-produced cancer appears to be limited to the tracheobronchial region. It would be of value to a number of occupations if the same changes in the lungs due to smoking could be produced in exposed workers in the absence of cigarette-smoking. Beta-carotene and vitamin A, which affect maintenance and secretion of the mucosal lining, appear to thicken mucus, thereby providing protection against radon-induced lung cancers that is similar to smoking-related changes in the lung.

  20. Dynamic Studies of Lung Fluid Clearance with Phase Contrast Imaging

    SciTech Connect

    Kitchen, Marcus J.; Williams, Ivan; Irvine, Sarah C.; Morgan, Michael J.; Paganin, David M.; Lewis, Rob A.; Pavlov, Konstantin; Hooper, Stuart B.; Wallace, Megan J.; Siu, Karen K. W.; Yagi, Naoto; Uesugi, Kentaro

    2007-01-19

    Clearance of liquid from the airways at birth is a poorly understood process, partly due to the difficulties of observing and measuring the distribution of air within the lung. Imaging dynamic processes within the lung in vivo with high contrast and spatial resolution is therefore a major challenge. However, phase contrast X-ray imaging is able to exploit inhaled air as a contrast agent, rendering the lungs of small animals visible due to the large changes in the refractive index at air/tissue interfaces. In concert with the high spatial resolution afforded by X-ray imaging systems (<100 {mu}m), propagation-based phase contrast imaging is ideal for studying lung development. To this end we have utilized intense, monochromatic synchrotron radiation, together with a fast readout CCD camera, to study fluid clearance from the lungs of rabbit pups at birth. Local rates of fluid clearance have been measured from the dynamic sequences using a single image phase retrieval algorithm.

  1. Dynamic Studies of Lung Fluid Clearance with Phase Contrast Imaging

    NASA Astrophysics Data System (ADS)

    Kitchen, Marcus J.; Lewis, Rob A.; Hooper, Stuart B.; Wallace, Megan J.; Siu, Karen K. W.; Williams, Ivan; Irvine, Sarah C.; Morgan, Michael J.; Paganin, David M.; Pavlov, Konstantin; Yagi, Naoto; Uesugi, Kentaro

    2007-01-01

    Clearance of liquid from the airways at birth is a poorly understood process, partly due to the difficulties of observing and measuring the distribution of air within the lung. Imaging dynamic processes within the lung in vivo with high contrast and spatial resolution is therefore a major challenge. However, phase contrast X-ray imaging is able to exploit inhaled air as a contrast agent, rendering the lungs of small animals visible due to the large changes in the refractive index at air/tissue interfaces. In concert with the high spatial resolution afforded by X-ray imaging systems (<100 μm), propagation-based phase contrast imaging is ideal for studying lung development. To this end we have utilized intense, monochromatic synchrotron radiation, together with a fast readout CCD camera, to study fluid clearance from the lungs of rabbit pups at birth. Local rates of fluid clearance have been measured from the dynamic sequences using a single image phase retrieval algorithm.

  2. Impairment of bronchial mucociliary clearance in long-term survivors of heart/lung and double-lung transplantation. The Paris-Sud Lung Transplant Group.

    PubMed

    Herve, P; Silbert, D; Cerrina, J; Simonneau, G; Dartevelle, P

    1993-01-01

    The study objective was to investigate bronchial mucociliary clearance after heart/lung and double lung transplantation. Bronchial mucociliary clearance was measured using a noninvasive radioaerosol technique: 99mTc-labeled albumin was aerosolized using a spinning-top generator (mass median aerodynamic diameter, 7.5 mu; geometric standard deviation, 1.5 mu). Radioactivity counts were acquired during 60 min with a gamma camera. A region of interest was drawn over the right lung delineated by a 133Xe lung ventilation image. Bronchial mucociliary clearance was assessed as the percentage of decrease in radioactivity per hour calculated on time-activity curves fitted by a monoexponential model. To exclude patients with acute lung rejection, opportunistic lung infection, and obliterative bronchiolitis, all patients with transplants underwent pulmonary function tests and bronchoscopic examination before clearance measurement. Eight heart/lung and five double-lung nonsmoking transplant patients with normal lung histology were studied 19.3 +/- 4.0 mo after surgery and compared to nine normal nonsmokers. A similar proximal deposition of the aerosol was obtained in patients with transplants and normal subjects; skew values of distribution histograms of aerosol radioactivity counts were 2.1 +/- 0.2 and 1.8 +/- 0.1, respectively, and the ratios between central and peripheral 99mTc radioactivity counts were 2.4 +/- 0.1 and 2.3 +/- 0.2, respectively. No significant difference was observed in bronchial clearance values between patients with heart/lung and double-lung transplants (26.4 +/- 3.0 percent/h vs 35.9 +/- 3.5 percent/h). Conversely, bronchial clearance was significantly lower in transplant recipients (30.0 +/- 2.5 percent/h) than in normal controls (58.7 +/- 6.2 percent/h; p < 0.001). This decreased bronchial clearance can be expected to increase the risk of lung infection in long-term survivors of heart/lung and double-lung transplantation. PMID:8380268

  3. Lung clearance index in the assessment of airways disease.

    PubMed

    Horsley, Alex

    2009-06-01

    In the last few years there has been a growing interest in lung clearance index (LCI), a measure of lung physiology derived from multiple breath washout tests. This resurgence of interest was initially driven by the recognition that such assessments were capable of detecting early airways disease in children, and are more sensitive and easier to perform in this population than conventional lung function tests [Aurora P, Kozlowska W, Stocks J. Gas mixing efficiency from birth to adulthood measured by multiple-breath washout. Respir Physiol Neurobiol, 2005;148(1-2):125-39]. With an appreciation of the importance of earlier identification of airways dysfunction, and prevention of irreversible structural airway changes, methods of following airways disease in these "silent years" are especially important. LCI has now been reported in studies involving all age groups, from infants to adults [Lum S, Gustafsson P, Ljungberg H, Hulskamp G, Bush A, Carr SB, et al. Early detection of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests. Thorax, 2007;62(4):341-7; Horsley AR, Gustafsson PM, Macleod K, Saunders CJ, Greening AP, Porteous D, et al. Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis. Thorax, 2008;63:135-40], and has a narrow range of normal over this wide age range, making it especially suitable for long-term follow-up studies. In cystic fibrosis (CF) particularly, there is a pressing need for sensitive and repeatable clinical endpoints for therapeutic interventions [Rosenfeld M. An overview of endpoints for cystic fibrosis clinical trials: one size does not fit all. Proc Am Thorac Soc, 2007;4(4):299-301], and LCI has been proposed as an outcome measure in future CF gene therapy studies [Davies JC, Cunningham S, Alton EW, Innes JA. Lung clearance index in CF: a sensitive marker of lung disease severity. Thorax, 2008;63(2):96-7]. This review will consider how LCI is

  4. Quantitation of deposition, clearance and routes of elimination of 3 um insoluble particles in the sheep lung

    SciTech Connect

    Langenback, E.G.

    1984-01-01

    This study is the first to completely determine the number of particles deposited in the lung, the number of particles cleared over a period of a hundred days and the pathways by which the particles exit the lungs. The study uses long lived radioactively (/sup 57/Co) tagged 3 um insoluble polystyrene particles to follow clearance in a sheep animal model. Particle clearance was characterized by 4 phases. Periodic sacrifice and autopsy showed no particle accumulation in regional lymph nodes draining the lung and no particle accumulation in the liver, spleen or kidneys. Urine and blood samples throughout clearance were devoid of particles, but fecal excretion of particles matched lung elimination of particles and mirrored clearance closely. Thus the avenues of long-term clearance of a 3 um polystrene particle has been established from the alveolar portion of the lung: virtually all particles cleared in 101 days were removed by transport from the alveoli to the mucociliary escalator, either as free particles and/or associated with macrophages and subsequently swallowed and excreted. Particles remaining in the lungs after 101 days continued to be cleared from the lungs via the mucociliary escalator with a t/sub 1/2/ = 38 days. This suggests that particles leave a sequestered state, re-enter the airways and are cleared.

  5. Biodistribution and clearance of instilled carbon nanotubes in rat lung

    PubMed Central

    Elgrabli, Dan; Floriani, Magali; Abella-Gallart, Steve; Meunier, Laurent; Gamez, Christelle; Delalain, Patrice; Rogerieux, Françoise; Boczkowski, Jorge; Lacroix, Ghislaine

    2008-01-01

    Background Constituted only by carbon atoms, CNT are hydrophobic and hardly detectable in biological tissues. These properties make biokinetics and toxicology studies more complex. Methods We propose here a method to investigate the biopersistence of CNT in organism, based on detection of nickel, a metal present in the MWCNT we investigated. Results and conclusion Our results in rats that received MWCNT by intratracheal instillation, reveal that MWCNT can be eliminated and do not significantly cross the pulmonary barrier but are still present in lungs 6 months after a unique instillation. MWCNT structure was also showed to be chemically modified and cleaved in the lung. These results provide the first data of CNT biopersistence and clearance at 6 months after respiratory administration. PMID:19068117

  6. Beta-adrenergic agonists increase lung liquid clearance in anesthetized sheep.

    PubMed Central

    Berthiaume, Y; Staub, N C; Matthay, M A

    1987-01-01

    We did experiments to determine whether beta-adrenergic agonists increase lung liquid clearance in anesthetized ventilated adult sheep and, if so, whether the increase is mediated by beta receptors and what mechanism is involved. We instilled 100 ml of autologous serum either alone or with a beta-adrenergic agonist (terbutaline, 10(-5) M, or epinephrine, 5.5 X 10(-6) M) into one lower lobe. After 4 h both terbutaline and epinephrine increased lung liquid clearance. The increase in lung liquid clearance was inhibited when propranolol (a beta blocker) or amiloride (a sodium channel blocker) was added to the terbutaline. Increased clearance was not explained by changes in pulmonary hemodynamics, pulmonary blood flow, or lung lymph flow. We conclude that beta-adrenergic agonists increase lung liquid clearance in anesthetized intact adult sheep. This increase is mediated through beta receptors and probably depends on increased active transport of sodium across the alveolar barrier. Images PMID:2879851

  7. Effect of oral bronchodilators on lung mucociliary clearance during sleep in patients with asthma.

    PubMed Central

    Hasani, A; Agnew, J E; Pavia, D; Vora, H; Clarke, S W

    1993-01-01

    BACKGROUND: Lung mucociliary clearance rates are reduced during sleep in patients with asthma. Methylxanthines and beta 2 agonists have been shown to enhance rates of lung mucociliary clearance. This study examined whether oral slow release bronchodilators may also have an effect on this clearance mechanism during sleep in patients with asthma. METHODS: Nine patients with asthma with a mean(SE) age of 65(5) years and percentage predicted forced expiratory volume in one second (FEV1 of 61(9)% participated in a double blind, placebo controlled, within subject crossover study to assess the effect of two weeks of treatment with salbutamol (Volmax; 8 mg twice daily) or theophylline (Phyllocontin; 350 mg twice daily) on lung mucociliary clearance during sleep. Lung mucociliary clearance rates were measured by a radioaerosol technique. RESULTS: The observation period for radioaerosol clearance was approximately 0.3 hours before sleep, 6.0 hours during sleep and 0.6 hours after sleep. Mean mucociliary clearance rates for theophylline, placebo and salbutamol before sleep were: 39, 39, and 32%/hour respectively; during sleep: 11, 10, and 9%/hour respectively; and after sleep: 39, 32, and 35%/hour respectively. CONCLUSION: During sleep lung mucociliary clearance in stable asthma was reduced, which is in agreement with the group's previous findings. Treatment with controlled/slow release oral bronchodilators had no effect on this reduced rate of clearance associated with sleep. Images PMID:8497831

  8. Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice.

    PubMed

    Fan, Ming-Hui; Zhu, Qiang; Li, Hui-Hua; Ra, Hyun-Jeong; Majumdar, Sonali; Gulick, Dexter L; Jerome, Jacob A; Madsen, Daniel H; Christofidou-Solomidou, Melpo; Speicher, David W; Bachovchin, William W; Feghali-Bostwick, Carol; Puré, Ellen

    2016-04-01

    Idiopathic pulmonary fibrosis is a disease characterized by progressive, unrelenting lung scarring, with death from respiratory failure within 2-4 years unless lung transplantation is performed. New effective therapies are clearly needed. Fibroblast activation protein (FAP) is a cell surface-associated serine protease up-regulated in the lungs of patients with idiopathic pulmonary fibrosis as well as in wound healing and cancer. We postulate that FAP is not only a marker of disease but influences the development of pulmonary fibrosis after lung injury. In two different models of pulmonary fibrosis, intratracheal bleomycin instillation and thoracic irradiation, we find increased mortality and increased lung fibrosis in FAP-deficient mice compared with wild-type mice. Lung extracellular matrix analysis reveals accumulation of intermediate-sized collagen fragments in FAP-deficient mouse lungs, consistent within vitrostudies showing that FAP mediates ordered proteolytic processing of matrix metalloproteinase (MMP)-derived collagen cleavage products. FAP-mediated collagen processing leads to increased collagen internalization without altering expression of the endocytic collagen receptor, Endo180. Pharmacologic FAP inhibition decreases collagen internalization as expected. Conversely, restoration of FAP expression in the lungs of FAP-deficient mice decreases lung hydroxyproline content after intratracheal bleomycin to levels comparable with that of wild-type controls. Our findings indicate that FAP participates directly, in concert with MMPs, in collagen catabolism and clearance and is an important factor in resolving scar after injury and restoring lung homeostasis. Our study identifies FAP as a novel endogenous regulator of fibrosis and is the first to show FAP's protective effects in the lung. PMID:26663085

  9. Air pollution particles diminish bacterial clearance in the primed lungs of mice

    SciTech Connect

    Sigaud, Samuel; Goldsmith, Carroll-Ann W.; Zhou Hongwei; Yang Zhiping; Fedulov, Alexey; Imrich, Amy; Kobzik, Lester

    2007-08-15

    Epidemiological studies reveal increased incidence of lung infection when air pollution particle levels are increased. We postulate that one risk factor for bacterial pneumonia, prior viral infection, can prime the lung for greater deleterious effects of particles via the interferon-gamma (IFN-{gamma}) characteristic of successful host anti-viral responses. To test this postulate, we developed a mouse model in which mice were treated with {gamma}-interferon aerosol, followed by exposure to concentrated ambient particles (CAPs) collected from urban air. The mice were then infected with Streptococcus pneumoniae and the effect of these treatments on the lung's innate immune response was evaluated. The combination of IFN-{gamma} priming and CAPs exposure enhanced lung inflammation, manifest as increased polymorphonuclear granulocyte (PMN) recruitment to the lung, and elevated expression of pro-inflammatory cytokine mRNAs. Combined priming and CAPs exposure resulted in impaired pulmonary bacterial clearance, as well as increased oxidant production and diminished bacterial uptake by alveolar macrophages (AMs) and PMNs. The data suggest that priming and CAPs exposure lead to an inflamed alveolar milieu where oxidant stress causes loss of antibacterial functions in AMs and recruited PMNs. The model reported here will allow further analysis of priming and CAPs exposure on lung sensitivity to infection.

  10. Influenza virus inhibits ENaC and lung fluid clearance.

    PubMed

    Chen, Xi-Juan; Seth, Shaguna; Yue, Gang; Kamat, Pradip; Compans, Richard W; Guidot, David; Brown, Lou Ann; Eaton, Douglas C; Jain, Lucky

    2004-08-01

    Fluid-free alveolar space is critical for normal gas exchange. Influenza virus alters fluid transport across respiratory epithelia producing rhinorrhea, middle ear effusions, and alveolar flooding. However, the mechanism of fluid retention remains unclear. We investigated influenza virus strain A/PR/8/34, which can attach and enter mammalian cells but is incapable of viral replication and productive infection in mammalian epithelia, on epithelial sodium channels (ENaC) in rat alveolar type II (ATII) cells. In parallel, we determined the effects of virus on amiloride-sensitive (i.e., ENaC-mediated) fluid clearance in rat lungs in vivo. Although influenza virus did not change the inulin permeability of ATII monolayers, it rapidly reduced the net volume transport across monolayers. Virus reduced the open probability of single ENaC channels in apical cell-attached patches. U-73122, a phospholipase C (PLC) inhibitor, and PP2, a Src inhibitor, blocked the effect of virus on ENaC. GF-109203X, a protein kinase C (PKC) inhibitor, also blocked the effect, suggesting a PKC-mediated mechanism. In parallel, intratracheal administration of influenza virus produced a rapid inhibition of amiloride-sensitive (i.e., ENaC-dependent) lung fluid transport. Together, these results show that influenza virus rapidly inhibits ENaC in ATII cells via a PLC- and Src-mediated activation of PKC but does not increase epithelial permeability in this same rapid time course. We speculate that this rapid inhibition of ENaC and formation of edema when the virus first attaches to the alveolar epithelium might facilitate subsequent influenza infection and may exacerbate influenza-mediated alveolar flooding that can lead to acute respiratory failure and death. PMID:15121635

  11. Transient proteolytic modification of mesenchymal stromal cells increases lung clearance rate and targeting to injured tissue.

    PubMed

    Kerkelä, Erja; Hakkarainen, Tanja; Mäkelä, Tuomas; Raki, Mari; Kambur, Oleg; Kilpinen, Lotta; Nikkilä, Janne; Lehtonen, Siri; Ritamo, Ilja; Pernu, Roni; Pietilä, Mika; Takalo, Reijo; Juvonen, Tatu; Bergström, Kim; Kalso, Eija; Valmu, Leena; Laitinen, Saara; Lehenkari, Petri; Nystedt, Johanna

    2013-07-01

    Systemic infusion of therapeutic cells would be the most practical and least invasive method of administration in many cellular therapies. One of the main obstacles especially in intravenous delivery of cells is a massive cell retention in the lungs, which impairs homing to the target tissue and may decrease the therapeutic outcome. In this study we showed that an alternative cell detachment of mesenchymal stromal/stem cells (MSCs) with pronase instead of trypsin significantly accelerated the lung clearance of the cells and, importantly, increased their targeting to an area of injury. Cell detachment with pronase transiently altered the MSC surface protein profile without compromising cell viability, multipotent cell characteristics, or immunomodulative and angiogenic potential. The transient modification of the cell surface protein profile was sufficient to produce effective changes in cell rolling behavior in vitro and, importantly, in the in vivo biodistribution of the cells in mouse, rat, and porcine models. In conclusion, pronase detachment could be used as a method to improve the MSC lung clearance and targeting in vivo. This may have a major impact on the bioavailability of MSCs in future therapeutic regimes. PMID:23734061

  12. Transient Proteolytic Modification of Mesenchymal Stromal Cells Increases Lung Clearance Rate and Targeting to Injured Tissue

    PubMed Central

    Hakkarainen, Tanja; Mäkelä, Tuomas; Raki, Mari; Kambur, Oleg; Kilpinen, Lotta; Nikkilä, Janne; Lehtonen, Siri; Ritamo, Ilja; Pernu, Roni; Pietilä, Mika; Takalo, Reijo; Juvonen, Tatu; Bergström, Kim; Kalso, Eija; Valmu, Leena; Laitinen, Saara; Lehenkari, Petri; Nystedt, Johanna

    2013-01-01

    Systemic infusion of therapeutic cells would be the most practical and least invasive method of administration in many cellular therapies. One of the main obstacles especially in intravenous delivery of cells is a massive cell retention in the lungs, which impairs homing to the target tissue and may decrease the therapeutic outcome. In this study we showed that an alternative cell detachment of mesenchymal stromal/stem cells (MSCs) with pronase instead of trypsin significantly accelerated the lung clearance of the cells and, importantly, increased their targeting to an area of injury. Cell detachment with pronase transiently altered the MSC surface protein profile without compromising cell viability, multipotent cell characteristics, or immunomodulative and angiogenic potential. The transient modification of the cell surface protein profile was sufficient to produce effective changes in cell rolling behavior in vitro and, importantly, in the in vivo biodistribution of the cells in mouse, rat, and porcine models. In conclusion, pronase detachment could be used as a method to improve the MSC lung clearance and targeting in vivo. This may have a major impact on the bioavailability of MSCs in future therapeutic regimes. PMID:23734061

  13. Relationship of end-expiratory pressure, lung volume, and /sup 99m/Tc-DTPA clearance

    SciTech Connect

    Cooper, J.A.; van der Zee, H.; Line, B.R.; Malik, A.B.

    1987-10-01

    We investigated the dose-response effect of positive end-expiratory pressure (PEEP) and increased lung volume on the pulmonary clearance rate of aerosolized technetium-99m-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA). Clearance of lung radioactivity was expressed as percent decrease per minute. Base-line clearance was measured while anesthetized sheep (n = 20) were ventilated with 0 cmH/sub 2/O end-expiratory pressure. Clearance was remeasured during ventilation at 2.5, 5, 10, 15, or 20 cmH/sub 2/O PEEP. Further studies showed stepwise increases in functional residual capacity (FRC) (P less than 0.05) measured at 0, 2.5, 5, 10, 15, and 20 cmH/sub 2/O PEEP. At 2.5 cmH/sub 2/O PEEP, the clearance rate was not different from that at base line (P less than 0.05), although FRC was increased from base line. Clearance rate increased progressively with increasing PEEP at 5, 10, and 15 cmH/sub 2/O (P less than 0.05). Between 15 and 20 cmH/sub 2/O PEEP, clearance rate was again unchanged, despite an increase in FRC. The pulmonary clearance of aerosolized /sup 99m/Tc-DTPA shows a sigmoidal response to increasing FRC and PEEP, having both threshold and maximal effects. This relationship is most consistent with the hypothesis that alveolar epithelial permeability is increased by lung inflation.

  14. Lung clearance index for monitoring early lung disease in alpha-1-antitrypsin deficiency.

    PubMed

    Fuchs, Susanne I; Schwerk, Nicolaus; Pittschieler, Klaus; Ahrens, Frank; Baden, Winfried; Bals, Robert; Fähndrich, Sebastian; Gleiber, Wolfgang; Griese, Matthias; Hülskamp, Georg; Köhnlein, Thomas; Reckling, Ludmilla; Rietschel, Ernst; Staab, Doris; Gappa, Monika

    2016-07-01

    Patients with alpha-1-antitrypsin deficiency (AATD) and a PI-ZZ genotype are at high risk to develop severe emphysema during adulthood. However, little is known about early stages of emphysema and disease manifestation in other PI-types. Spirometry is commonly used for monitoring although early manifestation of emphysema is suspected within the peripheral airways that are not accessible by forced expiratory manoeuvres. We hypothesized that the Lung Clearance Index (LCI) derived from multiple breath nitrogen-washout (N2-washout) is useful to bridge this diagnostic gap. Patients from age 4 years onward and different PI-types performed N2-washout and spirometry. Results were compared to controls. 193 patients (4-79 years, 75% PI-ZZ) and 33 controls (8-60 years) were included. Mean (SD) LCI in patients was 9.1 (3.1) and 6.3 (0.6) in controls (p ≤ 0.001). 47% of adult patients with other than PI-ZZ genotypes and 39% of all patients with normal spirometry had abnormal LCIs. The LCI measured by N2-washout discriminates between patients with AATD and controls, reflects AATD related lung disease in all stages and appears to identify early peripheral lung changes in younger age than spirometry. We conclude that a normal spirometry does not exclude presence of AATD related lung disease even in genotypes other than PI-ZZ. PMID:27296827

  15. Clearance of Tc-99m DTPA aerosol from coal miners' lungs

    SciTech Connect

    Susskind, H.; Brill, A.B.; Harold, W.H.

    1985-07-01

    Alterations in regional epithelial permeability were assessed in 22 retired West Virginia coal miners' lungs by measuring the clearance of inhaled 0.5-..mu..m Tc-99m DTPA aerosol. Activity was measured in both lungs and in regions of interest placed over the lung periphery in the apical, middle, and basal portions of each lung. Clearance rates (T/sub 1/2/) for 5 nonsmokers, 8 ex-smokers, and 9 smokers were significantly faster than for comparable subjects measured elsewhere, who were not coal miners. Regional apex-to-base distributions of DTPA were measured as a function of clearance time and compared with regional ventilation and perfusion. Regional, as well as overall lung clearance curves of 8 smokers and 4 ex-smokers had two components, with overall T/sub 1/2/ of <7 min for the faster one. No correlations were found between T/sub 1/2/ and DLCO or with P(A-a)O/sub 2/. The results of our study suggest that measurement of DTPA clearance is a potentially useful noninvasive technique to assess lung injury in miners exposed to coal dust. 14 refs., 6 figs., 2 tabs.

  16. The airborne survival of Pasteurella haemolytica and its deposition in and clearance from the mouse lung.

    PubMed

    Gilmour, M I; Wathes, C M; Taylor, F G

    1990-02-01

    Pasteurella haemolytica A1 was aerosolised by a Collison nebuliser in a Henderson apparatus and its survival in air was measured. The organism was fragile in aerosol and survived best at high humidity and warm temperature. Mice were exposed to the aerosol and clearance from the lung measured. Deposition in the mouse lung showed a good linear correlation with bacterial concentration in the spray suspension fluid. Clearance from the lung was rapid over 24 h although some bacteria could be detected 2 and 4 days after exposure. Mice which received a second exposure 2 weeks later exhibited accelerated clearance from the lung whereby no bacteria could be detected after 12 h. This was associated with serum IgG antibody production, and local and splenic lymphocyte responses to bacterial antigen in vitro. PMID:2138372

  17. Clinical grade allogeneic human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation

    PubMed Central

    Curley, G. F.; Hamid, U. I.; Laffey, J. G.; Abbott, J.; McKenna, D. H.; Fang, X.; Matthay, M. A.; Lee, J. W.

    2014-01-01

    The lack of suitable donors for all solid-organ transplant programs is exacerbated in lung transplantation by the low utilization of potential donor lungs, due primarily to donor lung injury and dysfunction, including pulmonary edema. The current studies were designed to determine if intravenous clinical-grade human mesenchymal stem (stromal) cells (hMSCs) would be effective in restoring alveolar fluid clearance (AFC) in the human ex vivo lung perfusion model, using lungs that had been deemed unsuitable for transplantation and had been subjected to prolonged ischemic time. The human lungs were perfused with 5% albumin in a balanced electrolyte solution and oxygenated with continuous positive airway pressure. Baseline AFC was measured in the control lobe and if AFC was impaired (defined as <10%/h), the lungs received either hMSC (5 × 106 cells) added to the perfusate or perfusion only as a control. AFC was measured in a different lung lobe at 4 h. Intravenous hMSC restored AFC in the injured lungs to a normal level. In contrast, perfusion only did not increase AFC. This positive effect on AFC was reduced by intrabronchial administration of a neutralizing antibody to keratinocyte growth factor (KGF). Thus, intravenous allogeneic hMSCs are effective in restoring the capacity of the alveolar epithelium to remove alveolar fluid at a normal rate, suggesting that this therapy may be effective in enhancing the resolution of pulmonary edema in human lungs deemed clinically unsuitable for transplantation. PMID:24532289

  18. Respirable industrial fibres: deposition, clearance and dissolution in animal models.

    PubMed

    Jones, A D

    1993-04-01

    This paper examines the available experimental and theoretical results describing deposition and clearance of mineral fibres inhaled by animals and humans in order to define the limits which these mechanisms impose on the relevance of animal experiments in the assessment of potential human health risks. Direct experimental data for deposition of spherical particles are extended by examination of the physical processes and by some limited experimental data for fibres. This shows that alveolar deposition efficiency (in rat and in man) is sufficiently similar for particles and fibres with aerodynamic diameters less that 5 microns for rats to be a relevant model for airborne dusts in this size range. Inter-species differences in mechanical clearance are substantial, with clearance being faster in the rat than in man, and this is a factor which should be considered in interpreting animal toxicity studies. The durability of fibres in the biochemical conditions of the lung may be more important over the longer lifespan of humans. PMID:8317856

  19. Pulmonary clearance of radiotracers after positive end-expiratory pressure or acute lung injury

    SciTech Connect

    Barrowcliffe, M.P.; Zanelli, G.D.; Jones, J.G.

    1989-01-01

    In anesthetized rabbits we measured clearance from lung to blood of eight aerosolized technetium-99m-labeled compounds: diethylenetriaminepentaacetate (99mTc-DTPA); cytochrome c; myoglobin; a myoglobin polymer; albumin; and anionic, cationic, and neutral dextrans of equivalent molecular size. We investigated the effect of applying positive end-expiratory pressure (PEEP) and, on a subsequent occasion, of injecting oleic acid intravenously to produce acute lung injury on the pulmonary clearance rate. Base-line clearance rates were monoexponential and varied with the molecular weights of the radiotracers. For each tracer the rate of clearance was increased a similar degree by either PEEP or oleic acid. However, with PEEP, clearance remained monoexponential, whereas after oleic acid, smaller molecular-weight radiotracers had multiexponential clearance curves. This suggests that after oleic acid the alveolar epithelium breaks down in a nonuniform fashion. We conclude that differentiation of the effect of PEEP from that of severe lung injury caused by oleic acid is not readily accomplished by either increasing the size of the tracer molecule or by varying the molecular charge.

  20. Role of the lung in total body clearance of circulating drugs.

    PubMed

    Roth, R A; Wiersma, D A

    1979-01-01

    Attention in recent years has focused upon the ability of lung to accumulate and/or to metabolise circulating hormones, drugs and other xenobiotic agents. Although often studied in broken cell preparations, such functions must be examined in intact lung before extrapolation to the situation in vivo is possible. The role of lung in total body clearance of xenobiotic agents is often considered to be small, as compared with the liver it usually has much lower concentrations of degradative enzymes and a smaller mass. However, consideration of such factors as organ blood flow or stimulation of drug metabolising enzymes suggests that the contribution of the lung to total body clearance of some drugs is greater than previously recognised. This may explain some of the alterations in drug clearance seen clinically. For example, cigarette smoking may increase the clearance of certain xenobiotic compounds by stimulating pulmonary drug metabolising enzymes. Pulmonary drug disposition may also be altered by conditions affecting cardiac output, such as exercise, hypoxia, and circulatory shock, or those affecting acid-base balance, such as hyperventilation. In addition, pneumotoxicants may affect pulmonary clearance of circulating drugs and xenobiotics. PMID:41661

  1. Effect of exercise on redistribution and clearance of inhaled particles from hamster lungs

    SciTech Connect

    Sweeney, T.D.; Tryka, A.F.; Brain, J.D. )

    1990-03-01

    Does exercise alter the redistribution and clearance of particles from the lungs Sedentary hamsters and hamsters that were exercise trained by voluntary wheel running for the previous 5 wk were exposed to a 198Au-labeled aerosol for 25 min. Six trained and 6 sedentary animals were killed within 5 min after the exposure (day 0); the same number were killed 5 days later. The trained hamsters ran ad libitum during those 5 days. The lungs of all animals were excised, dried at total lung capacity, sliced into 1-mm-thick sections, and dissected into pieces that were counted for radioactivity and weighed. On day 0, trained hamsters had 80% more particles per milligram of lung than sedentary hamsters, although both were exposed under identical conditions of restraint. After five days, exercising hamsters cleared 38% of the particles present at day 0, whereas sedentary animals removed only 15%. Significant clearance was observed from the middle lung regions of sedentary hamsters and from all lung regions in exercising hamsters. We conclude that exercise can enhance the redistribution and clearance of particles from the lungs; the mechanisms responsible are as yet unclear.

  2. Lung-clearance mechanisms following inhalation of acid sulfates

    SciTech Connect

    Wolff, R.K.; Muggenburg, B.A.; Silbaugh, S.A.; Carpenter, R.L.; Rowatt, J.D.; Hill, J.O.

    1982-08-01

    These studies have indicated that acute exposures (1-6 hrs) to sulfuric acid at levels of 0.5 to 1.0 mg/m/sup 3/ can produce impairments in mucous clearance. The impairments can last for up to a week following a 1 hr exposure. These effects and studies by others suggest that high sulfate levels in polluted conditions may be one factor in observed increases of hospital visits for respiratory problems. Long term exposures to elevated levels of sulfates resulting in decreases of clearance could also be an initiating factor in producing chronic obstructive pulmonary disease (COPD). These studies have also shown that it is the larger size fraction (0.6 to 1.0 ..mu..m) of sulfuric acid mist in the urban aerosol which is predominantly responsible for at least the acute effects.

  3. The lung clearance index in young infants: impact of tidal volume and dead space.

    PubMed

    Schmalisch, Gerd; Wilitzki, Silke; Bührer, Christoph; Fischer, Hendrik S

    2015-07-01

    Lung clearance index (LCI), measured by multiple breath washout (MBW), is one of the most frequently used measures of ventilation inhomogeneity. This study was designed to investigate the effect of lung volumes on LCI in young infants. The dependence of LCI on dead space volume (VD), tidal volume (VT) and functional residual capacity (FRC) was investigated by mathematical modeling and by MBW measurements using sulfur hexafluoride (SF6) as a tracer gas. MBW was performed in 150 infants, of median postmenstrual age 46.7 weeks, followed up after neonatal intensive care. Wheezing was assessed in 90 of these infants by computerized respiratory sound analysis during quiet sleep. The strongest correlation was observed between LCI and the volume ratios VT/FRC (Spearman rank order correlation coefficient Rs = 0.688, p < 0.001), VD/VT (Rs = 0.733, p < 0.001) and VD/FRC (Rs = 0.854, p < 0.001). LCI calculated from VD, VT, and FRC was linearly related to measured LCI with a coefficient of determination of 75%. There were no significant differences between wheezers and non-wheezers in postmenstrual age and body weight, but FRC was significantly increased (p < 0.001) and median (interquartile range) LCI significantly decreased (5.83 (5.45-6.51) versus (6.54 (6.03-7.22), p < 0.001) in wheezing compared to non-wheezing infants. Model calculations also showed that LCI was significantly reduced in wheezing infants (5.09 (4.79-5.62) versus 5.43 (5.08-5.82), p < 0.018), indicating that the reduction can be explained by differences in the lung volumes, not by improved ventilation homogeneity. In conclusion, the strong dependence of LCI on lung volumes in young infants can lead to misinterpretations regarding the homogeneity of alveolar ventilation. PMID:26086894

  4. Megalin mediates transepithelial albumin clearance from the alveolar space of intact rabbit lungs

    PubMed Central

    Buchäckert, Yasmin; Rummel, Sebastian; Vohwinkel, Christine U; Gabrielli, Nieves M; Grzesik, Benno A; Mayer, Konstantin; Herold, Susanne; Morty, Rory E; Seeger, Werner; Vadász, István

    2012-01-01

    The alveolo-capillary barrier is effectively impermeable to large solutes such as proteins. A hallmark of acute lung injury/acute respiratory distress syndrome is the accumulation of protein-rich oedema fluid in the distal airspaces. Excess protein must be cleared from the alveolar space for recovery; however, the mechanisms of protein clearance remain incompletely understood. In intact rabbit lungs 29.8 ± 2.2% of the radio-labelled alveolar albumin was transported to the vascular compartment at 37°C within 120 min, as assessed by real-time measurement of 125I-albumin clearance from the alveolar space. At 4°C or 22°C significantly lower albumin clearance (3.7 ± 0.4 or 16.2 ± 1.1%, respectively) was observed. Deposition of a 1000-fold molar excess of unlabelled albumin into the alveolar space or inhibition of cytoskeletal rearrangement or clathrin-dependent endocytosis largely inhibited the transport of 125I-albumin to the vasculature, while administration of unlabelled albumin to the vascular space had no effect on albumin clearance. Furthermore, albumin uptake capacity was measured as about 0.37 mg ml−1 in cultured rat lung epithelial monolayers, further highlighting the (patho)physiological relevance of active alveolar epithelial protein transport. Moreover, gene silencing and pharmacological inhibition of the multi-ligand receptor megalin resulted in significantly decreased albumin binding and uptake in monolayers of primary alveolar type II and type I-like and cultured lung epithelial cells. Our data indicate that clearance of albumin from the distal air spaces is facilitated by an active, high-capacity, megalin-mediated transport process across the alveolar epithelium. Further understanding of this mechanism is of clinical importance, since an inability to clear excess protein from the alveolar space is associated with poor outcome in patients with acute lung injury/acute respiratory distress syndrome. PMID:22826129

  5. Pulmonary deposition and clearance of glass fiber in rat lungs after long-term inhalation.

    PubMed Central

    Tanaka, I; Oyabu, T; Ishimatsu, S; Hori, H; Higashi, T; Yamato, H

    1994-01-01

    In this study Wistar male rats were exposed to glass fiber obtained by the disintegration of a binderless glass fiber filter, for 6 hr/day, 5 days/week for 12 months. The mass median aerodynamic diameter (MMAD) of the fiber, determined with an Andersen sampler, was 2.6 microns. The count median diameter and length of the fibers measured by scanning electron microscopy (SEM) were 0.51 and 5.5 microns, respectively. The daily average exposure fiber concentration was 2.2 +/- 0.6 mg/m3. Some rats were sacrificed 24 hr after removal from the exposure chamber following the 12 months' exposure. Others were sacrificed 12 months after the end of exposure. The wet organ weights were recorded at the time of death and the silicon content of the lungs was determined by absorption spectrophotometry. After 12 months' exposure, the amount of glass fiber retained in the rat lungs was 1.49 mg, and after 12 months' clearance it was 0.61 mg. The biological half-life in a single exponential model was to be 8.7 months, much longer than the predicted value of 1.5 months obtained in a previous experiment in which rats were exposed for 4 weeks to the same glass fiber. PMID:7882935

  6. Microvesicles Derived From Human Mesenchymal Stem Cells Restore Alveolar Fluid Clearance in Human Lungs Rejected for Transplantation

    PubMed Central

    Gennai, S.; Monsel, A.; Hao, Q.; Park, J.; Matthay, M. A.; Lee, J. W.

    2016-01-01

    The need to increase the donor pool for lung transplantation is a major public health issue. We previously found that administration of mesenchymal stem cells “rehabilitated” marginal donor lungs rejected for transplantation using ex vivo lung perfusion. However, the use of stem cells has some inherent limitation such as the potential for tumor formation. In the current study, we hypothesized that microvesicles, small anuclear membrane fragments constitutively released from mesenchymal stem cells, may be a good alternative to using stem cells. Using our well established ex vivo lung perfusion model, microvesicles derived from human mesenchymal stem cells increased alveolar fluid clearance (i.e. ability to absorb pulmonary edema fluid) in a dose-dependent manner, decreased lung weight gain following perfusion and ventilation, and improved airway and hemodynamic parameters compared to perfusion alone. Microvesicles derived from normal human lung fibroblasts as a control had no effect. Co-administration of microvesicles with anti-CD44 antibody attenuated these effects, suggesting a key role of the CD44 receptor in the internalization of the microvesicles into the injured host cell and its effect. In summary, microvesicles derived from human mesenchymal stem cells were as effective as the parent mesenchymal stem cells in rehabilitating marginal donor human lungs. PMID:25847030

  7. Lung cinescintigraphy in the dynamic assessment of ventilation and mucociliary clearance of asbestos cement workers.

    PubMed Central

    Di Lorenzo, L; Mele, M; Pegorari, M M; Fratello, A; Zocchetti, C; Capozzi, D

    1996-01-01

    OBJECTIVES: To verify in vivo whether lung cinescintigraphy confirms the effect of asbestos on the patency of the smallest airways and on the efficiency of mucociliary clearance in asbestos cement workers. METHODS: 39 male subjects were examined: 30 asbestos cement workers and nine workers never exposed to occupational respiratory irritants. All subjects had a chest radiograph (International Labour Organisation (ILO) 1980); standard questionnaire on chronic bronchitis; spirometry; arterial blood gas analysis; carbon monoxide transfer factor (TLcosb); pulmonary O2 and CO2 ductances (DuO2, DuCO2); electrocardiogram; and lung cinescintigraphy after radioaerosol inhalation for the measurement of mucociliary clearance time in vivo in the smallest ciliated airways and for the assessment of radioaerosol deposition in alveoli (alveolar deposition index). RESULTS: Apart from nine non-exposed subjects, the 30 asbestos cement workers were so classified on the basis of chest radiography: nine of them as healthy exposed, 10 with pleural plaques, and 11 with asbestosis. The four groups had similar ages, work seniority, and smoking habits. Exercise dyspnoea was significantly more frequent in asbestos cement workers. Lung function variables of workers with effects related to asbestos were significantly lower than the other two groups. The PaO2, TLcOsb and DuO2 mean values were significantly lower in exposed workers than non-exposed. The mean PacO2 value was significantly higher in the asbestosis group than in the other three groups. Workers with effects related to asbestos showed a significantly lower alveolar deposition index and a significantly higher mucociliary clearance time than the other two groups. Subjects with asbestosis showed similar differences from those with pleural plaques. CONCLUSIONS: Lung cinescintigraphy confirms in vivo the effects of asbestos on bronchiolar and alveolar patency and on efficiency of mucociliary clearance in the smallest ciliated airways

  8. Xenogeneic lung transplantation models

    PubMed Central

    Burdorf, Lars; Azimzadeh, Agnes M.; Pierson, Richard N.

    2014-01-01

    Summary Study of lung xenografts has proven useful to understand the remaining barriers to successful transplantation of other organ xenografts. In this chapter, the history and current status of lung xenotransplantation will be briefly reviewed and two different experimental models, the ex vivo porcine-to-human lung perfusion and the in vivo xenogeneic lung transplantation, will be presented. We will focus on the technical details of these lung xenograft models in sufficient detail, list the needed materials and mention analysis techniques to allow others to adopt them with minimal learning curve. PMID:22565996

  9. Site of deposition and factors affecting clearance of aerosolized solute from canine lungs

    SciTech Connect

    Rizk, N.W.; Luce, J.M.; Hoeffel, J.M.; Price, D.C.; Murray, J.F.

    1984-01-01

    The influence of several factors on lung solute clearance using aerosolized /sup 99m/Tc-diethylenetriaminepentaacetate was determined. The authors used a jet nebulizer-plate separator-balloon system to generate particles with an activity median aerodynamic diameter of 1.1 ..mu..m, administered the aerosol in a standard fashion, and determined clearance half times (t/sub 1/2/) with a gamma-scintillation camera. The following serial studies were performed in five anesthetized, paralyzed, intubated, mechanically ventilated dogs: (1) control, with ventilatory frequency (f) = 15 breaths/min and tidal volume (V/sub T/) = 15 ml/kg during solute clearance; (2) repeat control, for reproducibility; (3) increased frequency, with f = 25 breaths/min and V/sub T/ = 10 ml/kg; (4) positive end-expiratory pressure (PEEP) of 10 cmH/sub 2/O; (5) unilateral pulmonary arterial occlusion (PAO); and (6) bronchial arterial occlusion (BAO). Control t/sub 1/2/ was 25 +/- 5 min and did not change in the repeat control, increased frequency, or BAO experiments. PEEP markedly decreased t/sub 1/2/ to 13 +/- 3 min (P < 0.01), and PAO increased it to 37 +/- 6 min (P < 0.05). We conclude that clearance from the lungs by our method is uninfluenced by increased frequency, increases markedly with PEEP, and depends on pulmonary, not bronchial, blood flow.

  10. Increased Myeloid Cell Production and Lung Bacterial Clearance in Mice Exposed to Cigarette Smoke.

    PubMed

    Basilico, Paola; Cremona, Tiziana P; Oevermann, Anna; Piersigilli, Alessandra; Benarafa, Charaf

    2016-03-01

    Pneumonia is a leading cause of hospitalization in patients with chronic obstructive pulmonary disease (COPD). Although most patients with COPD are smokers, the effects of cigarette smoke exposure on clearance of lung bacterial pathogens and on immune and inflammatory responses are incompletely defined. Here, clearance of Streptococcus pneumoniae and Pseudomonas aeruginosa and associated immune responses were examined in mice exposed to cigarette smoke or after smoking cessation. Mice exposed to cigarette smoke for 6 weeks or 4 months demonstrated decreased lung bacterial burden compared with air-exposed mice when infected 16 to 24 hours after exposure. When infection was performed after smoke cessation, bacterial clearance kinetics of mice previously exposed to smoke reversed to levels comparable to those of control mice, suggesting that the observed defects were not dependent on adaptive immunological memory to bacterial determinants found in smoke. Comparing cytokine levels and myeloid cell production before infection in mice exposed to cigarette smoke with mice never exposed or after smoke cessation revealed that reduced bacterial burden was most strongly associated with higher levels of IL-1β and granulocyte-macrophage colony-stimulating factor in the lungs and with increased neutrophil reserve and monocyte turnover in the bone marrow. Using Serpinb1a-deficient mice with reduced neutrophil numbers and treatment with granulocyte colony-stimulating factor showed that increased neutrophil numbers contribute only in part to the effect of smoke on infection. Our findings indicate that cigarette smoke induces a temporary and reversible increase in clearance of lung pathogens, which correlates with local inflammation and increased myeloid cell output from the bone marrow. PMID:26273827

  11. Clearance of polonium-210-enriched cigarette smoke from the rat trachea and lung

    SciTech Connect

    Cohen, B.S.; Harley, N.H.; Tso, T.C.

    1985-06-30

    The distribution and clearance of alpha radioactivity in the lungs of rats were measured after inhalation of smoke from cigarettes highly enriched in /sup 210/Po. Female Fischer rats were exposed daily for 6 months to smoke from cigarettes with 500 times the normal content of /sup 210/Po. Control rats were exposed to standard cigarette smoke. Animals were serially withdrawn and killed. After necropsy the trachea, major bronchi, larynx, and nasopharynx were examined for surface alpha activity by an etched track technique utilizing cellulose nitrate detectors. Areas of accumulated activity were seen on samples of larynx from rats exposed to the /sup 210/Po-enriched cigarettes. No other local accumulations were seen on the airways. The lower lungs were analyzed radiochemically for /sup 210/Po. Both radiochemical analysis and track measurements showed highly elevated activity concentrations in rats exposed to the /sup 210/Po-enriched cigarettes. Following withdrawal from smoking, both short- and long-term clearance components were seen. The parameters which fit the postexposure data for clearance of the lung burden cannot fit the buildup during the exposure period.

  12. Pulmonary and thoracic macrophage subpopulations and clearance of particles from the lung.

    PubMed Central

    Lehnert, B E

    1992-01-01

    Pulmonary macrophages consist of several subpopulations that can be defined by their anatomical locations as well as by other criteria. In addition to the well-known alveolar macrophages that reside on the alveolar surface, pulmonary macrophages also occur in the conducting airways, in various pulmonary interstitial regions, and, in some mammalian species, in the lung's intravascular compartment. Other thoracic macrophages of relevance to pulmonary defense and some lung disease processes are the pleural macrophages resident in the pleural space and macrophages present in regional lymph nodes that receive lymphatic drainage from the lung. Of the above subpopulations of pulmonary and thoracic macrophages, the alveolar macrophages have received the most experimental attention in the context of the pulmonary clearance and retention of deposited particles. Accordingly, less information is currently available regarding the roles other pulmonary and thoracic populations of macrophages may play in the removal of particles from the lower respiratory tract and associated tissue compartments. This report provides an overview of the various subpopulations of pulmonary and thoracic macrophages, as defined by their anatomical locations. The known and postulated roles of macrophages in the pulmonary clearance and retention of particles are reviewed, with particular emphasis on macrophage-associated processes involved in the pulmonary clearance of relatively insoluble particles. Images FIGURE 1. FIGURE 2. FIGURE 3. FIGURE 5. FIGURE 8. FIGURE 12. FIGURE 14. FIGURE 15. FIGURE 16. FIGURE 17. FIGURE 18. FIGURE 19. A FIGURE 19. B FIGURE 21. FIGURE 22. PMID:1396454

  13. Cell surface structures influence lung clearance rate of systemically infused mesenchymal stromal cells.

    PubMed

    Nystedt, Johanna; Anderson, Heidi; Tikkanen, Jonne; Pietilä, Mika; Hirvonen, Tia; Takalo, Reijo; Heiskanen, Annamari; Satomaa, Tero; Natunen, Suvi; Lehtonen, Siri; Hakkarainen, Tanja; Korhonen, Matti; Laitinen, Saara; Valmu, Leena; Lehenkari, Petri

    2013-02-01

    The promising clinical effects of mesenchymal stromal/stem cells (MSCs) rely especially on paracrine and nonimmunogenic mechanisms. Delivery routes are essential for the efficacy of cell therapy and systemic delivery by infusion is the obvious goal for many forms of MSC therapy. Lung adhesion of MSCs might, however, be a major obstacle yet to overcome. Current knowledge does not allow us to make sound conclusions whether MSC lung entrapment is harmful or beneficial, and thus we wanted to explore MSC lung adhesion in greater detail. We found a striking difference in the lung clearance rate of systemically infused MSCs derived from two different clinical sources, namely bone marrow (BM-MSCs) and umbilical cord blood (UCB-MSCs). The BM-MSCs and UCB-MSCs used in this study differed in cell size, but our results also indicated other mechanisms behind the lung adherence. A detailed analysis of the cell surface profiles revealed differences in the expression of relevant adhesion molecules. The UCB-MSCs had higher expression levels of α4 integrin (CD49d, VLA-4), α6 integrin (CD49f, VLA-6), and the hepatocyte growth factor receptor (c-Met) and a higher general fucosylation level. Strikingly, the level of CD49d and CD49f expression could be functionally linked with the lung clearance rate. Additionally, we saw a possible link between MSC lung adherence and higher fibronectin expression and we show that the expression of fibronectin increases with MSC culture confluence. Future studies should aim at developing methods of transiently modifying the cell surface structures in order to improve the delivery of therapeutic cells. PMID:23132820

  14. Dynamic modelling and experimental study of cantilever beam with clearance

    NASA Astrophysics Data System (ADS)

    Li, B.; Jin, W.; Han, L.; He, Z.

    2012-05-01

    Clearances occur in almost all mechanical systems, typically such as the clearance between slide plate of gun barrel and guide. Therefore, to study the clearances of mechanisms can be very important to increase the working performance and lifetime of mechanisms. In this paper, rigid dynamic modelling of cantilever with clearance was done according to the subject investigated. In the rigid dynamic modelling, clearance is equivalent to the spring-dashpot model, the impact of beam and boundary face was also taken into consideration. In ADAMS software, the dynamic simulation was carried out according to the model above. The software simulated the movement of cantilever with clearance under external excitation. Research found: When the clearance is larger, the force of impact will become larger. In order to study how the stiffness of the cantilever's supporting part influences natural frequency of the system, A Euler beam which is restricted by a draught spring and a torsion spring at its end was raised. Through numerical calculation, the relationship between natural frequency and stiffness was found. When the value of the stiffness is close to the limit value, the corresponding boundary condition is illustrated. An ADAMS experiment was carried out to check the theory and the simulation.

  15. Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection

    PubMed Central

    Peteranderl, Christin; Morales-Nebreda, Luisa; Lecuona, Emilia; Vadász, István; Morty, Rory E.; Schmoldt, Carole; Bespalowa, Julia; Pleschka, Stephan; Mayer, Konstantin; Gattenloehner, Stefan; Fink, Ludger; Lohmeyer, Juergen; Seeger, Werner; Sznajder, Jacob I.; Mutlu, Gökhan M.; Budinger, G.R. Scott

    2016-01-01

    Influenza A viruses (IAV) can cause lung injury and acute respiratory distress syndrome (ARDS), which is characterized by accumulation of excessive fluid (edema) in the alveolar airspaces and leads to hypoxemia and death if not corrected. Clearance of excess edema fluid is driven mostly by the alveolar epithelial Na,K-ATPase and is crucial for survival of patients with ARDS. We therefore investigated whether IAV infection alters Na,K-ATPase expression and function in alveolar epithelial cells (AECs) and the ability of the lung to clear edema. IAV infection reduced Na,K-ATPase in the plasma membrane of human and murine AECs and in distal lung epithelium of infected mice. Moreover, induced Na,K-ATPase improved alveolar fluid clearance (AFC) in IAV-infected mice. We identified a paracrine cell communication network between infected and noninfected AECs and alveolar macrophages that leads to decreased alveolar epithelial Na,K-ATPase function and plasma membrane abundance and inhibition of AFC. We determined that the IAV-induced reduction of Na,K-ATPase is mediated by a host signaling pathway that involves epithelial type I IFN and an IFN-dependent elevation of macrophage TNF-related apoptosis–inducing ligand (TRAIL). Our data reveal that interruption of this cellular crosstalk improves edema resolution, which is of biologic and clinical importance to patients with IAV-induced lung injury. PMID:26999599

  16. Transfer of a CD4+ Th1 cell line to nude mice effects clearance of Rhodococcus equi from the lung.

    PubMed Central

    Kanaly, S T; Hines, S A; Palmer, G H

    1996-01-01

    Rhodococcus equi, and intracellular respiratory pathogen, causes sever e granulomatous pneumonia in humans with AIDS and in young horses. Pulmonary clearance of R. equi requires functional CD4+ T cells and gamma interferon (IFN-gamma) expression from bronchial lymph node cells. The purpose of this study was to investigate whether R. equi-specific CD4+ Th1 cells could effect clearance of R. equi from the lung. Adoptive transfer of a clearance of R. equi from the lungs. In contrast, mice transfused with a R. equi-specific CD4+ Th2 cell line expressed interleukin-4 but not IFN-gamma mRNA, failed to clear pulmonary infection, and developed granulomas in the lung. Control mice, which did not receive cells, did not produce IFN-gamma or interleukin-4 and developed small pulmonary granulomas. These results clearly show that a Th1 response is sufficient to effect pulmonary clearance of R. equi. PMID:8606068

  17. Hyaluronic Acid Molecular Weight Determines Lung Clearance and Biodistribution after Instillation.

    PubMed

    Kuehl, Christopher; Zhang, Ti; Kaminskas, Lisa M; Porter, Christopher J H; Davies, Neal M; Forrest, Laird; Berkland, Cory

    2016-06-01

    Hyaluronic acid (HA) has emerged as a versatile polymer for drug delivery. Multiple commercial products utilize HA, it can be obtained in a variety of molecular weights, and it offers chemical handles for cross-linkers, drugs, or imaging agents. Previous studies have investigated multiple administration routes, but the absorption, biodistribution, and pharmacokinetics of HA after delivery to the lung is relatively unknown. Here, pharmacokinetic parameters were investigated by delivering different molecular weights of HA (between 7 and 741 kDa) to the lungs of mice. HA was labeled with either a near-infrared dye or with iodine-125 conjugated to HA using a tyrosine linker. In initial studies, dye-labeled HA was instilled into the lungs and fluorescent images of organs were collected at 1, 8, and 24 h post administration. Data suggested longer lung persistence of higher molecular weight HA, but signal diminished for all molecular weights at 8 h. To better quantitate pharmacokinetic parameters, different molecular weights of iodine-125 labeled HA were instilled and organ radioactivity was determined after 1, 2, 4, 6, and 8 h. The data showed that, after instillation, the lungs contained the highest levels of HA, as expected, followed by the gastrointestinal tract. Smaller molecular weights of HA showed more rapid systemic distribution, while 67 and 215 kDa HA showed longer persistence in the lungs. Lung exposure appeared to be optimum in this size range due to the rapid absorption of <67 kDa HA and the poor lung penetration and mucociliary clearance of viscous solutions of HA > 215 kDa. The versatility of HA molecular weight and conjugation chemistries may, therefore, provide new opportunities to extend pulmonary drug exposure and potentially facilitate access to lymph nodes draining the pulmonary bed. PMID:27157508

  18. Negligible clearance of ultrafine particles retained in healthy and affected human lungs.

    PubMed

    Wiebert, P; Sanchez-Crespo, A; Seitz, J; Falk, R; Philipson, K; Kreyling, W G; Möller, W; Sommerer, K; Larsson, S; Svartengren, M

    2006-08-01

    Ambient particles are believed to be a specific health hazard, although the underlying mechanisms are not fully understood. There are data in the literature indicating fast and substantial systemic uptake of particles from the lung. The present authors have developed an improved method to produce ultrafine particles with more stable radiolabelling and defined particle size range. Fifteen subjects inhaled technetium 99m (99mTc)-labelled carbonaceous particles of 100 nm in size. Radioactivity over the lung was followed for 70 h. The clearance of these ultrafine particles from the lungs and specifically translocation to the circulation was tested. Lung retention for all subjects at 46 h was mean+/-sd 99+/-4.6%. Cumulative leaching of 99mTc activity from the particles was 2.6+/-0.96% at 70 h. The 24-h activity leaching in urine was 1.0+/-0.55%. No evidence of a quantitatively important translocation of 100-nm particles to the systemic circulation from the lungs was found. More research is needed to establish if the approximately 1% cleared activity originates from leached activity or insoluble translocated particles, and whether a few per cent of translocated particles is sufficient to cause harmful effects. PMID:16641121

  19. Lung clearance of neutron-activated Mount St. Helens volcanic ash in the rat.

    PubMed

    Wehner, A P; Wilerson, C L; Stevens, D L

    1984-10-01

    To determine pulmonary deposition and clearance of inhaled volcanic ash, rats received a single 60-min, nose-only exposure to neutron-activated ash. Over a period of 128 days after exposure, the rats were sacrificed in groups of five animals. Lungs were analyzed for the radionuclide tracers 46Sc, 59Fe, and 60Co by gamma-ray spectrometry. The alveolar ash burdens, determined by the radionuclides 46Sc and 59Fe, are in good agreement for the majority of samples analyzed, indicating ash particulate levels in the lungs, rather than leached radionuclides. The ash deposition estimates based on 60Co were appreciably lower for the lungs, indicating that 60Co leached from the ash. Approximately 110 micrograms ash, or 6% of the inhaled ash, was initially retained in the deep lung. The biological half-time of the alveolar ash burden was 39 days. After 90 days, the mean lung burden had decreased to about 20% of its initial value; 128 days after exposure, about 10% remained. PMID:6489290

  20. The Role of CD1d-Restricted NKT Cells in the Clearance of Pseudomonas aeruginosa from the Lung Is Dependent on the Host Genetic Background

    PubMed Central

    Benoit, Patrick; Sigounas, Vaia Yioula; Thompson, Jenna L.; van Rooijen, Nico; Poynter, Matthew E.; Wargo, Matthew J.

    2015-01-01

    Pseudomonas aeruginosa is an important human opportunistic pathogen, accounting for a significant fraction of hospital-acquired lung infections. CD1d-restricted NKT cells comprise an unusual innate-like T cell subset that plays important roles in both bacterial and viral infections. Previous reports have differed in their conclusions regarding the role of NKT cells in clearance of P. aeruginosa from the lung. Since there is significant strain-dependent variation in NKT cell number and function among different inbred strains of mice, we investigated whether the role of NKT cells was dependent on the host genetic background. We found that NKT cells did indeed play a critical role in the clearance of P. aeruginosa from the lungs of BALB/c mice but that they played no discernible role in clearance from the lungs of C57BL/6 mice. We found that the strain-dependent role of NKT cells was associated with significant strain-dependent differences in cytokine production by lung NKT cells and that impaired clearance of P. aeruginosa in BALB/c CD1d−/− mice was associated with an increase in neutrophil influx to the lung and increased levels of proinflammatory cytokines and chemokines after infection. Finally, we found that the role of alveolar macrophages was also dependent on the genetic background. These data provide further support for a model in which the unusually high level of variability in NKT cell number and function among different genetic backgrounds may be an important contributor to infectious-disease susceptibility and pathology. PMID:25870224

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

    PubMed Central

    Button, Brenda M.; Button, Brian

    2013-01-01

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

  2. Deposition and clearance of monodisperse aerosols in the calf lung: effects of particle size and a mucolytic agent (bromhexine)

    PubMed Central

    Davies, C P; Webster, A J

    1987-01-01

    Mucociliary clearance and retention of monodisperse aerosols of radiolabelled polystyrene particles of both 3.3 microns and 5 microns diameter were investigated in four healthy calves and two sick calves. The effect of the mucolytic agent bromhexine was also assessed at two dosage levels. There were significant differences (P less than 0.05) in clearance rate constant between calves, but similar patterns of clearance for each calf. These characteristics of mechanical lung clearance did not vary over a two month period. Values of clearance rate constant and percentage retention varied significantly (P less than 0.001) between the two different particle sizes, 5 microns particles giving faster clearance and lower retention of particles than 3.3 microns particles. Bromhexine at the recommended dose of 1.6 mg/kg 0.75 caused a significant (P less than 0.05) increase in clearance rate in both healthy and sick calves, but affected percentage retention only in sick calves. This study illustrates the variation in mucociliary clearance rates shown by individuals and also underlines the importance of particle size in aerosols used for studies of pulmonary deposition and clearance. The work also indicates that bromhexine may be of use in the therapy of respiratory disease in calves. PMID:3651885

  3. Deposition and clearance of monodisperse aerosols in the calf lung: effects of particle size and a mucolytic agent (bromhexine)

    PubMed

    Davies, C P; Webster, A J

    1987-07-01

    Mucociliary clearance and retention of monodisperse aerosols of radiolabelled polystyrene particles of both 3.3 microns and 5 microns diameter were investigated in four healthy calves and two sick calves. The effect of the mucolytic agent bromhexine was also assessed at two dosage levels. There were significant differences (P less than 0.05) in clearance rate constant between calves, but similar patterns of clearance for each calf. These characteristics of mechanical lung clearance did not vary over a two month period. Values of clearance rate constant and percentage retention varied significantly (P less than 0.001) between the two different particle sizes, 5 microns particles giving faster clearance and lower retention of particles than 3.3 microns particles. Bromhexine at the recommended dose of 1.6 mg/kg 0.75 caused a significant (P less than 0.05) increase in clearance rate in both healthy and sick calves, but affected percentage retention only in sick calves. This study illustrates the variation in mucociliary clearance rates shown by individuals and also underlines the importance of particle size in aerosols used for studies of pulmonary deposition and clearance. The work also indicates that bromhexine may be of use in the therapy of respiratory disease in calves. PMID:3651885

  4. The role of airway macrophages in apoptotic cell clearance following acute and chronic lung inflammation.

    PubMed

    Grabiec, Aleksander M; Hussell, Tracy

    2016-07-01

    Acute and chronic inflammatory responses in the lung are associated with the accumulation of large quantities of immune and structural cells undergoing apoptosis, which need to be engulfed by phagocytes in a process called 'efferocytosis'. Apoptotic cell recognition and removal from the lung is mediated predominantly by airway macrophages, though immature dendritic cells and non-professional phagocytes, such as epithelial cells and mesenchymal cells, can also display this function. Efficient clearance of apoptotic cells from the airways is essential for successful resolution of inflammation and the return to lung homeostasis. Disruption of this process leads to secondary necrosis of accumulating apoptotic cells, release of necrotic cell debris and subsequent uncontrolled inflammatory activation of the innate immune system by the released 'damage associated molecular patterns' (DAMPS). To control the duration of the immune response and prevent autoimmune reactions, anti-inflammatory signalling cascades are initiated in the phagocyte upon apoptotic cell uptake, mediated by a range of receptors that recognise specific phospholipids or proteins externalised on, or secreted by, the apoptotic cell. However, prolonged activation of apoptotic cell recognition receptors, such as the family of receptor tyrosine kinases Tyro3, Axl and MerTK (TAM), may delay or prevent inflammatory responses to subsequent infections. In this review, we will discuss recent advances in our understanding of the mechanism controlling apoptotic cell recognition and removal from the lung in homeostasis and during inflammation, the contribution of defective efferocytosis to chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease, asthma and cystic fibrosis, and implications of the signals triggered by apoptotic cells in the susceptibility to pulmonary microbial infections. PMID:26957481

  5. Effect of SO/sub 2/ on the clearance of Listeria monocytogenes from the lungs of emphysematous hamsters

    SciTech Connect

    Trimpe, K.L.; Weiss, H.; Zwilling, B.S.

    1986-10-01

    The effect of sulfur dioxide on the clearance of Listeria monocytogenes from normal and emphysematous hamsters was assessed by measuring the number of colony forming units recovered from whole lung homogenates. Continuous exposure to SO/sub 2/ after intratracheal instillation of Listeria significantly altered the clearance of viable bacteria from the lungs of emphysematous but not normal hamsters. Pre-exposure of hamsters to SO/sub 2/ for 2 weeks prior to respiratory infection had similar effects. The emphysematous hamsters exposed to SO/sub 2/ had a lower average number of Listeria in the lungs after the first week of infection than control groups. This effect appears to result from the combined influence of the SO/sub 2/, the Listeria infection, and the emphysematous condition within the lungs.

  6. The reproducibility and responsiveness of the lung clearance index in bronchiectasis.

    PubMed

    Grillo, Lizzie; Irving, Samantha; Hansell, David M; Nair, Arjun; Annan, Bertrand; Ward, Simon; Bilton, Diana; Main, Eleanor; Davies, Jane; Bush, Andrew; Wilson, Robert; Loebinger, Michael R

    2015-12-01

    Lung clearance index (LCI) is a potential clinical outcome marker in bronchiectasis. Its responsiveness to therapeutic intervention has not been determined. This study evaluates its responsiveness to a session of physiotherapy and intravenous antibiotic treatment of an exacerbation.32 stable and 32 exacerbating bronchiectasis patients and 26 healthy controls were recruited. Patients had LCI and lung function performed before and after physiotherapy on two separate occasions in the stable patients and at the beginning and end of an intravenous antibiotic course in the exacerbating patients.LCI was reproducible between visits in 25 stable patients, with an intraclass correlation of 0.978 (0.948, 0.991; p<0.001). There was no significant difference in LCI (mean±sd) between stable 11.91±3.39 and exacerbating patients 12.76±3.47, but LCI was significantly higher in both bronchiectasis groups compared with healthy controls (7.36±0.99) (p<0.001). Forced expiratory volume in 1 s improved after physiotherapy, as did alveolar volume after intravenous antibiotics, but LCI did not change significantly.LCI is reproducible in stable bronchiectasis but unlike conventional lung function tests, is unresponsive to two short-term interventions and hence is unlikely to be a useful clinical tool for short-term acute assessment in these patients. Further evaluation is required to establish its role in milder disease and in the evaluation of long-term interventions. PMID:26341989

  7. Influence of clearance model on numerical simulation of centrifugal pump

    NASA Astrophysics Data System (ADS)

    Wang, Z.; Gao, B.; Yang, L.; Du, W. Q.

    2016-05-01

    Computing models are always simplified to save the computing resources and time. Particularly, the clearance that between impeller and pump casing is always ignored. But the completer model is, the more precise result of numerical simulation is in theory. This paper study the influence of clearance model on numerical simulation of centrifugal pump. We present such influence via comparing performance, flow characteristic and pressure pulsation of two cases that the one of two cases is the model pump with clearance and the other is not. And the results show that the head decreases and power increases so that efficiency decreases after computing with front and back cavities. Then no-leakage model would improve absolute velocity magnitude in order to reach the rated flow rate. Finally, more disturbance induced by front cavity flow and wear-ring flow would change the pressure pulsation of impeller and volute. The performance of clearance flow is important for the whole pump in performance, flow characteristic, pressure pulsation and other respects.

  8. Clearance mechanism assignment and total clearance prediction in human based upon in silico models.

    PubMed

    Lombardo, Franco; Obach, R Scott; Varma, Manthena V; Stringer, Rowan; Berellini, Giuliano

    2014-05-22

    We introduce a two-tier model based on an exhaustive data set, where discriminant models based on principal component analysis (PCA) and partial least squares (PLS) are used separately and in conjunction, and we show that PCA is highly discriminant approaching 95% accuracy in the assignment of the primary clearance mechanism. Furthermore, the PLS model achieved a quantitative predictive performance comparable to methods based on scaling of animal data while not requiring the use of either in vivo or in vitro data, thus sparing the use of animal. This is likely the highest performance that can be expected from a computational approach, and further improvements may be difficult to reach. We further offer the medicinal scientist a PCA model to guide in vitro and/or in vivo studies to help limit the use of resources via very rapid computations. PMID:24773013

  9. Model 200 crane, general arrangement & clearances. Colby Steel & ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Model 200 crane, general arrangement & clearances. Colby Steel & Engineering Company, Vancouver B.C., Seattle, New York. Two elevations and cab plan. No architect noted, drawn by Gould. Sheet A2, no 6365. Scaled not given. August 10, 1942. Proposal no. 318. - United Engineering Company Shipyard, Crane, 2900 Main Street, Alameda, Alameda County, CA

  10. Effect of bronchopulmonary lavage on lung retention and clearance of particulate material in hamsters

    SciTech Connect

    Ellender, M.; Hodgson, A.; Wood, K.L.; Moody, J.C. )

    1992-07-01

    Hamsters were exposed to an aerosol of fused aluminosilicate particles (FAP) labeled with [sup 57]CO. Three groups of animals were given bronchopulmonary lavage, beginning at either 1 week, 1 month, or 6 months after exposure. Each treated group was lavaged eight times over a period of 25 days. Each lavage involved 10 saline washes of the lungs. For each group, about 60-70% of the body content of [sup 57]CO at the start of lavage treatment was removed; nearly half of this was recovered in the first two lavages. A positive correlation was demonstrated between the macrophage content and [sup 57]Co activity of the washings. The subsequent fractional clearance rate of [sup 57]Co from lavaged animals was not significantly different from that in a group of untreated control animals. 30 refs., 2 figs., 2 tabs.

  11. Pseudomonas infection and mucociliary and absorptive clearance in the cystic fibrosis lung.

    PubMed

    Locke, Landon W; Myerburg, Michael M; Weiner, Daniel J; Markovetz, Matthew R; Parker, Robert S; Muthukrishnan, Ashok; Weber, Lawrence; Czachowski, Michael R; Lacy, Ryan T; Pilewski, Joseph M; Corcoran, Timothy E

    2016-05-01

    Airway surface liquid hyperabsorption and mucus accumulation are key elements of cystic fibrosis lung disease that can be assessed in vivo using functional imaging methods. In this study we evaluated experimental factors affecting measurements of mucociliary clearance (MCC) and small-molecule absorption (ABS) and patient factors associated with abnormal absorption and mucus clearance.Our imaging technique utilises two radiopharmaceutical probes delivered by inhalation. Measurement repeatability was assessed in 10 adult cystic fibrosis subjects. Experimental factors were assessed in 29 adult and paediatric cystic fibrosis subjects (51 scans). Patient factors were assessed in a subgroup with optimal aerosol deposition (37 scans; 24 subjects). Paediatric subjects (n=9) underwent initial and 2-year follow-up scans. Control subjects from a previously reported study are included for comparison.High rates of central aerosol deposition influenced measurements of ABS and, to a lesser extent, MCC. Depressed MCC in cystic fibrosis was only detectable in subjects with previous Pseudomonas aeruginosa infection. Cystic fibrosis subjects without P. aeruginosa had similar MCC to control subjects. Cystic fibrosis subjects had consistently higher ABS rates.We conclude that the primary experimental factor affecting MCC/ABS measurements is central deposition percentage. Depressed MCC in cystic fibrosis is associated with P. aeruginosa infection. ABS is consistently increased in cystic fibrosis. PMID:27009167

  12. Pneumocystis pneumonia increases the clearance rate of inhaled /sup 99m/Tc DTPA from lung to blood

    SciTech Connect

    Jones, D.K.; Higenbottam, T.W.

    1985-10-01

    Despite no radiographic change, a patient with Pneumocystis pneumonia showed increased clearance of inhaled /sup 99m/Tc DTPA from lung to blood. Gas transfer for carbon monoxide was also reduced, but improved with treatment. This was paralleled by serial increase in the t1/2 LB.

  13. Lung epithelial MyD88 drives early pulmonary clearance of Pseudomonas aeruginosa by a flagellin dependent mechanism.

    PubMed

    Anas, Adam A; van Lieshout, Miriam H P; Claushuis, Theodora A M; de Vos, Alex F; Florquin, Sandrine; de Boer, Onno J; Hou, Baidong; Van't Veer, Cornelis; van der Poll, Tom

    2016-08-01

    Pseudomonas aeruginosa is a flagellated pathogen frequently causing pneumonia in hospitalized patients and sufferers of chronic lung disease. Here we investigated the role of the common Toll-like receptor (TLR) adaptor myeloid differentiation factor (MyD)88 in myeloid vs. lung epithelial cells in clearance of P. aeruginosa from the airways. Mice deficient for MyD88 in lung epithelial cells (Sftpccre-MyD88-lox mice) or myeloid cells (LysMcre-MyD88-lox mice) and bone marrow chimeric mice deficient for TLR5 (the receptor recognizing Pseudomonas flagellin) in either parenchymal or hematopoietic cells were infected with P. aeruginosa via the airways. Sftpccre-MyD88-lox mice demonstrated a reduced influx of neutrophils into the bronchoalveolar space and an impaired early antibacterial defense after infection with P. aeruginosa, whereas the response of LysMcre-MyD88-lox mice did not differ from control mice. The immune-enhancing role of epithelial MyD88 was dependent on recognition of pathogen-derived flagellin by epithelial TLR5, as demonstrated by an unaltered clearance of mutant P. aeruginosa lacking flagellin from the lungs of Sftpccre-MyD88-lox mice and an impaired bacterial clearance in bone marrow chimeric mice lacking TLR5 in parenchymal cells. These data indicate that early clearance of P. aeruginosa from the airways is dependent on flagellin-TLR5-MyD88-dependent signaling in respiratory epithelial cells. PMID:27288486

  14. Mechanisms underlying the redistribution of particles among the lung's alveolar macrophages during alveolar phase clearance

    SciTech Connect

    Lehnert, B.E.; Oritz, J.B.; Steinkamp, J.A.; Tietjen, G.L.; Sebring, R.J. ); Oberdorster, G. )

    1991-01-01

    In order to obtain information about the particle redistribution phenomenon following the deposition of inhaled particles, as well as to obtain information about some of the mechanisms that may be operable in the redistribution of particles, lavaged lung free cell analyses and transmission electron microscopic (TEM) analyses of lung tissue and were performed using lungs from rats after they were subchronically exposed to aerosolized dioxide (TiO{sub 2}). TEM analyses indicated that the in situ autolysis of particle-containing Alveolar Macropages (AM) is one important mechanism involved in the redistribution of particles. Evidence was also obtained that indicated that the engulfment of one particle-containing phagocyte by another phagocyte also occurs. Another prominent mechanism of the particle redistribution phenomenon may be the in situ proliferation of particle-laden AM. We used the macrophage cell line J774A.1 as a surrogate for AM to investigate how different particulate loads in macrophages may affect their abilities to proliferate. These in vitro investigations indicated that the normal rate of proliferation of macrophages is essentially unaffected by the containment of relatively high particulate burdens. Overall, the results of our investigations suggest that in situ autolysis of particle-containing AM and the rephagocytosis of freed particles by other phagocytes, the phagocytosis of effete and disintegrating particle-containing phagocytes by other AM, and the in situ division of particle-containing AM are likely mechanisms that underlie the post-depositional redistribution of particles among the lung's AM during alveolar phase clearance. 19 refs., 8 figs., 2 tabs.

  15. Influence of Particle Size on Persistence and Clearance of Aerosolized Silver Nanoparticles in the Rat Lung

    PubMed Central

    Anderson, Donald S.; Patchin, Esther S.; Silva, Rona M.; Uyeminami, Dale L.; Sharmah, Arjun; Guo, Ting; Das, Gautom K.; Brown, Jared M.; Shannahan, Jonathan; Gordon, Terry; Chen, Lung Chi; Pinkerton, Kent E.; Van Winkle, Laura S.

    2015-01-01

    The growing use of silver nanoparticles (AgNPs) in consumer products raises concerns about potential health effects. This study investigated the persistence and clearance of 2 different size AgNPs (20 and 110 nm) delivered to rats by single nose-only aerosol exposures (6 h) of 7.2 and 5.4 mg/m3, respectively. Rat lung tissue was assessed for silver accumulations using inductively-coupled plasma mass spectrometry (ICP-MS), autometallography, and enhanced dark field microscopy. Involvement of tissue macrophages was assessed by scoring of silver staining in bronchoalveolar lavage fluid (BALF). Silver was abundant in most macrophages at 1 day post-exposure. The group exposed to 20 nm AgNP had the greatest number of silver positive BALF macrophages at 56 days post-exposure. While there was a significant decrease in the amount of silver in lung tissue at 56 days post-exposure compared with 1 day following exposure, at least 33% of the initial delivered dose was still present for both AgNPs. Regardless of particle size, silver was predominantly localized within the terminal bronchial/alveolar duct junction region of the lung associated with extracellular matrix and within epithelial cells. Inhalation of both 20 and 110 nm AgNPs resulted in a persistence of silver in the lung at 56 days post-exposure and local deposition as well as accumulation of silver at the terminal bronchiole alveolar duct junction. Further the smaller particles, 20 nm AgNP, produced a greater silver burden in BALF macrophages as well as greater persistence of silver positive macrophages at later timepoints (21 and 56 days). PMID:25577195

  16. Mucociliary clearance defects in a murine in vitro model of pneumococcal airway infection.

    PubMed

    Fliegauf, Manfred; Sonnen, Andreas F-P; Kremer, Bernhard; Henneke, Philipp

    2013-01-01

    Mucociliary airway clearance is an innate defense mechanism that protects the lung from harmful effects of inhaled pathogens. In order to escape mechanical clearance, airway pathogens including Streptococcus pneumoniae (pneumococcus) are thought to inactivate mucociliary clearance by mechanisms such as slowing of ciliary beating and lytic damage of epithelial cells. Pore-forming toxins like pneumolysin, may be instrumental in these processes. In a murine in vitro airway infection model using tracheal epithelial cells grown in air-liquid interface cultures, we investigated the functional consequences on the ciliated respiratory epithelium when the first contact with pneumococci is established. High-speed video microscopy and live-cell imaging showed that the apical infection with both wildtype and pneumolysin-deficient pneumococci caused insufficient fluid flow along the epithelial surface and loss of efficient clearance, whereas ciliary beat frequency remained within the normal range. Three-dimensional confocal microscopy demonstrated that pneumococci caused specific morphologic aberrations of two key elements in the F-actin cytoskeleton: the junctional F-actin at the apical cortex of the lateral cell borders and the apical F-actin, localized within the planes of the apical cell sides at the ciliary bases. The lesions affected the columnar shape of the polarized respiratory epithelial cells. In addition, the planar architecture of the entire ciliated respiratory epithelium was irregularly distorted. Our observations indicate that the mechanical supports essential for both effective cilia strokes and stability of the epithelial barrier were weakened. We provide a new model, where--in pneumococcal infection--persistent ciliary beating generates turbulent fluid flow at non-planar distorted epithelial surface areas, which enables pneumococci to resist mechanical cilia-mediated clearance. PMID:23527286

  17. Influences of parameter uncertainties within the ICRP-66 respiratory tract model: particle clearance.

    PubMed

    Bolch, Wesley E; Huston, Thomas E; Farfán, Eduardo B; Vernetson, William G; Bolch, W Emmett

    2003-04-01

    Quantifying radiological risk following the inhalation of radioactive aerosols entails not only an assessment of particle deposition within respiratory tract regions but a full accounting of clearance mechanisms whereby particles may be translocated to adjacent respiratory tissue regions, absorbed to blood, or released to the gastrointestinal tract. The model outlined in ICRP Publication 66 represents to date one of the most complete overall descriptions of particle deposition and clearance, as well as localized radiation dosimetry, within the respiratory tract. In this study, a previous review of the ICRP-66 deposition model is extended to the study of the subsequent clearance model. A systematic review of the clearance component within the ICRP 66 respiratory tract model was conducted in which probability density functions were assigned to all input parameters for both 239PuO2 and 238UO2/238U3O8. These distributions were subsequently incorporated within a computer code LUDUC (Lung Dose Uncertainty Code) in which Latin hypercube sampling techniques are used to generate multiple (e.g., 1,000) sets of input vectors (i.e., trials) for all model parameters needed to assess mechanical clearance and particle dissolution/absorption. Integral numbers of nuclear disintegrations, U(s), in various lung regions were shown to be well-described by lognormal probability distributions. Of the four extrathoracic clearance compartments of the respiratory tract, uncertainties in U(s), expressed as the ratio of its 95% to 5% confidence levels, were highest within the LN(ET) tissues for 239PuO2 (ratio of 50 to 130) and within the ET(seq) tissues for 238UO2/238U3O8 (ratio of 12 to 50). Peak uncertainties in U(s) in these respiratory regions occurred at particle sizes of approximately 0.5-0.6 microm where uncertainties in ET2 particle deposition fractions accounted for only approximately 10% of the total U(s) uncertainty for 239PuO2, and only approximately 30% of the total U

  18. Rate-Based Model Predictive Control of Turbofan Engine Clearance

    NASA Technical Reports Server (NTRS)

    DeCastro, Jonathan A.

    2006-01-01

    An innovative model predictive control strategy is developed for control of nonlinear aircraft propulsion systems and sub-systems. At the heart of the controller is a rate-based linear parameter-varying model that propagates the state derivatives across the prediction horizon, extending prediction fidelity to transient regimes where conventional models begin to lose validity. The new control law is applied to a demanding active clearance control application, where the objectives are to tightly regulate blade tip clearances and also anticipate and avoid detrimental blade-shroud rub occurrences by optimally maintaining a predefined minimum clearance. Simulation results verify that the rate-based controller is capable of satisfying the objectives during realistic flight scenarios where both a conventional Jacobian-based model predictive control law and an unconstrained linear-quadratic optimal controller are incapable of doing so. The controller is evaluated using a variety of different actuators, illustrating the efficacy and versatility of the control approach. It is concluded that the new strategy has promise for this and other nonlinear aerospace applications that place high importance on the attainment of control objectives during transient regimes.

  19. Antagonism of miR-328 Increases the Antimicrobial Function of Macrophages and Neutrophils and Rapid Clearance of Non-typeable Haemophilus Influenzae (NTHi) from Infected Lung

    PubMed Central

    Tay, Hock L.; Kaiko, Gerard E.; Plank, Maximilian; Li, JingJing; Maltby, Steven; Essilfie, Ama-Tawiah; Jarnicki, Andrew; Yang, Ming; Mattes, Joerg; Hansbro, Philip M.; Foster, Paul S.

    2015-01-01

    Pathogenic bacterial infections of the lung are life threatening and underpin chronic lung diseases. Current treatments are often ineffective potentially due to increasing antibiotic resistance and impairment of innate immunity by disease processes and steroid therapy. Manipulation miRNA directly regulating anti-microbial machinery of the innate immune system may boost host defence responses. Here we demonstrate that miR-328 is a key element of the host response to pulmonary infection with non-typeable haemophilus influenzae and pharmacological inhibition in mouse and human macrophages augments phagocytosis, the production of reactive oxygen species, and microbicidal activity. Moreover, inhibition of miR-328 in respiratory models of infection, steroid-induced immunosuppression, and smoke-induced emphysema enhances bacterial clearance. Thus, miRNA pathways can be targeted in the lung to enhance host defence against a clinically relevant microbial infection and offer a potential new anti-microbial approach for the treatment of respiratory diseases. PMID:25894560

  20. In vitro dissolution of strontium titanate to estimate clearance rates in human lungs

    NASA Astrophysics Data System (ADS)

    Anderson, Jeri Lynn

    At the In-Tank Precipitation facility (ITP) of the Savannah River Site, strontium and other radionuclides are removed from high-level radioactive waste and sent to the Defense Waste Processing Facility (DWPF). Strontium removal is accomplished by ion-exchange using monosodium titanate slurry which creates a form of strontium titanate with unknown solubility characteristics. In the case of accidental inhalation of a compound containing radioactive strontium, the ICRP, in Publication 66, recommends using default values for rates of absorption into body fluids at the lungs in the absence of reliable human or animal data. The default value depends on whether the absorption is considered to be fast, moderate, or slow (Type F, M, or S). Current dose assessment for an individual upon inadvertent exposure to airborne radioactive strontium assumes that all strontium compounds are Type F (soluble) or Type S (insoluble). Pure high-fired strontium titanate (SrTiOsb3) is considered Type S. The purpose of this project was to determine the solubility of strontium titanate in the form created at the ITP facility. An in vitro dissolution study was done with a precipitate simulant and with several types of strontium titanate and the results were compared. An in vivo study was also performed with high-fired SrTiOsb3 in rats. The data from both studies were used independently to assign the compounds to absorption type based on criteria specified in ICRP 71. Results of the in vitro studies showed that the DWPF simulant should be assigned to Type M and the strontium titanate should be assigned to Type S. It is possible the difference in the DWPF simulant is due to the other chemicals present. Results of the in vivo study verified that SrTiOsb3 should be assigned to Type S. Lung clearance data of SrTiOsb3 from rats showed that 85% cleared within the first 24 hours and the remaining 15% with a half-time of 130 days. The initial rapid clearance is attributed to deposition in airways as

  1. Lung clearance index in cystic fibrosis subjects treated for pulmonary exacerbations.

    PubMed

    Sonneveld, Nicole; Stanojevic, Sanja; Amin, Reshma; Aurora, Paul; Davies, Jane; Elborn, J Stuart; Horsley, Alex; Latzin, Philipp; O'Neill, Katherine; Robinson, Paul; Scrase, Emma; Selvadurai, Hiran; Subbarao, Padmaja; Welsh, Liam; Yammine, Sophie; Ratjen, Felix

    2015-10-01

    Pulmonary exacerbations are important clinical events for cystic fibrosis (CF) patients. Studies assessing the ability of the lung clearance index (LCI) to detect treatment response for pulmonary exacerbations have yielded heterogeneous results. Here, we conduct a retrospective analysis of pooled LCI data to assess treatment with intravenous antibiotics for pulmonary exacerbations and to understand factors explaining the heterogeneous response.A systematic literature search was performed to identify prospective observational studies. Factors predicting the relative change in LCI and spirometry were evaluated while adjusting for within-study clustering.Six previously reported studies and one unpublished study, which included 176 pulmonary exacerbations in both paediatric and adult patients, were included. Overall, LCI significantly decreased by 0.40 units (95% CI -0.60- -0.19, p=0.004) or 2.5% following treatment. The relative change in LCI was significantly correlated with the relative change in forced expiratory volume in 1 s (FEV1), but results were discordant in 42.5% of subjects (80 out of 188). Higher (worse) baseline LCI was associated with a greater improvement in LCI (slope: -0.9%, 95% CI -1.0- -0.4%).LCI response to therapy for pulmonary exacerbations is heterogeneous in CF patients; the overall effect size is small and results are often discordant with FEV1. PMID:26160868

  2. Influence of respiratory dead space on lung clearance index in preterm infants.

    PubMed

    Neumann, Roland P; Pillow, J Jane; Thamrin, Cindy; Frey, Urs; Schulzke, Sven M

    2016-03-01

    Lung clearance index (LCI), a marker of ventilation inhomogeneity derived from multiple breath washout (MBW), is used for clinical monitoring and as a key outcome of clinical trials in infants and children with cystic fibrosis. Utility of LCI is controversial in preterm infants with bronchopulmonary dysplasia (BPD) who tend to have high dead space to tidal volume ratio (VD/VT). We investigated the effect of VD/VT on LCI in a cohort of preterm infants with and without BPD and term healthy controls. We analyzed MBW data from 455 infants at a mean (SD) of 43.4 (3.5) w postmenstrual age. VD was estimated from the molar mass signal of an ultrasonic flowmeter (VD,MM). LCI was associated with VD,MM/VT (r(2)=0.13, p<0.001) but was not associated with BPD. Adjusting for VD,MM/VT did not reveal an association between LCI and BPD. We conclude that VD,MM/VT is a relevant factor when interpreting LCI in this population but the effect size of this association is moderate. PMID:26742626

  3. Pharmacotherapy of impaired mucociliary clearance in non-CF pediatric lung disease. A review of the literature.

    PubMed

    Boogaard, Ruben; de Jongste, Johan C; Merkus, Peter J F M

    2007-11-01

    Mucoactive agents are used to treat a variety of lung diseases involving impaired mucociliary clearance or mucus hypersecretion. The mucoactive agents studied most frequently are N-acetylcysteine (NAC), recombinant human DNase (rhDNase), and hypertonic saline. Studies on the efficacy of these have been mainly conducted in adults, and in patients with cystic fibrosis (CF). The exact role of mucoactive agents in children with non-CF lung disease is not well established. We present an overview of the current literature reporting clinical outcome measures of treatment with NAC, rhDNase, and hypertonic saline in children. PMID:17902149

  4. Pulmonary response to impaired lung clearance in rats following excessive TiO/sub 2/ dust deposition

    SciTech Connect

    Lee, K.P.; Henry, N.W. III; Trochimowicz, H.J.; Reinhardt, C.F.

    1986-10-01

    Rats were exposed to TiO/sub 2/ by the inhalation route at concentrations of 0, 10, 50, or 250 mg/m/sup 3/ for 6 hr/day, 5 days/week for 2 years. Lung weights of rats at 10 mg/m/sup 2/ were within normal limits after 2 years exposure. Lung weights increased significantly after 6 months at 50 mg/m/sup 3/ and after 3 months at 250 mg/m/sup 3/. After 2 years exposure, TiO/sub 2/ retention in dried lung was 3.1% at 10 mg/m/sup 3/, 16.9% at 50 mg/m/sup 3/, 28% at 250 mg/m/sup 3/. Lung clearance mechanisms appeared to be overloaded at 250 mg/m/sup 3/. Dust particles were retained in the lung in a dose-related fashion, but there was no significant difference in lung clearance rate between 10 and 50 mg/m/sup 3/. Lung response at 10 mg/m/sup 3/ satisfied the biological criteria for a nuisance dust, while adverse effects resulting from gradually accumulated particles (8.1%, 67.7 mg per lung) were found after 1 year of exposure to 50 mg/m/sup 3/. Cholesterol granulomas were developed with degenerative foamy dust cells at 50 and 250 mg/m/sup 3/ after 1 year or exposure. After 2 years exposure at 250 mg/m/sup 3/, bronchioloalveolar adenomas occurred in the alveoli showing type II pneumocyte hyperplasia, while cystic keratinizing squamous carcinomas were developed from squamous metaplasia of alveoli showing bronchiolarization in the alveolar duct region.

  5. Long-term improvement of lung clearance index in patients with mild cystic fibrosis lung disease: Does hypertonic saline play a role?

    PubMed

    Ellemunter, Helmut; Eder, Johannes; Fuchs, Susanne; Gappa, Monika; Steinkamp, Gratiana

    2016-01-01

    To assess whether long-term inhalation with hypertonic saline is able to halt the progression of mild CF lung disease, we analysed longitudinal data of lung clearance index (LCI) and spirometry. A total of 34 patients with mild lung disease (FEV1 ≥ 70% of predicted) had at least one LCI result before and ≥2 LCI measurements after start of hypertonic saline (HS) therapy. After a mean follow-up of 39.7 (SD 7.4) months after starting HS, LCI improved significantly from 7.89 (SD 1.35) at baseline to 6.96 (SD 1.03), and 19/34 patients had a normal LCI value at the last measurement. No decrease in mean FEV1 was observed. Thus, ventilation inhomogeneity can improve in patients with mild lung disease. PMID:26190829

  6. Imaging Lung Clearance of Radiolabeled Tumor Cells to Study Mice with Normal, Activated or Depleted Natural Killer (NK) Cells

    SciTech Connect

    Kulkarni, P.V.; Bennett, M.; Constantinescu, A.; Arora, V.; Viguet, M.; Antich, P.; Parkey, R.W.; Mathews, D.; Mason, R.P.; Oz, O.K.

    2003-08-26

    Lung clearance of 51CR and 125I iododeoxyuridine (IUDR) labeled cancer cells assess NK cell activity. It is desirable to develop noninvasive imaging technique to assess NK activity in mice. We labeled target YAC-1 tumor cells with 125I, 111In, 99mTc, or 67Ga and injected I.V. into three groups of BALB/c mice. Animals were treated with medium (group I), 300mg/kg cyclophosmamide (CY) to kill NK cell (group II), or anti-LY49C/1) (ab')2 mAb to augment NK function (group III). Lungs were removed 15 min or 2 h later for tissue counting. Control and treated mice were imaged every 5 min with a scintillating camera for 1 h after 15 min of infusion of the 111In labeled cells. Lung clearance increased after 15 min (lodging: 60-80%) and (2 h retention: 3-7%). Similar results were obtained with all the isotopes studied. Images distinguished the control and treated mice for lung activity. Cells labeled with 111In, 99mTc or 67Ga are cleared similar to those labeled with 51Cr or 125I. NK cell destruction of tumor cells may be assessed by noninvasive imaging method either by SPECT (99mTc, 111In, 67Ga) or by PET (68Ga)

  7. Imaging Lung Clearance of Radiolabeled Tumor Cells to Study Mice with Normal, Activated or Depleted Natural Killer (NK) Cells

    NASA Astrophysics Data System (ADS)

    Kulkarni, P. V.; Bennett, M.; Constantinescu, A.; Arora, V.; Viguet, M.; Antich, P.; Parkey, R. W.; Mathews, D.; Mason, R. P.; Oz, O. K.

    2003-08-01

    Lung clearance of 51CR and 125I iododeoxyuridine (IUDR) labeled cancer cells assess NK cell activity. It is desirable to develop noninvasive imaging technique to assess NK activity in mice. We labeled target YAC-1 tumor cells with 125I, 111In, 99mTc, or 67Ga and injected I.V. into three groups of BALB/c mice. Animals were treated with medium (group I), 300mg/kg cyclophosmamide (CY) to kill NK cell (group II), or anti-LY49C/1) (ab')2 mAb to augment NK function (group III). Lungs were removed 15 min or 2 h later for tissue counting. Control and treated mice were imaged every 5 min with a scintillating camera for 1 h after 15 min of infusion of the 111In labeled cells. Lung clearance increased after 15 min (lodging: 60-80%) and (2 h retention: 3-7%). Similar results were obtained with all the isotopes studied. Images distinguished the control and treated mice for lung activity. Cells labeled with 111In, 99mTc or 67Ga are cleared similar to those labeled with 51Cr or 125I. NK cell destruction of tumor cells may be assessed by noninvasive imaging method either by SPECT (99mTc, 111In, 67Ga) or by PET (68Ga).

  8. Lung inflammation in coal miners assessed by uptake of 67Ga-citrate and clearance of inhaled 99mTc-labeled diethylenetriamine pentaacetate aerosol

    SciTech Connect

    Susskind, H.; Rom, W.N. )

    1992-07-01

    The authors compared the diffuse lung uptake of 67Ga-citrate, an index of inflammatory lung activity, with the lung clearance of inhaled 99mTc-labeled diethylenetriamine pentaacetate (DTPA) aerosol, an index of pulmonary epithelial permeability, in a group of 19 West Virginia coal miners whose pulmonary status was compatible with coal worker's pneumoconiosis. 99mTc-DTPA clearance alone and 67Ga-citrate uptake alone were measured in nine and five additional subjects, respectively. The objective of this study was to determine if increased 99mTc-DTPA lung clearance was caused by inflammation at the lung epithelial surfaces. Subjects inhaled approximately 150 microCi (approximately 5.6 MBq) of 99mTc-DTPA aerosol, and quantitative gamma camera images of the lungs were acquired at 1-min increments for 25 min. Regions of interest (ROI) were selected to include (1) both lungs; (2) each individual lung; and (3) the upper, middle, and lower thirds of each lung. 99mTc-DTPA clearance was determined from the slopes of the respective time-activity plots for the different ROI. Each subject was intravenously administered 50 miCroCk (1.9 MBq)/kg 67Ga-citrate 48 to 72 h before imaging the body between neck and pelvis. The extent of 67Ga-citrate lung uptake was expressed as the gallium index (GI). Mean radioaerosol clearance half-time (T1/2) for the six nonsmoking coal miners (60.6 +/- 16.0 min) was significantly shorter (p less than 0.001) than for the nonsmoking control group (123.8 +/- 28.7 min). T1/2 for the 12 smoking miners (18.4 +/- 10.2 min) was shorter than for the smoking control group (33.1 +/- 17.8 min), but the difference did not attain statistical significance.

  9. Clearance of bile and trypsin in rat lungs following aspiration of human gastric fluid

    PubMed Central

    Leung, Jason H.; Chang, Jui-Chih; Foltz, Emily; Bell, Sadé M.; Pi, Cinthia; Azad, Sassan; Everett, Mary Lou; Holzknecht, Zoie E.; Sanders, Nathan L.; Parker, William; Davis, R. Duane; Keshavjee, Shaf; Lin, Shu S.

    2016-01-01

    ABSTRACT Purpose: In the clinical setting, there is no reliable tool for diagnosing gastric aspiration. A potential way of diagnosing gastric fluid aspiration entails bronchoalveolar lavage (BAL) with subsequent examination of the BAL fluid for gastric fluid components that are exogenous to the lungs. The objective of this study was to determine the longevity of the gastric fluid components bile and trypsin in the lung, in order to provide an estimate of the time frame in which assessment of these components in the BAL might effectively be used as a measure of aspiration. Materials and Methods: Human gastric fluid (0.5 mg/kg) was infused in the right lung of intubated male Fischer 344 rats (n = 30). Animals were sacrificed at specified times following the experimentally induced aspiration, and bronchoalveolar lavage fluid (BALF) was collected. Bile concentrations were analyzed by an enzyme-linked chromatogenic method, and the concentration of trypsin was quantified using an ELISA. Data were analyzed using non-linear regression and a one-phase decay equation. Results: In this experimental model, the half-life of bile was 9.3 hours (r 2 = 0.81), and the half-life of trypsin was 9.0 hours (r 2 = 0.68). Conclusions: The half-lives of bile and trypsin in the rodent aspiration model suggest that the ability to detect aspiration may be limited to a few days post-aspiration. If studies using rats are any indication, it may be most effective to collect BAL samples within the first 24 hours of suspected aspiration events in order to detect aspiration. PMID:26873328

  10. An Evaluation of the Venous Equilibrium Model for Hepatic Clearance using Isolated Perfused Rainbow Trout Livers

    EPA Science Inventory

    The venous equilibrium model is widely used to describe hepatic clearance (CLH) of chemicals metabolized by the liver. If chemical delivery to the tissue does not limit CLH, this model predicts that CLH will approximately equal the product of intrinsic metabolic clearance and a t...

  11. A Reduced Model for Prediction of Thermal and Rotational Effects on Turbine Tip Clearance

    NASA Technical Reports Server (NTRS)

    Kypuros, Javier A.; Melcher, Kevin J.

    2003-01-01

    This paper describes a dynamic model that was developed to predict changes in turbine tip clearance the radial distance between the end of a turbine blade and the abradable tip seal. The clearance is estimated by using a first principles approach to model the thermal and mechanical effects of engine operating conditions on the turbine sub-components. These effects are summed to determine the resulting clearance. The model is demonstrated via a ground idle to maximum power transient and a lapse-rate takeoff transient. Results show the model demonstrates the expected pinch point behavior. The paper concludes by identifying knowledge gaps and suggesting additional research to improve the model.

  12. Comparison of early lung clearance of yellowcake aerosols in rats with in vitro dissolution and IR analysis.

    PubMed

    Damon, E G; Eidson, A F; Hahn, F F; Griffith, W C; Guilmette, R A

    1984-04-01

    The lung retention of uranium was determined in rats that inhaled aerosols of commercial yellowcake powders obtained from two mills (Mill A and Mill D) and whose chemical composition and solubilities in vitro were significantly different. Analysis by IR absorption indicated Mill A yellowcake contained 82% ammonium diuranate (ADU) and 18% U3O8. The Mill D powder contained 25% ADU and 75% U3O8. In vitro dissolution studies indicated for the Mill A sample, approximately 85% of the uranium had a dissolution half-time (T 1/2) of less than one day, with the remainder dissolving with a half-time of 500 days. For the Mill D sample, 25% had T 1/2 less than one day and 75% had T 1/2 of 300 days. Groups of 50 rats were exposed by nose-only inhalation to aerosols of either the Mill A or the Mill D yellowcake. Rats were sacrificed in groups of five at intervals through six months after exposure. Selected tissues and excreta samples were assayed by fluorometry to determine their uranium contents. For the Mill A yellowcake, 78% initial lung (broncho-alveolar) burden cleared with T 1/2 of 0.5 days, and 22% with T 1/2 of 240 days. For the Mill D yellowcake, 25% initial lung burden cleared with T 1/2 of 3.5 days and 75% with T 1/2 of 110 days. Thus, the lung clearance of uranium in the rat mimicked the in vitro dissolution data and supported the contention that ADU should be considered as a Class D compound (T 1/2 = 0.5 days) and U3O8 behaves in the lung as a Class Y (T 1/2 greater than 100 days) material. PMID:6706593

  13. A2B adenosine receptor signaling attenuates acute lung injury by enhancing alveolar fluid clearance in mice.

    PubMed

    Eckle, Tobias; Grenz, Almut; Laucher, Stefanie; Eltzschig, Holger K

    2008-10-01

    Although acute lung injury contributes significantly to critical illness, resolution often occurs spontaneously via activation of incompletely understood pathways. We recently found that mechanical ventilation of mice increases the level of pulmonary adenosine, and that mice deficient for extracellular adenosine generation show increased pulmonary edema and inflammation after ventilator-induced lung injury (VILI). Here, we profiled the response to VILI in mice with genetic deletions of each of the 4 adenosine receptors (ARs) and found that deletion of the A2BAR gene was specifically associated with reduced survival time and increased pulmonary albumin leakage after injury. In WT mice, treatment with an A2BAR-selective antagonist resulted in enhanced pulmonary inflammation, edema, and attenuated gas exchange, while an A2BAR agonist attenuated VILI. In bone marrow-chimeric A2BAR mice, although the pulmonary inflammatory response involved A2BAR signaling from bone marrow-derived cells, A2BARs located on the lung tissue attenuated VILI-induced albumin leakage and pulmonary edema. Furthermore, measurement of alveolar fluid clearance (AFC) demonstrated that A2BAR signaling enhanced amiloride-sensitive fluid transport and elevation of pulmonary cAMP levels following VILI, suggesting that A2BAR agonist treatment protects by drying out the lungs. Similar enhancement of pulmonary cAMP and AFC were also observed after beta-adrenergic stimulation, a pathway known to promote AFC. Taken together, these studies reveal a role for A2BAR signaling in attenuating VILI and implicate this receptor as a potential therapeutic target during acute lung injury. PMID:18787641

  14. Expression of Suppressor of Cytokine Signaling 1 (SOCS1) Impairs Viral Clearance and Exacerbates Lung Injury during Influenza Infection

    PubMed Central

    Sun, Keer; Salmon, Sharon; Yajjala, Vijaya Kumar; Bauer, Christopher; Metzger, Dennis W.

    2014-01-01

    Suppressor of cytokine signaling (SOCS) proteins are inducible feedback inhibitors of cytokine signaling. SOCS1−/− mice die within three weeks postnatally due to IFN-γ-induced hyperinflammation. Since it is well established that IFN-γ is dispensable for protection against influenza infection, we generated SOCS1−/−IFN-γ−/− mice to determine whether SOCS1 regulates antiviral immunity in vivo. Here we show that SOCS1−/−IFN-γ−/− mice exhibited significantly enhanced resistance to influenza infection, as evidenced by improved viral clearance, attenuated acute lung damage, and consequently increased survival rates compared to either IFN-γ−/− or WT animals. Enhanced viral clearance in SOCS1−/−IFN-γ−/− mice coincided with a rapid onset of adaptive immune responses during acute infection, while their reduced lung injury was associated with decreased inflammatory cell infiltration at the resolution phase of infection. We further determined the contribution of SOCS1-deficient T cells to antiviral immunity. Anti-CD4 antibody treatment of SOCS1−/−IFN-γ−/− mice had no significant effect on their enhanced resistance to influenza infection, while CD8+ splenocytes from SOCS1−/−IFN-γ−/− mice were sufficient to rescue RAG1−/− animals from an otherwise lethal infection. Surprisingly, despite their markedly reduced viral burdens, RAG1−/− mice reconstituted with SOCS1−/−IFN-γ−/− adaptive immune cells failed to ameliorate influenza-induced lung injury. In conclusion, in the absence of IFN-γ, the cytoplasmic protein SOCS1 not only inhibits adaptive antiviral immune responses but also exacerbates inflammatory lung damage. Importantly, these detrimental effects of SOCS1 are conveyed through discrete cell populations. Specifically, while SOCS1 expression in adaptive immune cells is sufficient to inhibit antiviral immunity, SOCS1 in innate/stromal cells is responsible for aggravated lung injury. PMID:25500584

  15. siRNA delivery targeting to the lung via agglutination-induced accumulation and clearance of cationic tetraamino fullerene

    NASA Astrophysics Data System (ADS)

    Minami, Kosuke; Okamoto, Koji; Doi, Kent; Harano, Koji; Noiri, Eisei; Nakamura, Eiichi

    2014-05-01

    The efficient treatment of lung diseases requires lung-selective delivery of agents to the lung. However, lung-selective delivery is difficult because the accumulation of micrometer-sized carriers in the lung often induces inflammation and embolization-related toxicity. Here we demonstrate a lung-selective delivery system of small interfering RNA (siRNA) by controlling the size of carrier vehicle in blood vessels. The carrier is made of tetra(piperazino)fullerene epoxide (TPFE), a water-soluble cationic tetraamino fullerene. TPFE and siRNA form sub-micrometer-sized complexes in buffered solution and these complexes agglutinate further with plasma proteins in the bloodstream to form micrometer-sized particles. The agglutinate rapidly clogs the lung capillaries, releases the siRNA into lung cells to silence expression of target genes, and is then cleared rapidly from the lung after siRNA delivery. We applied our delivery system to an animal model of sepsis, indicating the potential of TPFE-based siRNA delivery for clinical applications.

  16. Model-based lamotrigine clearance changes during pregnancy: clinical implication

    PubMed Central

    Polepally, Akshanth R; Pennell, Page B; Brundage, Richard C; Stowe, Zachary N; Newport, Donald J; Viguera, Adele C; Ritchie, James C; Birnbaum, Angela K

    2014-01-01

    Objective The objective of the study was to characterize changes in the oral clearance (CL/F) of lamotrigine (LTG) over the course of pregnancy and the postpartum period through a model-based approach incorporating clinical characteristics that may influence CL/F, in support of developing clinical management guidelines. Methods Women receiving LTG therapy who were pregnant or planning pregnancy were enrolled. Maternal blood samples were collected at each visit. A pharmacokinetic analysis was performed using a population-based, nonlinear, mixed-effects model. Results A total of 600 LTG concentrations from 60 women (64 pregnancies) were included. The baseline LTG CL/F was 2.16 L/h with a between-subject variability of 40.6%. The influence of pregnancy on CL/F was described by gestational week. Two subpopulations of women emerged based on the rate of increase in LTG CL/F during pregnancy. The gestational age-associated increase in CL/F displayed a 10-fold higher rate in 77% of the women (0.118 L/h per week) compared to 23% (0.0115 L/h per week). The between-subject variability in these slopes was 43.0%. The increased CL/F at delivery declined to baseline values with a half-life of 0.55 weeks. Interpretation The majority of women had a substantial increase in CL/F from 2.16 to 6.88 L/h by the end of pregnancy, whereas 23% of women had a minimal increase. An increase in CL/F may correspond to decreases in LTG blood concentrations necessitating the need for more frequent dosage adjustments and closer monitoring in some pregnant women with epilepsy. Postpartum doses should be tapered to preconception dose ranges within 3 weeks of delivery. PMID:24883336

  17. Enhanced respiratory clearance of nontypeable Haemophilus influenzae following mucosal immunization with P6 in a rat model.

    PubMed

    Kyd, J M; Dunkley, M L; Cripps, A W

    1995-08-01

    Nontypeable Haemophilus influenzae (NTHi) is a common cause of infection of the respiratory tract in children and adults. The search for an effective vaccine against this pathogen has focused on components of the outer membrane, and peptidoglycan-associated lipoprotein P6 is among the proposed candidates. This study investigated the immunogenicity of P6 in a rat respiratory model. P6 was purified from two strains of NTHi, one capsule-deficient strain and an H. influenzae type b strain, and assessed for clearance of both homologous and heterologous bacterial strains following mucosal immunization. A protective immune response was determined by enhancement of pulmonary clearance of live bacteria and an increased rate of recruitment of phagocytic cells to the lungs. This was most effective when Peyer's patch immunization was accompanied by an intratracheal (IT) boost. However, the rate of bacterial clearance varied between strains, which suggests some differences in anti-P6 immunological defenses recognizing the expression of the highly conserved P6 lipoprotein on the bacterial surface in some strains. P6-specific antibodies in both serum and bronchoalveolar lavage fluid were cross-reactive and did not differ significantly in strain specificity, demonstrating that difference in clearance was unlikely due to differences in P6-specific antibody levels. Serum homologous and heterologous P6-antibody was bactericidal against NTHi even when enhanced clearance had not been observed. Peyer's patch immunization induced P6-specific CD4+ T-helper cell proliferation in lymphocytes isolated from the mesenteric lymph nodes. An IT boost increased the level of P6-specific antibodies in serum and bronchoalveolar lavage fluid, and P6-specific mesenteric node lymphocyte proliferation. Cells from rats immunized with P6 demonstrated proliferation following stimulation with P6 from nonhomologous strains; however, there was some variation in proliferative responses to P6 from different

  18. Influence of posture and positive end-tidal expiratory pressure (PEEP) on clearance of Tc99m-DTPA from the lungs

    SciTech Connect

    Mason, G.R.; Maublant, J.; Sietsema, K.; Effros, R.M.; Mena, I.

    1984-01-01

    The clearance of Tc99m-DTPA aerosols from the lung has been used to detect and quantitate alterations in the permeability of the pulmonary epithelium. Clearance of the radionuclide is accelerated by both chronic and acute injuries to the lung and by smoking. Several laboratories have reported that Tc99m-DTPA clearance from upper lobes exceeded that from lower lobes in upright subjects. To investigate this phenomenon further the authors studied subjects with simultaneous anterior and posterior cameras in upright and supine positions. In the upright position, clearance from both the anterior and posterior upper regions of interest (ROI's) exceeded the lower regions (-1.64 +- .42 S.D. vs. -0.75 +- .41, anterior, p < .05, n=6), -1.04 +- .23 vs. -0.50 +- .36, posterior. All units = %/min. This difference was not observed in the supine subjects. Clearance from the anterior chest exceeded that from the posterior chest in the supine subjects (-1.28 +- .45 vs. -0.05 +- 1.08) and a small increase in radio-activity was observed in at least one ROI of 5 of 6 subjects from the posterior camera. An increase in activity is likely to be secondary to labeling of blood pool, which would have greatest affect where pulmonary blood volume is largest. Computer processing of the entire lung without observer bias in ROI placement showed similar effects of posture over non-peripheral ROI's. Five subjects breathed on PEEP to cause airspace distention, causing clearance to double. Both dependency and airspace distention appear to influence clearance of aerosolized DTPA, the latter may occur by stretching of epithelial pores.

  19. Mathematical modeling of clearance between wall of coke oven and coke cake

    SciTech Connect

    Nushiro, K.; Matsui, T.; Hanaoka, K.; Igawa, K.; Sorimachi, K.

    1995-12-01

    A mathematical model was developed for estimating the clearance between the wall of the coke oven and the coke cake. The prediction model is based on the balance between the contractile force and the coking pressure. A clearance forms when the contractile force exceeds the coking pressure in this model. The contractile force is calculated in consideration of the visco-elastic behavior of the thermal shrinkage of the coke. The coking pressure is calculated considering the generation and dispersion of gas in the melting layer. The relaxation time off coke used in this model was obtained with a dilatometer under the load application. The clearance was measured by the laser sensor, and the internal gas pressure was measured in a test oven. The clearance calculated during the coking process were in good agreement with the experimental results, which supported the validity of the mathematical model.

  20. 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.

  1. Establishment and use of surgical rat models for assessment of organ specific in vivo clearance.

    PubMed

    Vestergaard, Bill

    2016-06-01

    Knowledge of clearance plays a key role in the development of new drug entities, especially in the development of improved analogues for treatment of chronic conditions. Improved pharmacokinetic properties can be used to increase dosing interval and thereby improve patient compliance. This will lead to improved treatment outcome or decreased risk of treatment failure when treating chronic conditions. Therefore, animal models for assessment of organ-specific clearance are of great value in preclinical drug development. These models can be used to obtain insights into the relative importance of a clearance organ and thereby guide drug design of new analogues in early drug discovery. The current PhD project was undertaken to explore surgical in vivo models, which could be used in the assessment of the relative importance of major clearance organs. It was the aim of the PhD project to establish and validate both a nephrectomy model and a hepatectomy model as tools to investigate relative importance of renal and hepatic clearance. Furthermore, the project aim was to investigate renal clearance of rFVIIa and rhGH using a nephrectomy model in rats. The thesis is composed of a short theoretical background, a literature review, two papers based on experimental work as well as experimental work not included in the papers. Chapter one is an introduction with the specific aims and hypotheses. The chapters from two to five contain theoretical background of the clearance concept, anatomical and physiological description of clearance organs and a brief overview of potential clearance models including in vivo models. Chapters six through nine highlight the experimental work with the results obtained during the PhD project. Lastly, the chapters from ten to twelve contain a general discussion, conclusion and perspectives of the current thesis. Paper I "Nephrectomized and hepatectomized animal models as tools in preclinical pharmacokinetics" provides a literature review of animal

  2. Modelling of Outer and Inner Film Oil Pressure for Floating Ring Bearing Clearance in Turbochargers

    NASA Astrophysics Data System (ADS)

    Zhang, Hao; Shi, Zhanqun; Gu, Fengshou; Ball, Andrew

    2011-07-01

    Floating ring bearing is widely used in turbochargers to undertake the extreme condition of high rotating speed and high operating temperature. It is also the most concerned by the designers and users alike due to its high failure rate and high maintenance cost. Any little clearance change may result in oil leakage, which in turn cause blue smoke or black smoke according to leakage types. However, there is no condition monitoring of this bearing because it is almost impossible to measure the clearance especially the inner clearance, in which the inner oil film directly bears the high speed rotation. In stead of measuring clearance directly, this paper has proposed a method that uses film pressure as a measure to monitor the bearing clearance and its variation. A non-linear mathematical model is developed by using Reynolds equations with non-linear oil film pressure. A full description of the outer and inner film is provided along both axial and radial directions. A numerical simulation is immediately carried out. Variable clearance changes are investigated using the mathematical model. Results show the relationship between clearance and film pressure.

  3. GERMINATION, VIABILITY AND CLEARANCE OF STACHYBOTRYS CHARTARUM IN THE LUNGS OF INFANT RATS

    EPA Science Inventory

    The fungus Stachybotrys chartarum has been associated with many adverse health effects including the condition known as idiopathic pulmonary hemorrhage in infants. In order to gain some insight into possible mechanisms, viable conidia of S. chartarum were instilled into the lung...

  4. Mouse models for lung cancer.

    PubMed

    Kwon, Min-chul; Berns, Anton

    2013-04-01

    Lung cancer is a devastating disease and a major therapeutic burden with poor survival rates. It is responsible for 30% of all cancer deaths. Lung cancer is strongly associated with smoking, although some subtypes are also seen in non-smokers. Tumors in the latter group are mostly adenocarcinomas with many carrying mutations in the epidermal growth factor receptor (EGFR). Survival statistics of lung cancer are grim because of its late detection and frequent local and distal metastases. Although DNA sequence information from tumors has revealed a number of frequently occurring mutations, affecting well-known tumor suppressor genes and proto-oncogenes, many of the driver mutations remain ill defined. This is likely due to the involvement of numerous rather infrequently occurring driver mutations that are difficult to distinguish from the very large number of passenger mutations detected in smoking-related lung cancers. Therefore, experimental model systems are indispensable to validate putative driver lesions and to gain insight into their mechanisms of action. Whereas a large fraction of these analyzes can be performed in cell cultures in vitro, in many cases the consequences of the mutations have to be assessed in the context of an intact organism, as this is the context in which the Mendelian selection process of the tumorigenic process took place and the advantages of particular mutations become apparent. Current mouse models for cancer are very suitable for this as they permit mimicking many of the salient features of human tumors. The capacity to swiftly re-engineer complex sets of lesions found in human tumors in mice enables us to assess the contribution of defined combinations of lesions to distinct tumor characteristics such as metastatic behavior and response to therapy. In this review we will describe mouse models of lung cancer and how they are used to better understand the disease and how they are exploited to develop better intervention strategies

  5. Lung models: strengths and limitations.

    PubMed

    Martonen, T B; Musante, C J; Segal, R A; Schroeter, J D; Hwang, D; Dolovich, M A; Burton, R; Spencer, R M; Fleming, J S

    2000-06-01

    The most widely used particle dosimetry models are those proposed by the National Council on Radiation Protection, International Commission for Radiological Protection, and the Netherlands National Institute of Public Health and the Environment (the RIVM model). Those models have inherent problems that may be regarded as serious drawbacks: for example, they are not physiologically realistic. They ignore the presence and commensurate effects of naturally occurring structural elements of lungs (eg, cartilaginous rings, carinal ridges), which have been demonstrated to affect the motion of inhaled air. Most importantly, the surface structures have been shown to influence the trajectories of inhaled particles transported by air streams. Thus, the model presented herein by Martonen et al may be perhaps the most appropriate for human lung dosimetry. In its present form, the model's major "strengths" are that it could be used for diverse purposes in medical research and practice, including: to target the delivery of drugs for diseases of the respiratory tract (eg, cystic fibrosis, asthma, bronchogenic carcinoma); to selectively deposit drugs for systemic distribution (eg, insulin); to design clinical studies; to interpret scintigraphy data from human subject exposures; to determine laboratory conditions for animal testing (ie, extrapolation modeling); and to aid in aerosolized drug delivery to children (pediatric medicine). Based on our research, we have found very good agreement between the predictions of our model and the experimental data of Heyder et al, and therefore advocate its use in the clinical arena. In closing, we would note that for the simulations reported herein the data entered into our computer program were the actual conditions of the Heyder et al experiments. However, the deposition model is more versatile and can simulate many aerosol therapy scenarios. For example, the core model has many computer subroutines that can be enlisted to simulate the

  6. Dissolution and clearance of titanium tritide particles in the lungs of F344/Crl rats

    SciTech Connect

    Cheng, Yung-Sung; Snipes, M.B.; Wang, Yansheng

    1995-12-01

    Metal tritides are compounds in which the radioactive isotope tritium, following adsorption onto the metal, forms a stable chemical compound with the metal. When particles of tritiated metals become airborne, they can be inhaled by workers. Because the particles may be retained in the lung for extended periods, the resulting dose will be greater than doses following exposure to tritium gas or tritium oxide (HTO). Particles of triated metals may be dispersed into the air during routine handling, disruption of contaminated metals, or as a result of spontaneous radioactive decay processes. Unlike metal hydrides and deuterides, tritides are radioactive, and the decay of the tritium atoms affects the metal. Because helium is a product of the decay, helium bubbles form within the metal tritide matrix. The pressure from these bubbles leads to respirable particles breaking off from the tritide surface. Our results show that a substantial amount of titanium tritide remains in the rat lung 10 d after intratracheal instillation, confirming results previously obtain in an in vitro dissolution study.

  7. Inhibition of Lung Fluid Clearance and Epithelial Na+ Channels by Chlorine, Hypochlorous Acid, and Chloramines*

    PubMed Central

    Song, Weifeng; Wei, Shipeng; Zhou, Yongjian; Lazrak, Ahmed; Liu, Gang; Londino, James D.; Squadrito, Giuseppe L.; Matalon, Sadis

    2010-01-01

    We investigated the mechanisms by which chlorine (Cl2) and its reactive byproducts inhibit Na+-dependent alveolar fluid clearance (AFC) in vivo and the activity of amiloride-sensitive epithelial Na+ channels (ENaC) by measuring AFC in mice exposed to Cl2 (0–500 ppm for 30 min) and Na+ and amiloride-sensitive currents (INa and Iamil, respectively) across Xenopus oocytes expressing human α-, β-, and γ-ENaC incubated with HOCl (1–2000 μm). Both Cl2 and HOCl-derived products decreased AFC in mice and whole cell and single channel INa in a dose-dependent manner; these effects were counteracted by serine proteases. Mass spectrometry analysis of the oocyte recording medium identified organic chloramines formed by the interaction of HOCl with HEPES (used as an extracellular buffer). In addition, chloramines formed by the interaction of HOCl with taurine or glycine decreased INa in a similar fashion. Preincubation of oocytes with serine proteases prevented the decrease of INa by HOCl, whereas perfusion of oocytes with a synthetic 51-mer peptide corresponding to the putative furin and plasmin cleaving segment in the γ-ENaC subunit restored the ability of HOCl to inhibit INa. Finally, INa of oocytes expressing wild type α- and γ-ENaC and a mutant form of βENaC (S520K), known to result in ENaC channels locked in the open position, were not altered by HOCl. We concluded that HOCl and its reactive intermediates (such as organic chloramines) inhibit ENaC by affecting channel gating, which could be relieved by proteases cleavage. PMID:20106988

  8. Maximal mid-expiratory flow is a surrogate marker of lung clearance index for assessment of adults with bronchiectasis.

    PubMed

    Guan, Wei-Jie; Yuan, Jing-Jing; Gao, Yong-Hua; Li, Hui-Min; Zheng, Jin-Ping; Chen, Rong-Chang; Zhong, Nan-Shan

    2016-01-01

    Little is known about the comparative diagnostic value of lung clearance index (LCI) and maximal mid-expiratory flow (MMEF) in bronchiectasis. We compared the diagnostic performance, correlation and concordance with clinical variables, and changes of LCI and MMEF% predicted during bronchiectasis exacerbations (BEs). Patients with stable bronchiectasis underwent history inquiry, chest high-resolution computed tomography (HRCT), multiple-breath nitrogen wash-out test, spirometry and sputum culture. Patients who experienced BEs underwent these measurements during onset of BEs and 1 week following antibiotics therapy. Sensitivity analyses were performed in mild, moderate and severe bronchiectasis. We recruited 110 bronchiectasis patients between March 2014 and September 2015. LCI demonstrated similar diagnostic value with MMEF% predicted in discriminating moderate-to-severe from mild bronchiectasis. LCI negatively correlated with MMEF% predicted. Both parameters had similar concordance in reflecting clinical characteristics of bronchiectasis and correlated significantly with forced expiratory flow in one second, age, HRCT score, Pseudomonas aeruginosa colonization, cystic bronchiectasis, ventilation heterogeneity and bilateral bronchiectasis. In exacerbation cohort (n = 22), changes in LCI and MMEF% predicted were equally minimal during BEs and following antibiotics therapy. In sensitivity analyses, both parameters had similar diagnostic value and correlation with clinical variables. MMEF% predicted is a surrogate of LCI for assessing bronchiectasis severity. PMID:27339787

  9. Maximal mid-expiratory flow is a surrogate marker of lung clearance index for assessment of adults with bronchiectasis

    PubMed Central

    Guan, Wei-jie; Yuan, Jing-jing; Gao, Yong-hua; Li, Hui-min; Zheng, Jin-ping; Chen, Rong-chang; Zhong, Nan-shan

    2016-01-01

    Little is known about the comparative diagnostic value of lung clearance index (LCI) and maximal mid-expiratory flow (MMEF) in bronchiectasis. We compared the diagnostic performance, correlation and concordance with clinical variables, and changes of LCI and MMEF% predicted during bronchiectasis exacerbations (BEs). Patients with stable bronchiectasis underwent history inquiry, chest high-resolution computed tomography (HRCT), multiple-breath nitrogen wash-out test, spirometry and sputum culture. Patients who experienced BEs underwent these measurements during onset of BEs and 1 week following antibiotics therapy. Sensitivity analyses were performed in mild, moderate and severe bronchiectasis. We recruited 110 bronchiectasis patients between March 2014 and September 2015. LCI demonstrated similar diagnostic value with MMEF% predicted in discriminating moderate-to-severe from mild bronchiectasis. LCI negatively correlated with MMEF% predicted. Both parameters had similar concordance in reflecting clinical characteristics of bronchiectasis and correlated significantly with forced expiratory flow in one second, age, HRCT score, Pseudomonas aeruginosa colonization, cystic bronchiectasis, ventilation heterogeneity and bilateral bronchiectasis. In exacerbation cohort (n = 22), changes in LCI and MMEF% predicted were equally minimal during BEs and following antibiotics therapy. In sensitivity analyses, both parameters had similar diagnostic value and correlation with clinical variables. MMEF% predicted is a surrogate of LCI for assessing bronchiectasis severity. PMID:27339787

  10. Respiratory tract clearance model for dosimetry and bioassay of inhaled radionuclides

    SciTech Connect

    Bailey, M.R.; Birchall, A. ); Cuddihy, R.G. ); James, A.C. ); Roy, M. . Inst. de Protection et de Surete Nucleaire)

    1990-07-01

    The ICRP Task Group on Respiratory Tract Models is developing a model to describe the retention and clearance of deposited radionuclides for dose-intake calculations and interpretation of bioassay data. Clearance from each region is treated as competition between mechanical transport, which moves particles to the gastro-intestinal tract and lymph nodes, and the translocation of material to blood. It is assumed that mechanical transport rates are the same for all materials, and that rates of translocation to blood are the same in all regions. Time-dependent clearance is represented by combinations of compartments. Representative values of parameters to describe mechanical transport from the human respiratory tract have been estimated, and guidance is given on the determination of translocation rates. It is emphasized that the current version of the model described here is still provisional. 30 refs.

  11. Improved Temperature Dynamic Model of Turbine Subcomponents for Facilitation of Generalized Tip Clearance Control

    NASA Technical Reports Server (NTRS)

    Kypuros, Javier A.; Colson, Rodrigo; Munoz, Afredo

    2004-01-01

    This paper describes efforts conducted to improve dynamic temperature estimations of a turbine tip clearance system to facilitate design of a generalized tip clearance controller. This work builds upon research previously conducted and presented in and focuses primarily on improving dynamic temperature estimations of the primary components affecting tip clearance (i.e. the rotor, blades, and casing/shroud). The temperature profiles estimated by the previous model iteration, specifically for the rotor and blades, were found to be inaccurate and, more importantly, insufficient to facilitate controller design. Some assumptions made to facilitate the previous results were not valid, and thus improvements are presented here to better match the physical reality. As will be shown, the improved temperature sub- models, match a commercially validated model and are sufficiently simplified to aid in controller design.

  12. A parameters optimization method for planar joint clearance model and its application for dynamics simulation of reciprocating compressor

    NASA Astrophysics Data System (ADS)

    Hai-yang, Zhao; Min-qiang, Xu; Jin-dong, Wang; Yong-bo, Li

    2015-05-01

    In order to improve the accuracy of dynamics response simulation for mechanism with joint clearance, a parameter optimization method for planar joint clearance contact force model was presented in this paper, and the optimized parameters were applied to the dynamics response simulation for mechanism with oversized joint clearance fault. By studying the effect of increased clearance on the parameters of joint clearance contact force model, the relation of model parameters between different clearances was concluded. Then the dynamic equation of a two-stage reciprocating compressor with four joint clearances was developed using Lagrange method, and a multi-body dynamic model built in ADAMS software was used to solve this equation. To obtain a simulated dynamic response much closer to that of experimental tests, the parameters of joint clearance model, instead of using the designed values, were optimized by genetic algorithms approach. Finally, the optimized parameters were applied to simulate the dynamics response of model with oversized joint clearance fault according to the concluded parameter relation. The dynamics response of experimental test verified the effectiveness of this application.

  13. Clearance of circulating radio-antibodies using streptavidin or second antibodies in a xenograft model.

    PubMed Central

    Marshall, D.; Pedley, R. B.; Boden, J. A.; Boden, R.; Begent, R. H.

    1994-01-01

    The improved tumour to non-tumour ratios needed for effective tumour targeting with antibodies requires that blood background radioactivity is reduced. We investigated the effect of streptavidin as a clearing agent for 125I-labelled biotinylated anti-CEA antibodies in a human colon carcinoma xenograft model. By comparing the biodistribution of the monoclonal antibody A5B7 with four, nine or 22 biotins per antibody molecule, we investigated how the degree of biotinylation of the primary radiolabelled antibody affects its clearance with streptavidin. Limiting the degree of biotinylation limited blood clearance, whereas nine or 22 biotins per antibody molecule resulted in a 13- to 14-fold reduction in blood radioactivity, the streptavidin-biotinylated antibody complexes clearing rapidly via the liver and spleen. Although a reduction in tumour activity was also seen, a 6.6-fold improvement in the tumour to blood ratio was achieved. A comparative study of streptavidin versus second antibody clearance was carried out using the polyclonal antibody PK4S biotinylated with 12 biotins per antibody molecule. This study indicated that second antibody was superior for clearance of the polyclonal antibody, resulting in a larger and faster reduction in blood radioactivity and improved tumour to blood ratios. In this case the primary antibody was polyclonal, and therefore non-uniformity of biotinylation may affect complexation with streptavidin. Therefore, the degree of biotinylation and type of antibody must be carefully considered before the use of streptavidin clearance. PMID:8123481

  14. The severity of shock is associated with impaired rates of net alveolar fluid clearance in clinical acute lung injury.

    PubMed

    Zeyed, Yosaf F; Bastarache, Julie A; Matthay, Michael A; Ware, Lorraine B

    2012-09-15

    The rate of alveolar fluid clearance (AFC) is associated with mortality in clinical acute lung injury (ALI). Patients with ALI often develop circulatory shock, but how shock affects the rate of AFC is unknown. To determine the effect of circulatory shock on the rate of AFC in patients with ALI, the rate of net AFC was measured in 116 patients with ALI by serial sampling of pulmonary edema fluid. The primary outcome was the rate of AFC in patients with shock compared with those without shock. We also tested the effects of shock severity and bacteremia. Patients with ALI and shock (n = 86) had significantly slower rates of net AFC compared with those without shock (n = 30, P = 0.03), and AFC decreased significantly as the number of vasopressors increased. Patients with positive blood cultures (n = 21) had slower AFC compared with patients with negative blood cultures (n = 96, P = 0.023). In addition, the edema fluid-to-plasma protein ratio, an index of alveolar-capillary barrier permeability, was highest in patients requiring the most vasopressors (P < 0.05). Patients with ALI complicated by circulatory shock and bacteremia had slower rates of AFC compared with patients without shock or bacteremia. An impaired capacity to reabsorb alveolar edema fluid may contribute to high mortality among patients with sepsis-induced ALI. These findings also suggest that vasopressor use may be a marker of alveolar-capillary barrier permeability in ALI and provide justification for new therapies that enhance alveolar epithelial and endothelial barrier integrity in ALI, particularly in patients with shock. PMID:22821995

  15. Cultured lung epithelium: A cellular model for lung preservation.

    PubMed

    Lee, C Y; Matsumoto-Pon, J; Widdicombe, J H

    1997-11-01

    Cellular models have helped with the development of conditions needed for hypothermic preservation of kidney, liver, and heart. Recently, highly differentiated cultured lung epithelial cell lines grown with basolateral side feeding technique have become available that can mimic airspace, epithelium, and interstitium of lung parenchyma. Cultured lung epithelium coupled with Ussing's short-circuit current technique was used as a cellular model system for lung preservation. A parametric study was conducted to correlate the effects of luminal fluid composition (University of Wisconsin (UW) solution and phosphate-buffered saline) and storage gas (air vs nitrogen) at 4 degrees C for 24 h on postischemic electrogenic properties (transepithelial ion transport and resistance). The results showed that cells were better preserved with the UW solution on both sides as measured by their transepithelial resistance, an indicator of tight junction integrity (Rte approximately 65% of control values approximately 135 Omega cm2). In addition, they responded better to mediators that stimulate chloride secretion than cells preserved with other conditions. Cells preserved with no additional fluid on the apical side had substantially lowered Rte (<20%) than those preserved with an additional thin layer of fluid ( approximately 35-65%). This cellular model system is a realistic representation of lung epithelium and can provide an accurate assessment of preservation quality through the measurements of tight junction integrity and active ion transport. PMID:9367609

  16. Animal models of acute lung injury

    PubMed Central

    Matute-Bello, Gustavo; Frevert, Charles W.; Martin, Thomas R.

    2008-01-01

    Acute lung injury in humans is characterized histopathologically by neutrophilic alveolitis, injury of the alveolar epithelium and endothelium, hyaline membrane formation, and microvascular thrombi. Different animal models of experimental lung injury have been used to investigate mechanisms of lung injury. Most are based on reproducing in animals known risk factors for ARDS, such as sepsis, lipid embolism secondary to bone fracture, acid aspiration, ischemia-reperfusion of pulmonary or distal vascular beds, and other clinical risks. However, none of these models fully reproduces the features of human lung injury. The goal of this review is to summarize the strengths and weaknesses of existing models of lung injury. We review the specific features of human ARDS that should be modeled in experimental lung injury and then discuss specific characteristics of animal species that may affect the pulmonary host response to noxious stimuli. We emphasize those models of lung injury that are based on reproducing risk factors for human ARDS in animals and discuss the advantages and disadvantages of each model and the extent to which each model reproduces human ARDS. The present review will help guide investigators in the design and interpretation of animal studies of acute lung injury. PMID:18621912

  17. Does the Clearance of Inhaled (99m)Tc-Sestamibi Correlate with Multidrug Resistance Protein 1 Expression in the Human Lung?

    PubMed

    Mohan, Hosahalli K; Routledge, Thomas; Cane, Paul; Livieratos, Lefteris; Ballinger, James R; Peters, Adrien M

    2016-09-01

    Purpose To examine the relation between the lung elimination rate of inhaled technetium 99m ((99m)Tc)-sestamibi and immunohistochemical expression of bronchopulmonary multidrug resistance protein 1 (MRP1) and permeability glycoprotein (P-gp) and assess the repeatability of the inhaled (99m)Tc-sestamibi clearance technique. Materials and Methods (99m)Tc-sestamibi is a known substrate for P-gp and MRP1, which are established cellular drug efflux transporters. The elimination rate of (99m)Tc-sestamibi from the lungs after inhalation as an aerosol has been hypothesized to be regulated by expression of these transporters. Institutional ethics committee approval was received for this prospective study. Written informed consent was obtained from all participants. The clearance of inhaled (99m)Tc-sestamibi from the lungs of 13 patients due to undergo surgery for primary lung cancer (five of 13) or spontaneous pneumothorax (eight of 13) was estimated after dynamic imaging of the lungs during a period of 40 minutes. The time taken to clear 50% of inhaled sestamibi (T1/2) was compared with a semiquantitative immunohistochemical assessment (grade 0-3) of MRP1 and P-gp expression in the lung by using parametric and nonparametric tests. The study was repeated in five participants to assess the repeatability of the technique by using a Bland Altman analysis method. Results MRP1 expression was seen in 12 of 13 patients, while P-gp expression was seen in only two. The mean (99m)Tc-sestamibi elimination rate was faster in patients (n = 6) with low levels of MRP1 expression (grade 0-1) and mean T1/2 of 105 minutes ± 20 (standard deviation), compared with those with higher levels of MRP1 expression (grade 2-3, n = 7) and mean T1/2 of 149 minutes ± 28 (P = .008). Bland-Altman analysis revealed excellent agreement between test and retest values. Conclusion Inhaled (99m)Tc-sestamibi clearance study is a repeatable technique demonstrating significant correlation with MRP1 expression in

  18. Lung proliferative and clearance responses to inhaled para-aramid RFP in exposed hamsters and rats: comparisons with chrysotile asbestos fibers.

    PubMed Central

    Warheit, D B; Snajdr, S I; Hartsky, M A; Frame, S R

    1997-01-01

    This study compared pulmonary effects of para-aramid respirable-sized, fiber-shaped particles (RFP) (p-aramid fibrils) and chrysotile asbestos fiber exposures in rats. Additional p-aramid inhalation studies were conducted in hamsters to compare species responses. The hamster results are preliminary. The parameters studied were clearance/biopersistence of inhaled p-aramid RFP or size-separated asbestos fibers as well as pulmonary cell proliferation and inflammation indices after 2-week inhalation exposures. Rats were exposed nose only to chrysotile asbestos fibers at concentrations of 459 and 782 fibers/ml or to p-aramid RFP at 419 or 772 fibrils/ml. Hamsters were exposed whole body to p-aramid RFP at concentrations of 358 and 659 fibrils/ml. Subsequently, animals were assessed immediately (time 0) as well as 5 days (10 days for hamsters), 1, 3, 6, and 12 months postexposure. Lung burdens for the p-aramid-exposed rats were 4.8 x 10(7) and 7.6 x 10(7) fibrils/lung, with similar numbers of chrysotile fibers > 5 microns recovered from the lungs of asbestos-exposed rats. In comparison, 1.4 x 10(6) fibrils/lung were recovered in the high-dose hamster group. Biopersistence studies in p-aramid-exposed rats and hamsters demonstrated an initial increase (relative to time 0) in retained p-aramid fibrils during the first month postexposure, which indicated breakage or shortening of inhaled fibrils. This result was associated with a progressive reduction, and increased residence time in the lung, in the mean lengths of the fibrils, which signified biodegradability of inhaled p-aramid fibrils in both species. In contrast, clearance of short chrysotile asbestos fibers was rapid, but clearance of the long chrysotile fibers was slow or insignificant, as evidenced by a progressive increase over time in the mean lengths of fibers recovered from the lungs of exposed rats. Two-week, high-dose exposures to p-aramid in both rats and hamsters produced transient increases in pulmonary

  19. Lung proliferative and clearance responses to inhaled para-aramid RFP in exposed hamsters and rats: comparisons with chrysotile asbestos fibers.

    PubMed

    Warheit, D B; Snajdr, S I; Hartsky, M A; Frame, S R

    1997-09-01

    This study compared pulmonary effects of para-aramid respirable-sized, fiber-shaped particles (RFP) (p-aramid fibrils) and chrysotile asbestos fiber exposures in rats. Additional p-aramid inhalation studies were conducted in hamsters to compare species responses. The hamster results are preliminary. The parameters studied were clearance/biopersistence of inhaled p-aramid RFP or size-separated asbestos fibers as well as pulmonary cell proliferation and inflammation indices after 2-week inhalation exposures. Rats were exposed nose only to chrysotile asbestos fibers at concentrations of 459 and 782 fibers/ml or to p-aramid RFP at 419 or 772 fibrils/ml. Hamsters were exposed whole body to p-aramid RFP at concentrations of 358 and 659 fibrils/ml. Subsequently, animals were assessed immediately (time 0) as well as 5 days (10 days for hamsters), 1, 3, 6, and 12 months postexposure. Lung burdens for the p-aramid-exposed rats were 4.8 x 10(7) and 7.6 x 10(7) fibrils/lung, with similar numbers of chrysotile fibers > 5 microns recovered from the lungs of asbestos-exposed rats. In comparison, 1.4 x 10(6) fibrils/lung were recovered in the high-dose hamster group. Biopersistence studies in p-aramid-exposed rats and hamsters demonstrated an initial increase (relative to time 0) in retained p-aramid fibrils during the first month postexposure, which indicated breakage or shortening of inhaled fibrils. This result was associated with a progressive reduction, and increased residence time in the lung, in the mean lengths of the fibrils, which signified biodegradability of inhaled p-aramid fibrils in both species. In contrast, clearance of short chrysotile asbestos fibers was rapid, but clearance of the long chrysotile fibers was slow or insignificant, as evidenced by a progressive increase over time in the mean lengths of fibers recovered from the lungs of exposed rats. Two-week, high-dose exposures to p-aramid in both rats and hamsters produced transient increases in pulmonary

  20. Differences in amyloid-β clearance across mouse and human blood-brain barrier models: Kinetic analysis and mechanistic modeling

    PubMed Central

    Qosa, Hisham; Abuasal, Bilal S.; Romero, Ignacio A.; Weksler, Babette; Couraud, Pierre-Oliver; Keller, Jeffrey N.; Kaddoumi, Amal

    2014-01-01

    Alzheimer’s disease (AD) has a characteristic hallmark of amyloid-β (Aβ) accumulation in the brain. This accumulation of Aβ has been related to its faulty cerebral clearance. Indeed, preclinical studies that used mice to investigate Aβ clearance showed that efflux across blood-brain barrier (BBB) and brain degradation mediate efficient Aβ clearance. However, the contribution of each process to Aβ clearance remains unclear. Moreover, it is still uncertain how species differences between mouse and human could affect Aβ clearance. Here, a modified form of the brain efflux index method was used to estimate the contribution of BBB and brain degradation to Aβ clearance from the brain of wild type mice. We estimated that 62% of intracerebrally injected 125I-Aβ40 is cleared across BBB while 38% is cleared by brain degradation. Furthermore, in vitro and in silico studies were performed to compare Aβ clearance between mouse and human BBB models. Kinetic studies for Aβ40 disposition in bEnd3 and hCMEC/D3 cells, representative in vitro mouse and human BBB models, respectively, demonstrated 30-fold higher rate of 125I-Aβ40 uptake and 15-fold higher rate of degradation by bEnd3 compared to hCMEC/D3 cells. Expression studies showed both cells to express different levels of P-glycoprotein and RAGE, while LRP1 levels were comparable. Finally, we established a mechanistic model, which could successfully predict cellular levels of 125I-Aβ40 and the rate of each process. Established mechanistic model suggested significantly higher rates of Aβ uptake and degradation in bEnd3 cells as rationale for the observed differences in 125I-Aβ40 disposition between mouse and human BBB models. In conclusion, current study demonstrates the important role of BBB in the clearance of Aβ from the brain. Moreover, it provides insight into the differences between mouse and human BBB with regards to Aβ clearance and offer, for the first time, a mathematical model that describes A

  1. Differences in amyloid-β clearance across mouse and human blood-brain barrier models: kinetic analysis and mechanistic modeling.

    PubMed

    Qosa, Hisham; Abuasal, Bilal S; Romero, Ignacio A; Weksler, Babette; Couraud, Pierre-Oliver; Keller, Jeffrey N; Kaddoumi, Amal

    2014-04-01

    Alzheimer's disease (AD) has a characteristic hallmark of amyloid-β (Aβ) accumulation in the brain. This accumulation of Aβ has been related to its faulty cerebral clearance. Indeed, preclinical studies that used mice to investigate Aβ clearance showed that efflux across blood-brain barrier (BBB) and brain degradation mediate efficient Aβ clearance. However, the contribution of each process to Aβ clearance remains unclear. Moreover, it is still uncertain how species differences between mouse and human could affect Aβ clearance. Here, a modified form of the brain efflux index method was used to estimate the contribution of BBB and brain degradation to Aβ clearance from the brain of wild type mice. We estimated that 62% of intracerebrally injected (125)I-Aβ40 is cleared across BBB while 38% is cleared by brain degradation. Furthermore, in vitro and in silico studies were performed to compare Aβ clearance between mouse and human BBB models. Kinetic studies for Aβ40 disposition in bEnd3 and hCMEC/D3 cells, representative in vitro mouse and human BBB models, respectively, demonstrated 30-fold higher rate of (125)I-Aβ40 uptake and 15-fold higher rate of degradation by bEnd3 compared to hCMEC/D3 cells. Expression studies showed both cells to express different levels of P-glycoprotein and RAGE, while LRP1 levels were comparable. Finally, we established a mechanistic model, which could successfully predict cellular levels of (125)I-Aβ40 and the rate of each process. Established mechanistic model suggested significantly higher rates of Aβ uptake and degradation in bEnd3 cells as rationale for the observed differences in (125)I-Aβ40 disposition between mouse and human BBB models. In conclusion, current study demonstrates the important role of BBB in the clearance of Aβ from the brain. Moreover, it provides insight into the differences between mouse and human BBB with regards to Aβ clearance and offer, for the first time, a mathematical model that describes

  2. SMTP (Stachybotrys microspora triprenyl phenol) enhances clot clearance in a pulmonary embolism model in rats

    PubMed Central

    2012-01-01

    Background Stachybotrys microspora triprenyl phenols (SMTPs) are a novel family of small molecules that enhance both activation and fibrin-binding of plasminogen. While their effects on fibrinolysis have been characterized in vitro, little is known about their activity in vivo with respect to plasminogen activation and blood clot clearance. Results To select a potent SMTP congener for the evaluation of its action in vitro and in vivo, we tested several SMTP congeners with distinct structural properties for their effects on plasminogen activation. As a result, SMTP-7 (orniplabin) was found to have distinguished activity. Several lines of biochemical evidence supported the idea that SMTP-7 acted as a plasminogen modulator. SMTP-7 elevated plasma level of plasmin-α2-antiplasmin complex, an index of plasmin formation in vivo, 1.5-fold in mice after the intravenous injections at doses of 5 and 10 mg kg-1. In a rat pulmonary embolism model, SMTP-7 (5 mg kg-1) enhanced the rate of clot clearance ~3-fold in the absence of exogenous plasminogen activator. Clot clearance was enhanced further by 5 mg kg-1 of SMTP-7 in combination with single-chain urokinase-type plasminogen activator. Conclusions Our results show that SMTP-7 is a superior plasminogen modulator among the SMTP family compounds and suggest that the agent enhances plasmin generation in vivo, leading to clearance of thrombi in a model of pulmonary embolism. PMID:22230042

  3. Predicting lung dosimetry of inhaled particleborne benzo[a]pyrene using physiologically based pharmacokinetic modeling.

    PubMed

    Campbell, Jerry; Franzen, Allison; Van Landingham, Cynthia; Lumpkin, Michael; Crowell, Susan; Meredith, Clive; Loccisano, Anne; Gentry, Robinan; Clewell, Harvey

    2016-09-01

    Benzo[a]pyrene (BaP) is a by-product of incomplete combustion of fossil fuels and plant/wood products, including tobacco. A physiologically based pharmacokinetic (PBPK) model for BaP for the rat was extended to simulate inhalation exposures to BaP in rats and humans including particle deposition and dissolution of absorbed BaP and renal elimination of 3-hydroxy benzo[a]pyrene (3-OH BaP) in humans. The clearance of particle-associated BaP from lung based on existing data in rats and dogs suggest that the process is bi-phasic. An initial rapid clearance was represented by BaP released from particles followed by a slower first-order clearance that follows particle kinetics. Parameter values for BaP-particle dissociation were estimated using inhalation data from isolated/ventilated/perfused rat lungs and optimized in the extended inhalation model using available rat data. Simulations of acute inhalation exposures in rats identified specific data needs including systemic elimination of BaP metabolites, diffusion-limited transfer rates of BaP from lung tissue to blood and the quantitative role of macrophage-mediated and ciliated clearance mechanisms. The updated BaP model provides very good prediction of the urinary 3-OH BaP concentrations and the relative difference between measured 3-OH BaP in nonsmokers versus smokers. This PBPK model for inhaled BaP is a preliminary tool for quantifying lung BaP dosimetry in rat and humans and was used to prioritize data needs that would provide significant model refinement and robust internal dosimetry capabilities. PMID:27569524

  4. Predicting the Toxicokinetics of Trifluralin in Rainbow Trout Using Clearance-Volume Pharmacokinetic Models

    SciTech Connect

    Schultz, Irv R. ); Hayton, William L.; David J.Smith, William H.Gingerich, Maria G.Barker

    1999-10-13

    Trifluralin (TF) is a lipophilic, pre-emergent herbicide widely used in agriculture and known to bioconcentrate in fish. We have characterized the accumulation of TF in rainbow trout under a variety of experimental conditions. Our approach has been to use static water exposure systems and intra-vascular dosing in combination with clearance-volume pharmacokinetic (CV-PK) models to obtain quantitative estimates of uptake clearance, apparent volume of distribution and elimination due to xenobiotic metabolism. This paper will briefly discuss pertinent physicochemical data for TF and review the toxicokinetics of TF in rainbow trout. Emphasis will be placed on physiological interpretations of TF model parameters and practical aspects of modeling TF toxicokinetics with CV-PK models.

  5. A mathematical model of particle retention in the air-spaces of human lungs.

    PubMed Central

    Gerrity, T R; Garrard, C S; Yeates, D B

    1983-01-01

    Knowledge of the total and regional lung retention of particles inhaled continuously by man over long periods can be useful in understanding the potential role of inhaled particles in the pathogenesis of lung diseases. Owing to practical and ethical considerations, however, little or no experimental information exists. A mathematical model of particle retention simulating environmental and occupational exposures has therefore been developed that takes into account particle deposition, tracheobronchial clearance, and two phases of alveolar clearance in the Weibel A anatomical lung model. The derived equations of retention kinetics predict retention of particles as a function of exposure time. For a continuous exposure (simulating environmental conditions) to 4 microns particles, the model predicts that retained particles approach an equilibrium between deposited and cleared particles with the 95% level being reached in 293 days. For an intermittent exposure (simulating occupational conditions) equilibrium is approached in five years. The whole lung burden of particles is predicted to be 9% of the total mass that entered the lung after a one-year environmental exposure and 1.5% after a 25-year occupational exposure. The equilibrium surface concentration and integrated dose of particles per airway generation predict enhanced risk to the pathogenic effects of inhaled particles in the large airways and respiratory bronchioles. PMID:6830707

  6. A Physiologically-Motivated Compartment-Based Model of the Effect of Inhaled Hypertonic Saline on Mucociliary Clearance and Liquid Transport in Cystic Fibrosis

    PubMed Central

    Markovetz, Matthew R.; Corcoran, Timothy E.; Locke, Landon W.; Myerburg, Michael M.; Pilewski, Joseph M.; Parker, Robert S.

    2014-01-01

    Background Cystic Fibrosis (CF) lung disease is characterized by liquid hyperabsorption, airway surface dehydration, and impaired mucociliary clearance (MCC). Herein, we present a compartment-based mathematical model of the airway that extends the resolution of functional imaging data. Methods Using functional imaging data to inform our model, we developed a system of mechanism-motivated ordinary differential equations to describe the mucociliary clearance and absorption of aerosolized radiolabeled particle and small molecules probes from human subjects with and without CF. We also utilized a novel imaging metric in vitro to gauge the fraction of airway epithelial cells that have functional ciliary activity. Results This model, and its incorporated kinetic rate parameters, captures the MCC and liquid dynamics of the hyperabsorptive state in CF airways and the mitigation of that state by hypertonic saline treatment. Conclusions We postulate, based on the model structure and its ability to capture clinical patient data, that patients with CF have regions of airway with diminished MCC function that can be recruited with hypertonic saline treatment. In so doing, this model structure not only makes a case for durable osmotic agents used in lung-region specific treatments, but also may provide a possible clinical endpoint, the fraction of functional ciliated airway. PMID:25383714

  7. Hydrogen sulfide decreases β-adrenergic agonist-stimulated lung liquid clearance by inhibiting ENaC-mediated transepithelial sodium absorption.

    PubMed

    Agné, Alisa M; Baldin, Jan-Peter; Benjamin, Audra R; Orogo-Wenn, Maria C; Wichmann, Lukas; Olson, Kenneth R; Walters, Dafydd V; Althaus, Mike

    2015-04-01

    In pulmonary epithelia, β-adrenergic agonists regulate the membrane abundance of the epithelial sodium channel (ENaC) and, thereby, control the rate of transepithelial electrolyte absorption. This is a crucial regulatory mechanism for lung liquid clearance at birth and thereafter. This study investigated the influence of the gaseous signaling molecule hydrogen sulfide (H2S) on β-adrenergic agonist-regulated pulmonary sodium and liquid absorption. Application of the H2S-liberating molecule Na2S (50 μM) to the alveolar compartment of rat lungs in situ decreased baseline liquid absorption and abrogated the stimulation of liquid absorption by the β-adrenergic agonist terbutaline. There was no additional effect of Na2S over that of the ENaC inhibitor amiloride. In electrophysiological Ussing chamber experiments with native lung epithelia (Xenopus laevis), Na2S inhibited the stimulation of amiloride-sensitive current by terbutaline. β-adrenergic agonists generally increase ENaC abundance by cAMP formation and activation of PKA. Activation of this pathway by forskolin and 3-isobutyl-1-methylxanthine increased amiloride-sensitive currents in H441 pulmonary epithelial cells. This effect was inhibited by Na2S in a dose-dependent manner (5-50 μM). Na2S had no effect on cellular ATP concentration, cAMP formation, and activation of PKA. By contrast, Na2S prevented the cAMP-induced increase in ENaC activity in the apical membrane of H441 cells. H441 cells expressed the H2S-generating enzymes cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, and they produced H2S amounts within the employed concentration range. These data demonstrate that H2S prevents the stimulation of ENaC by cAMP/PKA and, thereby, inhibits the proabsorptive effect of β-adrenergic agonists on lung liquid clearance. PMID:25632025

  8. Hydrogen sulfide decreases β-adrenergic agonist-stimulated lung liquid clearance by inhibiting ENaC-mediated transepithelial sodium absorption

    PubMed Central

    Agné, Alisa M.; Baldin, Jan-Peter; Benjamin, Audra R.; Orogo-Wenn, Maria C.; Wichmann, Lukas; Olson, Kenneth R.; Walters, Dafydd V.

    2015-01-01

    In pulmonary epithelia, β-adrenergic agonists regulate the membrane abundance of the epithelial sodium channel (ENaC) and, thereby, control the rate of transepithelial electrolyte absorption. This is a crucial regulatory mechanism for lung liquid clearance at birth and thereafter. This study investigated the influence of the gaseous signaling molecule hydrogen sulfide (H2S) on β-adrenergic agonist-regulated pulmonary sodium and liquid absorption. Application of the H2S-liberating molecule Na2S (50 μM) to the alveolar compartment of rat lungs in situ decreased baseline liquid absorption and abrogated the stimulation of liquid absorption by the β-adrenergic agonist terbutaline. There was no additional effect of Na2S over that of the ENaC inhibitor amiloride. In electrophysiological Ussing chamber experiments with native lung epithelia (Xenopus laevis), Na2S inhibited the stimulation of amiloride-sensitive current by terbutaline. β-adrenergic agonists generally increase ENaC abundance by cAMP formation and activation of PKA. Activation of this pathway by forskolin and 3-isobutyl-1-methylxanthine increased amiloride-sensitive currents in H441 pulmonary epithelial cells. This effect was inhibited by Na2S in a dose-dependent manner (5–50 μM). Na2S had no effect on cellular ATP concentration, cAMP formation, and activation of PKA. By contrast, Na2S prevented the cAMP-induced increase in ENaC activity in the apical membrane of H441 cells. H441 cells expressed the H2S-generating enzymes cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, and they produced H2S amounts within the employed concentration range. These data demonstrate that H2S prevents the stimulation of ENaC by cAMP/PKA and, thereby, inhibits the proabsorptive effect of β-adrenergic agonists on lung liquid clearance. PMID:25632025

  9. Computational fluid dynamics modeling of airflow inside lungs using heterogenous anisotropic lung tissue elastic properties.

    PubMed

    Ilegbusi, Olusegun; Li, Ziang; Min, Yugang; Meeks, Sanford; Kupelian, Patrick; Santhanam, Anand P

    2012-01-01

    The aim of this paper is to model the airflow inside lungs during breathing and its fluid-structure interaction with the lung tissues and the lung tumor using subject-specific elastic properties. The fluid-structure interaction technique simultaneously simulates flow within the airway and anisotropic deformation of the lung lobes. The three-dimensional (3D) lung geometry is reconstructed from the end-expiration 3D CT scan datasets of humans with lung cancer. The lung is modeled as a poro-elastic medium with anisotropic elastic property (non-linear Young's modulus) obtained from inverse lung elastography of 4D CT scans for the same patients. The predicted results include the 3D anisotropic lung deformation along with the airflow pattern inside the lungs. The effect is also presented of anisotropic elasticity on both the spatio-temporal volumetric lung displacement and the regional lung hysteresis. PMID:22356987

  10. Clearance Rate and BP-ANN Model in Paraquat Poisoned Patients Treated with Hemoperfusion

    PubMed Central

    Hu, Lufeng; Hong, Guangliang; Ma, Jianshe; Wang, Xianqin; Lin, Guanyang; Zhang, Xiuhua; Lu, Zhongqiu

    2015-01-01

    In order to investigate the effect of hemoperfusion (HP) on the clearance rate of paraquat (PQ) and develop a clearance model, 41 PQ-poisoned patients who acquired acute PQ intoxication received HP treatment. PQ concentrations were determined by high performance liquid chromatography (HPLC). According to initial PQ concentration, study subjects were divided into two groups: Low-PQ group (0.05–1.0 μg/mL) and High-PQ group (1.0–10 μg/mL). After initial HP treatment, PQ concentrations decreased in both groups. However, in the High-PQ group, PQ levels remained in excess of 0.05 μg/mL and increased when the second HP treatment was initiated. Based on the PQ concentrations before and after HP treatment, the mean clearance rate of PQ calculated was 73 ± 15%. We also established a backpropagation artificial neural network (BP-ANN) model, which set PQ concentrations before HP treatment as input data and after HP treatment as output data. When it is used to predict PQ concentration after HP treatment, high prediction accuracy (R = 0.9977) can be obtained in this model. In conclusion, HP is an effective way to clear PQ from the blood, and the PQ concentration after HP treatment can be predicted by BP-ANN model. PMID:25695058

  11. Animal model for anaerobic lung abscess.

    PubMed Central

    Kannangara, D W; Thadepalli, H; Bach, V T; Webb, D

    1981-01-01

    There are no satisfactory animal models for the study of anaerobic lung abscess. Aspiration of food, gastric mucin, or hydrochloric acid, or any combination of these, along with oropharyngeal bacteria, is commonly believed to cause aspiration pneumonia and lung abscess. In the animal model described, none of the adjuvants was effective in producing anaerobic lung abscesses. Anaerobic bacteria derived from dental scrapings of a healthy adult (Peptococcus morbillorum, Fusobacterium nucleatum, Eubacterium lentum, and Bacteroides fragilis), when inoculated transtracheally without any adjuvants into New Zealand male white rabbits, consistently produced lung abscesses. Neither B fragilis by itself nor a mixture of P. morbillorum, F. nucleatum, and E. lentum without the addition of B. fragilis produced lung abscesses. The bacterial isolates used in this study were stored in prereduced chopped-meat-glucose medium and subcultured several times and were found effective in reproducing anaerobic lung abscesses repeatedly. This animal model is suitable for the study of pathogenesis, diagnosis, and treatment of B. fragilis-associated anaerobic lung abscess. Images PMID:7216463

  12. Reduced erythrocyte susceptibility and increased host clearance of young parasites slows Plasmodium growth in a murine model of severe malaria

    NASA Astrophysics Data System (ADS)

    Khoury, David S.; Cromer, Deborah; Best, Shannon E.; James, Kylie R.; Sebina, Ismail; Haque, Ashraful; Davenport, Miles P.

    2015-05-01

    The best correlate of malaria severity in human Plasmodium falciparum (Pf) infection is the total parasite load. Pf-infected humans could control parasite loads by two mechanisms, either decreasing parasite multiplication, or increasing parasite clearance. However, few studies have directly measured these two mechanisms in vivo. Here, we have directly quantified host clearance of parasites during Plasmodium infection in mice. We transferred labelled red blood cells (RBCs) from Plasmodium infected donors into uninfected and infected recipients, and tracked the fate of donor parasites by frequent blood sampling. We then applied age-based mathematical models to characterise parasite clearance in the recipient mice. Our analyses revealed an increased clearance of parasites in infected animals, particularly parasites of a younger developmental stage. However, the major decrease in parasite multiplication in infected mice was not mediated by increased clearance alone, but was accompanied by a significant reduction in the susceptibility of RBCs to parasitisation.

  13. Particle Image Velocimetry in Lung Bifurcation Models

    NASA Astrophysics Data System (ADS)

    Theunissen, Raf; Riethmuller, Michel L.

    To better understand the human pulmonary system and governing aerosol deposition mechanisms within the lung, an accurate description of the airflow in the conductive and respiratory pulmonary airways is considered to be essential. In-vivo measurements are deemed impossible due to the small scales in the lung structure. Though numerical simulations can improve the insight, validation of the results is mostly lacking, especially in the extraction of particle trajectories. Numerical and experimental studies have been performed at the von Karman Institute for Fluid Dynamics on single and multiple bifurcation models representing simplifications of the lung system. Both steady and oscillating flows have been studied for the upper lung airways, while steady flow conditions were imposed in the modeling of the alveolar zones. Further experiments consisted in the extraction of particle trajectories in the models of the respiratory airways. This chapter presents an overview of the conducted measurement campaigns complemented with the main observations and results.

  14. A free-breathing lung motion model

    NASA Astrophysics Data System (ADS)

    Zhao, Tianyu

    Lung cancer has been the leading cause of cancer deaths for decades in the United States. Although radiotherapy is one of the most effective treatments, side effects from error in delivery of radiation due to organ motion during breathing remain a significant issue. To compensate the breathing motion during the treatment, a free breathing lung motion model, x= x0+αv+betaf, was developed and discussed, where x is the position of a piece of tissue located at reference position x0. α is a parameter which characterizes the motion due to local air filling (motion as a function of tidal volume) and beta is the parameter that accounts for the motion due to the imbalance of dynamical stress distributions during inspiration and exhalation which cause lung motion hysteresis (motion as a function of airflow). The parameters α and beta together provide a quantitative characterization of breathing motion that inherently includes the complex hysteresis interplay. The theoretical foundation of the model was built by investigating the stress distribution inside of a lung and the biomechanical properties of the lung tissues. Accuracy of the model was investigated by using 49 free-breathing patient data sets. Applications of the model in localizing lung cancer, monitoring radiation damage and suppressing artifacts in free-breathing PET images were also discussed. This work supported in part by NIHR01CA096679 and NIHR01CA116712.

  15. CISNET lung models: Comparison of model assumptions and model structures

    PubMed Central

    McMahon, Pamela M.; Hazelton, William; Kimmel, Marek; Clarke, Lauren

    2012-01-01

    Sophisticated modeling techniques can be powerful tools to help us understand the effects of cancer control interventions on population trends in cancer incidence and mortality. Readers of journal articles are however rarely supplied with modeling details. Six modeling groups collaborated as part of the National Cancer Institute’s Cancer Intervention and Surveillance Modeling Network (CISNET) to investigate the contribution of US tobacco control efforts towards reducing lung cancer deaths over the period 1975 to 2000. The models included in this monograph were developed independently and use distinct, complementary approaches towards modeling the natural history of lung cancer. The models used the same data for inputs and agreed on the design of the analysis and the outcome measures. This article highlights aspects of the models that are most relevant to similarities of or differences between the results. Structured comparisons can increase the transparency of these complex models. PMID:22882887

  16. Reduced Bacterial Colony Count of Anaerobic Bacteria Is Associated with a Worsening in Lung Clearance Index and Inflammation in Cystic Fibrosis

    PubMed Central

    Bradley, Judy M.; Johnston, Elinor; McGrath, Stephanie; McIlreavey, Leanne; Rowan, Stephen; Reid, Alastair; Bradbury, Ian; Einarsson, Gisli

    2015-01-01

    Anaerobic bacteria have been identified in abundance in the airways of cystic fibrosis (CF) subjects. The impact their presence and abundance has on lung function and inflammation is unclear. The aim of this study was to investigate the relationship between the colony count of aerobic and anaerobic bacteria, lung clearance index (LCI), spirometry and C-Reactive Protein (CRP) in patients with CF. Sputum and blood were collected from CF patients at a single cross-sectional visit when clinically stable. Community composition and bacterial colony counts were analysed using extended aerobic and anaerobic culture. Patients completed spirometry and a multiple breath washout (MBW) test to obtain LCI. An inverse correlation between colony count of aerobic bacteria (n = 41, r = -0.35; p = 0.02), anaerobic bacteria (n = 41, r = -0.44, p = 0.004) and LCI was observed. There was an inverse correlation between colony count of anaerobic bacteria and CRP (n = 25, r = -0.44, p = 0.03) only. The results of this study demonstrate that a lower colony count of aerobic and anaerobic bacteria correlated with a worse LCI. A lower colony count of anaerobic bacteria also correlated with higher CRP levels. These results indicate that lower abundance of aerobic and anaerobic bacteria may reflect microbiota disruption and disease progression in the CF lung. PMID:25992575

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

    PubMed Central

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

    2012-01-01

    OBJECTIVE: 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. METHOD: 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. RESULTS: 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 H2O in Group 1 and 49.3 ml/cm H2O 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). CONCLUSION: 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. PMID:23018310

  18. A clinically relevant canine lung cancer model

    SciTech Connect

    Benfield, J.R.; Shors, E.C.; Hammond, W.G.; Paladugu, R.R.; Cohen, A.H.; Jensen, T.; Fu, P.C.; Pak, H.Y.; Teplitz, R.L.

    1981-12-01

    Research on early human lung cancer is difficult; we have sought a canine correlate. Regimens included endobronchial submucosal injections and topical focal applications of benzo(a)pyrene, nitrosomethylurea, dimethylbenzanthracene, and methylcholanthrene, singly or in combinations. Sustained-release discs were placed into lung parenchyma or sutured into major bronchi. Tracheal segments were isolated as cervical pedicle grafts. Gross and histological evolution was reproducible. Columnar and basal hyperplasia and squamous metaplasia were early changes. Atypia occurred within 6 weeks and was found in all dogs within 16 to 18 weeks. Invasive cancers occurred within 8 to 65 months. No tracheal graft developed cancer. Of 15 dogs with parenchymal sustained-release implants, 1 to date has developed cancer in 8 months. Four endobronchial regimens have produced 16 cancers in 56 lungs at risk for 18 to 65 months. No cancers developed in 23 lungs at risk from eight other regimens. Of 10 dogs at risk for unilateral endobronchial cancer, 5 have had cancer. Of 23 dogs with both lungs at risk, 9 developed cancer. We have shown focal carcinogenesis with well-defined pathogenesis and an extended preneoplastic period at predictable sites in a lung cancer model.

  19. Neutrophils and their Fcγ receptors are essential in a mouse model of transfusion-related acute lung injury

    PubMed Central

    Looney, Mark R.; Su, Xiao; Van Ziffle, Jessica A.; Lowell, Clifford A.; Matthay, Michael A.

    2006-01-01

    Transfusion-related acute lung injury (TRALI) is the most common cause of transfusion-related mortality. To explore the pathogenesis of TRALI, we developed an in vivo mouse model based on the passive transfusion of an MHC class I (MHC I) mAb (H2Kd) to mice with the cognate antigen. Transfusion of the MHC I mAb to BALB/c mice produced acute lung injury with increased excess lung water, increased lung vascular and lung epithelial permeability to protein, and decreased alveolar fluid clearance. There was 50% mortality at a 2-hour time point after Ab administration. Pulmonary histology and immunohistochemistry revealed prominent neutrophil sequestration in the lung microvasculature that occurred concomitantly with acute peripheral blood neutropenia, all within 2 hours of administration of the mAb. Depletion of neutrophils by injection of anti-granulocyte mAb Gr-1 protected mice from lung injury following MHC I mAb challenge. FcRγ–/– mice were resistant to MHC I mAb–induced lung injury, while adoptive transfer of wild-type neutrophils into the FcRγ–/– animals restored lung injury following MHC I mAb challenge. In conclusion, in a clinically relevant in vivo mouse model of TRALI using an MHC I mAb, the mechanism of lung injury was dependent on neutrophils and their Fcγ receptors. PMID:16710475

  20. Retention and clearance of inhaled submicron carbon black particles.

    PubMed

    Strom, K A; Johnson, J T; Chan, T L

    1989-01-01

    Carbon black aerosols were used as a probe of the pulmonary retention and clearance of submicron particles. Male Fischer rats (COBS CD) were exposed for 20 h/d, 7 d/wk for 1, 3, or 6 wk to either 7 +/- 2 mg/m3 carbon black or filtered air. The submicron aerosol (mass median aerodynamic diameter, MMAD, 0.24 microns) was generated with a Wright dust feed-cyclone system. Lung and hilar lymph node particle burdens were determined immediately following the exposure and at preselected intervals up to 1 yr postexposure. After 1-, 3-, and 6-wk exposures, the lung burdens were 1.1 +/- 0.1, 3.5 +/- 0.2, and 5.9 +/- 0.1 mg, respectively. One year after a 1-, 3-, or 6-wk exposure, 8%, 46%, and 61% of the initial lung burden remained in the lungs. Initially, the hilar lymph nodes contained 0.2%, 0.9%, and 2.0% of the lung burdens in the 3 exposure groups, respectively. At 1 yr postexposure, particle translocation from the lungs led to a rise in lymph node burdens to 1%, 21%, and 27% of the initial lung burden. The retention of carbon black in both the lungs and lymph nodes combined was 9%, 67%, and 89% for the 1-, 3-, and 6-wk exposed animals. Lung clearance was modeled as a compartmental system consisting of four lung compartments and a regional lymph node compartment. The results from the model are similar for carbon black and diesel engine exhaust particles. However, the compartmental kinetics of carbon black differed in two ways: the deposition efficiency in the alveolar region was lower than that for diesel exhaust particles, and there was earlier transport of particles to the regional lymph nodes. These results showed that when lung burdens reached 0.8 mg, lung clearance was decreased by 50% and lymphatic transport of insoluble particles was increased. PMID:2466129

  1. Diverse Data Sets Can Yield Reliable Information through Mechanistic Modeling: Salicylic Acid Clearance

    PubMed Central

    Raymond, G. M.; Bassingthwaighte, J. B.

    2016-01-01

    This is a practical example of a powerful research strategy: putting together data from studies covering a diversity of conditions can yield a scientifically sound grasp of the phenomenon when the individual observations failed to provide definitive understanding. The rationale is that defining a realistic, quantitative, explanatory hypothesis for the whole set of studies, brings about a “consilience” of the often competing hypotheses considered for individual data sets. An internally consistent conjecture linking multiple data sets simultaneously provides stronger evidence on the characteristics of a system than does analysis of individual data sets limited to narrow ranges of conditions. Our example examines three very different data sets on the clearance of salicylic acid from humans: a high concentration set from aspirin overdoses; a set with medium concentrations from a research study on the influences of the route of administration and of sex on the clearance kinetics, and a set on low dose aspirin for cardiovascular health. Three models were tested: (1) a first order reaction, (2) a Michaelis-Menten (M-M) approach, and (3) an enzyme kinetic model with forward and backward reactions. The reaction rates found from model 1 were distinctly different for the three data sets, having no commonality. The M-M model 2 fitted each of the three data sets but gave a reliable estimates of the Michaelis constant only for the medium level data (Km = 24±5.4 mg/L); analyzing the three data sets together with model 2 gave Km = 18±2.6 mg/L. (Estimating parameters using larger numbers of data points in an optimization increases the degrees of freedom, constraining the range of the estimates). Using the enzyme kinetic model (3) increased the number of free parameters but nevertheless improved the goodness of fit to the combined data sets, giving tighter constraints, and a lower estimated Km = 14.6±2.9 mg/L, demonstrating that fitting diverse data sets with a single model

  2. Cystic Fibrosis Transmembrane Conductance Regulator is an Epithelial Cell Receptor for Clearance of Pseudomonas aeruginosa from the Lung

    NASA Astrophysics Data System (ADS)

    Pier, Gerald B.; Grout, Martha; Zaidi, Tanweer S.

    1997-10-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride ion channel, but its relationship to the primary clinical manifestation of CF, chronic Pseudomonas aeruginosa pulmonary infection, is unclear. We report that CFTR is a cellular receptor for binding, endocytosing, and clearing P. aeruginosa from the normal lung. Murine cells expressing recombinant human wild-type CFTR ingested 30-100 times as many P. aeruginosa as cells lacking CFTR or expressing mutant Δ F508 CFTR protein. Purified CFTR inhibited ingestion of P. aeruginosa by human airway epithelial cells. The first extracellular domain of CFTR specifically bound to P. aeruginosa and a synthetic peptide of this region inhibited P. aeruginosa internalization in vivo, leading to increased bacterial lung burdens. CFTR clears P. aeruginosa from the lung, indicating a direct connection between mutations in CFTR and the clinical consequences of CF.

  3. 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.

  4. Complement facilitates macrophage phagocytosis of inhaled iron particles but has little effect in mediating silica-induced lung inflammatory and clearance responses

    SciTech Connect

    Warheit, D.B.; Carakostas, M.C.; Bamberger, J.R.; Hartsky, M.A. )

    1991-12-01

    The present studies were undertaken to investigate the role of complement in mediating pulmonary inflammation and/or phagocytosis as a function of particle clearance in rats exposed to silica or carbonyl iron (CI) particles. Both particle types were shown to be weak activators of serum complement in vitro. In these studies, normal and complement-depressed (CVFD-treated) rats were exposed to aerosols of Ci or silica particles for 6 hr at 100 mg/m{sup 3}. Following exposure, alveolar fluids and cells from sham and dust-exposed animals were recovered by bronchoalveolar lavage (BAL) at several time periods postexposure and measured for a variety of biochemical and cellular indices. In addition, pulmonary macrophages were cultured and studied for morphology and phagocytosis. The authors results showed that CI exposure did not produce cellular or biochemical indices of pulmonary inflammation, either in normal or complement-depleted rats. However, fewer phagocytic macrophages were recovered from the lungs of CVF-treated, CI-exposed rats than from normal exposed animals. In contrast, silica inhalation produced a sustained PMN inflammatory response in the lungs of exposed rats, measured up through 1 month postexposure, along with significant increases in BAL fluid levels of LDH, protein, and alkaline phosphatase and deficits in pulmonary macrophage phagocytic functions.

  5. Defective bacterial clearance is responsible for the enhanced lung pathology characteristic of Mannheimia haemolytica pneumonia in bighorn sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The molecular and cellular basis for the enhanced lung pathology and mortality caused by Mannheimia haemolytica in bighorn sheep (BHS, Ovis canadenesis), in comparison to domestic sheep (DS, Ovis aries), is not clear. Polymorphonuclear leukocytes (PMNs) of BHS are four- to eight-fold more susceptibl...

  6. Effect of mouse strain as a background for Alzheimer’s disease models on the clearance of amyloid-β

    PubMed Central

    Qosa, Hisham; Kaddoumi, Amal

    2016-01-01

    Novel animal models of Alzheimer’s disease (AD) are relentlessly being developed and existing ones are being fine-tuned; however, these models face multiple challenges associated with the complexity of the disease where most of these models do not reproduce the full phenotypical disease spectrum. Moreover, different AD models express different phenotypes that could affect their validity to recapitulate disease pathogenesis and/or response to a drug. One of the most important and understudied differences between AD models is differences in the phenotypic characteristics of the background species. Here, we used the brain clearance index (BCI) method to investigate the effect of strain differences on the clearance of amyloid β (Aβ) from the brains of four mouse strains. These mouse strains, namely C57BL/6, FVB/N, BALB/c and SJL/J, are widely used as a background for the development of AD mouse models. Findings showed that while Aβ clearance across the blood-brain barrier (BBB) was comparable between the 4 strains, levels of LRP1, an Aβ clearance protein, was significantly lower in SJL/J mice compared to other mouse strains. Furthermore, these mouse strains showed a significantly different response to rifampicin treatment with regard to Aβ clearance and effect on brain level of its clearance-related proteins. Our results provide for the first time an evidence for strain differences that could affect ability of AD mouse models to recapitulate response to a drug, and opens a new research avenue that requires further investigation to successfully develop mouse models that could simulate clinically important phenotypic characteristics of AD.

  7. Human models of acute lung injury

    PubMed Central

    Proudfoot, Alastair G.; McAuley, Danny F.; Griffiths, Mark J. D.; Hind, Matthew

    2011-01-01

    Acute lung injury (ALI) is a syndrome that is characterised by acute inflammation and tissue injury that affects normal gas exchange in the lungs. Hallmarks of ALI include dysfunction of the alveolar-capillary membrane resulting in increased vascular permeability, an influx of inflammatory cells into the lung and a local pro-coagulant state. Patients with ALI present with severe hypoxaemia and radiological evidence of bilateral pulmonary oedema. The syndrome has a mortality rate of approximately 35% and usually requires invasive mechanical ventilation. ALI can follow direct pulmonary insults, such as pneumonia, or occur indirectly as a result of blood-borne insults, commonly severe bacterial sepsis. Although animal models of ALI have been developed, none of them fully recapitulate the human disease. The differences between the human syndrome and the phenotype observed in animal models might, in part, explain why interventions that are successful in models have failed to translate into novel therapies. Improved animal models and the development of human in vivo and ex vivo models are therefore required. In this article, we consider the clinical features of ALI, discuss the limitations of current animal models and highlight how emerging human models of ALI might help to answer outstanding questions about this syndrome. PMID:21357760

  8. Cryptococcus neoformans Infection in Mice Lacking Type I Interferon Signaling Leads to Increased Fungal Clearance and IL-4-Dependent Mucin Production in the Lungs

    PubMed Central

    Sato, Ko; Yamamoto, Hideki; Nomura, Toshiki; Matsumoto, Ikumi; Miyasaka, Tomomitsu; Zong, Tong; Kanno, Emi; Uno, Kazuko; Ishii, Keiko; Kawakami, Kazuyoshi

    2015-01-01

    Type I interferons (IFNs) are secreted by many cell types upon stimulation via pattern recognition receptors and bind to IFN-α/β receptor (IFNAR), which is composed of IFNAR1 and IFNAR2. Although type I IFNs are well known as anti-viral cytokines, limited information is available on their role during fungal infection. In the present study, we addressed this issue by examining the effect of IFNAR1 defects on the host defense response to Cryptococcus neoformans. In IFNAR1KO mice, the number of live colonies was lower and the host immune response mediated not only by Th1 but also by Th2 and Th17-related cytokines was more accelerated in the infected lungs than in WT mice. In addition, mucin production by bronchoepithelial cells and expression of MUC5AC, a major core protein of mucin in the lungs, were significantly higher in IFNAR1KO mice than in WT mice. This increase in mucin and MUC5AC production was significantly inhibited by treatment with neutralizing anti-IL-4 mAb. In contrast, administration of recombinant IFN-αA/D significantly suppressed the production of IL-4, but not of IFN-γ and IL-17A, in the lungs of WT mice after cryptococcal infection. These results indicate that defects of IFNAR1 led to improved clearance of infection with C. neoformans and enhanced synthesis of IFN-γ and the IL-4-dependent production of mucin. They also suggest that type I IFNs may be involved in the negative regulation of early host defense to this infection. PMID:26384031

  9. Effects of Chinese medicinal herbs on a rat model of chronic Pseudomonas aeruginosa lung infection.

    PubMed

    Song, Z; Johansen, H K; Moser, C; Høiby, N

    1996-05-01

    The aim of the study was to evaluate the effects of two kinds of Chinese medicinal herbs, Isatis tinctoria L (ITL) and Daphne giraldii Nitsche (DGN), on a rat model of chronic Pseudomonas aeruginosa lung infection mimicking cystic fibrosis (CF). Compared to the control group, both drugs were able to reduce the incidence of lung abscess (p < 0.05) and to decrease the severity of the macroscopic pathology in lungs (p < 0.05). In the great majority of the rats, the herbs altered the inflammatory response in the lungs from an acute type inflammation, dominated by polymorphonuclear leukocytes (PMN), to a chronic type inflammation, dominated by mononuclear leukocytes (MN). DGN also improved the clearance of P. aeruginosa from the lungs (p < 0.03) compared with the control group. There were no significant differences between the control group and the two herbal groups with regard to serum IgG and IgA anti-P. aeruginosa sonicate antibodies. However, the IgM concentration in the ITL group was significantly lower than in the control group (p < 0.03). These results suggest that the two medicinal herbs might be helpful to CF patients with chronic P. aeruginosa lung infection, DGN being the most favorable. PMID:8703440

  10. Lung Deposition and Clearance of Inhaled Vanadium Pentoxide in Chronically Exposed F344 Rats and B6C3F1 Mice

    SciTech Connect

    Dill, Jeffrey A.; Lee, Kyeonghee M.; Mellinger, Kathleen H.; Bates, Derrick J.; Burka, Leo T.; Roycroft, Joseph H.

    2004-01-01

    Female F344 rats and B6C3F1 mice were exposed to vanadium pentoxide (V{sub 2}O{sub 5}) at concentrations of 0, 0.5, 1, or 2 mg/m{sup 3} (rats) and 0, 1, 2, or 4 mg/m{sup 3} (mice) for 6 h/day, 5 days/week (for up to 18 months), by whole-body inhalation. Lung weights and lung burdens of vanadium were determined for exposed animals after 1, 5, and 12 days and after 1, 2, 6, 12, and 18 months of V{sub 2}O{sub 5} exposure. Blood vanadium concentrations were determined at 1, 2, 6, 12, and 18 months for all animals including controls. A model that assumed a first-order deposition rate and a first-order elimination rate for vanadium was employed to fit the lung burden data. Comparisons between exposed groups indicated a progressive increase in lung weight with exposure concentration and time on exposure for both species. The vanadium lung burdens appeared to reach steady state in the lowest exposure groups (0.5 and 1 mg/m{sup 3} for rats and mice, respectively) but showed a decline in the higher exposure groups. This deposition pattern was similar between rats and mice but the maximum lung burdens were observed at different times (1 or 2 months in mice vs. 6 months in rats). The vanadium deposition rate decreased faster in mice, while the elimination half-lives of vanadium lung burdens were about six- to nine-fold shorter in mice than in rats at 1 and 2 mg/m{sup 3}. Thus, the retention of vanadium in the lungs at 18 months was lower in mice ({approx}2% retained) compared with rats (13-15% retained) at the common exposure concentrations of 1 and 2 mg/m{sup 3}. The lung burden data were approximately proportional to the exposure concentration in both species, likely due to concomitant decreases in deposition and elimination to a similar extent with increasing exposure. The area under the lung burden versus time curves and the area under the blood concentration (control-normalized) versus time curves were also proportional to exposure concentration. The progression of

  11. Mesenchymal stem cells enhance autophagy and increase β-amyloid clearance in Alzheimer disease models

    PubMed Central

    Shin, Jin Young; Park, Hyun Jung; Kim, Ha Na; Oh, Se Hee; Bae, Jae-Sung; Ha, Hee-Jin; Lee, Phil Hyu

    2014-01-01

    Current evidence suggests a central role for autophagy in Alzheimer disease (AD), and dysfunction in the autophagic system may lead to amyloid-β (Aβ) accumulation. Using in vitro and in vivo AD models, the present study investigated whether mesenchymal stem cells (MSCs) could enhance autophagy and thus exert a neuroprotective effect through modulation of Aβ clearance In Aβ-treated neuronal cells, MSCs increased cellular viability and enhanced LC3-II expression compared with cells treated with Aβ only. Immunofluorescence revealed that MSC coculture in Aβ-treated neuronal cells increased the number of LC3-II-positive autophagosomes that were colocalized with a lysosomal marker. Ultrastructural analysis revealed that most autophagic vacuoles (AVs) in Aβ-treated cells were not fused with lysosomes, whereas a large portion of autophagosomes were conjoined with lysosomes in MSCs cocultured with Aβ-treated neuronal cells. Furthermore, MSC coculture markedly increased Aβ immunoreactivity colocalized within lysosomes and decreased intracellular Aβ levels compared with Aβ-treated cells. In Aβ-treated animals, MSC administration significantly increased autophagosome induction, final maturation of late AVs, and fusion with lysosomes. Moreover, MSC administration significantly reduced the level of Aβ in the hippocampus, which was elevated in Aβ-treated mice, concomitant with increased survival of hippocampal neurons. Finally, MSC coculture upregulated BECN1/Beclin 1 expression in AD models. These results suggest that MSCs significantly enhance autolysosome formation and clearance of Aβ in AD models, which may lead to increased neuronal survival against Aβ toxicity. Modulation of the autophagy pathway to repair the damaged AD brain using MSCs would have a significant impact on future strategies for AD treatment. PMID:24149893

  12. A model of ventilation of the healthy human lung.

    PubMed

    Steimle, K L; Mogensen, M L; Karbing, D S; Bernardino de la Serna, J; Andreassen, S

    2011-02-01

    This paper presents a model of the lung mechanics which simulates the pulmonary alveolar ventilation. The model includes aspects of: the alveolar geometry; pressure due to the chest wall; pressure due to surface tension determined by surfactant activity; pressure due to lung tissue elasticity; and pressure due to the hydrostatic effects of the lung tissue and blood. The cross-sectional area of the lungs in the supine position derived from computed tomography is used to construct a horizontally layered model, which simulates heterogeneous ventilation distribution from the non-dependent to the dependent layers of the lungs. The model is in agreement with experimentally measured hysteresis of the pressure-volume curve of the lungs, static lung compliance, changes in lung depth during breathing and density distributions at total lung capacity (TLC) and residual volume (RV). In the dependent layers of the lungs, alveolar collapse may occur at RV, depending on the assumptions concerning lung tissue elasticity at very low alveolar volumes. The model simulations showed that ventilation increased with depth in the lungs, although not as pronounced as observed experimentally. The model simulates alveolar ventilation including all of the mentioned components of the respiratory system and to be validated against all the above mentioned experimental data. PMID:20655612

  13. 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. PMID:24008585

  14. 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.

  15. Towards improved models for predicting bioconcentration of well-metabolized compounds by rainbow trout using measured rates of in vitro intrinsic clearance

    EPA Science Inventory

    Consensus models were developed to predict the bioconcentration of well-metabolized chemicals by rainbow trout. The models employ intrinsic clearance data from in vitro studies with liver S9 fractions or isolated hepatocytes to estimate a liver clearance rate which is extrapolat...

  16. Genetically engineered mouse models for lung cancer.

    PubMed

    Kwak, I; Tsai, S Y; DeMayo, F J

    2004-01-01

    The lung is a complex organ consisting of numerous cell types that function to ensure sufficient gas exchange to oxygenate the blood. In order to accomplish this function, the lung must be exposed to the external environment and at the same time maintain a homeostatic balance between its function in gas exchange and the maintenance of inflammatory balance. During the past two decades, as molecular methodologies have evolved with the sequencing of entire genomes, the use of in vivo models to elucidate the molecular mechanisms involved in pulmonary physiology and disease have increased. The mouse has emerged as a potent model to investigate pulmonary physiology due to the explosion in molecular methods that now allow for the developmental and tissue-specific regulation of gene transcription. Initial efforts to manipulate gene expression in the mouse genome resulted in the generation of transgenic mice characterized by the constitutive expression of a specific gene and knockout mice characterized by the ablation of a specific gene. The utility of these original mouse models was limited, in many cases, by phenotypes resulting in embryonic or neonatal lethality that prevented analysis of the impact of the genetic manipulation on pulmonary biology. Second-generation transgenic mouse models employ multiple strategies that can either activate or silence gene expression thereby providing extensive temporal and spatial control of the experimental parameters of gene expression. These highly regulated mouse models are intended to serve as a foundation for further investigation of the molecular basis of human disease such as tumorigenesis. This review describes the principles, progress, and application of systems that are currently employed in the conditional regulation of gene expression in the investigation of lung cancer. PMID:14977417

  17. LUNG MODEL CASTING TECHNIQUES FOR INTERSPECIES MORPHOMETRIC COMPARISONS

    EPA Science Inventory

    Techniques have been developed for casting both solid and hollow lung models from lung specimens. These techniques have been used to make casts of rat, rabbit, baboon, and human lungs and may be used for other species. An air line at a positive pressure of 25 cm of water is conne...

  18. Discrete-Layer Piezoelectric Plate and Shell Models for Active Tip-Clearance Control

    NASA Technical Reports Server (NTRS)

    Heyliger, P. R.; Ramirez, G.; Pei, K. C.

    1994-01-01

    The objectives of this work were to develop computational tools for the analysis of active-sensory composite structures with added or embedded piezoelectric layers. The targeted application for this class of smart composite laminates and the analytical development is the accomplishment of active tip-clearance control in turbomachinery components. Two distinct theories and analytical models were developed and explored under this contract: (1) a discrete-layer plate theory and corresponding computational models, and (2) a three dimensional general discrete-layer element generated in curvilinear coordinates for modeling laminated composite piezoelectric shells. Both models were developed from the complete electromechanical constitutive relations of piezoelectric materials, and incorporate both displacements and potentials as state variables. This report describes the development and results of these models. The discrete-layer theories imply that the displacement field and electrostatic potential through-the-thickness of the laminate are described over an individual layer rather than as a smeared function over the thickness of the entire plate or shell thickness. This is especially crucial for composites with embedded piezoelectric layers, as the actuating and sensing elements within these layers are poorly represented by effective or smeared properties. Linear Lagrange interpolation polynomials were used to describe the through-thickness laminate behavior. Both analytic and finite element approximations were used in the plane or surface of the structure. In this context, theoretical developments are presented for the discrete-layer plate theory, the discrete-layer shell theory, and the formulation of an exact solution for simply-supported piezoelectric plates. Finally, evaluations and results from a number of separate examples are presented for the static and dynamic analysis of the plate geometry. Comparisons between the different approaches are provided when

  19. Real-time imaging of glutamate clearance reveals normal striatal uptake in Huntington disease mouse models.

    PubMed

    Parsons, Matthew P; Vanni, Matthieu P; Woodard, Cameron L; Kang, Rujun; Murphy, Timothy H; Raymond, Lynn A

    2016-01-01

    It has become well accepted that Huntington disease (HD) is associated with impaired glutamate uptake, resulting in a prolonged time-course of extracellular glutamate that contributes to excitotoxicity. However, the data supporting this view come largely from work in synaptosomes, which may overrepresent nerve-terminal uptake over astrocytic uptake. Here, we quantify real-time glutamate dynamics in HD mouse models by high-speed imaging of an intensity-based glutamate-sensing fluorescent reporter (iGluSnFR) and electrophysiological recordings of synaptically activated transporter currents in astrocytes. These techniques reveal a disconnect between the results obtained in synaptosomes and those in situ. Exogenous glutamate uptake is impaired in synaptosomes, whereas real-time measures of glutamate clearance in the HD striatum are normal or even accelerated, particularly in the aggressive R6/2 model. Our results highlight the importance of quantifying glutamate dynamics under endogenous release conditions, and suggest that the widely cited uptake impairment in HD does not contribute to pathogenesis. PMID:27052848

  20. Real-time imaging of glutamate clearance reveals normal striatal uptake in Huntington disease mouse models

    PubMed Central

    Parsons, Matthew P.; Vanni, Matthieu P.; Woodard, Cameron L.; Kang, Rujun; Murphy, Timothy H.; Raymond, Lynn A.

    2016-01-01

    It has become well accepted that Huntington disease (HD) is associated with impaired glutamate uptake, resulting in a prolonged time-course of extracellular glutamate that contributes to excitotoxicity. However, the data supporting this view come largely from work in synaptosomes, which may overrepresent nerve-terminal uptake over astrocytic uptake. Here, we quantify real-time glutamate dynamics in HD mouse models by high-speed imaging of an intensity-based glutamate-sensing fluorescent reporter (iGluSnFR) and electrophysiological recordings of synaptically activated transporter currents in astrocytes. These techniques reveal a disconnect between the results obtained in synaptosomes and those in situ. Exogenous glutamate uptake is impaired in synaptosomes, whereas real-time measures of glutamate clearance in the HD striatum are normal or even accelerated, particularly in the aggressive R6/2 model. Our results highlight the importance of quantifying glutamate dynamics under endogenous release conditions, and suggest that the widely cited uptake impairment in HD does not contribute to pathogenesis. PMID:27052848

  1. Depletion of M. tuberculosis GlmU from Infected Murine Lungs Effects the Clearance of the Pathogen

    PubMed Central

    Soni, Vijay; Upadhayay, Sandeep; Suryadevara, Priyanka; Samla, Ganesh; Singh, Archana; Yogeeswari, Perumal; Sriram, Dharmarajan; Nandicoori, Vinay Kumar

    2015-01-01

    M. tuberculosis N-acetyl-glucosamine-1-phosphate uridyltransferase (GlmUMtb) is a bi-functional enzyme engaged in the synthesis of two metabolic intermediates N-acetylglucosamine-1-phosphate (GlcNAc-1-P) and UDP-GlcNAc, catalyzed by the C- and N-terminal domains respectively. UDP-GlcNAc is a key metabolite essential for the synthesis of peptidoglycan, disaccharide linker, arabinogalactan and mycothiols. While glmUMtb was predicted to be an essential gene, till date the role of GlmUMtb in modulating the in vitro growth of Mtb or its role in survival of pathogen ex vivo / in vivo have not been deciphered. Here we present the results of a comprehensive study dissecting the role of GlmUMtb in arbitrating the survival of the pathogen both in vitro and in vivo. We find that absence of GlmUMtb leads to extensive perturbation of bacterial morphology and substantial reduction in cell wall thickness under normoxic as well as hypoxic conditions. Complementation studies show that the acetyl- and uridyl- transferase activities of GlmUMtb are independently essential for bacterial survival in vitro, and GlmUMtb is also found to be essential for mycobacterial survival in THP-1 cells as well as in guinea pigs. Depletion of GlmUMtb from infected murine lungs, four weeks post infection, led to significant reduction in the bacillary load. The administration of Oxa33, a novel oxazolidine derivative that specifically inhibits GlmUMtb, to infected mice resulted in significant decrease in the bacillary load. Thus our study establishes GlmUMtb as a strong candidate for intervention measures against established tuberculosis infections. PMID:26489015

  2. Efficacy and safety of mesenchymal stromal cells in preclinical models of acute lung injury: a systematic review protocol

    PubMed Central

    2014-01-01

    Background Acute respiratory distress syndrome (ARDS) in humans is caused by an unchecked proinflammatory response that results in diffuse and severe lung injury, and it is associated with a mortality rate of 35 to 45%. Mesenchymal stromal cells (MSCs; ‘adult stem cells’) could represent a promising new therapy for this syndrome, since preclinical evidence suggests that MSCs may ameliorate lung injury. Prior to a human clinical trial, our aim is to conduct a systematic review to compare the efficacy and safety of MSC therapy versus controls in preclinical models of acute lung injury that mimic some aspects of the human ARDS. Methods/Design We will include comparative preclinical studies (randomized and non-randomized) of acute lung injury in which MSCs were administered and outcomes compared to animals given a vehicle control. The primary outcome will be death. Secondary outcomes will include the four key features of preclinical acute lung injury as defined by the American Thoracic Society consensus conference (histologic evidence of lung injury, altered alveolar capillary barrier, lung inflammatory response, and physiological dysfunction) and pathogen clearance for acute lung injury models that are caused by infection. Electronic searches of MEDLINE, Embase, BIOSIS Previews, and Web of Science will be constructed and reviewed by the Peer Review of Electronic Search Strategies (PRESS) process. Search results will be screened independently and in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias will be assessed using the Cochrane risk of bias tool, and individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. Discussion The results of this systematic review will comprehensively summarize the safety and efficacy of MSC therapy in preclinical models of acute lung injury. Our results will help translational scientists and

  3. 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. PMID:6893348

  4. Prediction of Drug Clearance in Premature and Mature Neonates, Infants, and Children ≤2 Years of Age: A Comparison of the Predictive Performance of 4 Allometric Models.

    PubMed

    Mahmood, Iftekhar

    2016-06-01

    The objective of this study was to evaluate the predictive performance of 4 allometric models to predict clearance in pediatric ages ranging from premature neonates to children ≤2 years of age. Four allometric models were used to predict clearances of 28 drugs in children from preterm neonates to 2 years of age (n = 564). The 4 models are (1) basal metabolic rate-dependent model; (2) age-dependent exponent model; (3) an allometric model based on kidney and liver weights as well as kidney and liver blood flow; and (4) an allometric model based on a fixed exponent of 0.75. The predictive performance of these models was evaluated by comparing the predicted clearance of the studied drugs with the observed clearance in an individual child. The results of the study indicated that the 3 new proposed models predicted the mean clearance of the drugs with reasonable accuracy (≤50% prediction error). On the other hand, the exponent of 0.75 produced substantial prediction error. Predicted individual clearance values were ≥50% in approximately 30% of the children by the proposed 3 methods and 73% by exponent 0.75. The 3 new proposed allometric models can predict mean clearances of drugs in children from premature neonates to ≤2 years of age with reasonable accuracy and are of practical value during pediatric drug development. PMID:26437918

  5. 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.

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

    PubMed

    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

  7. 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

  8. Quantitative structure-activity relationship models of clinical pharmacokinetics: clearance and volume of distribution.

    PubMed

    Gombar, Vijay K; Hall, Stephen D

    2013-04-22

    Reliable prediction of two fundamental human pharmacokinetic (PK) parameters, systemic clearance (CL) and apparent volume of distribution (Vd), determine the size and frequency of drug dosing and are at the heart of drug discovery and development. Traditionally, estimated CL and Vd are derived from preclinical in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) measurements. In this paper, we report quantitative structure-activity relationship (QSAR) models for prediction of systemic CL and steady-state Vd (Vdss) from intravenous (iv) dosing in humans. These QSAR models avoid uncertainty associated with preclinical-to-clinical extrapolation and require two-dimensional structure drawing as the sole input. The clean, uniform training sets for these models were derived from the compilation published by Obach et al. (Drug Metab. Disp. 2008, 36, 1385-1405). Models for CL and Vdss were developed using both a support vector regression (SVR) method and a multiple linear regression (MLR) method. The SVR models employ a minimum of 2048-bit fingerprints developed in-house as structure quantifiers. The MLR models, on the other hand, are based on information-rich electro-topological states of two-atom fragments as descriptors and afford reverse QSAR (RQSAR) analysis to help model-guided, in silico modulation of structures for desired CL and Vdss. The capability of the models to predict iv CL and Vdss with acceptable accuracy was established by randomly splitting data into training and test sets. On average, for both CL and Vdss, 75% of test compounds were predicted within 2.5-fold of the value observed and 90% of test compounds were within 5.0-fold of the value observed. The performance of the final models developed from 525 compounds for CL and 569 compounds for Vdss was evaluated on an external set of 56 compounds. The predictions were either better or comparable to those predicted by other in silico models reported in the literature. To

  9. Hepatic and Extrahepatic Insulin Clearance Are Differentially Regulated: Results From a Novel Model-Based Analysis of Intravenous Glucose Tolerance Data.

    PubMed

    Polidori, David C; Bergman, Richard N; Chung, Stephanie T; Sumner, Anne E

    2016-06-01

    Insulin clearance is a highly variable and important factor that affects circulating insulin concentrations. We developed a novel model-based method to estimate both hepatic and extrahepatic insulin clearance using plasma insulin and C-peptide profiles obtained from the insulin-modified frequently sampled intravenous glucose tolerance test. Data from 100 African immigrants without diabetes (mean age 38 years, body weight 81.7 kg, fasting plasma glucose concentration 83 mg/dL, and fasting insulin concentration 37 pmol/L) were used. Endogenous insulin secretion (calculated by C-peptide deconvolution) and insulin infusion rates were used as inputs to a new two-compartment model of insulin kinetics and hepatic and extrahepatic clearance parameters were estimated. Good agreement between modeled and measured plasma insulin profiles was observed (mean normalized root mean square error 6.8%), and considerable intersubject variability in parameters of insulin clearance among individuals was identified (the mean [interquartile range] for hepatic extraction was 25.8% [32.7%], and for extrahepatic insulin clearance was 20.7 mL/kg/min [11.7 mL/kg/min]). Parameters of insulin clearance were correlated with measures of insulin sensitivity and acute insulin response to glucose. The method described appears promising for future research aimed at characterizing variability in insulin clearance and the mechanisms involved in the regulation of insulin clearance. PMID:26993071

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

    NASA Astrophysics Data System (ADS)

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

    2012-02-01

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

  11. Clearance Deficiency and Cell Death Pathways: A Model for the Pathogenesis of SLE

    PubMed Central

    Mahajan, Aparna; Herrmann, Martin; Muñoz, Luis E.

    2016-01-01

    Alterations of cell death pathways, including apoptosis and the neutrophil specific kind of death called NETosis, can represent a potential source of autoantigens. Defects in the clearance of apoptotic cells may be responsible for the initiation of systemic autoimmunity in several chronic inflammatory diseases, including systemic lupus erythematosus (SLE). Autoantigens are released mainly from secondary necrotic cells because of a defective clearance of apoptotic cells or an inefficient degradation of DNA-containing neutrophil extracellular traps (NETs). These modified autoantigens are presented by follicular dendritic cells to autoreactive B cells in germinal centers of secondary lymphoid organs. This results in the loss of self-tolerance and production of autoantibodies, a unifying feature of SLE. Immune complexes (IC) are formed from autoantibodies bound to uncleared cellular debris in blood or tissues. Clearance of IC by blood phagocytes, macrophages, and dendritic cells leads to proinflammatory cytokine secretion. In particular, plasmacytoid dendritic cells produce high amounts of interferon-α upon IC uptake, thereby contributing to the interferon signature of patients with SLE. The clearance of antinuclear IC via Fc-gamma receptors is considered a central event in amplifying inflammatory immune responses in SLE. Along with this, the accumulation of cell remnants represents an initiating event of the etiology, while the subsequent generation of autoantibodies against nuclear antigens (including NETs) results in the perpetuation of inflammation and tissue damage in patients with SLE. Here, we discuss the implications of defective clearance of apoptotic cells and NETs in the development of clinical manifestations in SLE. PMID:26904025

  12. Investigation of intrapartum clearance of the upper airway in the presence of meconium contaminated amniotic fluid using an animal model.

    PubMed

    Pfenninger, E; Dick, W; Brecht-Krauss, D; Bitter, F; Hofmann, H; Bowdler, I

    1984-01-01

    In order to define as effective a procedure as possible for the intra- and post-partum clearance of the upper airways of meconium contaminated infants, three methods of suction clearance, nasal, oral and combined nasal and oral, were carried out on each of five kittens aged between 17 to 19 weeks. There was an interval of at least one week between each investigation. The animals were anaesthetized with ketamine intramuscularly. The pressure changes during delivery were simulated using a compressed blood pressure cuff around the kittens thorax. During the first minute of thoracic compression Tc 99 labeled synthetic sputum was introduced into both the oro- and nasopharynx, then during the 2nd minute the instilled fluid was removed using a conventional extractor with mucus trap. Solely oral or solely nasal routes were used, suction was carried out for 60 secs, whereas when the combined technique was applied the oral and nasal cavities were cleared for only 30 secs each. At the end at the 2nd minute thoracic compression was released and a deep inspiration occurred. After five minutes the radioactivity remaining after suction was documented using a gamma-camera. We attempted to answer the following questions: How much mucus could be extracted with each different method, and where the remaining amount was later distributed? Nasal suction alone was found to be inefficient; using this route an average of 13% (only an eight of the amount instilled) could be removed. Oral suction led to the recovery of an average of 52% of the material instilled, the combined technique much as 56%. After re-establishment of spontaneous respiration, it could be clearly seen that, independent of the efficacy of the technique used, the majority of the remaining radioactivity (55 relative percent) is localized in the head and neck area. Absolute values are 45% for nasal suction, 26% for oral, and 24% for the combined oro-nasal route. The other part of the remaining radioactivity was found in the

  13. A Novel Bioluminescence Orthotopic Mouse Model for Advanced Lung Cancer

    PubMed Central

    Li, Bo; Torossian, Artour; Li, Wenyan; Schleicher, Stephen; Niu, Kathy; Giacalone, Nicholas J.; Kim, Sung June; Chen, Heidi; Gonzalez, Adriana; Moretti, Luigi; Lu, Bo

    2011-01-01

    Lung cancer is the leading cause of cancer-related death in the United States despite recent advances in our understanding of this challenging disease. An animal model for high-throughput screening of therapeutic agents for advanced lung cancer could help promote the development of more successful treatment interventions. To develop our orthotopic lung cancer model, luciferase-expressing A549 cancer cells were injected into the mediastinum of athymic nude mice. To determine whether the model would allow easy monitoring of response to therapeutic interventions, tumors were treated with 30 mg/kg Paclitaxel or were irradiated with 5 fractions of 2 Gy, and tumor burden was monitored using bioluminescence imaging. Evidence of radiation-induced lung injury was assessed using immunohistochemical staining for phospho-Smad2/3 and cleaved caspase-3. We found that tumor implantation recapitulated advanced human lung cancer as evidenced by tumor establishment and proliferation within the mediastinum. The tumor responded to Paclitaxel or radiation as shown by decreased tumor bioluminescence and improved overall survival. Immunohistochemistry revealed increased phospho-Smad2/3 and cleaved caspase-3 in irradiated lungs, consistent with radiation-induced lung injury. This orthotopic lung cancer model may help provide a method to assess therapeutic interventions in a preclinical setting that recapitulates locally advanced lung cancer. PMID:21663394

  14. Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both β-amyloid production and clearance.

    PubMed

    Zhu, Zhiyuan; Yan, Jianming; Jiang, Wei; Yao, Xin-gang; Chen, Jing; Chen, Lili; Li, Chenjing; Hu, Lihong; Jiang, Hualiang; Shen, Xu

    2013-08-01

    Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery. PMID:23926267

  15. 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.

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

    PubMed

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

    2015-10-01

    Human lung undergoes breathing-induced deformation in the form of inhalation and exhalation. Modeling the dynamics is numerically complicated by the lack of information on lung elastic behavior and fluid-structure interactions between air and the tissue. A mathematical method is developed to integrate deformation results from a deformable image registration (DIR) and physics-based modeling approaches in order to represent consistent volumetric lung dynamics. The computational fluid dynamics (CFD) simulation assumes the lung is a poro-elastic medium with spatially distributed elastic property. Simulation is performed on a 3D lung geometry reconstructed from four-dimensional computed tomography (4DCT) dataset of a human subject. The heterogeneous Young's modulus (YM) is estimated from a linear elastic deformation model with the same lung geometry and 4D lung DIR. The deformation obtained from the CFD is then coupled with the displacement obtained from the 4D lung DIR by means of the Tikhonov regularization (TR) algorithm. The numerical results include 4DCT registration, CFD, and optimal displacement data which collectively provide consistent estimate of the volumetric lung dynamics. The fusion method is validated by comparing the optimal displacement with the results obtained from the 4DCT registration. PMID:26292034

  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. Rapid in vivo measurement of β-amyloid reveals biphasic clearance kinetics in an Alzheimer's mouse model.

    PubMed

    Yuede, Carla M; Lee, Hyo; Restivo, Jessica L; Davis, Todd A; Hettinger, Jane C; Wallace, Clare E; Young, Katherine L; Hayne, Margaret R; Bu, Guojun; Li, Chen-Zhong; Cirrito, John R

    2016-05-01

    Findings from genetic, animal model, and human studies support the observation that accumulation of the β-amyloid (Aβ) peptide in the brain plays a central role in the pathogenic cascade of Alzheimer's disease (AD). Human studies suggest that one key factor leading to accumulation is a defect in brain Aβ clearance. We have developed a novel microimmunoelectrode (MIE) to study the kinetics of Aβ clearance using an electrochemical approach. This is the first study using MIEs in vivo to measure rapid changes in Aβ levels in the brains of living mice. Extracellular, interstitial fluid (ISF) Aβ levels were measured in the hippocampus of APP/PS1 mice. Baseline levels of Aβ40 in the ISF are relatively stable and begin to decline within minutes of blocking Aβ production with a γ-secretase inhibitor. Pretreatment with a P-glycoprotein inhibitor, which blocks blood-brain barrier transport of Aβ, resulted in significant prolongation of Aβ40 half-life, but only in the latter phase of Aβ clearance from the ISF. PMID:27069115

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

    PubMed Central

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

    2012-01-01

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

  20. Heart and lung support interaction--modeling and simulation.

    PubMed

    Darowski, M

    2000-01-01

    Mechanical support of the lungs used to preserve life or during any kind of surgery may have an adverse effect on the cardiovascular system. Usually, positive pressure in alveoli diminishes lung perfusion, venous return and cardiac output. Positive pressure during the respiratory cycle is transfered into the thoracic space. The aim of this study was to assess how synchronization of the respirator with spontaneous breathing influences the distribution of pressure and ventilation in nonhomogeneous lungs and how it should influence hemodynamics. For this purpose a multicompartmental model of respiratory system mechanics was used in the electrical analog of a respirator-lung circuit, which enabled us to simultaneously simulate ventilatory support and spontaneous breathing. Mechanical properties of the respiratory system were modeled by lumped parameters: resistances and capacitances of constant values, independent of lung volume or inspiratory flow changes. A multicompartmental model of the respiratory system enabled us to simulate lung pathology characterized by non-homogeneity of the mechanical properties of the different parts of the lungs. The results of simulations presented in the paper enable us to conclude that lung volume increase, independent of the respirator-patient breathing synchronization, may be modeled as the increase in pulmonary vascular resistance and alveolar pressure increase, dependent on respirator-patient breathing synchronization, may be averaged by esophageous balloon measurements which show intrathoracic pressure changes. PMID:11014677

  1. High mass clearance of autoantibodies from a murine model of lupus nephritis by immunoadsorption using star-configured polyethylene glycols.

    PubMed

    Ross, E A; Branham, M L; Tebbett, I R

    2001-04-01

    The extracorporeal immunoadsorption of antibodies as part of the therapy for human autoimmune diseases has been limited by technology with inadequate and nonselective mass clearance or problems with bioincompatibility. To overcome these shortcomings, we designed a method utilizing star-configured polyethylene glycols (star-PEGs) having up to 63 free arms with immunoreactive (tresylate ester) end-groups for each arm immobilized to a polymer support substrate. The flexibility and length of the arms are thought to allow optimization of epitope presentation and to permit interaction with immunoligands on adjacent arms. To demonstrate efficacy we used an in vitro murine antibody model of human lupus nephritis, wherein we could study the kinetics and mass clearance of hybridoma derived antihistone antibodies from human plasma. Histones were covalently bound to the star-PEG end-groups and the kinetics of antibody adsorption were assessed using a surface plasmon resonance technique. The equilibrium constants of antihistone antibody binding to histone-star-PEGs that were linked to a support grid demonstrated high affinity with a KA of 3.56E + 07 and a KD of 2.81E - 08. The optimum reaction conditions were determined to accomplish the hydrophilization of polysulfone (PS; by an aqueous nitration method) and polymethylmethacrylate substrates (PMMA; by hydrazine), using sheet casts of both polymer substances. Hollow fiber devices of these polymers (commercial hemodialyzers) were modified so that histone-bound star-PEGs were linked to their intracapillary luminal surfaces, using a process which we have shown retains their immunoadsorption properties for antihistone antibodies. A closed loop recirculating model was constructed to measure mass clearance of antibodies from a reservoir. After optimizing conditions using extraction from saline solutions, the removal of antibody from human plasma by control and surface-modified devices was assessed over 4 h. There was no measurable

  2. A computational model that simulates mucociliary clearance in the bronchial tree, and a concomitant study on energetics and optimality

    NASA Astrophysics Data System (ADS)

    Manolidis, Michail; Isabey, Daniel; Louis, Bruno; Grotberg, James; Filoche, Marcel

    2015-11-01

    Systemic deterministic models of mucociliary clearance in the bronchial tree are currently scarce. While analytical/computational efforts have focused on microscopic modeling of mucociliary propulsion, macroscopic approaches have been restricted mainly to stochastic methods. We present an analytical/computational model that simulates mucociliary clearance in macroscopic physical domains. The analytical foundations of the model are based on a Stokes flow assumption, whereby, in addition to viscous forces originating in ciliary forcing, the role of surface tension is also considered. The governing equations are solved computationally on a three-dimensional surface mesh. Flow is simulated in an anatomically/geometrically representative bifurcation of the bronchial tree. The directionality of ciliary forcing in our model is optimized in order to maintain near-uniform mucus film thickness throughout the flow field. Based on the optimized version of the model, energetic considerations, as well as aspects of optimality in nature are analyzed and presented. 2nd affiliation: Professor, Physique de la Matière Condensée, Ecole Polytechnique, Palaiseau, France.

  3. 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

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

    PubMed Central

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

    2013-01-01

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

  5. Modelling Virus and Antibody Dynamics during Dengue Virus Infection Suggests a Role for Antibody in Virus Clearance

    PubMed Central

    Clapham, Hannah E; Dorigatti, Ilaria; Simmons, Cameron P; Ferguson, Neil M

    2016-01-01

    Dengue is an infection of increasing global importance, yet uncertainty remains regarding critical aspects of its virology, immunology and epidemiology. One unanswered question is how infection is controlled and cleared during a dengue infection. Antibody is thought to play a role, but little past work has examined the kinetics of both virus and antibody during natural infections. We present data on multiple virus and antibody titres measurements recorded sequentially during infection from 53 Vietnamese dengue patients. We fit mechanistic mathematical models of the dynamics of viral replication and the host immune response to these data. These models fit the data well. The model with antibody removing virus fits the data best, but with a role suggested for ADCC or other infected cell clearance mechanisms. Our analysis therefore shows that the observed viral and antibody kinetics are consistent with antibody playing a key role in controlling viral replication. This work gives quantitative insight into the relationship between antibody levels and the efficiency of viral clearance. It will inform the future development of mechanistic models of how vaccines and antivirals might modify the course of natural dengue infection. PMID:27213681

  6. Modelling Virus and Antibody Dynamics during Dengue Virus Infection Suggests a Role for Antibody in Virus Clearance.

    PubMed

    Clapham, Hannah E; Quyen, Than Ha; Kien, Duong Thi Hue; Dorigatti, Ilaria; Simmons, Cameron P; Ferguson, Neil M

    2016-05-01

    Dengue is an infection of increasing global importance, yet uncertainty remains regarding critical aspects of its virology, immunology and epidemiology. One unanswered question is how infection is controlled and cleared during a dengue infection. Antibody is thought to play a role, but little past work has examined the kinetics of both virus and antibody during natural infections. We present data on multiple virus and antibody titres measurements recorded sequentially during infection from 53 Vietnamese dengue patients. We fit mechanistic mathematical models of the dynamics of viral replication and the host immune response to these data. These models fit the data well. The model with antibody removing virus fits the data best, but with a role suggested for ADCC or other infected cell clearance mechanisms. Our analysis therefore shows that the observed viral and antibody kinetics are consistent with antibody playing a key role in controlling viral replication. This work gives quantitative insight into the relationship between antibody levels and the efficiency of viral clearance. It will inform the future development of mechanistic models of how vaccines and antivirals might modify the course of natural dengue infection. PMID:27213681

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

    PubMed Central

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

    2008-01-01

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

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

    PubMed

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

    2008-08-01

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

  9. Computational Models of Ventilator Induced Lung Injury and Surfactant Dysfunction

    PubMed Central

    Bates, Jason H.T.; Smith, Bradford J.; Allen, Gilman B.

    2014-01-01

    Managing acute respiratory distress syndrome (ARDS) invariably involves the administration of mechanical ventilation, the challenge being to avoid the iatrogenic sequellum known as ventilator-induced lung injury (VILI). Devising individualized ventilation strategies in ARDS requires that patient-specific lung physiology be taken into account, and this is greatly aided by the use of computational models of lung mechanical function that can be matched to physiological measurements made in a given patient. In this review, we discuss recent models that have the potential to serve as the basis for devising minimally injurious modes of mechanical ventilation in ARDS patients. PMID:26904138

  10. 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.

  11. 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

  12. Effect of cocaine on striatal dopamine clearance in a rat model of developmental stress and attention-deficit/hyperactivity disorder.

    PubMed

    Womersley, Jacqueline S; Kellaway, Lauriston A; Stein, Dan J; Gerhardt, Greg A; Russell, Vivienne A

    2016-01-01

    Attention-deficit/hyperactivity disorder (ADHD) and developmental stress are considered risk factors for the development of drug abuse. Though the physiological mechanisms underlying this risk are not yet clear, ADHD, developmental stress and drug abuse are known to share underlying disturbances in dopaminergic neurotransmission. Thus, we hypothesized that clearance of cocaine-induced elevations in striatal dopamine would be prolonged in a rat model of ADHD and that this would be further increased by exposure to developmental stress. In the current study, male spontaneously hypertensive rats (SHRs), a well-validated model of ADHD, and control Wistar-Kyoto (WKY) rats were exposed to either standard rearing (nMS) or a maternal separation (MS) paradigm involving removal of the pups from the dam for 180 min/day over 13 days. This produced a 2 × 2 factorial design (SHR/WKY × nMS/MS) with 5-6 rats/group. Striatal clearance of exogenously applied dopamine was measured via in vivo chronoamperometry, and the difference in dopamine uptake parameters before and after cocaine administration was compared between experimental groups. Cocaine, a potent dopamine transporter inhibitor, reliably increased the clearance time of dopamine though no difference in this parameter was found between SHR and WKY strains. However, developmental stress elevated the cocaine-induced increase in time to clear 50% of exogenously applied dopamine (T50) in SHR but had no effect in WKY rats. These findings suggest that a strain × environment interaction prolongs elevated levels of dopamine thereby potentially increasing the rewarding properties of this drug in SHR. PMID:26394534

  13. 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. PMID:25997727

  14. 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. PMID:26738123

  15. 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.

  16. 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.

  17. Microwave Blade Tip Clearance System: An Update

    NASA Technical Reports Server (NTRS)

    Geisheimer, Jon

    2006-01-01

    Newer engines use compressor bleed air and a model to close clearances open loop. Measuring clearances and closing the control loop can add additional efficiencies. Tip clearance control has been identified as a key technology for future engines Additional benefits in prognostics, NSMS, and condition-based maintenance. In the HPT for every 1 mil improvement in clearance: a) SFC decreases 0.1%; and b) EGT margin increases 1 C.

  18. A Comparative Study of Lung Host Defense in Murine Obesity Models. Insights into Neutrophil Function.

    PubMed

    Ubags, Niki D J; Burg, Elianne; Antkowiak, Maryellen; Wallace, Aaron M; Dilli, Estee; Bement, Jenna; Wargo, Matthew J; Poynter, Matthew E; Wouters, Emiel F M; Suratt, Benjamin T

    2016-08-01

    We have shown that obesity-associated attenuation of murine acute lung injury is driven, in part, by blunted neutrophil chemotaxis, yet differences were noted between the two models of obesity studied. We hypothesized that obesity-associated impairment of multiple neutrophil functions contributes to increased risk for respiratory infection but that such impairments may vary between murine models of obesity. We examined the most commonly used murine obesity models (diet-induced obesity, db/db, CPE(fat/fat), and ob/ob) using a Klebsiella pneumoniae pneumonia model and LPS-induced pneumonitis. Marrow-derived neutrophils from uninjured lean and obese mice were examined for in vitro functional responses. All obesity models showed impaired clearance of K. pneumoniae, but in differing temporal patterns. Failure to contain infection in obese mice was seen in the db/db model at both 24 and 48 hours, yet this defect was only evident at 24 hours in CPE(fat/fat) and ob/ob models, and at 48 hours in diet-induced obesity. LPS-induced airspace neutrophilia was decreased in all models, and associated with blood neutropenia in the ob/ob model but with leukocytosis in the others. Obese mouse neutrophils from all models demonstrated impaired chemotaxis, whereas neutrophil granulocyte colony-stimulating factor-mediated survival, LPS-induced cytokine transcription, and mitogen-activated protein kinase and signal transducer and activator of transcription 3 activation in response to LPS and granulocyte colony-stimulating factor, respectively, were variably impaired across the four models. Obesity-associated impairment of host response to lung infection is characterized by defects in neutrophil recruitment and survival. However, critical differences exist between commonly used mouse models of obesity and may reflect variable penetrance of elements of the metabolic syndrome, as well as other factors. PMID:27128821

  19. Preclinical Murine Models for Lung Cancer: Clinical Trial Applications

    PubMed Central

    Kellar, Amelia; Egan, Cay; Morris, Don

    2015-01-01

    Murine models for the study of lung cancer have historically been the backbone of preliminary preclinical data to support early human clinical trials. However, the availability of multiple experimental systems leads to debate concerning which model, if any, is best suited for a particular therapeutic strategy. It is imperative that these models accurately predict clinical benefit of therapy. This review provides an overview of the current murine models used to study lung cancer and the advantages and limitations of each model, as well as a retrospective evaluation of the uses of each model with respect to accuracy in predicting clinical benefit of therapy. A better understanding of murine models and their uses, as well as their limitations may aid future research concerning the development and implementation of new targeted therapies and chemotherapeutic agents for lung cancer. PMID:26064932

  20. Towards a porous media model of the human lung

    NASA Astrophysics Data System (ADS)

    DeGroot, Christopher T.; Straatman, Anthony G.

    2012-05-01

    In this article, progress towards building a complete porous media model of the human lung is discussed. While the recent trend in computational fluid dynamics studies of airflow in the human lung has been to continually increase the size and detail of the airway tree under consideration, it is proposed in this work that simulating flow in the human lung as a coupled fluid-porous system is an effective method to simulate the flow in the whole lung. Under the proposed modeling paradigm, a truncated airway tree constitutes a fluid region which is coupled to a porous region that represents the remainder of the lung volume, containing small airways and alveoli. The first part of this work describes pore-level simulations conducted in an alveolated duct geometry, which are present in large quantities in the human lung, to determine its permeability. Next, volume-averaged simulations incorporating the results of the pore-level simulations and using a realistic lung geometry based on computed tomography images are discussed along with future directions for this work.

  1. Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs.

    PubMed

    Ehre, Camille; Worthington, Erin N; Liesman, Rachael M; Grubb, Barbara R; Barbier, Diane; O'Neal, Wanda K; Sallenave, Jean-Michel; Pickles, Raymond J; Boucher, Richard C

    2012-10-01

    MUC5AC, a major gel-forming mucin expressed in the lungs, is secreted at increased rates in response to infectious agents, implying that mucins exert a protective role against inhaled pathogens. However, epidemiological and pathological studies suggest that excessive mucin secretion causes airways obstruction and inflammation. To determine whether increased MUC5AC secretion alone produces airway obstruction and/or inflammation, we generated a mouse model overexpressing Muc5ac mRNA ~20-fold in the lungs, using the rCCSP promoter. The Muc5ac cDNA was cloned from mouse lungs and tagged internally with GFP. Bronchoalveolar lavage fluid (BALF) analysis demonstrated an approximate 18-fold increase in Muc5ac protein, which formed high-molecular-weight polymers. Histopathological studies and cell counts revealed no airway mucus obstruction or inflammation in the lungs of Muc5ac-transgenic (Muc5ac-Tg) mice. Mucus clearance was preserved, implying that the excess Muc5ac secretion produced an "expanded" rather than more concentrated mucus layer, a prediction confirmed by electron microscopy. To test whether the larger mucus barrier conferred increased protection against pathogens, Muc5ac-Tg animals were challenged with PR8/H1N1 influenza viruses and showed significant decreases in infection and neutrophilic responses. Plaque assay experiments demonstrated that Muc5ac-Tg BALF and purified Muc5ac reduced infection, likely via binding to α2,3-linked sialic acids, consistent with influenza protection in vivo. In conclusion, the normal mucus transport and absence of a pulmonary phenotype in Muc5ac-Tg mice suggests that mucin hypersecretion alone is not sufficient to trigger luminal mucus plugging or airways inflammation/goblet cell hyperplasia. In contrast, increased Muc5ac secretion appears to exhibit a protective role against influenza infection. PMID:23012413

  2. Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs

    PubMed Central

    Ehre, Camille; Worthington, Erin N.; Liesman, Rachael M.; Grubb, Barbara R.; Barbier, Diane; O’Neal, Wanda K.; Sallenave, Jean-Michel; Pickles, Raymond J.; Boucher, Richard C.

    2012-01-01

    MUC5AC, a major gel-forming mucin expressed in the lungs, is secreted at increased rates in response to infectious agents, implying that mucins exert a protective role against inhaled pathogens. However, epidemiological and pathological studies suggest that excessive mucin secretion causes airways obstruction and inflammation. To determine whether increased MUC5AC secretion alone produces airway obstruction and/or inflammation, we generated a mouse model overexpressing Muc5ac mRNA ∼20-fold in the lungs, using the rCCSP promoter. The Muc5ac cDNA was cloned from mouse lungs and tagged internally with GFP. Bronchoalveolar lavage fluid (BALF) analysis demonstrated an approximate 18-fold increase in Muc5ac protein, which formed high-molecular-weight polymers. Histopathological studies and cell counts revealed no airway mucus obstruction or inflammation in the lungs of Muc5ac-transgenic (Muc5ac-Tg) mice. Mucus clearance was preserved, implying that the excess Muc5ac secretion produced an “expanded” rather than more concentrated mucus layer, a prediction confirmed by electron microscopy. To test whether the larger mucus barrier conferred increased protection against pathogens, Muc5ac-Tg animals were challenged with PR8/H1N1 influenza viruses and showed significant decreases in infection and neutrophilic responses. Plaque assay experiments demonstrated that Muc5ac-Tg BALF and purified Muc5ac reduced infection, likely via binding to α2,3-linked sialic acids, consistent with influenza protection in vivo. In conclusion, the normal mucus transport and absence of a pulmonary phenotype in Muc5ac-Tg mice suggests that mucin hypersecretion alone is not sufficient to trigger luminal mucus plugging or airways inflammation/goblet cell hyperplasia. In contrast, increased Muc5ac secretion appears to exhibit a protective role against influenza infection. PMID:23012413

  3. Tc-99m radioaerosol clearance as an index of pulmonary epithelial permeability

    SciTech Connect

    Waldman, D.L.

    1988-01-01

    This investigation examines radiopharmaceutical clearance as an index of alveolar-capillary membrane permeability and as an indicator of disease. Specific objectives include: evaluation of radiopharmaceutical chemical purity following aerosolization, investigation of a chemically related family of compounds to develop new radiopharmaceuticals with improved chemical properties, determination of reproducibility of the radiopharmaceutical clearance technique and the evaluation of the sensitivity of aerosolized solute clearance as an indicator of lung injury. The integrity of the radiopharmaceutical was examined prior to and following aerosol generation. The in vivo pharmacokinetics of a family of aerosolized solutes was evaluated in the beagle dog. The reproducibility of the biological response to radiopharmaceutical deposition was evaluated using dynamic functional imaging in humans and in the beagle. The sensitivity of the technique was evaluated using Tc-99m DTPA and an animal model for lung injury.

  4. Radioactivity and lung cancer-mathematical models of radionuclide deposition in the human lungs

    PubMed Central

    Sturm, Robert

    2011-01-01

    The human respiratory tract is regarded as pathway for radionuclides and other hazardous airborne materials to enter the body. Radioactive particles inhaled and deposited in the lungs cause an irradiation of bronchial/alveolar tissues. At the worst, this results in a malignant cellular transformation and, as a consequence of that, the development of lung cancer. In general, naturally occurring radionuclides (e.g., 222Rn, 40K) are attached to so-called carrier aerosols. The aerodynamic diameters of such radioactively labeled particles generally vary between several nanometers (ultrafine particles) and few micrometers, whereby highest particle fractions adopt sizes around 100 nm. Theoretical simulations of radioactive particle deposition in the human lungs were based on a stochastic lung geometry and a particle transport/deposition model using the random-walk algorithm. Further a polydisperse carrier aerosol (diameter: 1 nm–10 µm, ρ ≈ 1 g cm−3) with irregularly shaped particles and the effect of breathing characteristics and certain respiratory parameters on the transport of radioactive particles to bronchial/alveolar tissues were considered. As clearly shown by the results of deposition modeling, distribution patterns of radiation doses mainly depend on the size of the carrier aerosol. Ultrafine (< 10 nm) and large (> 2 µm) aerosol particles are preferentially deposited in the extrathoracic and upper bronchial region, whereas aerosol particles with intermediate size (10 nm–2 µm) may penetrate to deeper lung regions, causing an enhanced damage of the alveolar tissue by the attached radionuclides. PMID:22263097

  5. Lung deposition and clearance of microparticle and nanoparticle C60 fullerene aggregates in B6C3F1 mice and Wistar Han rats following nose-only inhalation for 13 weeks.

    PubMed

    Sayers, Brian C; Walker, Nigel J; Roycroft, Joseph H; Germolec, Dori R; Baker, Gregory L; Clark, Mark L; Hayden, Barry K; DeFord, Henry; Dill, Jeffrey A; Gupta, Amit; Stout, Matthew D

    2016-01-01

    C60 fullerenes (C60) are spherical structures consisting of 60 carbon atoms that are generated via combustion from both natural and anthropogenic sources. C60 are also synthesized intentionally for industrial applications. Individual C60 structures have an approximate diameter of 1nm; however, C60 readily forms aggregates and typically exist as larger particles that range from nanometers to micrometers in diameter. In this report, lung and extrapulmonary tissue deposition and lung clearance of C60 nanoparticles (nano-C60, 50nm) and microparticles (micro-C60, 1μm) were examined in Wistar Han rats and B6C3F1/N mice after nose-only inhalation for 90 days. Exposure concentrations were 0.5 and 2mg/m(3) (nano-C60) and 2, 15, and 30mg/m(3) (micro-C60). For both C60 particle sizes, the C60 lung burden increased proportionally to exposure concentration. The C60 lung burden was greater in both species at all time points following exposure to nano-C60 particle exposure compared to micro-C60 exposure at the common exposure concentration 2mg/m(3). The calculated C60 particle lung retention half-times were similar for both nano-C60 and micro-C60 exposure at 2mg/m(3) in male mice (15-16 days). In contrast, in male rats, the half-time of C60 particles following nano-C60 exposure (61 days) was roughly twice as long as the half-time following micro-C60 exposure (27 days) at the same exposure concentration (2mg/m(3)) and was similar to the clearance following micro-C60 exposure at higher exposure concentrations (15 and 30mg/m(3)). C60 was detected in bronchial lymph nodes but the burden was not quantified due to the high variability in the data. C60 concentrations were below the experimental limit of quantitation (ELOQ) in liver, spleen, blood, brain and kidney tissues. These tissue burden data provide information for comparison between nanometer and micrometer sized C60 particle exposure and will aid in the interpretation of toxicity data. PMID:26612504

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

    PubMed

    Wojtczak, Jacek A

    2014-12-01

    Lung sonography allows rapid diagnosis of lung emergencies such as pulmonary edema, hemothorax or pneumothorax. The ability to timely diagnose an intraoperative pneumothorax is an important skill for the anesthesiologist. However, lung ultrasound exams require an interpretation of not only real images but also complex acoustic artifacts such as A-lines and B-lines. Therefore, appropriate training to gain proficiency is important. Simulated environment using ultrasound phantom models allows controlled, supervised learning. We have developed hybrid models that combine dry or wet polyurethane foams, porcine rib cages and human hand simulating a rib cage. These models simulate fairly accurately pulmonary sonopathology and allow supervised teaching of lung sonography with the immediate feedback. In-vitro models can also facilitate learning of procedural skills, improving transducer and needle positioning and movement, rapid recognition of thoracic anatomy and hand - eye coordination skills. We described a new model to teach an ultrasound guided thoracentesis. This model consists of the experimenter's hand placed on top of the water-filled container with a wet foam. Metacarpal bones of the human hand simulate a rib cage and a wet foam simulates a diseased lung immersed in the pleural fluid. Positive fluid flow offers users feedback when a simulated pleural effusion is accurately assessed. PMID:26672739

  7. 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

  8. A microfluidic model to study fluid dynamics of mucus plug rupture in small lung airways

    PubMed Central

    Hu, Yingying; Bian, Shiyao; Grotberg, John; Filoche, Marcel; White, Joshua; Takayama, Shuichi; Grotberg, James B.

    2015-01-01

    Fluid dynamics of mucus plug rupture is important to understand mucus clearance in lung airways and potential effects of mucus plug rupture on epithelial cells at lung airway walls. We established a microfluidic model to study mucus plug rupture in a collapsed airway of the 12th generation. Mucus plugs were simulated using Carbopol 940 (C940) gels at concentrations of 0.15%, 0.2%, 0.25%, and 0.3%, which have non-Newtonian properties close to healthy and diseased lung mucus. The airway was modeled with a polydimethylsiloxane microfluidic channel. Plug motion was driven by pressurized air. Global strain rates and shear stress were defined to quantitatively describe plug deformation and rupture. Results show that a plug needs to overcome yield stress before deformation and rupture. The plug takes relatively long time to yield at the high Bingham number. Plug length shortening is the more significant deformation than shearing at gel concentration higher than 0.15%. Although strain rates increase dramatically at rupture, the transient shear stress drops due to the shear-thinning effect of the C940 gels. Dimensionless time-averaged shear stress, Txy, linearly increases from 3.7 to 5.6 times the Bingham number as the Bingham number varies from 0.018 to 0.1. The dimensionless time-averaged shear rate simply equals to Txy/2. In dimension, shear stress magnitude is about one order lower than the pressure drop, and one order higher than yield stress. Mucus with high yield stress leads to high shear stress, and therefore would be more likely to cause epithelial cell damage. Crackling sounds produced with plug rupture might be more detectable for gels with higher concentration. PMID:26392827

  9. ANATOMICAL MODELING OF MICRODOSIMETRY OF INHALED PARTICLES IN THE LUNG

    EPA Science Inventory

    Determining the dose delivered to specific sites in the lungs is a critical first step in modeling the potential toxic effects of airborne pollutants. n important recent development in estimating site specific dosimetry has been combining sophisticated analytical models to determ...

  10. Prediction of in vivo clearance and associated variability of CYP2C19 substrates by genotypes in populations utilizing a pharmacogenetics-based mechanistic model.

    PubMed

    Steere, Boyd; Baker, Jessica A Roseberry; Hall, Stephen D; Guo, Yingying

    2015-06-01

    It is important to examine the cytochrome P450 2C19 (CYP2C19) genetic contribution to drug disposition and responses of CYP2C19 substrates during drug development. Design of such clinical trials requires projection of genotype-dependent in vivo clearance and associated variabilities of the investigational drug, which is not generally available during early stages of drug development, but is essential for CYP2C19 substrates with multiple clearance pathways. This study evaluated the utility of pharmacogenetics-based mechanistic modeling in predicting such parameters. Hepatic CYP2C19 activity and variability within genotypes were derived from in vitro S-mephenytoin metabolic activity in genotyped human liver microsomes (N = 128). These data were then used in mechanistic models to predict genotype-dependent disposition of CYP2C19 substrates (i.e., S-mephenytoin, citalopram, pantoprazole, and voriconazole) by incorporating in vivo clearance or pharmacokinetics of wild-type subjects and parameters of other clearance pathways. Relative to the wild-type, the CYP2C19 abundance (coefficient of variation percentage) in CYP2C19*17/*17, *1/*17, *1/*1, *17/null, *1/null, and null/null microsomes was estimated as 1.85 (117%), 1.79 (155%), 1.00 (138%), 0.83 (80%), 0.38 (130%), and 0 (0%), respectively. The subsequent modeling and simulations predicted, within 2-fold of the observed, the means and variabilities of urinary S/R-mephenytoin ratio (36 of 37 genetic groups), the oral clearance of citalopram (9 of 9 genetic groups) and pantoprazole (6 of 6 genetic groups), and voriconazole oral clearance (4 of 4 genetic groups). Thus, relative CYP2C19 genotype-dependent hepatic activity and variability were quantified in vitro and used in a mechanistic model to predict pharmacokinetic variability, thus allowing the design of pharmacogenetics and drug-drug interaction trials for CYP2C19 substrates. PMID:25845826

  11. 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

  12. Mouse Model for ROS1-Rearranged Lung Cancer

    PubMed Central

    Takahashi, Hiroyuki; Nakamura, Hiromi; Hama, Natsuko; Kohno, Takashi; Tsuta, Koji; Yoshida, Akihiko; Asamura, Hisao; Mutoh, Michihiro; Hosoda, Fumie; Tsuda, Hitoshi; Shibata, Tatsuhiro

    2013-01-01

    Genetic rearrangement of the ROS1 receptor tyrosine kinase was recently identified as a distinct molecular signature for human non-small cell lung cancer (NSCLC). However, direct evidence of lung carcinogenesis induced by ROS1 fusion genes remains to be verified. The present study shows that EZR-ROS1 plays an essential role in the oncogenesis of NSCLC harboring the fusion gene. EZR-ROS1 was identified in four female patients of lung adenocarcinoma. Three of them were never smokers. Interstitial deletion of 6q22–q25 resulted in gene fusion. Expression of the fusion kinase in NIH3T3 cells induced anchorage-independent growth in vitro, and subcutaneous tumors in nude mice. This transforming ability was attributable to its kinase activity. The ALK/MET/ROS1 kinase inhibitor, crizotinib, suppressed fusion-induced anchorage-independent growth of NIH3T3 cells. Most importantly, established transgenic mouse lines specifically expressing EZR-ROS1 in lung alveolar epithelial cells developed multiple adenocarcinoma nodules in both lungs at an early age. These data suggest that the EZR-ROS1 is a pivotal oncogene in human NSCLC, and that this animal model could be valuable for exploring therapeutic agents against ROS1-rearranged lung cancer. PMID:23418494

  13. Renal Clearance of Nanoparticles

    PubMed Central

    Choi, Hak Soo; Liu, Wenhao; Misra, Preeti; Tanaka, Eiichi; Zimmer, John P.; Ipe, Binil Itty; Bawendi, Moungi G.; Frangioni, John V.

    2008-01-01

    SUMMARY The field of nanotechnology holds great promise for the diagnosis and treatment of human disease. However, the size and charge of most nanoparticles preclude their efficient clearance from the body as intact nanoparticles. Without such clearance or their biodegradation into biologically benign components, toxicity is potentially amplified and radiological imaging is hindered. Using quantum dots (QDs) as a model system, we have precisely defined the requirements for renal filtration and urinary excretion of inorganic, metal-containing nanoparticles. Zwitterionic or neutral organic coatings prevented adsorption of serum proteins, which otherwise increased hydrodynamic diameter (HD) by over 15 nm and prevented renal excretion. A final HD smaller than 5.5 nm resulted in rapid and efficient urinary excretion, and elimination of QDs from the body. This study provides a foundation for the design and development of biologically targeted nanoparticles for biomedical applications. PMID:17891134

  14. A protocol for a lung neovascularization model in rodents

    PubMed Central

    Jones, Rosemary C; Capen, Diane E; Petersen, Bodil; Jain, Rakesh K; Duda, Dan G

    2009-01-01

    By providing insight into the cellular events of vascular injury and repair, experimental model systems seek to promote timely therapeutic strategies for human disease. The goal of many current studies of neovascularization is to identify cells critical to the process and their role in vascular channel assembly. We propose here a protocol to analyze, in an in vivo rodent model, vessel and capillary remodeling (reorganization and growth) in the injured lung. Sequential analyses of stages in the assembly of vascular structures, and of relevant cell types, provide further opportunities to study the molecular and cellular determinants of lung neovascularization. PMID:18323809

  15. A simplified experimental model for clearance of some pathogenic bacteria using common bacterivorous ciliated spp. in Tigris river

    NASA Astrophysics Data System (ADS)

    Ali, Talib Hassan; Saleh, Dhuha Saad

    2014-03-01

    Bacteria-specific uptake rates of three different protozoan taxa on a pure and mixed bacterial community was studied by means of a simplified and functionally reproducible experimental model. The bacterial species Shigella flexneri, Escherichia coli and Salmonella typhi were isolated and classified from stool samples of patients suffering from diarrhea. Paramecium caudatum, Tetrahymena pyriformis and Halteria grandinella, free living ciliate Protozoans, were isolated and identified from Tigris river water. Pure and mixed ( E. coli + S. typhi), ( E. coli + Sh. flexneri) bacterial cultures were used with each ciliate genera to evaluate the following: predator duplication rate, prey reduction rate, clearance rate and net grazing rate. We used selective lactose fermentation phenomena of enteric bacteria on MacConkey medium for the quantification of bacteria cultural characteristics. The final bacteria concentration was reduced by growing protozoa of 98-99.9 % compared to protozoa-free controls. It showed that Tetrahymena pyriformis had the highest duplication rate (4.13 time/day) in both types of cultures (pure and mixed), followed by Paramecium caudatum and Halteria grandinella, respectively. Paramecium caudatum had the highest rate of ingestion in both types of cultures (26 × 103 bacteria/organism/hr) and yielded the longest time required for 90 % bacterial reduction in a pure suspension of S. typhi (166 h). Clearance rates of pathogenic bacteria by ciliates ranged between 106 nanoliter/organism/h by P. caudatum to S. typhi and 1.92 nanoliter/organism/h seen in T. pyriformis in ( E. coli + S. typhi) mixed culture. We used aquatic experimental microcosms under controlled conditions to explore bacteria-dependent ciliate growth and examined whether these ciliates could discriminate between equally sized bacterial preys in a mixture.

  16. 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. PMID:3597273

  17. Prediction of drug clearance in children.

    PubMed

    Foissac, Frantz; Bouazza, Naïm; Valade, Elodie; De Sousa Mendes, Mailys; Fauchet, Floris; Benaboud, Sihem; Hirt, Déborah; Tréluyer, Jean-Marc; Urien, Saïk

    2015-07-01

    The pediatric population is often exposed to drugs without sufficient knowledge about pharmacokinetics. The prediction of accurate clearance values in children, especially in neonates and infants, will improve the rational in dosing decisions. Drug clearances from birth to adulthood were compiled after a systematic review of pharmacokinetic reports. The analysis was performed using NONMEM. Clearance predictions were then evaluated by external validation. Prediction errors were also compared with those obtained from weight-based allometric scaling and physiologically based clearance (PBCL) models. For the analysis, 17 and 15 drugs were used for model building and external validation, respectively. A model based on the adult drug clearance value and taking into account both weight and age was retained. Age-related maturation of clearance reached 90% of the adult value within 1.5 years of life. For children less than 2 years old, allometric scaling alone systematically overestimated clearances. Accounting for age improved the clearance prediction in the 6 months-2 years age group (prediction error < 25%). Predictions obtained from the PBCL approach were close to our results. This analysis established a single equation using the adult clearance value as well as individual age and weight to predict drug clearance in children older than 6 months. PMID:25721251

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

    PubMed

    D'yachenko, A I; Manyuhina, O V

    2006-01-01

    Blast injuries of the lung are the most life-threatening after an explosion. The choice of physical parameters responsible for trauma is important to understand its mechanism. We developed a one-dimensional linear model of an elastic wave propagation in foam-like pulmonary parenchyma to identify the possible cause of edema due to the impact load. The model demonstrates different injury localizations for free and rigid boundary conditions. The following parameters were considered: strain, velocity, pressure in the medium and stresses in structural elements, energy dissipation, parameter of viscous criterion. Maximum underpressure is the most suitable wave parameter to be the criterion for edema formation in a rabbit lung. We supposed that observed scattering of experimental data on edema severity is induced by the physiological variety of rabbit lungs. The criterion and the model explain this scattering. The model outlines the demands for experimental data to make an unambiguous choice of physical parameters responsible for lung trauma due to impact load. PMID:16214154

  19. Mathematical model of the human lungs during phonation

    NASA Astrophysics Data System (ADS)

    Meshcheryakov, R. V.

    2012-08-01

    Modeling of the human lungs during phonation is considered. The main relationships during physiological phonation process and air passage through vocal folds are established. Results of investigation are presented for statements of various types corresponding to different intonation patterns of the statement.

  20. 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)

  1. Modeling Air Flow in the Lungs during In-exsufflation

    NASA Astrophysics Data System (ADS)

    Bukiet, Bruce; Chaudhry, Hans; Kirshblum, Steven; Bach, John

    2003-11-01

    Patients with weak respiratory systems experience build-up of fluid in the lungs. This can lead to infection and hospitalization. Although endotracheal suctioning can help relieve this problem, it is invasive and uncomfortable. Patients prefer the non-invasive mechanical in-exsufflation technique. In this talk, we describe these techniques for easing the problem of mucus build-up and present ideas for mathematical and computational modeling of the flow in the branches of the lungs during mechanical in-exsufflation. The implications of the results of the computations on the safety of the technique and on patient treatment are also discussed.

  2. An ex vivo human lung model for ultrasound-guided high-intensity focused ultrasound therapy using lung flooding.

    PubMed

    Wolfram, Frank; Reichenbach, Jürgen R; Lesser, Thomas G

    2014-03-01

    The usability of an ex vivo human lung model for ablation of lung cancer tissue with high-intensity focused ultrasound (HIFU) is described. Lung lobes were flooded with saline, with no gas remaining after complete atelectasis. The tumor was delineated sono-morphologically. Speed of sound, tissue density and ultrasound attenuation were measured for flooded lung and different pulmonary cancer tissues. The acoustic impedance of lung cancer tissue (1.6-1.9 mega-Rayleighs) was higher than that of water, as was its attenuation coefficient (0.31-0.44 dB/cm/MHz) compared with that of the flooded lung (0.12 dB/cm/MHz). After application of HIFU, the temperature in centrally located lung cancer surrounded by the flooded lung increased as high as 80°C, which is sufficient for treatment. On the basis of these preliminary results, ultrasound-guided HIFU ablation of lung cancer, by lung flooding with saline, appears feasible and should be explored in future clinical studies. PMID:24412177

  3. 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. PMID:26100614

  4. Pancreatitis-induced acute lung injury. An ARDS model.

    PubMed Central

    Guice, K S; Oldham, K T; Johnson, K J; Kunkel, R G; Morganroth, M L; Ward, P A

    1988-01-01

    Cerulein-induced acute pancreatitis in rats is associated with acute lung injury characterized by increased pulmonary microvascular permeability, increased wet lung weights, and histologic features of alveolar capillary endothelial cell and pulmonary parenchymal injury. The alveolar capillary permeability index is increased 1.8-fold after a 3-hour injury (0.30 to 0.54, p less than 0.05). Gravimetric analysis shows a similar 1.5-fold increase in wet lung weights at 3 hours (0.35% vs. 0.51% of total body weight, p less than 0.05). Histologic features assessed by quantitative morphometric analysis include significant intra-alveolar hemorrhage (0.57 +/- 0.08 vs. 0.12 +/- 0.02 RBC/alveolus at 6 hours, p less than 0.001); endothelial cell disruption (28.11% vs. 4.3%, p less than 0.001); and marked, early neutrophil infiltration (7.45 +/- 0.53 vs. 0.83 +/- 0.18 PMN/hpf at 3 hours, p less than 0.001). The cerulein peptide itself, a cholecystokinin (CCK) analog, is naturally occurring and is not toxic and in several in vitro settings including exposure to pulmonary artery endothelial cells, Type II epithelial cells, and an ex vivo perfused lung preparation. The occurrence of this ARDS-like acute lung injury with acute pancreatitis provides an excellent experimental model to investigate mechanisms and mediators involved in the pathogenesis of ARDS. Images Fig. 1. PMID:3389946

  5. Pancreatitis-induced acute lung injury. An ARDS model.

    PubMed

    Guice, K S; Oldham, K T; Johnson, K J; Kunkel, R G; Morganroth, M L; Ward, P A

    1988-07-01

    Cerulein-induced acute pancreatitis in rats is associated with acute lung injury characterized by increased pulmonary microvascular permeability, increased wet lung weights, and histologic features of alveolar capillary endothelial cell and pulmonary parenchymal injury. The alveolar capillary permeability index is increased 1.8-fold after a 3-hour injury (0.30 to 0.54, p less than 0.05). Gravimetric analysis shows a similar 1.5-fold increase in wet lung weights at 3 hours (0.35% vs. 0.51% of total body weight, p less than 0.05). Histologic features assessed by quantitative morphometric analysis include significant intra-alveolar hemorrhage (0.57 +/- 0.08 vs. 0.12 +/- 0.02 RBC/alveolus at 6 hours, p less than 0.001); endothelial cell disruption (28.11% vs. 4.3%, p less than 0.001); and marked, early neutrophil infiltration (7.45 +/- 0.53 vs. 0.83 +/- 0.18 PMN/hpf at 3 hours, p less than 0.001). The cerulein peptide itself, a cholecystokinin (CCK) analog, is naturally occurring and is not toxic and in several in vitro settings including exposure to pulmonary artery endothelial cells, Type II epithelial cells, and an ex vivo perfused lung preparation. The occurrence of this ARDS-like acute lung injury with acute pancreatitis provides an excellent experimental model to investigate mechanisms and mediators involved in the pathogenesis of ARDS. PMID:3389946

  6. Parallel Computation of Airflow in the Human Lung Model

    NASA Astrophysics Data System (ADS)

    Lee, Taehun; Tawhai, Merryn; Hoffman, Eric. A.

    2005-11-01

    Parallel computations of airflow in the human lung based on domain decomposition are performed. The realistic lung model is segmented and reconstructed from CT images as part of an effort to build a normative atlas (NIH HL-04368) documenting airway geometry over 4 decades of age in healthy and disease-state adult humans. Because of the large number of the airway generation and the sheer complexity of the geometry, massively parallel computation of pulmonary airflow is carried out. We present the parallel algorithm implemented in the custom-developed characteristic-Galerkin finite element method, evaluate the speed-up and scalability of the scheme, and estimate the computing resources needed to simulate the airflow in the conducting airways of the human lungs. It is found that the special tree-like geometry enables the inter-processor communications to occur among only three or four processors for optimal parallelization irrespective of the number of processors involved in the computation.

  7. Theoretical modeling of a gas clearance phase regulation mechanism for a pneumatically-driven split-Stirling-cycle cryocooler

    NASA Astrophysics Data System (ADS)

    Zhang, Cun-quan; Zhong, Cheng

    2015-03-01

    The concept of a new type of pneumatically-driven split-Stirling-cycle cryocooler with clearance-phase-adjustor is proposed. In this implementation, the gap between the phase-adjusting part and the cylinder of the spring chamber is used, instead of dry friction acting on the pneumatically-driven rod to control motion damping of the displacer and to adjust the phase difference between the compression piston and displacer. It has the advantages of easy damping adjustment, low cost, and simplified manufacturing and assembly. A theoretical model has been established to simulate its dynamic performance. The linear compressor is modeled under adiabatic conditions, and the displacement of the compression piston is experimentally rectified. The working characteristics of the compressor motor and the principal losses of cooling, including regenerator inefficiency loss, solid conduction loss, shuttle loss, pump loss and radiation loss, are taken into account. The displacer motion was modeled as a single-degree-of-freedom (SDOF) forced system. A set of governing equations can be solved numerically to simulate the cooler's performance. The simulation is useful for understanding the physical processes occurring in the cooler and for predicting the cooler's performance.

  8. Effective Rat Lung Tumor Model for Stereotactic Body Radiation Therapy.

    PubMed

    Zhang, Zhang; Wodzak, Michelle; Belzile, Olivier; Zhou, Heling; Sishc, Brock; Yan, Hao; Stojadinovic, Strahinja; Mason, Ralph P; Brekken, Rolf A; Chopra, Rajiv; Story, Michael D; Timmerman, Robert; Saha, Debabrata

    2016-06-01

    Stereotactic body radiation therapy (SBRT) has found an important role in the treatment of patients with non-small cell lung cancer, demonstrating improvements in dose distribution and even tumor cure rates, particularly for early-stage disease. Despite its emerging clinical efficacy, SBRT has primarily evolved due to advances in medical imaging and more accurate dose delivery, leaving a void in knowledge of the fundamental biological mechanisms underlying its activity. Thus, there is a critical need for the development of orthotropic animal models to further probe the biology associated with high-dose-per-fraction treatment typical of SBRT. We report here on an improved surgically based methodology for generating solitary intrapulmonary nodule tumors, which can be treated with simulated SBRT using the X-RAD 225Cx small animal irradiator and Small Animal RadioTherapy (SmART) Plan treatment system. Over 90% of rats developed solitary tumors in the right lung. Furthermore, the tumor response to radiation was monitored noninvasively via bioluminescence imaging (BLI), and complete ablation of tumor growth was achieved with 36 Gy (3 fractions of 12 Gy each). We report a reproducible, orthotopic, clinically relevant lung tumor model, which better mimics patient treatment regimens. This system can be utilized to further explore the underlying biological mechanisms relevant to SBRT and high-dose-per-fraction radiation exposure and to provide a useful model to explore the efficacy of radiation modifiers in the treatment of non-small cell lung cancer. PMID:27223828

  9. A method for avoiding overlap of left and right lungs in shape model guided segmentation of lungs in CT volumes

    PubMed Central

    Gill, Gurman; Bauer, Christian; Beichel, Reinhard R.

    2014-01-01

    Purpose: The automated correct segmentation of left and right lungs is a nontrivial problem, because the tissue layer between both lungs can be quite thin. In the case of lung segmentation with left and right lung models, overlapping segmentations can occur. In this paper, the authors address this issue and propose a solution for a model-based lung segmentation method. Methods: The thin tissue layer between left and right lungs is detected by means of a classification approach and utilized to selectively modify the cost function of the lung segmentation method. The approach was evaluated on a diverse set of 212 CT scans of normal and diseased lungs. Performance was assessed by utilizing an independent reference standard and by means of comparison to the standard segmentation method without overlap avoidance. Results: For cases where the standard approach produced overlapping segmentations, the proposed method significantly (p = 1.65 × 10−9) reduced the overlap by 97.13% on average (median: 99.96%). In addition, segmentation accuracy assessed with the Dice coefficient showed a statistically significant improvement (p = 7.5 × 10−5) and was 0.9845 ± 0.0111. For cases where the standard approach did not produce an overlap, performance of the proposed method was not found to be significantly different. Conclusions: The proposed method improves the quality of the lung segmentations, which is important for subsequent quantitative analysis steps. PMID:25281960

  10. Automated 3-D Segmentation of Lungs With Lung Cancer in CT Data Using a Novel Robust Active Shape Model Approach

    PubMed Central

    Sun, Shanhui; Bauer, Christian; Beichel, Reinhard

    2013-01-01

    Segmentation of lungs with (large) lung cancer regions is a nontrivial problem. We present a new fully automated approach for segmentation of lungs with such high-density pathologies. Our method consists of two main processing steps. First, a novel robust active shape model (RASM) matching method is utilized to roughly segment the outline of the lungs. The initial position of the RASM is found by means of a rib cage detection method. Second, an optimal surface finding approach is utilized to further adapt the initial segmentation result to the lung. Left and right lungs are segmented individually. An evaluation on 30 data sets with 40 abnormal (lung cancer) and 20 normal left/right lungs resulted in an average Dice coefficient of 0.975 ± 0.006 and a mean absolute surface distance error of 0.84 ± 0.23 mm, respectively. Experiments on the same 30 data sets showed that our methods delivered statistically significant better segmentation results, compared to two commercially available lung segmentation approaches. In addition, our RASM approach is generally applicable and suitable for large shape models. PMID:21997248

  11. Mucociliary clearance mechanism in smoking and nonsmoking normal subjects

    SciTech Connect

    Isawa, T.; Teshima, T.; Hirano, T.; Ebina, A.; Konno, K.

    1984-03-01

    Mucociliary clearance mechanisms were evaluated in 17 normal subjects visually and qualitatively by radioaerosol inhalation cinescintigraphy of the lung, and quantitatively by calculating the following indices: (a) overall or regional lung retention ratio; (b) airway deposition ratio; (c) airway retention ratio; (d) airway clearance efficiency; and (e) alveolar deposition ratio. The inhaled aerosol deposited homogeneously throughout the lungs, and mucus transport was always cephalad in direction and constant in velocity, although a temporary stasis of mucus was seen in smokers. Overall lung retention ratio was significantly smaller and airway deposition ratio was significantly larger in the smokers than in nonsmokers, but there was no difference between the groups in airway retention ratio or airway clearance efficiency. There was an inverse relationship between alveolar deposition ratio and cigarette consumption. Mucociliary clearance mechanisms were well maintained in the normal subjects, but in the smokers inhaled aerosol tended to deposit more proximally.

  12. Modelling and experimental verification of an asymmetric Jeffcott rotor with radial clearance

    NASA Astrophysics Data System (ADS)

    Páez Chávez, Joseph; Vaziri Hamaneh, Vahid; Wiercigroch, Marian

    2015-01-01

    This paper presents a new mathematical model of a Jeffcott rotor within a snubber ring with anisotropic support. The derivation and validation of the model are based on an experimental rig designed and developed in Aberdeen University. Special attention is given to the estimation of the physical parameters of the snubber ring support, which reveals the presence of damping effects that are incorporated in the mathematical model. Furthermore, the numerical implementation of the model is described and mathematically justified in detail. The experimental investigation shows a sequence of different dynamical scenarios obtained under variation of the rotational speed, which in turn is satisfactorily reproduced by the theoretical model. The experimental and numerical results demonstrate the predictive capabilities of the model around the onset of impacts between the rotor and the snubber ring, which is one of the most common unwanted phenomena encountered in industrial applications of rotating machinery.

  13. The effect of solubility on inhaled uranium compound clearance: a review.

    PubMed

    Eidson, A F

    1994-07-01

    Research on inhaled industrial uranium compounds has shown that solubility influences the target organ, the toxic response, and the mode of uranium excretion. Consideration of physical chemical properties indicates that the dissolution of industrial uranium oxides is expected to be strongly dependent on process history, and that dissolved uranium exists in vivo in the hexavalent state regardless of the oxidation state of the inhaled compound. The overall clearance rate of uranium compounds from the lung reflects both mechanical and dissolution processes. Mechanical clearance rates are highly variable among individual workers studied, but dissolution rates of inhaled compounds are similar among the mammalian species studied. Results from experiments in vivo and accidental worker exposures indicate that the uptake of dissolved uranium from the lung is more rapid than the dissolution rate of most industrial uranium compounds. These results indicate that the absorption rate of inhaled uranium can be approximated by the dissolution rate of most industrial compounds. Dissolution rates of UF6 and UO2(NO3)2 are more rapid than the mechanical clearance rates and dominate the overall lung clearance rate. UF4, UO3, and ammonium diuranate have intermediate dissolution rates that are similar to mechanical clearance rates and exhibit high variability among uranium specimens. U3O8 and UO2 have slow dissolution rates such that pulmonary clearance rates are dominated by mechanical processes. Industrial uranium ores, oxides, and fluorides are often variable mixtures of relatively soluble and insoluble fractions. Dissolution rates measured in vitro can be used with biokinetics models to reduce the uncertainties in dosimetry associated with inhalation exposures to mixtures. PMID:8200796

  14. 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

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

    PubMed Central

    2014-01-01

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

  16. 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. PMID:25526737

  17. 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

  18. F/A-18 E/F flutter clearance model in the Langley TDT

    NASA Technical Reports Server (NTRS)

    1994-01-01

    An 18 percent aeroelastically-scaled, full span F/A-18 E/F model was tested during multiple wind-tunnel entries in the Langley Transonic Dynamics Tunnel. The primary purpose of these entries was to assist in clearing the flight vehicle design of flutter within its operating envelope. The wind-tunnel model was tested on a string and on a cable- mount system The model is shown on the cable-mount system with Langley engineer, Stanley Cole, checking tension in one of the support cables. All lifting surfaces were flutter cleared up to M=1.2 with the model string mounted. The model was then flutter cleared on the cable- mount system to assess the influence of rigid-body dynamics and fuselage flexibility on flutter. Several configuration parametric studies were also completed, including many external store configurations.

  19. 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

  20. F/A-18 E/F flutter clearance model in the Langley TDT

    NASA Technical Reports Server (NTRS)

    1994-01-01

    An 18 percent aeroelastically-scaled, full span F/A-18 E/F model was tested during multiple wind-tunnel entries in the Langley Transonic Dynamics Tunnel. The primary purpose of these entries was to assist in clearing the flight vehicle design of flutter within its operating envelope. The wind-tunnel model was tested on a string and on a cable-mount system (as shown). All lifting surfaces were flutter cleared up to M=1.2 with the model string mounted. The model was then flutter cleared on the cable-mount system to assess the influence of rigid-body dynamics and fuselage flexibility on flutter. Several configuration parametric studies were also completed, including many external store configurations.

  1. Antibody-mediated immune suppression of erythrocyte alloimmunization can occur independently from red cell clearance or epitope masking in a murine model.

    PubMed

    Yu, Honghui; Stowell, Sean R; Bernardo, Lidice; Hendrickson, Jeanne E; Zimring, James C; Amash, Alaa; Uchikawa, Makoto; Lazarus, Alan H

    2014-09-15

    Anti-D can prevent immunization to the RhD Ag on RBCs, a phenomenon commonly termed Ab-mediated immune suppression (AMIS). The most accepted theory to explain this effect has been the rapid clearance of RBCs. In mouse models using SRBC, these xenogeneic cells are always rapidly cleared even without Ab, and involvement of epitope masking of the SRBC Ags by the AMIS-inducing Ab (anti-SRBC) has been suggested. To address these hypotheses, we immunized mice with murine transgenic RBCs expressing the HOD Ag (hen egg lysozyme [HEL], in sequence with ovalbumin, and the human Duffy transmembrane protein) in the presence of polyclonal Abs or mAbs to the HOD molecule. The isotype, specificity, and ability to induce AMIS of these Abs were compared with accelerated clearance as well as steric hindrance of the HOD Ag. Mice made IgM and IgG reactive with the HEL portion of the molecule only. All six of the mAbs could inhibit the response. The HEL-specific Abs (4B7, IgG1; GD7, IgG2b; 2F4, IgG1) did not accelerate clearance of the HOD-RBCs and displayed partial epitope masking. The Duffy-specific Abs (MIMA 29, IgG2a; CBC-512, IgG1; K6, IgG1) all caused rapid clearance of HOD RBCs without steric hindrance. To our knowledge, this is the first demonstration of AMIS to erythrocytes in an all-murine model and shows that AMIS can occur in the absence of RBC clearance or epitope masking. The AMIS effect was also independent of IgG isotype and epitope specificity of the AMIS-inducing Ab. PMID:25122924

  2. Organoids as a model system for studying human lung development and disease.

    PubMed

    Nadkarni, Rohan R; Abed, Soumeya; Draper, Jonathan S

    2016-05-01

    The lung is a complex organ comprising multiple cell types that perform a variety of vital processes, including immune defense and gas exchange. Diseases of the lung, such as chronic obstructive pulmonary disease, asthma and lung cancer, together represent one of the largest causes of patient suffering and mortality. Logistical barriers that hamper access to embryonic, normal adult or diseased lung tissue currently hinder the study of lung disease. In vitro lung modeling represents an attractive and accessible avenue for investigating lung development, function and disease pathology, but accurately modeling the lung in vitro requires a system that recapitulates the structural features of the native lung. Organoids are stem cell-derived three-dimensional structures that are supported by an extracellular matrix and contain multiple cell types whose spatial arrangement and interactions mimic those of the native organ. Recently, organoids representative of the respiratory system have been generated from adult lung stem cells and human pluripotent stem cells. Ongoing studies are showing that organoids may be used to model human lung development, and can serve as a platform for interrogating the function of lung-related genes and signalling pathways. In a therapeutic context, organoids may be used for modeling lung diseases, and as a platform for screening for drugs that alleviate respiratory disease. Here, we summarize the organoid-forming capacity of respiratory cells, current lung organoid technologies and their potential use in future therapeutic applications. PMID:26721435

  3. Modeling soil magnetic susceptibility and frequency-dependent susceptibility to aid landmine clearance.

    NASA Astrophysics Data System (ADS)

    Hannam, Jacqueline A.; Dearing, John A.

    2006-05-01

    Information on the electromagnetic properties of soils and their effects on metal detectors is increasingly necessary for effective demining due to limited detector efficacy in highly magnetic soils and the difficulty of detecting minimummetal mines. Magnetic measurements of soils, such as magnetic susceptibility and frequency dependent susceptibility can aid the detection of problem soils, but are not part of standard soil analyses. Consequently, little information about soil magnetism exists within the soil, environmental science and environmental geophysics communities. Lack of empirical data may be compensated through the estimation of soil magnetic characteristics by predictive modeling approaches. Initial modeling of soil types in Bosnia and Herzegovina (BiH) was attempted by expert and analogue approaches, using only coarse scale soil type information, which resulted in the production of national soil maps for low field and frequency-dependent susceptibility. Validation of the maps was achieved by comparison of empirical magnetic data from soil samples in the National Bosnian soil archive in Sarajevo. Discrepancies between the model and empirical data are explained in part by the differences in soil parent material within each soil type, which controls the amount of Fe released into the soil system available for in situ conversion to magnetic Fe oxides. The integration of soil information (type and parent material), expert knowledge and empirical data refines the predictive modeling of soil magnetic characteristics in temperate-Mediterranean environments such as BiH. Further spatial separation of soil types in the landscape can be achieved by digital terrain modeling. Preliminary fine-scale, landscape-soil modeling indicates improved spatial resolution of soil types compared with the original coarsely-mapped soil units, and the potential to synthesize local scale soil magnetic maps.

  4. Mucus clearance, MyD88-dependent and MyD88-independent immunity modulate lung susceptibility to spontaneous bacterial infection and inflammation

    PubMed Central

    Livraghi-Butrico, Alessandra; Kelly, E. Jane; Klem, Erich R.; Dang, Hong; Wolfgang, Matthew C.; Boucher, Richard C.; Randell, Scott H.; O’Neal, Wanda K.

    2012-01-01

    It has been postulated that mucus stasis is central to the pathogenesis of obstructive lung diseases. In Scnn1b-transgenic (Scnn1b-Tg+) mice, airway-targeted overexpression of the epithelial Na+ channel β subunit causes airway surface dehydration, which results in mucus stasis and inflammation. Bronchoalveolar lavage from neonatal Scnn1b-Tg+ mice, but not wild-type littermates, contained increased mucus, bacteria, and neutrophils, which declined with age. Scnn1b-Tg+ mice lung bacterial flora included environmental and oropharyngeal species, suggesting inhalation and/or aspiration as routes of entry. Genetic deletion of the Toll/Interleukin-1 receptor adapter molecule MyD88 in Scnn1b-Tg+ mice did not modify airway mucus obstruction, but caused defective neutrophil recruitment and increased bacterial infection, which persisted into adulthood. Scnn1b-Tg+ mice derived into germ-free conditions exhibited mucus obstruction similar to conventional Scnn1b-Tg+ mice and sterile inflammation. Collectively, these data suggest that dehydration-induced mucus stasis promotes infection, compounds defects in other immune mechanisms, and alone is sufficient to trigger airway inflammation. PMID:22419116

  5. Bevacizumab clearance through the iridocorneal angle following intravitreal injection in a rat model.

    PubMed

    Gal-Or, Orly; Dotan, Assaf; Dachbash, Mor; Tal, Kfir; Nisgav, Yael; Weinberger, Dov; Ehrlich, Rita; Livnat, Tami

    2016-04-01

    Antivascular endothelial growth factor (Anti-VEGF) agents have been widely used for a variety of ocular disorders. The etiology of sustained ocular hypertension following intravitreal administration of anti-VEGF agents is yet to be unraveled. Our study investigates and characterizes the presence of intravitreally injected bevacizumab in the aqueous outflow channels of a rat model. Choroidal neovascularization (CNV) was induced by diode laser photocoagulation to the right eye of twelve Brown Norway rats. Bevacizumab (25 mg/ml) was injected intravitreally after 3 days. Immediately after bevacizumab injection, and 3, 6, 24 and 48 h later, animals were euthanized for immunofluorescence staining. Donkey anti-human IgG labeled with Alexa Fluor(®) 488 was used for bevacizumab immunoreactivity detection. Anti-CD31 antibody was used as a marker for Schlemm's canal endothelial cells. Untreated eyes were used as negative controls. The intensity of the immunostaining was analyzed qualitatively. Bevacizumab immunoreactivity was found in the aqueous outflow channels including the trabecular meshwork and Schlemm's canal immediately after injection, and declined incrementally within the following hours. Forty-eight hours after the injection, no bevacizumab staining was detected in the aqueous outflow channel structures. Our manuscript demonstrates the presence of bevacizumab in the trabecular meshwork and Schlemm's canal structures after intravitreal injection in a CNV induced rat model. Bevacizumab molecules passed through the aqueous outflow channels within 48 h after intravitreal bevacizumab injection. PMID:26923799

  6. 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. PMID:22767866

  7. A Simulation Model of Periarterial Clearance of Amyloid-β from the Brain

    PubMed Central

    Diem, Alexandra K.; Tan, Mingyi; Bressloff, Neil W.; Hawkes, Cheryl; Morris, Alan W. J.; Weller, Roy O.; Carare, Roxana O.

    2016-01-01

    The accumulation of soluble and insoluble amyloid-β (Aβ) in the brain indicates failure of elimination of Aβ from the brain with age and Alzheimer's disease (AD). There is a variety of mechanisms for elimination of Aβ from the brain. They include the action of microglia and enzymes together with receptor-mediated absorption of Aβ into the blood and periarterial lymphatic drainage of Aβ. Although the brain possesses no conventional lymphatics, experimental studies have shown that fluid and solutes, such as Aβ, are eliminated from the brain along 100 nm wide basement membranes in the walls of cerebral capillaries and arteries. This lymphatic drainage pathway is reflected in the deposition of Aβ in the walls of human arteries with age and AD as cerebral amyloid angiopathy (CAA). Initially, Aβ diffuses through the extracellular spaces of gray matter in the brain and then enters basement membranes in capillaries and arteries to flow out of the brain. Although diffusion through the extracellular spaces of the brain has been well characterized, the exact mechanism whereby perivascular elimination of Aβ occurs has not been resolved. Here we use a computational model to describe the process of periarterial drainage in the context of diffusion in the brain, demonstrating that periarterial drainage along basement membranes is very rapid compared with diffusion. Our results are a validation of experimental data and are significant in the context of failure of periarterial drainage as a mechanism underlying the pathogenesis of AD as well as complications associated with its immunotherapy. PMID:26903861

  8. A Simulation Model of Periarterial Clearance of Amyloid-β from the Brain.

    PubMed

    Diem, Alexandra K; Tan, Mingyi; Bressloff, Neil W; Hawkes, Cheryl; Morris, Alan W J; Weller, Roy O; Carare, Roxana O

    2016-01-01

    The accumulation of soluble and insoluble amyloid-β (Aβ) in the brain indicates failure of elimination of Aβ from the brain with age and Alzheimer's disease (AD). There is a variety of mechanisms for elimination of Aβ from the brain. They include the action of microglia and enzymes together with receptor-mediated absorption of Aβ into the blood and periarterial lymphatic drainage of Aβ. Although the brain possesses no conventional lymphatics, experimental studies have shown that fluid and solutes, such as Aβ, are eliminated from the brain along 100 nm wide basement membranes in the walls of cerebral capillaries and arteries. This lymphatic drainage pathway is reflected in the deposition of Aβ in the walls of human arteries with age and AD as cerebral amyloid angiopathy (CAA). Initially, Aβ diffuses through the extracellular spaces of gray matter in the brain and then enters basement membranes in capillaries and arteries to flow out of the brain. Although diffusion through the extracellular spaces of the brain has been well characterized, the exact mechanism whereby perivascular elimination of Aβ occurs has not been resolved. Here we use a computational model to describe the process of periarterial drainage in the context of diffusion in the brain, demonstrating that periarterial drainage along basement membranes is very rapid compared with diffusion. Our results are a validation of experimental data and are significant in the context of failure of periarterial drainage as a mechanism underlying the pathogenesis of AD as well as complications associated with its immunotherapy. PMID:26903861

  9. Noninvasive clearance of airway secretions.

    PubMed

    Hardy, K A; Anderson, B D

    1996-06-01

    Airway clearance techniques are indicated for specific diseases that have known clearance abnormalities (Table 2). Murray and others have commented that such techniques are required only for patients with a daily sputum production of greater than 30 mL. The authors have observed that patients with diseases known to cause clearance abnormalities can have sputum clearance with some techniques, such as positive expiratory pressure, autogenic drainage, and active cycle of breathing techniques, when PDPV has not been effective. Hasani et al has shown that use of the forced exhalatory technique in patients with nonproductive cough still resulted in movement of secretions proximally from all regions of the lung in patients with airway obstruction. It is therefore reasonable to consider airway clearance techniques for any patient who has a disease known to alter mucous clearance, including CF, dyskinetic cilia syndromes, and bronchiectasis from any cause. Patients with atelectasis from mucous plugs and hypersecretory states, such as asthma and chronic bronchitis, patients with pain secondary to surgical procedures, and patients with neuromuscular disease, weak cough, and abnormal patency of the airway may also benefit from the application of airway clearance techniques. Infants and children up to 3 years of age with airway clearance problems need to be treated with PDPV. Manual percussion with hands alone or a flexible face mask or cup and small mechanical vibrator/percussors, such as the ultrasonic devices, can be used. The intrapulmonary percussive ventilator shows growing promise in this area. The high-frequency oscillator is not supplied with vests of appropriate sizes for tiny babies and has not been studied in this group. Young patients with neuromuscular disease may require assisted ventilation and airway oscillations can be applied. CPAP alone has been shown to improve achievable flow rates that will increase air-liquid interactions for patients with these diseases

  10. A three-dimensional model of tracheobronchial particle distribution during mucociliary clearance in the human respiratory tract.

    PubMed

    Sturm, Robert

    2013-05-01

    Although theoretical approaches to tracheobronchial (TB) clearance have been continuously refined during the past decades, questions concerning the exact course of particle removal from the TB tree have been largely remained unsolved. In order to clarify this problem, three-dimensional patterns of mucociliary particle clearance have to be generated at pre-defined time points after particle exposure. Here, we present a mathematical method for the generation of respective clearance patterns. Three-dimensional transport paths of inhaled particles as well as spatial deposition patterns were generated by determining spatial information of all airway tubes passed by the particles and the particle deposition sites. Three-dimensional data were converted to a coordinate system, within which the trachea represented the z-axis. Visualization of stored data was realized with the help of a freely available program code that is specialized in processing huge data sets. Mucociliary clearance of deposited particular mass was computed by assuming (1) an interrelationship between mucus velocity and airway caliber and (2) an average tracheal mucus velocity of 5.5mm min(-1). Position of cleared particles within the spatial TB tree was determined at t=0 h (immediately after exposure), t=12 h and t=24 h. Spatial patterns of mucociliary clearance were computed for particles with a uniform geometric diameter of 5μm and a density of 1g cm(-3). Inhalation of the aerosol loaded with those particles took place under sitting breathing conditions (breathing frequency: 15min(-1), tidal volume: 750 ml). As demonstrated by the generated clearance patterns, mucociliary transport of 5μm particles is completed after 30 h. Within the first 12 h following aerosol exposure, about 75% of the initially deposited particular mass is removed from the TB tree. After 24 h, 95% of the particles have been cleared. Clearance patterns are characterized by a successive transition of maximal particle

  11. TLR4 PROMOTES CRYPTOSPORIDIUM PARVUM CLEARANCE IN A MOUSE MODEL OF BILIARY CRYPTOSPORIDIOSIS

    PubMed Central

    O’Hara, Steven P.; Tietz Bogert, Pamela S.; Chen, Xianming; LaRusso, Nicholas F.

    2011-01-01

    Cholangiocytes, the epithelial cells lining intrahepatic bile ducts, express multiple toll-like receptors (TLRs) and thus have the capacity to recognize and respond to microbial pathogens. In previous work we demonstrated that TLR4, which is activated by gram-negative lipopolysaccharide (LPS), is upregulated in cholangiocytes in response to infection with Cryptosporidium parvum in vitro and contributes to NFkB activation. Here, using an in vivo model of biliary cryptosporidiosis we addressed the functional role of TLR4 in C. parvum infection dynamics and hepatobiliary pathophysiology. We observed that C57BL mice clear the infection by three weeks post-infection. In contrast, parasites were detected in bile and stool in TLR4 deficient mice at four weeks post-infection. The liver enzymes, alanine transaminase (ALT) and aspartate transaminase (AST), and the proinflammatory cytokines Tumor Necrosis Factor (TNF)-α, Interferon (IFN)-γ, and Interleukin (IL)-6 peaked at one to two weeks postinfection and normalized by four weeks in infected C57BL mice. C57BL mice also demonstrated increased cholangiocyte proliferation (PCNA staining) at one-week post-infection, which was resolved by two weeks post-infection. In contrast, TLR4 deficient mice showed persistently elevated serum ALT and AST, elevated hepatic IL-6 levels, and histological evidence of hepatocyte necrosis, increased inflammatory cell infiltration, and cholangiocyte proliferation through four weeks post-infection. These data suggest that a TLR4-mediated response is required for efficient eradication of biliary C. parvum infection in vivo, and lack of this pattern recognition receptor contributes to an altered inflammatory response and an increase in hepatobiliary pathology. PMID:21506806

  12. Altered hepatic clearance and killing of Candida albicans in the isolated perfused mouse liver model.

    PubMed Central

    Sawyer, R T; Horst, M N; Garner, R E; Hudson, J; Jenkins, P R; Richardson, A L

    1990-01-01

    The adherence of Candida albicans was studied in situ by using the perfused mouse liver model. After exhaustive washing, 10(6) C. albicans were infused into mouse livers. At the time of recovery, 62 +/- 5% (mean +/- standard error of the mean) of the infused C. albicans were recovered from the liver and 14 +/- 3% were recovered from the effluent for a total recovery of 76 +/- 4%. This indicates that 86 +/- 3% of the original inoculum was trapped by the liver and that 24 +/- 4% was killed within the liver. Chemical pretreatment of C. albicans with 8 M urea, 12 mM dithiothreitol, 2% beta-mercaptoethanol, 1% sodium dodecyl sulfate, 10% Triton X-100, or 3 M potassium chloride or enzyme pretreatment with alpha-mannosidase, alpha-chymotrypsin, subtilisin, beta-N-acetyl-glucosaminidase, pronase, trypsin, papain, or lipase did not alter adherence of C. albicans to hepatic tissue. By contrast, pepsin pretreatment significantly decreased hepatic trapping. Simultaneous perfusion with either 100 mg of C. albicans glycoprotein per liter or 100 mg of C. albicans mannan per liter also decreased trapping. Furthermore, both substances eluted previously trapped C. albicans from hepatic tissue. Chemical pretreatment with 8 M urea, 12 mM dithiothreitol, or 3 M KCI or enzymatic pretreatment with alpha-mannosidase, subtilisin, alpha-chymotrypsin, or papain increased killing of C. albicans three- to fivefold within hepatic tissue. The data suggest that mannose-containing structures on the surface of C. albicans, for example. mannans or glucomannoproteins, mediate adherence of C. albicans within the liver. Indirectly, chemical and enzymatic pretreatment renders C. albicans more susceptible to hepatic killing. PMID:2117571

  13. Modeling the impact of hepatitis C viral clearance on end-stage liver disease in an HIV co-infected cohort with Targeted Maximum Likelihood Estimation

    PubMed Central

    Schnitzer, Mireille E; Moodie, Erica EM; van der Laan, Mark J; Platt, Robert W; Klein, Marina B

    2013-01-01

    Summary Despite modern effective HIV treatment, hepatitis C virus (HCV) co-infection is associated with a high risk of progression to end-stage liver disease (ESLD) which has emerged as the primary cause of death in this population. Clinical interest lies in determining the impact of clearance of HCV on risk for ESLD. In this case study, we examine whether HCV clearance affects risk of ESLD using data from the multicenter Canadian Co-infection Cohort Study. Complications in this survival analysis arise from the time-dependent nature of the data, the presence of baseline confounders, loss to follow-up, and confounders that change over time, all of which can obscure the causal effect of interest. Additional challenges included non-censoring variable missingness and event sparsity. In order to efficiently estimate the ESLD-free survival probabilities under a specific history of HCV clearance, we demonstrate the doubly-robust and semiparametric efficient method of Targeted Maximum Likelihood Estimation (TMLE). Marginal structural models (MSM) can be used to model the effect of viral clearance (expressed as a hazard ratio) on ESLD-free survival and we demonstrate a way to estimate the parameters of a logistic model for the hazard function with TMLE. We show the theoretical derivation of the efficient influence curves for the parameters of two different MSMs and how they can be used to produce variance approximations for parameter estimates. Finally, the data analysis evaluating the impact of HCV on ESLD was undertaken using multiple imputations to account for the non-monotone missing data. PMID:24571372

  14. Choroid plexus dysfunction impairs beta-amyloid clearance in a triple transgenic mouse model of Alzheimer's disease.

    PubMed

    González-Marrero, Ibrahim; Giménez-Llort, Lydia; Johanson, Conrad E; Carmona-Calero, Emilia María; Castañeyra-Ruiz, Leandro; Brito-Armas, José Miguel; Castañeyra-Perdomo, Agustín; Castro-Fuentes, Rafael

    2015-01-01

    Compromised secretory function of choroid plexus (CP) and defective cerebrospinal fluid (CSF) production, along with accumulation of beta-amyloid (Aβ) peptides at the blood-CSF barrier (BCSFB), contribute to complications of Alzheimer's disease (AD). The AD triple transgenic mouse model (3xTg-AD) at 16 month-old mimics critical hallmarks of the human disease: β-amyloid (Aβ) plaques and neurofibrillary tangles (NFT) with a temporal- and regional- specific profile. Currently, little is known about transport and metabolic responses by CP to the disrupted homeostasis of CNS Aβ in AD. This study analyzed the effects of highly-expressed AD-linked human transgenes (APP, PS1 and tau) on lateral ventricle CP function. Confocal imaging and immunohistochemistry revealed an increase only of Aβ42 isoform in epithelial cytosol and in stroma surrounding choroidal capillaries; this buildup may reflect insufficient clearance transport from CSF to blood. Still, there was increased expression, presumably compensatory, of the choroidal Aβ transporters: the low density lipoprotein receptor-related protein 1 (LRP1) and the receptor for advanced glycation end product (RAGE). A thickening of the epithelial basal membrane and greater collagen-IV deposition occurred around capillaries in CP, probably curtailing solute exchanges. Moreover, there was attenuated expression of epithelial aquaporin-1 and transthyretin (TTR) protein compared to Non-Tg mice. Collectively these findings indicate CP dysfunction hypothetically linked to increasing Aβ burden resulting in less efficient ion transport, concurrently with reduced production of CSF (less sink action on brain Aβ) and diminished secretion of TTR (less neuroprotection against cortical Aβ toxicity). The putative effects of a disabled CP-CSF system on CNS functions are discussed in the context of AD. PMID:25705176

  15. Choroid plexus dysfunction impairs beta-amyloid clearance in a triple transgenic mouse model of Alzheimer’s disease

    PubMed Central

    González-Marrero, Ibrahim; Giménez-Llort, Lydia; Johanson, Conrad E.; Carmona-Calero, Emilia María; Castañeyra-Ruiz, Leandro; Brito-Armas, José Miguel; Castañeyra-Perdomo, Agustín; Castro-Fuentes, Rafael

    2015-01-01

    Compromised secretory function of choroid plexus (CP) and defective cerebrospinal fluid (CSF) production, along with accumulation of beta-amyloid (Aβ) peptides at the blood-CSF barrier (BCSFB), contribute to complications of Alzheimer’s disease (AD). The AD triple transgenic mouse model (3xTg-AD) at 16 month-old mimics critical hallmarks of the human disease: β-amyloid (Aβ) plaques and neurofibrillary tangles (NFT) with a temporal- and regional- specific profile. Currently, little is known about transport and metabolic responses by CP to the disrupted homeostasis of CNS Aβ in AD. This study analyzed the effects of highly-expressed AD-linked human transgenes (APP, PS1 and tau) on lateral ventricle CP function. Confocal imaging and immunohistochemistry revealed an increase only of Aβ42 isoform in epithelial cytosol and in stroma surrounding choroidal capillaries; this buildup may reflect insufficient clearance transport from CSF to blood. Still, there was increased expression, presumably compensatory, of the choroidal Aβ transporters: the low density lipoprotein receptor-related protein 1 (LRP1) and the receptor for advanced glycation end product (RAGE). A thickening of the epithelial basal membrane and greater collagen-IV deposition occurred around capillaries in CP, probably curtailing solute exchanges. Moreover, there was attenuated expression of epithelial aquaporin-1 and transthyretin (TTR) protein compared to Non-Tg mice. Collectively these findings indicate CP dysfunction hypothetically linked to increasing Aβ burden resulting in less efficient ion transport, concurrently with reduced production of CSF (less sink action on brain Aβ) and diminished secretion of TTR (less neuroprotection against cortical Aβ toxicity). The putative effects of a disabled CP-CSF system on CNS functions are discussed in the context of AD. PMID:25705176

  16. Description of MISCAN-Lung, the Erasmus MC Lung Cancer Micro-Simulation Model for Evaluating Cancer Control Interventions

    PubMed Central

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

    2012-01-01

    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 micro-simulation 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 paper 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 U.S. 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. PMID:22882895

  17. Pharmacologic agents for mucus clearance in bronchiectasis.

    PubMed

    Nair, Girish B; Ilowite, Jonathan S

    2012-06-01

    There are no approved pharmacologic agents to enhance mucus clearance in non-cystic fibrosis (CF) bronchiectasis. Evidence supports the use of hyperosmolar agents in CF, and studies with inhaled mannitol and hypertonic saline are ongoing in bronchiectasis. N-acetylcysteine may act more as an antioxidant than a mucolytic in other lung diseases. Dornase α is beneficial to patients with CF, but is not useful in patients with non-CF bronchiectasis. Mucokinetic agents such as β-agonists have the potential to improve mucociliary clearance in normals and many disease states, but have not been adequately studied in patients with bronchiectasis. PMID:22640851

  18. In vitro-in vivo extrapolation of hepatic clearance: biological tools, scaling factors, model assumptions and correct concentrations.

    PubMed

    Pelkonen, O; Turpeinen, M

    2007-01-01

    Although the measurement of metabolite formation or substrate depletion in in vitro systems, from recombinant enzymes to tissue slices, is a relatively routine task, there are a number of more or less unresolved issues in the extrapolation of the enzymatic intrinsic clearance into hepatic metabolic clearance. Nominal concentrations of the drug added to the incubation system are not necessarily the concentration the transporter or the metabolizing enzyme sees. In addition, peculiarities of incubation set-ups should be assessed. Unbound drug fractions (concentrations) in the in vitro system itself should be measured or estimated for the appropriate assessment of enzymatic intrinsic clearance. In addition, blood and/or plasma concentrations to be encountered in the in vivo situation should be measured or estimated for the extrapolation. Extrapolation always means making a number of assumptions and the most important of these, such as scaling factors from recombinant enzymes, microsomes or hepatocytes to the mass unit of the liver, liver weight, blood flow, and distribution volume amongst others, and so on, should be explicitly stated and included in the extrapolation process. Despite all the above-mentioned reservations the in vitro-in vivo extrapolation of metabolic clearance seems to be a useful and mostly fairly precise tool for predicting the important pharmacokinetic processes of a drug. PMID:17968737

  19. In vitro-in vivo extrapolation of quantitative hepatic biotransformation data for fish - I. A review of methods, and strategies for incorporating intrinsic clearance estimates into chemical kinetic models

    SciTech Connect

    Nichols, John W.; Schultz, Irv R.; Fitzsimmons, Patrick N..

    2006-06-10

    Mammalian researchers have developed a stepwise approach to predict in vivo hepatic clearance from measurements of in vitro hepatic metabolism. The resulting clearance estimates have been used to screen drug candidates, identify potential drug-drug interactions, investigate idiosyncratic drug responses, and support toxicology risk assessments. In this report we review these methods, discuss their potential application to studies with fish, and describe how extrapolated values could be incorporated into well-known compartmental kinetic models. Empirical equations that relate extrapolation factors to chemical log Kow are given to facilitate the incorporation of metabolism data into bioconcentration and bioaccumulation models. Because they explicitly incorporate the concept of clearance, compartmental clearance volume models are particularly well suited for incorporating hepatic clearance estimates. The manner in which these clearance values are incorporated into a given model depends, however, on the measurement frame of reference. Procedures for the incorporation of in vitro metabolism data into physiologically based toxicokinetic (PBTK) models are also described. Unlike most compartmental models, PBTK models are developed to describe the effects of metabolism in the tissue where it occurs. In addition, PBTK models are well suited to modeling metabolism in more than one tissue.

  20. Wear analysis of revolute joints with clearance in multibody systems

    NASA Astrophysics Data System (ADS)

    Bai, ZhengFeng; Zhao, Yang; Wang, XingGui

    2013-08-01

    In this work, the prediction of wear for revolute joint with clearance in multibody systems is investigated using a computational methodology. The contact model in clearance joint is established using a new hybrid nonlinear contact force model and the friction effect is considered by using a modified Coulomb friction model. The dynamics model of multibody system with clearance is established using dynamic segmentation modeling method and the computational process for wear analysis of clearance joint in multibody systems is presented. The main computational process for wear analysis of clearance joint includes two steps, which are dynamics analysis and wear analysis. The dynamics simulation of multibody system with revolute clearance joint is carried out and the contact forces are drawn and used to calculate the wear amount of revolute clearance joint based on the Archard's wear model. Finally, a four-bar multibody mechanical system with revolute clearance joint is used as numerical example application to perform the simulation and show the dynamics responses and wear characteristics of multibody systems with revolute clearance joint. The main results of this work indicate that the contact between the joint elements is wider and more frequent in some specific regions and the wear phenomenon is not regular around the joint surface, which causes the clearance size increase non-regularly after clearance joint wear. This work presents an effective method to predict wear of revolute joint with clearance in multibody systems.

  1. A canine model of beryllium-induced granulomatous lung disease

    SciTech Connect

    Haley, P.J.; Finch, G.L.; Mewhinney, J.A.; Harmsen, A.G.; Hahn, F.F.; Hoover, M.D.; Muggenburg, B.A.; Bice, D.E. )

    1989-08-01

    Groups of beagle dogs were exposed by inhalation to attain either low or high initial lung burdens (ILB) of BeO calcined at 500 degrees or 1000 degrees C. Dogs were killed at 8, 32, 64, 180, and 365 days after exposure for evaluation of beryllium tissue burdens and histopathologic examination. Histologic lesions were characterized by perivascular and peribronchiolar infiltrates of lymphocytes and macrophages 8 days after exposure. These lesions progressed to distinct microgranulomas accompanied by patchy granulomatous pneumonia. Lesions were more severe in dogs exposed to 500 degrees C BeO. Additional dogs were sampled by bronchoalveolar lavage at 3, 6, 7, 11, 15, 18, and 22 months after exposure for characterization of lung cytology and lung immune responses. Lymphocyte percentages and numbers were increased in lavage samples 3 months after exposure in dogs with both the high and low ILB of 500 degrees C. Values for both parameters decreased rapidly thereafter. Dogs with either low or high ILB of 1000 degrees C-treated BeO displayed negligible to low and variable changes in both lymphocyte percentages and numbers. In vitro lymphocyte stimulation by beryllium was increased 180 and 210 days after exposure in dogs with the high ILB 500 degrees C BeO only. A marked degree of individual variation in both histologic lesions and lymphocyte responses among dogs was noted. Less soluble 1000 degrees C-treated BeO was retained in the lung longer than the more soluble 500 degrees C-treated material that was cleared almost entirely by 1 year after exposure. Because these changes are similar to those reported in humans with chronic beryllium disease, these data suggest that the beagle represents a good model to study histologic and immunologic aspects of this disease syndrome.

  2. Image-based modeling of lung structure and function

    PubMed Central

    Tawhai, Merryn H.; Lin, Ching-Long

    2010-01-01

    Current state-of-the-art in image-based modeling allows derivation of patient-specific models of the lung, lobes, airways, and pulmonary vascular trees. The application of traditional engineering analyses of fluid and structural mechanics to image-based subject-specific models has the potential to provide new insight into structure-function relationships in the individual via functional interpretation that complements imaging and experimental studies. Three major issues that are encountered in studies of air flow through the bronchial airways are the representation of airway geometry, the imposition of physiological boundary conditions, and the treatment of turbulence. Here we review some efforts to resolve each of these issues, with particular focus on image-based models that have been developed to simulate air flow from the mouth to the terminal bronchiole, and subjected to physiologically meaningful boundary conditions via image registration and soft tissue mechanics models. PMID:21105146

  3. 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

  4. Lung cancer signatures in plasma based on proteome profiling of mouse tumor models.

    PubMed

    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

    2011-09-13

    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

  5. Pulmonary Toxicity, Distribution, and Clearance of Intratracheally Instilled Silicon Nanowires in Rats

    PubMed Central

    Roberts, Jenny R.; Mercer, Robert R.; Chapman, Rebecca S.; Cohen, Guy M.; Bangsaruntip, Sarunya; Schwegler-Berry, Diane; Scabilloni, James F.; Castranova, Vincent; Antonini, James M.; Leonard, Stephen S.

    2015-01-01

    Silicon nanowires (Si NWs) are being manufactured for use as sensors and transistors for circuit applications. The goal was to assess pulmonary toxicity and fate of Si NW using an in vivo experimental model. Male Sprague-Dawley rats were intratracheally instilled with 10, 25, 50, 100, or 250 μg of Si NW (~20–30 nm diameter; ~2–15 μm length). Lung damage and the pulmonary distribution and clearance of Si NW were assessed at 1, 3, 7, 28, and 91 days after-treatment. Si NW treatment resulted in dose-dependent increases in lung injury and inflammation that resolved over time. At day 91 after treatment with the highest doses, lung collagen was increased. Approximately 70% of deposited Si NW was cleared by 28 days with most of the Si NW localized exclusively in macrophages. In conclusion, Si NW induced transient lung toxicity which may be associated with an early rapid particle clearance; however, persistence of Si NW over time related to dose or wire length may lead to increased collagen deposition in the lung. PMID:26640479

  6. 24 CFR 3285.305 - Clearance under homes.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 24 Housing and Urban Development 5 2011-04-01 2011-04-01 false Clearance under homes. 3285.305... URBAN DEVELOPMENT MODEL MANUFACTURED HOME INSTALLATION STANDARDS Foundations § 3285.305 Clearance under homes. A minimum clearance of 12 inches must be maintained between the lowest member of the main...

  7. 24 CFR 3285.305 - Clearance under homes.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 5 2010-04-01 2010-04-01 false Clearance under homes. 3285.305... URBAN DEVELOPMENT MODEL MANUFACTURED HOME INSTALLATION STANDARDS Foundations § 3285.305 Clearance under homes. A minimum clearance of 12 inches must be maintained between the lowest member of the main...

  8. 24 CFR 3285.305 - Clearance under homes.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 24 Housing and Urban Development 5 2014-04-01 2014-04-01 false Clearance under homes. 3285.305... URBAN DEVELOPMENT MODEL MANUFACTURED HOME INSTALLATION STANDARDS Foundations § 3285.305 Clearance under homes. A minimum clearance of 12 inches must be maintained between the lowest member of the main...

  9. 24 CFR 3285.305 - Clearance under homes.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 24 Housing and Urban Development 5 2013-04-01 2013-04-01 false Clearance under homes. 3285.305... URBAN DEVELOPMENT MODEL MANUFACTURED HOME INSTALLATION STANDARDS Foundations § 3285.305 Clearance under homes. A minimum clearance of 12 inches must be maintained between the lowest member of the main...

  10. 24 CFR 3285.305 - Clearance under homes.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 24 Housing and Urban Development 5 2012-04-01 2012-04-01 false Clearance under homes. 3285.305... URBAN DEVELOPMENT MODEL MANUFACTURED HOME INSTALLATION STANDARDS Foundations § 3285.305 Clearance under homes. A minimum clearance of 12 inches must be maintained between the lowest member of the main...

  11. Modeling Granulomas in Response to Infection in the Lung.

    PubMed

    Hao, Wenrui; Schlesinger, Larry S; Friedman, Avner

    2016-01-01

    Alveolar macrophages play a large role in the innate immune response of the lung. However, when these highly immune-regulatory cells are unable to eradicate pathogens, the adaptive immune system, which includes activated macrophages and lymphocytes, particularly T cells, is called upon to control the pathogens. This collection of immune cells surrounds, isolates and quarantines the pathogen, forming a small tissue structure called a granuloma for intracellular pathogens like Mycobacterium tuberculosis (Mtb). In the present work we develop a mathematical model of the dynamics of a granuloma by a system of partial differential equations. The 'strength' of the adaptive immune response to infection in the lung is represented by a parameter α, the flux rate by which T cells and M1 macrophages that immigrated from the lymph nodes enter into the granuloma through its boundary. The parameter α is negatively correlated with the 'switching time', namely, the time it takes for the number of M1 type macrophages to surpass the number of infected, M2 type alveolar macrophages. Simulations of the model show that as α increases the radius of the granuloma and bacterial load in the granuloma both decrease. The model is used to determine the efficacy of potential host-directed therapies in terms of the parameter α, suggesting that, with fixed dosing level, an infected individual with a stronger immune response will receive greater benefits in terms of reducing the bacterial load. PMID:26986986

  12. Modeling Granulomas in Response to Infection in the Lung

    PubMed Central

    Hao, Wenrui; Schlesinger, Larry S.; Friedman, Avner

    2016-01-01

    Alveolar macrophages play a large role in the innate immune response of the lung. However, when these highly immune-regulatory cells are unable to eradicate pathogens, the adaptive immune system, which includes activated macrophages and lymphocytes, particularly T cells, is called upon to control the pathogens. This collection of immune cells surrounds, isolates and quarantines the pathogen, forming a small tissue structure called a granuloma for intracellular pathogens like Mycobacterium tuberculosis (Mtb). In the present work we develop a mathematical model of the dynamics of a granuloma by a system of partial differential equations. The ‘strength’ of the adaptive immune response to infection in the lung is represented by a parameter α, the flux rate by which T cells and M1 macrophages that immigrated from the lymph nodes enter into the granuloma through its boundary. The parameter α is negatively correlated with the ‘switching time’, namely, the time it takes for the number of M1 type macrophages to surpass the number of infected, M2 type alveolar macrophages. Simulations of the model show that as α increases the radius of the granuloma and bacterial load in the granuloma both decrease. The model is used to determine the efficacy of potential host-directed therapies in terms of the parameter α, suggesting that, with fixed dosing level, an infected individual with a stronger immune response will receive greater benefits in terms of reducing the bacterial load. PMID:26986986

  13. Enhancement of pulmonary clearance of Moraxella (Branhamella) catarrhalis following immunization with outer membrane protein CD in a mouse model.

    PubMed

    Murphy, T F; Kyd, J M; John, A; Kirkham, C; Cripps, A W

    1998-12-01

    Moraxella (Branhamella) catarrhalis is an important human respiratory tract pathogen. Outer membrane protein (OMP) CD is highly conserved among strains and has characteristics that indicate it may be an effective vaccine antigen. This study investigated the effect of immunization with OMP CD on pulmonary clearance following intratracheal challenge of mice with M. catarrhalis. Two routes of immunization were studied: mucosal immunization (intra-Peyer's patch followed by intratracheal boost) and intramuscular immunization with OMP CD. Both resulted in enhanced pulmonary clearance of M. catarrhalis compared with sham-immunized controls. Immunization with OMP CD induced specific antibodies in serum and bronchoalveolar lavage fluid and induced a specific lymphocyte proliferative response in T cells from mesenteric lymph nodes from mice mucosally immunized with OMP CD. On the basis of these results, OMP CD should undergo continued testing to determine whether it will induce a protective immune response in humans. PMID:9815219

  14. Mighty mouse breakthroughs: a Sox2-driven model for squamous cell lung cancer

    PubMed Central

    Mukhopadhyay, Anandaroop; Oliver, Trudy G

    2015-01-01

    Squamous lung cancer is a subtype of non-small cell lung cancer with a poor overall prognosis. We have recently generated a mouse model of squamous lung carcinoma by overexpressing Sex-determining region Y-box 2 (Sox2) and deleting liver kinase B1 (Lkb1) using a lentiviral approach. This model recapitulates the human disease in terms of histopathology, biomarker expression, and signaling pathway activation, making it an excellent model for preclinical studies. PMID:27308419

  15. Experimental evolution of sprays in a lung model

    NASA Astrophysics Data System (ADS)

    Burguete, Javier; Aliseda, Alberto

    2015-11-01

    We present the first results of an experiment conceived to observe the evolution of sprays inside the lungs. We have built a model that covers the first 6 generations (from the trachea to segmental bronchi of 5th generation). This setup is placed on a wind tunnel, and the flow inside the model is induced by a vacuum pump that emulates the breathing process using a valve. We inject a previously determined distribution of particles (water droplets), whose average diameter can be modified. Then, we measure the droplet distribution in different branches and compare how the droplet distribution is modified at each generation. The parameters that control the behavior are the average diameter of the original distribution, the airflow rate inside the model and the frequency of the breathing cycle.

  16. A Model of Anterograde Oxygenated Lung Blood Flow in Acardia.

    PubMed

    Marinakis, Sotirios; Burki, Marco; Abdel-Sayed, Saad; von Segesser, Ludwig Karl

    2016-01-01

    In extreme situations such as hyperacute rejection of heart transplant or major heart trauma, heart explantation and extracorporeal membrane oxygenation (ECMO) hemodynamic support might be the only means for survival. In our previous model of acardia, pulmonary artery (PA) was clamped and did not receive any anterograde blood flow. A model of anterograde PA perfusion might be necessary to avoid ischemic pulmonary damage in prolonged ECMO in acardia. The aim of this study was to describe the surgical technique and to determine the feasibility of an anterograde lung perfusion in acardia through the anastomosis of the right internal mammary artery (RIMA) to the PA. A venoarterial cardiopulmonary bypass was established in three pigs (72 ± 2.6 kg) by the transjugular insertion to the caval axis of a double-staged cannula with carotid artery return. Heart was excised and ECMO was established as previously reported. Right internal mammary artery was harvested and after measurement of its output (93.3 ± 5.8 ml/min, representing 2.17% ± 0.15% of total pump flow), it was anastomosed to PA. Right internal mammary artery anastomosis to PA is a feasible, safe, and easy to perform maneuver assuring an anterograde lung perfusion in acardia. PMID:27442854

  17. Multiresolution active contour model applied on lung and colon images

    NASA Astrophysics Data System (ADS)

    Dehmeshki, Jamshid; Siddique, Musib; Wong, Wing; Chis Ster, Irina

    2004-05-01

    This paper deploys a wavelet based scale-space approach to extract the boundary of the object of interest in medical CT images. The classical approach of the active contour models consists of starting with an initial contour, to deform it under the action of some forces attracting the contour towards the edges by means of a set of forces. The mathematical model involves in the minimisation of an objective function called energy functional, which depends on the geometry of the contour as well as of the image characteristics. Various strategies could be used for the formulation of the energy functional and its optimisation. In this study, a wavelet based scale-space approach has been adopted. The coarsest scale is able to enlarge the capture region surrounding an object and avoids the trapping of contour into weak edges. The finer scales are used to refine the contour as close as possible to the boundary of the object. An adaptive scale coefficient for the balloon energy has been introduced. Four levels of resolution have been applied in order to get reproducibility of the contour despite poor different initialisations. The scheme has been applied to segment the regions of interest in CT lung and colon images. The result has been shown to be accurate and reproducible for the cases containing fat, holes and other small high intensity objects inside lung nodules as well as colon polyps.

  18. 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.

  19. 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

  20. Nucleotide-mediated airway clearance.

    PubMed

    Schmid, Andreas; Clunes, Lucy A; Salathe, Mathias; Verdugo, Pedro; Dietl, Paul; Davis, C William; Tarran, Robert

    2011-01-01

    A thin layer of airway surface liquid (ASL) lines the entire surface of the lung and is the first point of contact between the lung and the environment. Surfactants contained within this layer are secreted in the alveolar region and are required to maintain a low surface tension and to prevent alveolar collapse. Mucins are secreted into the ASL throughout the respiratory tract and serve to intercept inhaled pathogens, allergens and toxins. Their removal by mucociliary clearance (MCC) is facilitated by cilia beating and hydration of the ASL by active ion transport. Throughout the lung, secretion, ion transport and cilia beating are under purinergic control. Pulmonary epithelia release ATP into the ASL which acts in an autocrine fashion on P2Y(2) (ATP) receptors. The enzymatic network describes in Chap. 2 then mounts a secondary wave of signaling by surface conversion of ATP into adenosine (ADO), which induces A(2B) (ADO) receptor-mediated responses. This chapter offers a comprehensive description of MCC and the extensive ramifications of the purinergic signaling network on pulmonary surfaces. PMID:21560046

  1. Hypervolemia induces and potentiates lung damage after recruitment maneuver in a model of sepsis-induced acute lung injury

    PubMed Central

    2010-01-01

    Introduction Recruitment maneuvers (RMs) seem to be more effective in extrapulmonary acute lung injury (ALI), caused mainly by sepsis, than in pulmonary ALI. Nevertheless, the maintenance of adequate volemic status is particularly challenging in sepsis. Since the interaction between volemic status and RMs is not well established, we investigated the effects of RMs on lung and distal organs in the presence of hypovolemia, normovolemia, and hypervolemia in a model of extrapulmonary lung injury induced by sepsis. Methods ALI was induced by cecal ligation and puncture surgery in 66 Wistar rats. After 48 h, animals were anesthetized, mechanically ventilated and randomly assigned to 3 volemic status (n = 22/group): 1) hypovolemia induced by blood drainage at mean arterial pressure (MAP)≈70 mmHg; 2) normovolemia (MAP≈100 mmHg), and 3) hypervolemia with colloid administration to achieve a MAP≈130 mmHg. In each group, animals were further randomized to be recruited (CPAP = 40 cm H2O for 40 s) or not (NR) (n = 11/group), followed by 1 h of protective mechanical ventilation. Echocardiography, arterial blood gases, static lung elastance (Est,L), histology (light and electron microscopy), lung wet-to-dry (W/D) ratio, interleukin (IL)-6, IL-1β, caspase-3, type III procollagen (PCIII), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) mRNA expressions in lung tissue, as well as lung and distal organ epithelial cell apoptosis were analyzed. Results We observed that: 1) hypervolemia increased lung W/D ratio with impairment of oxygenation and Est,L, and was associated with alveolar and endothelial cell damage and increased IL-6, VCAM-1, and ICAM-1 mRNA expressions; and 2) RM reduced alveolar collapse independent of volemic status. In hypervolemic animals, RM improved oxygenation above the levels observed with the use of positive-end expiratory pressure (PEEP), but increased lung injury and led to higher inflammatory and fibrogenetic

  2. CRM1-dependent p53 nuclear accumulation in lung lesions of a bitransgenic mouse lung tumor model.

    PubMed

    Chen, Lixia; Moore, Joseph E; Samathanam, Christina; Shao, Changxia; Cobos, Everardo; Miller, Mark Steven; Gao, Weimin

    2011-07-01

    The p53 tumor suppressor gene plays an essential role in tumorigenesis, and the chromosomal region maintenance 1 (CRM1) has been suggested to export p53 protein from the nucleus to the cytoplasm. The objectives of the present study were to evaluate p53 expression and subcellular localization as well as CRM1 expression using immunohistochemistry in our established bitransgenic mouse lung tumor model. In this model, expression of the mutant human Ki-rasG12C allele was regulated in a doxycycline (DOX)-inducible, lung-specific manner. Following treatment with curcumin, we found that although overall p53 expression levels were not significantly changed among the three groups, lung lesions in mice treated with DOX alone had the highest proportion of N>C (nucleus predominant) p53 staining (46±7%), followed by lung lesions in mice co-treated with DOX and curcumin (31±12%) and controls (17±4%). CRM1 expression was dramatically inhibited in lung lesions in mice treated with DOX (0±0) as compared to controls (90±17, P=0.001), and could be partially reversed after curcumin treatment (47±21, P=0.028, DOX vs. DOX+curcumin). Collectively, the results from this study demonstrated that p53 accumulated in the nucleus in lung lesions in mice expressing the mutant Ki-rasG12C transgene as a result of down-regulation of CRM1. Furthermore, these alterations could be partially reversed by curcumin treatment. p53 subcellular localization resulting from CRM1 alterations may play an important role in lung tumorigenesis. PMID:21519798

  3. Mean lung pressure during adult high-frequency oscillatory ventilation: an experimental study using a lung model.

    PubMed

    Hirayama, Takahiro; Nagano, Osamu; Shiba, Naoki; Yumoto, Tetsuya; Sato, Keiji; Terado, Michihisa; Ugawa, Toyomu; Ichiba, Shingo; Ujike, Yoshihito

    2014-12-01

    In adult high-frequency oscillatory ventilation (HFOV), stroke volume (SV) and mean lung pressure (PLung) are important for lung protection. We measured the airway pressure at the Y-piece and the lung pressure during HFOV using a lung model and HFOV ventilators for adults (R100 and 3100B). The lung model was made of a 20-liter, airtight rigid plastic container (adiabatic compliance: 19.3 ml/cmH2O) with or without a resistor (20 cmH2O/l/sec). The ventilator settings were as follows: mean airway pressure (MAP), 30 cmH2O; frequency, 5-15 Hz (every 1 Hz); airway pressure amplitude (AMP), maximum;and % of inspiratory time (IT), 50% for R100, 33% or 50% for 3100B. The measurements were also performed with an AMP of 2/3 or 1/3 maximum at 5, 10 and 15 Hz. The PLung and the measured MAP were not consistently identical to the setting MAP in either ventilator, and decreasing IT decreased the PLung in 3100B. In conclusion, we must pay attention to the possible discrepancy between the PLung and the setting MAP during adult HFOV. PMID:25519026

  4. 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

  5. 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. PMID:25190415

  6. Development and application of a random lung model for dose calculations in radiotherapy

    NASA Astrophysics Data System (ADS)

    Liang, Liang

    Radiotherapy requires accurate dose calculations in the human body, especially in disease sites with large variations of electron density in neighboring tissues, such as the lung. Currently, the lung is modeled by a voxelized geometry interpolated from computed tomography (CT) scans to various resolutions. The simplest such voxelized lung, the atomic mix model, is a homogenized whole lung with a volume-averaged bulk density. However, according traditional transport theory, even the relatively fine CT voxelization of the lung is not valid, due to the extremely small mean free path (MFP) of the electrons. The purpose of this thesis is to study the impact of the lung's heterogeneities on dose calculations in lung treatment planning. We first extend the traditional atomic mix theory for charged particles by approximating the Boltzmann equation for electrons to its Fokker-Planck (FP) limit, and then applying a formal asymptotic analysis to the BFP equation. This analysis raises the length scale for homogenizing a heterogeneous medium from the electron mean free path (MFP) to the much larger electron transport MFP. Then, using the lung's anatomical data and our new atomic mix theory, we build a realistic 2 1/2-D random lung model. The dose distributions for representative realizations of the random lung model are compared to those from the atomic mix approximation of the random lung model, showing that significant perturbations may occur with small field sizes and large lung structures. We also apply our random lung model to a more realistic lung phantom and investigate the effect of CT resolutions on lung treatment planning. We show that, compared to the reference 1 x 1 mm2 CT resolution, a 2 x 2 mm2 CT resolution is sufficient to voxelize the lung, while significant deviations in dose can be observed with a larger 4 x 4 mm 2 CT resolution. We use the Monte Carlo method extensively in this thesis, to avoid systematic errors caused by inaccurate heterogeneity corrections

  7. 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. PMID:16337418

  8. 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...

  9. 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...

  10. 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%.

  11. 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.

  12. 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.

  13. Aerosol Medications for Treatment of Mucus Clearance Disorders.

    PubMed

    Rubin, Bruce K

    2015-06-01

    Airway mucus hypersecretion and secretion retention can result from inflammation, irritation, stimulation, or mucus-producing tumors. Secretion clearance can be furthered hampered by ciliary dysfunction and by weakness or restrictive lung disease, leading to an ineffective cough. There are a number of different mucoactive medications that have been used to reduce hypersecretion, make secretions easier to transport, or increase the efficiency of cough or mucus clearance. In this paper, I review the pathophysiology of secretory hyper-responsiveness and mucus hypersecretion and discuss the different aerosol medications that can be used to augment secretion clearance. PMID:26070577

  14. Some experimental errors in calculating regional cerebral blood flow from the intracarotid 133Xe clearance curve. A quantitative evaluation employing a digital model.

    PubMed

    Kanno, I; Uemura, K

    1975-01-01

    A digital model study has been developed for quantitative assessment of experimental errors in the analysis of 133Xe clearance curve from the brain. A small computer synthesized a model of the clearance curve, varying combinations of fast and slow components. The curves were convoluted with Poisson random digits to simulate statistical fluctuations. Identical curves were overlapped with varying intervals to study the influence of remaining activity. The height over area method to ten minutes was confirmed to overestimate CBF by 10% to 15% with a slow component of 20 ml/100 gm per minute, and the overstimation was increased with a lower slow flow component. The initial slope value was shown to have a close relationship with the fast flow component when the latter was less than 100 ml/100 gm per minute. Errors due to statistical fluctuations were determined only by the initial height (Ho cps), as the percent standard deviation was deltaHo/Ho in the height over area method and 2 deltaHo/HologHo in the initial slope method, where deltaHo equals square rootHo. Remaining activity caused errors of 1% to 3% in the initial slope method with an injection interval of 15 minutes. The influence of remaining activity can be eliminated with an injection interval of more than 25 to 30 minutes in the initial slope method and more than 40 minutes in the height over area method. PMID:1154473

  15. Controls Considerations for Turbine Active Clearance Control

    NASA Technical Reports Server (NTRS)

    Melcher, Kevin J.

    2004-01-01

    This presentation discusses active control of turbine tip clearance from a control systems perspective. It is a subset of charts that were presented at the 2003 meeting of the International Society of Air Breathing Engines which was held August 31 through September 5 in Cleveland, Ohio. The associated reference paper is cited at the end of the presentation. The presentation describes active tip clearance control research being conducted by NASA to improve turbine engine systems. The target application for this effort is commercial aircraft engines. However, it is believed that the technologies developed as part of this research will benefit a broad spectrum of current and future turbomachinery. The first part of the presentation discusses the concept of tip clearance, problems associated with it, and the benefits of controlling it. It lays out a framework for implementing tip clearance controls that enables the implementation to progress from purely analytical to hardware-in-the-loop to fully experimental. And it briefly discusses how the technologies developed will be married to the previously described ACC Test Rig for hardware-in-the-loop demonstrations. The final portion of the presentation, describes one of the key technologies in some detail by presenting equations and results for a functional dynamic model of the tip clearance phenomena. As shown, the model exhibits many of the clearance dynamics found in commercial gas turbine engines. However, initial attempts to validate the model identified limitations that are being addressed to make the model more realistic.

  16. Neonatal Pulmonary Macrophage Depletion Coupled to Defective Mucus Clearance Increases Susceptibility to Pneumonia and Alters Pulmonary Immune Responses.

    PubMed

    Saini, Yogesh; Wilkinson, Kristen J; Terrell, Kristy A; Burns, Kimberlie A; Livraghi-Butrico, Alessandra; Doerschuk, Claire M; O'Neal, Wanda K; Boucher, Richard C

    2016-02-01

    Resident immune cells (e.g., macrophages [MΦs]) and airway mucus clearance both contribute to a healthy lung environment. To investigate interactions between pulmonary MΦ function and defective mucus clearance, a genetic model of lysozyme M (LysM) promoter-mediated MΦ depletion was generated, characterized, and crossed with the sodium channel β subunit transgenic (Scnn1b-Tg) mouse model of defective mucus clearance. Diphtheria toxin A-mediated depletion of LysM(+) pulmonary MΦs in wild-type mice with normal mucus clearance resulted in lethal pneumonia in 24% of neonates. The pneumonias were dominated by Pasteurella pneumotropica and accompanied by emaciation, neutrophilic inflammation, and elevated Th1 cytokines. The incidence of emaciation and pneumonia reached 51% when LysM(+) MΦ depletion was superimposed on the airway mucus clearance defect of Scnn1b-Tg mice. In LysM(+) MΦ-depleted Scnn1b-Tg mice, pneumonias were associated with a broader spectrum of bacterial species and a significant reduction in airway mucus plugging. Bacterial burden (CFUs) was comparable between Scnn1b-Tg and nonpneumonic LysM(+) MΦ-depleted Scnn1b-Tg mice. However, the nonpneumonic LysM(+) MΦ-depleted Scnn1b-Tg mice exhibited increased airway inflammation, the presence of neutrophilic infiltration, and increased levels of inflammatory cytokines in bronchoalveolar lavage fluid compared with Scnn1b-Tg mice. Collectively, these data identify key MΦ-mucus clearance interactions with respect to both infectious and inflammatory components of muco-obstructive lung disease. PMID:26121027

  17. Lung Macrophages “Digest” Carbon Nanotubes Using a Superoxide/Peroxynitrite Oxidative Pathway

    PubMed Central

    2015-01-01

    In contrast to short-lived neutrophils, macrophages display persistent presence in the lung of animals after pulmonary exposure to carbon nanotubes. While effective in the clearance of bacterial pathogens and injured host cells, the ability of macrophages to “digest” carbonaceous nanoparticles has not been documented. Here, we used chemical, biochemical, and cell and animal models and demonstrated oxidative biodegradation of oxidatively functionalized single-walled carbon nanotubes via superoxide/NO* → peroxynitrite-driven oxidative pathways of activated macrophages facilitating clearance of nanoparticles from the lung. PMID:24871084

  18. Pulmonary function and clearance after prolonged sulfuric acid aerosol exposure

    SciTech Connect

    Ives, P.J. ); Gerrity, T.R.; DeWitt, P.; Folinsbee, L.J. )

    1991-03-15

    The authors studied pulmonary function and clearance responses after a 4 H exposure to 75-100 {mu}g/m{sup 3} sulfuric acid aerosol (SAA). Healthy subjects, who exercised for 30 min/H at ventilation of about 25 L/min, were exposed once to clean air and once to SAA. Oral hygiene and acidic juice gargle were used to minimize oral ammonia. Lung function tests, including spirometry, plethysmography, and partial flow-volume (PEFV) curves were performed before and after exposure. Clearance of 99m-Technetium labeled iron oxide was assessed after each exposure. The first moment of fractional tracheobronchial retention (M1TBR), after correcting for 24 H retention and normalizing to time zero, was used as an index of clearance. There were no significant changes in lung volumes, airways resistance, or maximum expiratory flows after SAA exposure. Flow at 40% of total lung capacity on PEFV curves decreased 17% (NS) after SAA exposure. Tracheobronchial clearance was accelerated after a single exposure to SAA; M1TBR decreased from 73 {plus minus} 5 min (air) to 69 {plus minus} 5 min (SAA). These results suggest that acute prolonged exposure to low levels of SAA has minimal effects on lung mechanics in healthy subjects but does produce a modest acceleration of particle clearance.

  19. Toward the modeling of mucus draining from the human lung: role of the geometry of the airway tree

    NASA Astrophysics Data System (ADS)

    Mauroy, Benjamin; Fausser, Christian; Pelca, Dominique; Merckx, Jacques; Flaud, Patrice

    2011-10-01

    Mucociliary clearance and cough are the two main natural mucus draining methods in the bronchial tree. If they are affected by a pathology, they can become insufficient or even ineffective, then therapeutic draining of mucus plays a critical role to keep mucus levels in the lungs acceptable. The manipulations of physical therapists are known to be very efficient clinically but they are mostly empirical since the biophysical mechanisms involved in these manipulations have never been studied. We develop in this work a model of mucus clearance in idealized rigid human bronchial trees and focus our study on the interaction between (1) tree geometry, (2) mucus physical properties and (3) amplitude of flow rate in the tree. The mucus is considered as a Bingham fluid (gel-like) which is moved upward in the tree thanks to its viscous interaction with air flow. Our studies point out the important roles played both by the geometry and by the physical properties of mucus (yield stress and viscosity). More particularly, the yield stress has to be overcome to make mucus flow. Air flow rate and yield stress determine the maximal possible mucus thickness in each branch of the tree at equilibrium. This forms a specific distribution of mucus in the tree whose characteristics are strongly related to the multi-scaled structure of the tree. The behavior of any mucus distribution is then dependent on this distribution. Finally, our results indicate that increasing air flow rates ought to be more efficient to drain mucus out of the bronchial tree while minimizing patient discomfort.

  20. 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.

  1. 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. PMID:26531324

  2. Effects of sodium methyldithiocarbamate on selected parameters of innate immunity and clearance of bacteria in a mouse model of sepsis

    PubMed Central

    Tan, Wei; Pruett, Stephen B.

    2016-01-01

    Aims Sodium methyldithiocarbamate (SMD), the third most widely used conventional pesticide in the United States, has been reported to inhibit several parameters associated with inflammation and to decrease resistance to infection. In a previous study, survival time was markedly decreased when mice were treated orally with SMD shortly before challenge with a high dose of Escherichia coli (E. coli) that was lethal to most of the control mice. In the present study, we evaluated selected parameters of the innate immune system using a lower challenge dose of E. coli, to determine which (if any) of these parameters reflected continued changes through 24 h. Main methods Bacterial clearance from the peritoneal cavity, production of chemokines and cytokines, and body temperature were measured. Key findings All these parameters were reduced by SMD up to 12 h after bacterial challenge, but the concentration of the anti-inflammatory cytokine IL-10 was increased. Even so, mice in the control and SMD-treated groups cleared most bacteria by 24 h. Other parameters (cytokine concentrations and body temperature) were also normal or near normal by 24 h. The same dosage of SMD administered intranasally also did not significantly decrease survival. Hypothermia from 16 to 28 h correlated with lethal outcome, but SMD significantly increased hypothermia only at 2 and 4 h after challenge. Significance In spite of substantial early inhibition by SMD of parameters known to be important for resistance to infection, bacterial clearance and survival were not altered, suggesting immunological reserve and/or rapid recovery after transient effects of SMD. PMID:26281915

  3. Bone Marrow–Derived Mesenchymal Stem Cells Enhance Bacterial Clearance and Preserve Bioprosthetic Integrity in a Model of Mesh Infection

    PubMed Central

    Criman, Erik T.; Kurata, Wendy E.; Matsumoto, Karen W.; Aubin, Harry T.; Campbell, Carmen E.

    2016-01-01

    Background: The reported incidence of mesh infection in contaminated operative fields is as high as 30% regardless of the material used. Recently, mesenchymal stem cells (MSCs) have been shown to possess favorable immunomodulatory properties and improve tissue incorporation when seeded onto bioprosthetics. The aim of this study was to evaluate whether seeding noncrosslinked bovine pericardium (Veritas Collagen Matrix) with allogeneic bone marrow–derived MSCs improves infection resistance in vivo after inoculation with Escherichia coli (E. coli). Methods: Rat bone marrow–derived MSCs at passage 3 were seeded onto bovine pericardium and cultured for 7 days before implantation. Additional rats (n = 24) were implanted subcutaneously with MSC-seeded or unseeded mesh and inoculated with 7 × 105 colony-forming units of E. coli or saline before wound closure (group 1, unseeded mesh/saline; group 2, unseeded mesh/E. coli; group 3, MSC-seeded mesh/E. coli; 8 rats per group). Meshes were explanted at 4 weeks and underwent microbiologic and histologic analyses. Results: MSC-seeded meshes inoculated with E. coli demonstrated superior bacterial clearance and preservation of mesh integrity compared with E. coli–inoculated unseeded meshes (87.5% versus 0% clearance; p = 0.001). Complete mesh degradation concurrent with abscess formation was observed in 100% of rats in the unseeded/E. coli group, which is in contrast to 12.5% of rats in the MSC-seeded/E. coli group. Histologic evaluation determined that remodeling characteristics of E. coli–inoculated MSC-seeded meshes were similar to those of uninfected meshes 4 weeks after implantation. Conclusions: Augmenting a bioprosthetic material with stem cells seems to markedly enhance resistance to bacterial infection in vivo and preserve mesh integrity. PMID:27482490

  4. Assessing model uncertainty using hexavalent chromium and lung cancer mortality as an example [Abstract 2015

    EPA Science Inventory

    Introduction: The National Research Council recommended quantitative evaluation of uncertainty in effect estimates for risk assessment. This analysis considers uncertainty across model forms and model parameterizations with hexavalent chromium [Cr(VI)] and lung cancer mortality a...

  5. An anatomically realistic lung model for Monte Carlo-based dose calculations

    SciTech Connect

    Liang Liang; Larsen, Edward W.; Chetty, Indrin J.

    2007-03-15

    Treatment planning for disease sites with large variations of electron density in neighboring tissues requires an accurate description of the geometry. This self-evident statement is especially true for the lung, a highly complex organ having structures with a wide range of sizes that range from about 10{sup -4} to 1 cm. In treatment planning, the lung is commonly modeled by a voxelized geometry obtained using computed tomography (CT) data at various resolutions. The simplest such model, which is often used for QA and validation work, is the atomic mix or mean density model, in which the entire lung is homogenized and given a mean (volume-averaged) density. The purpose of this paper is (i) to describe a new heterogeneous random lung model, which is based on morphological data of the human lung, and (ii) use this model to assess the differences in dose calculations between an actual lung (as represented by our model) and a mean density (homogenized) lung. Eventually, we plan to use the random lung model to assess the accuracy of CT-based treatment plans of the lung. For this paper, we have used Monte Carlo methods to make accurate comparisons between dose calculations for the random lung model and the mean density model. For four realizations of the random lung model, we used a single photon beam, with two different energies (6 and 18 MV) and four field sizes (1x1, 5x5, 10x10, and 20x20 cm{sup 2}). We found a maximum difference of 34% of D{sub max} with the 1x1, 18 MV beam along the central axis (CAX). A ''shadow'' region distal to the lung, with dose reduction up to 7% of D{sub max}, exists for the same realization. The dose perturbations decrease for larger field sizes, but the magnitude of the differences in the shadow region is nearly independent of the field size. We also observe that, compared to the mean density model, the random structures inside the heterogeneous lung can alter the shape of the isodose lines, leading to a broadening or shrinking of the

  6. A comprehensive dynamic model of double-row spherical roller bearing—Model development and case studies on surface defects, preloads, and radial clearance

    NASA Astrophysics Data System (ADS)

    Cao, M.; Xiao, J.

    2008-02-01

    Bearing excitation is one of the most important mechanical sources for vibration and noise generation in machine systems of a broad range of industries. Although extensively investigated, accurately predicting the vibration/acoustic behavior of bearings remains a challenging task because of its complicated nonlinear behaviors. While some ground work has been laid out on single-row deep-grooved ball (DGB) bearing, comprehensive modeling effort on spherical roller bearing (SRB) has yet to be carried out. This is mainly due to the facts that SRB system carries one more extra degree of freedom (DOF) on the moving race (could be either inner or outer race) and in general has more rolling elements compared with DGB. In this study, a comprehensive SRB excitation source model is developed. In addition to the vertical and horizontal displacements considered in previous investigations, the impacts of axial displacement/load are addressed by introducing the DOF in the axial shaft direction. Hence, instead of being treated as pre-assumed constants, the roller-inner/outer race contact angles are formulated as functions of the axial displacement of the moving race to reflect their dependence on the axial movement. The approach presented in this paper accounts for the point contacts between rollers and inner/outer races, as well as line contacts when the loads on individual rollers exceed the limit for point contact. A detailed contact-damping model reflecting the influences of the surface profiles and the speeds of the both contacting elements is developed and applied in the SRB model. Waviness of all the contact surfaces (including inner race, outer race, and rollers) is included and compared in this analysis. Extensive case studies are carried out to reveal the impacts of surface waviness, radial clearance, surface defects, and loading conditions on the force and displacement responses of the SRB system. System design guidelines are recommended based on the simulation results

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

    PubMed

    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 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. PMID:23794749

  8. 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.

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

    PubMed Central

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

    2012-01-01

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

  10. 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). PMID:26267596

  11. Ovine pulmonary adenocarcinoma: a large animal model for human lung cancer.

    PubMed

    Youssef, Gehad; Wallace, William A H; Dagleish, Mark P; Cousens, Chris; Griffiths, David J

    2015-01-01

    Lung cancer is the leading cause of cancer deaths worldwide. Recent progress in understanding the molecular pathogenesis of this disease has resulted in novel therapeutic strategies targeting specific groups of patients. Further studies are required to provide additional advances in diagnosis and treatment. Animal models are valuable tools for studying oncogenesis in lung cancer, particularly during the early stages of disease where tissues are rarely available from human cases. Mice have traditionally been used for studying lung cancer in vivo, and a variety of spontaneous and transgenic models are available. However, it is recognized that other species may also be informative for studies of cancer. Ovine pulmonary adenocarcinoma (OPA) is a naturally occurring lung cancer of sheep caused by retrovirus infection and has several features in common with adenocarcinoma of humans, including a similar histological appearance and activation of common cell signaling pathways. Additionally, the size and organization of human lungs are much closer to those of sheep lungs than to those of mice, which facilitates experimental approaches in sheep that are not available in mice. Thus OPA presents opportunities for studying lung tumor development that can complement conventional murine models. Here we describe the potential applications of OPA as a model for human lung adenocarcinoma with an emphasis on the various in vivo and in vitro experimental systems available. PMID:25991702

  12. 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...

  13. Cigarette smoke induced changes in rat pulmonary clearance of /sup 99m/TcDTPA. A comparison of particulate and gas phases

    SciTech Connect

    Minty, B.D.; Royston, D.

    1985-12-01

    The rat model was developed to study the effects of cigarette smoke on pulmonary clearance of 99mTcDTPA. The method developed was sufficiently noninvasive to allow frequent repeat measurements to be made with a high degree of reproducibility. Animals exposed twice daily to 90 puffs of dilute whole cigarette smoke for 7 days showed an increase in /sup 99m/TcDTPA clearance from the lung which returned to normal within 3 wk of stopping exposure. Filtration of the smoke to remove all the particulate matter abolished the changes.

  14. The Lung Physiome: merging imaging-based measures with predictive computational models of structure and function

    PubMed Central

    Tawhai, Merryn H; Hoffman, Eric A; Lin, Ching-Long

    2009-01-01

    Global measurements of the lung provided by standard pulmonary function tests do not give insight into the regional basis of lung function and lung disease. Advances in imaging methodologies, computer technologies, and subject-specific simulations are creating new opportunities for studying structure-function relationships in the lung through multi-disciplinary research. The digital Human Lung Atlas is an imaging-based resource compiled from male and female subjects spanning several decades of age. The Atlas comprises both structural and functional measures, and includes computational models derived to match individual subjects for personalized prediction of function. The computational models in the Atlas form part of the Lung Physiome project, which is an international effort to develop integrative models of lung function at all levels of biological organization. The computational models provide mechanistic interpretation of imaging measures; the Atlas provides structural data upon which to base model geometry, and functional data against which to test hypotheses. The example of simulating air flow on a subject-specific basis is considered. Methods for deriving multi-scale models of the airway geometry for individual subjects in the Atlas are outlined, and methods for modeling turbulent flows in the airway are reviewed. PMID:20835982

  15. 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

  16. Prediction of hepatic microsomal intrinsic clearance and human clearance values for drugs.

    PubMed

    Nikolic, Katarina; Agababa, Danica

    2009-10-01

    Twenty-nine drugs of different structures were used in theoretical QSAR analysis of human hepatic microsomal intrinsic clearance (in vitro T(1/2) and in vitro CL'(int)) and whole body clearance (CL(blood)). The examined compounds demonstrated a wide range of scaled intrinsic clearance values. Constitutional, geometrical, physico-chemical and electronic descriptors were computed for the examined structures by use of the Marvin Sketch 5.1.3_2, the Chem3D Ultra 7.0.0 and the Dragon 5.4 program. Partial least squares regression (PLSR), has been applied for selection of the most relevant molecular descriptors and development of quantitative structure-activity relationship (QSAR) model for human hepatic microsomal intrinsic clearance (in vitro T(1/2)). Optimal QSAR models with nine and ten variables, R(2)>0.808 and cross-validation parameter q(pre)(2)>0.623, were selected and compared. Since the microsomal in vitro T(1/2) data can be used for calculation of in vitro CL'(int) and in vivo CL(blood), the developed QSAR model will enable one to analyze the kinetics of cytochrome P450-mediated reactions in term of intrinsic clearance and whole body clearance. A comparison is made between predictions produced from the QSAR analysis and experimental data, and there appears to be generally satisfactory correlations with the literature values for intrinsic clearance data. PMID:19713138

  17. Mediators and mucociliary clearance in asthma.

    PubMed

    Pavia, D; Lopez-Vidriero, M T; Clarke, S W

    1987-01-01

    Lung mucociliary clearance is significantly reduced in asthmatic patients compared to healthy controls even during clinical remission. Further retardation in mucous clearance occurs during sleep per se and this may be a contributing factor to nocturnal asthma. Chemical mediators of anaphylaxis appear to have various and, sometimes opposing effects on the two essential components for mucociliary clearance, namely cilia and mucus. Some mediators such as leukotrienes C4 and D4 are potent secretagogues and histamine increases the water flux into the lumen of the airways from the mucosa. Slow-reacting substance of anaphylaxis (SRS-A) reduces mucus transport whereas histamine enhances it. Ciliostimulation has been reported following allergen challenge and this contrasts with the cilioinhibitory effect of asthmatics' sputa. It appears however, that the net effect of the various chemicals of anaphylaxis is one of impairment of mucus clearance. Some pharmacological agents, used for the relief of bronchospasm and control of asthma, also stimulate mucociliary transport, a desirable additional effect. PMID:3311245

  18. The effects of smoking on the developing lung: insights from a biologic model for lung development, homeostasis, and repair.

    PubMed

    Rehan, Virender K; Asotra, Kamlesh; Torday, John S

    2009-01-01

    There is extensive epidemiologic and experimental evidence from both animal and human studies that demonstrates detrimental long-term pulmonary outcomes in the offspring of mothers who smoke during pregnancy. However, the molecular mechanisms underlying these associations are not understood. Therefore, it is not surprising that that there is no effective intervention to prevent the damaging effects of perinatal smoke exposure. Using a biologic model of lung development, homeostasis, and repair, we have determined that in utero nicotine exposure disrupts specific molecular paracrine communications between epithelium and interstitium that are driven by parathyroid hormone-related protein and peroxisome proliferator-activated receptor (PPAR)gamma, resulting in transdifferentiation of lung lipofibroblasts to myofibroblasts, i.e., the conversion of the lipofibroblast phenotype to a cell type that is not conducive to alveolar homeostasis, and is the cellular hallmark of chronic lung disease, including asthma. Furthermore, we have shown that by molecularly targeting PPAR gamma expression, nicotine-induced lung injury can not only be significantly averted, it can also be reverted. The concept outlined by us differs from the traditional paradigm of teratogenic and toxicological effects of tobacco smoke that has been proposed in the past. We have argued that since nicotine alters the normal homeostatic epithelial-mesenchymal paracrine signaling in the developing alveolus, rather than causing totally disruptive structural changes, it offers a unique opportunity to prevent, halt, and/or reverse this process through targeted molecular manipulations. PMID:19641967

  19. Response and resistance to NF-κB inhibitors in mouse models of lung adenocarcinoma

    PubMed Central

    Xue, Wen; Meylan, Etienne; Oliver, Trudy G.; Feldser, David M.; Winslow, Monte M.; Bronson, Roderick; Jacks, Tyler

    2011-01-01

    Lung adenocarcinoma is a frequently diagnosed cancer type and a leading cause of cancer death worldwide. We recently demonstrated in an autochthonous mouse model of this disease that genetic inhibition of the NF-κB pathway affects both the initiation and maintenance of lung cancer, identifying this pathway as a promising therapeutic target. In this study, we tested the efficacy of small molecule NF-κB inhibitors in mouse models of lung cancer. In murine lung adenocarcinoma cell lines with high NF-κB activity, the proteasome inhibitor Bortezomib efficiently reduced nuclear p65, repressed NF-κB target genes and rapidly induced apoptosis. Bortezomib also induced lung tumor regression in vivo and prolonged the survival of tumor bearing KrasLSL-G12D/wt;p53flox/flox mice. In contrast, KrasG12D/wt lung tumors, which have low levels of nuclear NF-κB, do not respond to Bortezomib, suggesting that nuclear NF-κB may be a biomarker to predict treatment response to drugs of this class. Following repeated treatment, initially sensitive lung tumors became resistant to Bortezomib. A second NF-κB inhibitor, Bay-117082, showed similar therapeutic efficacy and acquired-resistance in mice. Our results using preclinical mouse models support the NF-κB pathway as a potential therapeutic target for a defined subset of lung adenocarcinoma. PMID:21874163

  20. Dynamics analysis of space robot manipulator with joint clearance

    NASA Astrophysics Data System (ADS)

    Zhao, Yang; Bai, Zheng Feng

    2011-04-01

    A computational methodology for analysis of space robot manipulator systems, considering the effects of the clearances in the joint, is presented. The contact dynamics model in joint clearance is established using the nonlinear equivalent spring-damp model and the friction effect is considered using the Coulomb friction model. The space robot system dynamic equation of manipulator with clearance is established. Then the dynamics simulation is presented and the dynamics characteristics of robot manipulator with clearance are analyzed. This work provides a practical method to analyze the dynamics characteristics of space robot manipulator with joint clearance and improves the engineering application. The computational methodology can predict the effects of clearance on space robot manipulator preferably, which is the basis of space robot manipulator design, precision analysis and ground test.

  1. ADAPTIVE CLEARANCE CONTROL SYSTEMS FOR TURBINE ENGINES

    NASA Technical Reports Server (NTRS)

    Blackwell, Keith M.

    2004-01-01

    The Controls and Dynamics Technology Branch at NASA Glenn Research Center primarily deals in developing controls, dynamic models, and health management technologies for air and space propulsion systems. During the summer of 2004 I was granted the privilege of working alongside professionals who were developing an active clearance control system for commercial jet engines. Clearance, the gap between the turbine blade tip and the encompassing shroud, increases as a result of wear mechanisms and rubbing of the turbine blades on shroud. Increases in clearance cause larger specific fuel consumption (SFC) and loss of efficient air flow. This occurs because, as clearances increase, the engine must run hotter and bum more fuel to achieve the same thrust. In order to maintain efficiency, reduce fuel bum, and reduce exhaust gas temperature (EGT), the clearance must be accurately controlled to gap sizes no greater than a few hundredths of an inch. To address this problem, NASA Glenn researchers have developed a basic control system with actuators and sensors on each section of the shroud. Instead of having a large uniform metal casing, there would be sections of the shroud with individual sensors attached internally that would move slightly to reform and maintain clearance. The proposed method would ultimately save the airline industry millions of dollars.

  2. 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.

  3. COMPUTER MODEL OF HUMAN LUNG MORPHOLOGY TO COMPLEMENT SPECT ANALYSES

    EPA Science Inventory

    Aerosol therapy protocols could be improved if inhaled pharmacologic drugs were selectively deposited within the human lung. he targeted delivery to specific sites, such as receptors and sensitive airway cells, would enhance the efficacies of airborne pharmaceuticals. he high res...

  4. Toxicity assessment of aggregated/agglomerated cerium oxide nanoparticles in an in vitro 3D airway model: the influence of mucociliary clearance.

    PubMed

    Frieke Kuper, C; Gröllers-Mulderij, Mariska; Maarschalkerweerd, Thérèse; Meulendijks, Nicole M M; Reus, Astrid; van Acker, Frédérique; Zondervan-van den Beuken, Esther K; Wouters, Mariëlle E L; Bijlsma, Sabina; Kooter, Ingeborg M

    2015-03-01

    We investigated the toxicity of aggregated nanoparticles of cerium oxide (CeO2) using an in vitro 3D human bronchial epithelial model that included a mucociliary apparatus (MucilAir™). CeO2 was dispersed in saline and applied to the apical surface of the model. CeO2 did not induce distinct effects in the model, whereas it did in BEAS-2B and A549 cell cultures. The absence of effects of CeO2 was not because of the model's insensitivity. Nanoparticles of zinc oxide (ZnO) elicited positive responses in the toxicological assays. Respiratory mucus (0.1% and 1%) added to dispersions increased aggregation/agglomeration to such an extent that most CeO2 sedimented within a few minutes. Also, the mucociliary apparatus of the model removed CeO2 from the central part of the apical surface to the borders. This 'clearance' may have prevented the majority of CeO2 from reaching the epithelial cells. Chemical analysis of cerium in the basal tissue culture medium showed only minimal translocation of cerium across the 3D barrier. In conclusion, mucociliary defence appeared to prevent CeO2 reaching the respiratory epithelial cells in this 3D in vitro model. This model and approach can be used to study compounds of specific toxicological concern in airway defence mechanisms in vitro. PMID:25448805

  5. 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 Central

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

    2016-01-01

    ABSTRACT 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

  6. 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

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

    PubMed

    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

  8. 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

  9. Modeling the dynamics of recruitment and derecruitment in mice with acute lung injury.

    PubMed

    Massa, Christopher B; Allen, Gilman B; Bates, Jason H T

    2008-12-01

    Lung recruitment and derecruitment contribute significantly to variations in the elastance of the respiratory system during mechanical ventilation. However, the decreases in elastance that occur with deep inflation are transient, especially in acute lung injury. Bates and Irvin (8) proposed a model of the lung that recreates time-varying changes in elastance as a result of progressive recruitment and derecruitment of lung units. The model is characterized by distributions of critical opening and closing pressures throughout the lung and by distributions of speeds with which the processes of opening and closing take place once the critical pressures have been achieved. In the present study, we adapted this model to represent a mechanically ventilated mouse. We fit the model to data collected in a previous study from control mice and mice in various stages of acid-induced acute lung injury (3). Excellent fits to the data were obtained when the normally distributed critical opening pressures were about 5 cmH(2)O above the closing pressures and when the hyperbolically distributed opening velocities were about an order of magnitude greater than the closing velocities. We also found that, compared with controls, the injured mice had markedly increased opening and closing pressures but no change in the velocities, suggesting that the key biophysical change wrought by acid injury is dysfunction of surface tension at the air-liquid interface. Our computational model of lung recruitment and derecruitment dynamics is thus capable of accurately mimicking data from mice with acute lung injury and may provide insight into the altered biophysics of the injured lung. PMID:18948446

  10. Ex vivo Raman spectroscopic study of breast metastatic lesions in lungs in animal models.

    PubMed

    Bhattacharjee, Tanmoy; Tawde, Sneha; Hudlikar, Rasika; Mahimkar, Manoj; Maru, Girish; Ingle, Arvind; Murali Krishna, C

    2015-08-01

    The lung is one of the most common sites of metastases, with approximately 50% of patients with extrathoracic cancer exhibiting pulmonary metastases. Correct identification of the metastatic status of a lung lesion is vital to therapeutic planning and better prognosis. However, currently available diagnostic techniques, such as conventional radiography and low dose computed tomography (LDCT), may fail to identify metastatic lesions. Alternative techniques such as Raman spectroscopy (RS) are hence being extensively explored for correct diagnosis of metastasis. The current ex vivo study aims to evaluate the ability of a fiber optic-based Raman system to distinguish breast cancer metastasis in lung from primary breast and lung tumor in animal models. In this study, spectra were acquired from normal breast, primary breast tumor, normal lung, primary lung tumor, and breast cancer metastasis in lung tissues and analyzed using principal component analysis and principal component-linear discriminant analysis. Breast cancer metastasis in lung could be classified with 71% classification efficiency. Approximately 6% breast metastasis spectra were misclassified with breast tumor, probably due to the presence of breast cancer cells in metastasized lungs. Test prediction results show 64% correct prediction of breast metastasis, while 13% breast metastasis spectra were wrongly predicted as breast tumor, suggesting the possible influence of breast cancer cells. Thus, findings of this study, the first of such explorations, demonstrate the potential of RS in classifying breast metastasis in lungs from primary lung and primary breast tumor. Prospective evaluation on a larger cohort with better multivariate analysis, combined with LDCT and recently developed real-time in vivo probes, RS can play a significant role in nonsurgical screening of lesions, which can lead to individualized therapeutic regimes and improved prognoses. PMID:26295177

  11. Necessary Clearance to Prevent Side Flashes

    NASA Astrophysics Data System (ADS)

    Shindo, Takatoshi; Asakawa, Akira; Honda, Hideki; Sakae, Maki; Tanaka, Shuusaku

    Side flashes often occur when lightning strikes a tree and cause injury or death of human beings staying nearby the tree. Necessary clearance to prevent the side flash has been said to be 2 m, but the physical meaning of the value is unclear. In this paper, we have proposed a model of side flashes based on the physics of discharges and necessary clearance has been calculated. Furthermore, we have carried out model experiments of the side flash using real trees of a heights of 3.5 m and a naturally growing tree of a height of more than 10 m. The results of the model experiments have verified the proposed theory and it is concluded that clearance of more than 3 m from a tree is necessary to prevent side flashes from the tree.

  12. Advanced Thermal HPT Clearance Control

    NASA Technical Reports Server (NTRS)

    WojciechVoytek, Sak

    2006-01-01

    OBJECTIVE: Develop a fast acting HPT Active Clearance Control System to improve engine efficiency and reduce emissions CHALLENGE: Reduction of HPT blade clearance throughout engine operation System complexity, reliability and cost must remain comparable or surpass today s engines Reduced clearance may increase possibility of rubs

  13. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury.

    PubMed

    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. PMID:26617279

  14. 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.

  15. 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.

  16. 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

    2015-11-01

    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.

  17. Lung Segmentation in 4D CT Volumes Based on Robust Active Shape Model Matching

    PubMed Central

    Gill, Gurman; Beichel, Reinhard R.

    2015-01-01

    Dynamic and longitudinal lung CT imaging produce 4D lung image data sets, enabling applications like radiation treatment planning or assessment of response to treatment of lung diseases. In this paper, we present a 4D lung segmentation method that mutually utilizes all individual CT volumes to derive segmentations for each CT data set. Our approach is based on a 3D robust active shape model and extends it to fully utilize 4D lung image data sets. This yields an initial segmentation for the 4D volume, which is then refined by using a 4D optimal surface finding algorithm. The approach was evaluated on a diverse set of 152 CT scans of normal and diseased lungs, consisting of total lung capacity and functional residual capacity scan pairs. In addition, a comparison to a 3D segmentation method and a registration based 4D lung segmentation approach was performed. The proposed 4D method obtained an average Dice coefficient of 0.9773 ± 0.0254, which was statistically significantly better (p value ≪0.001) than the 3D method (0.9659 ± 0.0517). Compared to the registration based 4D method, our method obtained better or similar performance, but was 58.6% faster. Also, the method can be easily expanded to process 4D CT data sets consisting of several volumes. PMID:26557844

  18. Study of blade clearance effects on centrifugal pumps

    NASA Technical Reports Server (NTRS)

    Hoshide, R. K.; Nielson, C. E.

    1972-01-01

    A program of analysis, design, fabrication, and testing has been conducted to develop and experimentally verify analytical models to predict the effects of impeller blade clearance on centrifugal pumps. The effect of tip clearance on pump efficiency, and the relationship between the head coefficient and torque loss with tip clearance was established. Analysis were performed to determine the cost variation in design, manufacture, and test that would occur between unshrouded and shrouded impellers. An impeller, representative of typical rocket engine impellers, was modified by removing its front shroud to permit variation of its blade clearances. It was tested in water with special instrumentation to provide measurements of blade surface pressures during operation. Pump performance data were obtained from tests at various impeller tip clearances. Blade pressure data were obtained at the nominal tip clearance. Comparisons of predicted and measured data are given.

  19. Determination of the pharmacokinetics of glycopyrronium in the lung using a population pharmacokinetic modelling approach

    PubMed Central

    Bartels, Christian; Looby, Michael; Sechaud, Romain; Kaiser, Guenther

    2013-01-01

    Aims Glycopyrronium bromide (NVA237) is a once-daily long-acting muscarinic antagonist recently approved for the treatment of chronic obstructive pulmonary disease. In this study, we used population pharmacokinetic (PK) modelling to provide insights into the impact of the lung PK of glycopyrronium on its systemic PK profile and, in turn, to understand the impact of lung bioavailability and residence time on the choice of dosage regimen. Methods We developed and validated a population PK model to characterize the lung absorption of glycopyrronium using plasma PK data derived from studies in which this drug was administered by different routes to healthy volunteers. The model was also used to carry out simulations of once-daily and twice-daily regimens and to characterize amounts of glycopyrronium in systemic compartments and lungs. Results The model-derived PK parameters were comparable to those obtained with noncompartmental analysis, confirming the usefulness of our model. The model suggested that the lung absorption of glycopyrronium was dominated by slow-phase absorption with a half-life of about 3.5 days, which accounted for 79% of drug absorbed through the lungs into the bloodstream, from where glycopyrronium was quickly eliminated. Simulations of once-daily and twice-daily administration generated similar PK profiles in the lung compartments. Conclusions The slow absorption from the lungs, together with the rapid elimination from the systemic circulation, could explain how once-daily glycopyrronium provides sustained bronchodilatation with a low incidence of adverse effects in patients with chronic obstructive pulmonary disease. Its extended intrapulmonary residence time also provides pharmacokinetic evidence that glycopyrronium has the profile of a once-daily drug. PMID:23506208

  20. 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

  1. Airway geometry models of children's lungs for use in dosimetry modeling.

    PubMed

    Ménache, M G; Hofmann, W; Ashgarian, B; Miller, F J

    2008-01-01

    Single-path whole-lung and lobar models of the lungs of 11 children between 3 mo and 21 yr of age were developed based on a combination of cast data and published information on distal airway dimensions. The cast data used to generate these models were taken from one of the largest databases of actual measurements in children. The methods used to develop the children's models were based on techniques that have been used to develop adult single-path airway geometry models. Model dimensions for the conducting airways, as well as the estimated dead space, for all children fell within the range of the limited published information. Thus, the method for estimating airway dimensions in adults may be successfully applied to develop estimates of airway dimensions in children. The predicted total lung capacity (TLC) for the older children (aged 8 to 21 yr) fell within or near the range arising from published scaling equations. The assumptions used to generate the gas exchange region for children 8 yr and older produced results that were reasonably consistent with available physiological data. However, these assumptions do not result in a physiologically consistent gas exchange region for children 3 yr of age and younger; also, to maintain physiologically reasonable relationships between dead space and alveolar volume, the models for children 3 yr of age and younger resulted in predicted TLCs well below those predicted using published scaling equations. These discrepancies may be reflective of dysanaptic growth, in which the alveolar region is growing more rapidly than the airways. The results for children 3 yr of age and under suggest the need for a greater understanding of lung development during this critical period. This is particularly important considering the increasing evidence that exposure to pollutants and other toxicants and allergens during the first 2 yr of life may have long-term consequences on respiratory disease outcomes. Our results suggest that the

  2. 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

  3. Theoretical modeling of the interaction between alveoli during inflation and deflation in normal and diseased lungs.

    PubMed

    Schirrmann, Kerstin; Mertens, Michael; Kertzscher, Ulrich; Kuebler, Wolfgang M; Affeld, Klaus

    2010-04-19

    Alveolar recruitment is a central strategy in the ventilation of patients with acute lung injury and other lung diseases associated with alveolar collapse and atelectasis. However, biomechanical insights into the opening and collapse of individual alveoli are still limited. A better understanding of alveolar recruitment and the interaction between alveoli in intact and injured lungs is of crucial relevance for the evaluation of the potential efficacy of ventilation strategies. We simulated human alveolar biomechanics in normal and injured lungs. We used a basic simulation model for the biomechanical behavior of virtual single alveoli to compute parameterized pressure-volume curves. Based on these curves, we analyzed the interaction and stability in a system composed of two alveoli. We introduced different values for surface tension and tissue properties to simulate different forms of lung injury. The data obtained predict that alveoli with identical properties can coexist with both different volumes and with equal volumes depending on the pressure. Alveoli in injured lungs with increased surface tension will collapse at normal breathing pressures. However, recruitment maneuvers and positive endexpiratory pressure can stabilize those alveoli, but coexisting unaffected alveoli might be overdistended. In injured alveoli with reduced compliance collapse is less likely, alveoli are expected to remain open, but with a smaller volume. Expanding them to normal size would overdistend coexisting unaffected alveoli. The present simulation model yields novel insights into the interaction between alveoli and may thus increase our understanding of the prospects of recruitment maneuvers in different forms of lung injury. PMID:20031137

  4. 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

  5. Efficacy of Mesenchymal Stromal Cell Therapy for Acute Lung Injury in Preclinical Animal Models: A Systematic Review

    PubMed Central

    McIntyre, Lauralyn A.; Moher, David; Fergusson, Dean A.; Sullivan, Katrina J.; Mei, Shirley H. J.; Lalu, Manoj; Marshall, John; Mcleod, Malcolm; Griffin, Gilly; Grimshaw, Jeremy; Turgeon, Alexis; Avey, Marc T.; Rudnicki, Michael A.; Jazi, Mazen; Fishman, Jason; Stewart, Duncan J.

    2016-01-01

    The Acute Respiratory Distress Syndrome (ARDS) is a devastating clinical condition that is associated with a 30–40% risk of death, and significant long term morbidity for those who survive. Mesenchymal stromal cells (MSC) have emerged as a potential novel treatment as in pre-clinical models they have been shown to modulate inflammation (a major pathophysiological hallmark of ARDS) while enhancing bacterial clearance and reducing organ injury and death. A systematic search of MEDLINE, EMBASE, BIOSIS and Web of Science was performed to identify pre-clinical studies that examined the efficacy MSCs as compared to diseased controls for the treatment of Acute Lung Injury (ALI) (the pre-clinical correlate of human ARDS) on mortality, a clinically relevant outcome. We assessed study quality and pooled results using random effect meta-analysis. A total of 54 publications met our inclusion criteria of which 17 (21 experiments) reported mortality and were included in the meta-analysis. Treatment with MSCs, as compared to controls, significantly decreased the overall odds of death in animals with ALI (Odds Ratio 0.24, 95% Confidence Interval 0.18–0.34, I2 8%). Efficacy was maintained across different types of animal models and means of ALI induction; MSC origin, source, route of administration and preparation; and the clinical relevance of the model (timing of MSC administration, administration of fluids and or antibiotics). Reporting of standard MSC characterization for experiments that used human MSCs and risks of bias was generally poor, and although not statistically significant, a funnel plot analysis for overall mortality suggested the presence of publication bias. The results from our meta-analysis support that MSCs substantially reduce the odds of death in animal models of ALI but important reporting elements were sub optimal and limit the strength of our conclusions. PMID:26821255

  6. 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. PMID:25699030

  7. 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

  8. 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.

  9. 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. PMID:16920671

  10. 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

  11. 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. PMID:25450481

  12. A Highly Efficient Gene Expression Programming (GEP) Model for Auxiliary Diagnosis of Small Cell Lung Cancer

    PubMed Central

    Si, Hongzong; Liu, Shihai; Li, Xianchao; Gao, Caihong; Cui, Lianhua; Li, Chuan; Yang, Xue; Yao, Xiaojun

    2015-01-01

    Background Lung cancer is an important and common cancer that constitutes a major public health problem, but early detection of small cell lung cancer can significantly improve the survival rate of cancer patients. A number of serum biomarkers have been used in the diagnosis of lung cancers; however, they exhibit low sensitivity and specificity. Methods We used biochemical methods to measure blood levels of lactate dehydrogenase (LDH), C-reactive protein (CRP), Na+, Cl-, carcino-embryonic antigen (CEA), and neuron specific enolase (NSE) in 145 small cell lung cancer (SCLC) patients and 155 non-small cell lung cancer and 155 normal controls. A gene expression programming (GEP) model and Receiver Operating Characteristic (ROC) curves incorporating these biomarkers was developed for the auxiliary diagnosis of SCLC. Results After appropriate modification of the parameters, the GEP model was initially set up based on a training set of 115 SCLC patients and 125 normal controls for GEP model generation. Then the GEP was applied to the remaining 60 subjects (the test set) for model validation. GEP successfully discriminated 281 out of 300 cases, showing a correct classification rate for lung cancer patients of 93.75% (225/240) and 93.33% (56/60) for the training and test sets, respectively. Another GEP model incorporating four biomarkers, including CEA, NSE, LDH, and CRP, exhibited slightly lower detection sensitivity than the GEP model, including six biomarkers. We repeat the models on artificial neural network (ANN), and our results showed that the accuracy of GEP models were higher than that in ANN. GEP model incorporating six serum biomarkers performed by NSCLC patients and normal controls showed low accuracy than SCLC patients and was enough to prove that the GEP model is suitable for the SCLC patients. Conclusion We have developed a GEP model with high sensitivity and specificity for the auxiliary diagnosis of SCLC. This GEP model has the potential for the wide use

  13. Adenovirus-delivered wwox inhibited lung cancer growth in vivo in a mouse model.

    PubMed

    Zhou, Y; Shou, F; Zhang, H; You, Q

    2016-01-01

    Lung cancer is the most prevalent and deadly malignancy worldwide. This study investigated the possibility of inhibiting lung cancer in vivo with adenovirus-delivered WW domain-containing oxidoreductase (wwox). The lung cancer model was established by inoculating A549 lung cancer cells into the pleural space of nude mice. The control or wwox adenovirus was injected into the pleural space 7 days after cell inoculation and 14 days after first injection. The tumor number and burdens were measured 2 weeks after second virus injection. The carcinoembryonic antigen (CEA) and alpha-feto protein (AFP) levels in pleural effusion were analyzed by enzyme-linked immunosorbent assay. Apoptosis, proliferation and angiogenesis of tumor cells were assessed by terminal deoxinucleotidyl transferase-mediated dUTP-fluorescein nick end labeling assay, proliferating cell nuclear antigen (PCNA) and CD31 staining, respectively. Ectopic wwox significantly reduced both the number and size of lung tumors accompanied by substantially lower CEA and AFP levels in pleural effusion. The expression levels of Bcl2, Bcl-xL, vascular endothelial growth factor, PCNA-positive and CD31-positive cells in the tumors were significantly decreased, whereas levels of p21 and p73 and apoptotic cells markedly increased in mice receiving the wwox virus. These data demonstrated that wwox delivered by adenovirus was able to inhibit the growth of lung cancer in vivo, indicating the potential of using wwox as a gene therapy agent for lung cancer. PMID:26516139

  14. Effect of adrenergic stimulation on clearance from small ciliated airways in healthy subjects.

    PubMed

    Svartengren, K; Philipson, K; Svartengren, M; Camner, P

    1998-01-01

    Mucociliary transport is an important clearance mechanism of larger airways, but in the smallest ciliated airways (bronchioles) it may be less effective. The present study aimed at investigating whether clearance from the bronchioles in subjects with healthy airways was stimulated by an adrenergic agonist (terbutaline sulphate). Tracheobronchial clearance was studied twice in 10 healthy subjects after inhalation of 6-micron (aerodynamic diameter) monodisperse Teflon particles labeled with 111In. At one exposure, oral treatment with terbutaline sulphate, known to stimulate clearance in large airways, began immediately after inhalation of the particles. The other exposure was a control measurement. The particles were inhaled at an extremely slow flow, 0.05 L/s, which gave deposition mainly in the small ciliated airways (bronchioles). Lung retention was measured at 0, 24, 48, and 72 h. Clearance was significant every 24 h for both exposures (p < .05, two-tailed paired t-test), with similar fractions of retained particles at all time points. During treatment with terbutaline sulphate, the subjects' pulse rates tended to be higher, but clearance rates did not increase. We found, as expected, no significant correlation between lung retention and lung function in either exposure. This study shows that an adrenergic agonist does not significantly influence overall clearance from the bronchiolar region in healthy subjects. This suggests that mucociliary transport does not significantly contribute to clearance from the smallest ciliated airways. Other mechanisms may be more important for the transportation of mucus from these airways. PMID:9555573

  15. 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

    2014-08-01

    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. PMID:24852140

  16. 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.

  17. Progressive genomic instability in the FVB/KrasLA2 mouse model of lung cancer

    PubMed Central

    To, Minh D.; Quigley, David A.; Mao, Jian-Hua; Rosario, Reyno Del; Hsu, Jeff; Hodgson, Graeme; Jacks, Tyler; Balmain, Allan

    2011-01-01

    Alterations in DNA copy number contribute to the development and progression of cancers and are common in epithelial tumors. We have used array Comparative Genomic Hybridization (aCGH) to visualize DNA copy number alterations across the genomes of lung tumors in the KrasLA2 model of lung cancer. Copy number gain involving the Kras locus, as focal amplification or whole chromosome gain, is the most common alteration in these tumors, and with a prevalence that increased significantly with increasing tumor size. Furthermore, Kras amplification was the only major genomic event among the smallest lung tumors, suggesting that this alteration occurs early during the development of mutant Kras driven lung cancers. Recurring gains and deletions of other chromosomes occur progressively more frequently among larger tumors. These results are in contrast to a previous aCGH analysis of lung tumors from KrasLA2 mice on a mixed genetic background, in which relatively few DNA copy number alterations were observed regardless of tumor size. Our model features the KrasLA2 allele on the inbred FVB/N mouse strain, and in this genetic background there is a highly statistically significant increase in level of genomic instability with increasing tumor size. These data suggest that recurring DNA copy alterations are important for tumor progression in the KrasLA2 model of lung cancer, and that the requirement for these alterations may be dependent on the genetic background of the mouse strain. PMID:21807965

  18. 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. PMID:27345200

  19. 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.

  20. Animal models of ex vivo lung perfusion as a platform for transplantation research

    PubMed Central

    Nelson, Kevin; Bobba, Christopher; Ghadiali, Samir; Jr, Don Hayes; Black, Sylvester M; Whitson, Bryan A

    2014-01-01

    Ex vivo lung perfusion (EVLP) is a powerful experimental model for isolated lung research. EVLP allows for the lungs to be manipulated and characterized in an external environment so that the effect of specific ventilation/perfusion variables can be studied independent of other confounding physiologic contributions. At the same time, EVLP allows for normal organ level function and real-time monitoring of pulmonary physiology and mechanics. As a result, this technique provides unique advantages over in vivo and in vitro models. Small and large animal models of EVLP have been developed and each of these models has their strengths and weaknesses. In this manuscript, we provide insight into the relative strengths of each model and describe how the development of advanced EVLP protocols is leading to a novel experimental platform that can be used to answer critical questions in pulmonary physiology and transplant medicine. PMID:24977117

  1. Animal models of ex vivo lung perfusion as a platform for transplantation research.

    PubMed

    Nelson, Kevin; Bobba, Christopher; Ghadiali, Samir; Hayes, Don; Black, Sylvester M; Whitson, Bryan A

    2014-05-20

    Ex vivo lung perfusion (EVLP) is a powerful experimental model for isolated lung research. EVLP allows for the lungs to be manipulated and characterized in an external environment so that the effect of specific ventilation/perfusion variables can be studied independent of other confounding physiologic contributions. At the same time, EVLP allows for normal organ level function and real-time monitoring of pulmonary physiology and mechanics. As a result, this technique provides unique advantages over in vivo and in vitro models. Small and large animal models of EVLP have been developed and each of these models has their strengths and weaknesses. In this manuscript, we provide insight into the relative strengths of each model and describe how the development of advanced EVLP protocols is leading to a novel experimental platform that can be used to answer critical questions in pulmonary physiology and transplant medicine. PMID:24977117

  2. Trappin-2 promotes early clearance of Pseudomonas aeruginosa through CD14-dependent macrophage activation and neutrophil recruitment.

    PubMed

    Wilkinson, Thomas S; Dhaliwal, Kevin; Hamilton, Thomas W; Lipka, Alexander F; Farrell, Lesley; Davidson, Donald J; Duffin, Rodger; Morris, Andrew Conway; Haslett, Chris; Govan, John R W; Gregory, Christopher D; Sallenave, Jean-Michel; Simpson, A John

    2009-04-01

    Microaspiration of Pseudomonas aeruginosa contributes to the pathogenesis of nosocomial pneumonia. Trappin-2 is a host defense peptide that assists with the clearance of P. aeruginosa through undefined mechanisms. A model of macrophage interactions with replicating P. aeruginosa (strain PA01) in serum-free conditions was developed, and the influence of subantimicrobial concentrations of trappin-2 was subsequently studied. PA01 that was pre-incubated with trappin-2 (at concentrations that have no direct antimicrobial effects), but not control PA01, was cleared by alveolar and bone marrow-derived macrophages. However, trappin-2-enhanced clearance of PA01 was completely abrogated by CD14- null macrophages. Fluorescence microscopy demonstrated the presence of trappin-2 on the bacterial cell surface of trappin-2-treated PA01. In a murine model of early lung infection, trappin-2-treated PA01 was cleared more efficiently than control PA01 2 hours of intratracheal instillation. Furthermore, trappin-2-treated PA01 up-regulated the murine chemokine CXCL1/KC after 2 hours with a corresponding increase in neutrophil recruitment 1 hour later. These in vivo trappin-2-treated PA01 effects were absent in CD14-deficient mice. Trappin-2 appears to opsonize P. aeruginosa for more efficient, CD14-dependent clearance by macrophages and contributes to the induction of chemokines that promote neutrophil recruitment. Trappin-2 may therefore play an important role in innate recognition and clearance of pathogens during the very earliest stages of pulmonary infection. PMID:19264904

  3. Trappin-2 Promotes Early Clearance of Pseudomonas aeruginosa through CD14-Dependent Macrophage Activation and Neutrophil Recruitment

    PubMed Central

    Wilkinson, Thomas S.; Dhaliwal, Kevin; Hamilton, Thomas W.; Lipka, Alexander F.; Farrell, Lesley; Davidson, Donald J.; Duffin, Rodger; Morris, Andrew Conway; Haslett, Chris; Govan, John R.W.; Gregory, Christopher D.; Sallenave, Jean-Michel; Simpson, A. John

    2009-01-01

    Microaspiration of Pseudomonas aeruginosa contributes to the pathogenesis of nosocomial pneumonia. Trappin-2 is a host defense peptide that assists with the clearance of P. aeruginosa through undefined mechanisms. A model of macrophage interactions with replicating P. aeruginosa (strain PA01) in serum-free conditions was developed, and the influence of subantimicrobial concentrations of trappin-2 was subsequently studied. PA01 that was pre-incubated with trappin-2 (at concentrations that have no direct antimicrobial effects), but not control PA01, was cleared by alveolar and bone marrow-derived macrophages. However, trappin-2-enhanced clearance of PA01 was completely abrogated by CD14- null macrophages. Fluorescence microscopy demonstrated the presence of trappin-2 on the bacterial cell surface of trappin-2-treated PA01. In a murine model of early lung infection, trappin-2-treated PA01 was cleared more efficiently than control PA01 2 hours of intratracheal instillation. Furthermore, trappin-2-treated PA01 up-regulated the murine chemokine CXCL1/KC after 2 hours with a corresponding increase in neutrophil recruitment 1 hour later. These in vivo trappin-2-treated PA01 effects were absent in CD14-deficient mice. Trappin-2 appears to opsonize P. aeruginosa for more efficient, CD14-dependent clearance by macrophages and contributes to the induction of chemokines that promote neutrophil recruitment. Trappin-2 may therefore play an important role in innate recognition and clearance of pathogens during the very earliest stages of pulmonary infection. PMID:19264904

  4. The MGH-HMS Lung Cancer Policy Model: Tobacco Control versus Screening

    PubMed Central

    McMahon, Pamela M.; Kong, Chung Yin; Johnson, Bruce E.; Weinstein, Milton C.; Weeks, Jane C.; Tramontano, Angela C.; Cipriano, Lauren E.; Bouzan, Colleen; Gazelle, G. Scott

    2012-01-01

    Background The natural history model underlying the MGH Lung Cancer Policy Model (LCPM) does not include the two-stage clonal expansion model employed in other CISNET lung models. We used the LCPM to predict numbers of U.S. lung cancer deaths for ages 30–84 between 1975 and 2000 under 4 scenarios as part of the comparative modeling analysis described in this monograph. Methods The LCPM is a comprehensive microsimulation model of lung cancer development, progression, detection, treatment, and survival. Individual-level patient histories are aggregated to estimate cohort or population-level outcomes. Lung cancer states are defined according to underlying disease variables, test results, and clinical events. By simulating detailed clinical procedures, the LCPM can predict benefits and harms attributable to a variety of patient management practices, including annual screening programs. Results Under the scenario of observed smoking patterns, predicted numbers of deaths from the calibrated LCPM were within 2% of observed over all years (1975–2000). The LCPM estimated that historical tobacco control policies achieved 28.6% (25.2% in men, 30.5% in women) of the potential reduction in U.S. lung cancer deaths had smoking had been eliminated entirely. The hypothetical adoption in 1975 of annual helical CT screening of all persons aged 55–74 with at least 30 pack-years of cigarette exposure to historical tobacco control would have yielded a proportion realized of 39.0% (42.0% in men, 33.3% in women). Conclusions The adoption of annual screening would have prevented less than half as many lung cancer deaths as the elimination of cigarette smoking. PMID:22882882

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

    PubMed

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

    2016-07-01

    An Active Appearance Model (AAM) is a computer vision model which can be used to effectively segment lung fields in CT images. However, the fitting result is often inadequate when the lungs are affected by high-density pathologies. To overcome this problem, we propose a Higher-order Singular Value Decomposition (HOSVD)-based Three-dimensional (3D) AAM. An evaluation was performed on 310 diseased lungs form the Lung Image Database Consortium Image Collection. Other contemporary AAMs operate directly on patterns represented by vectors, i.e., before applying the AAM to a 3D lung volume,it has to be vectorized first into a vector pattern by some technique like concatenation. However, some implicit structural or local contextual information may be lost in this transformation. According to the nature of the 3D lung volume, HOSVD is introduced to represent and process the lung in tensor space. Our method can not only directly operate on the original 3D tensor patterns, but also efficiently reduce the computer memory usage. The evaluation resulted in an average Dice coefficient of 97.0 % ± 0.59 %, a mean absolute surface distance error of 1.0403 ± 0.5716 mm, a mean border positioning errors of 0.9187 ± 0.5381 pixel, and a Hausdorff Distance of 20.4064 ± 4.3855, respectively. Experimental results showed that our methods delivered significant and better segmentation results, compared with the three other model-based lung segmentation approaches, namely 3D Snake, 3D ASM and 3D AAM. PMID:27277277

  6. 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

  7. 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. PMID:27003297

  8. Geometric dose prediction model for hemithoracic intensity-modulated radiation therapy in mesothelioma patients with two intact lungs.

    PubMed

    Kuo, LiCheng; Yorke, Ellen D; Dumane, Vishruta A; Foster, Amanda; Zhang, Zhigang; Mechalakos, James G; Wu, Abraham J; Rosenzweig, Kenneth E; Rimner, Andreas

    2016-01-01

    The presence of two intact lungs makes it challenging to reach a tumoricidal dose with hemithoracic pleural intensity-modulated radiation therapy (IMRT) in patients with malignant pleural mesothelioma (MPM) who underwent pleurectomy/decor-tications or have unresectable disease. We developed an anatomy-based model to predict attainable prescription dose before starting optimization. Fifty-six clinically delivered IMRT plans were analyzed regarding correlation of prescription dose and individual and total lung volumes, planning target volume (PTV), ipsilateral normal lung volume and ratios: contralateral/ipsilateral lung (CIVR); contralateral lung/PTV (CPVR); ipsilateral lung /PTV (IPVR); ipsilateral normal lung /total lung (INTLVR); ipsilateral normal lung/PTV (INLPVR). Spearman's rank correlation and Fisher's exact test were used. Correlation between mean ipsilateral lung dose (MILD) and these volume ratios and between prescription dose and single lung mean doses were studied. The prediction models were validated in 23 subsequent MPM patients. CIVR showed the strongest correlation with dose (R = 0.603, p < 0.001) and accurately predicted prescription dose in the validation cases. INLPVR and MILD as well as MILD and prescription dose were significantly correlated (R = -0.784, p < 0.001 and R = 0.554, p < 0.001, respectively) in the training and validation cases. Parameters obtainable directly from planning scan anatomy predict achievable prescription doses for hemithoracic IMRT treatment of MPM patients with two intact lungs. PMID:27167294

  9. Site clearance working group

    SciTech Connect

    1997-03-01

    The Gulf of Mexico and Louisiana continue to be areas with a high level of facility removal, and the pace of removal is projected to increase. Regulations were promulgated for the Gulf of Mexico and Louisiana requiring that abandoned sites be cleared of debris that could interfere with fishing and shrimping activities. The site clearance regulations also required verification that the sites were clear. Additionally, government programs were established to compensate fishermen for losses associated with snagging their equipment on oil and gas related objects that remained on the water bottoms in areas other than active producing sites and sites that had been verified as clear of obstructions and snags. The oil and gas industry funds the compensation programs. This paper reviews the regulations and evolving operating practices in the Gulf of Mexico and Louisiana where site clearance and fisherman`s gear compensation regulations have been in place for a number of years. Although regulations and guidelines may be in place elsewhere in the world, this paper focuses on the Gulf of Mexico and Louisiana. Workshop participants are encouraged to bring up international issues during the course of the workshop. Additionally, this paper raises questions and focuses on issues that are of concern to the various Gulf of Mexico and Louisiana water surface and water bottom stakeholders. This paper does not have answers to the questions or issues. During the workshop participants will debate the questions and issues in an attempt to develop consensus opinions and/or make suggestions that can be provided to the appropriate organizations, both private and government, for possible future research or policy adjustments. Site clearance and facility removal are different activities. Facility removal deals with removal of the structures used to produce oil and gas including platforms, wells, casing, piles, pipelines, well protection structures, etc.

  10. A useful model capable of predicting the clearance of cytochrome 3A4 (CYP3A4) substrates in humans: validity of CYP3A4 transgenic mice lacking their own Cyp3a enzymes.

    PubMed

    Mitsui, Tetsuya; Nemoto, Takayuki; Miyake, Taiji; Nagao, Shunsuke; Ogawa, Kotaro; Kato, Motohiro; Ishigai, Masaki; Yamada, Hideyuki

    2014-09-01

    The accurate prediction for the body clearance of a novel drug candidate by humans during the preclinical stage contributes to its successful development. To improve the predictability of human hepatic clearance, we focused on CYP3A4, which is involved in the metabolism of more than 50% of all currently marketed drugs. In this study, we investigated the validity of the in vivo model using transgenic mice carrying the human CYP3A4 gene and lacking their own Cyp3a genes (CYP3A4-Tg mice). The CYP3A4 activity toward its substrates in liver microsomes was similar in CYP3A4-Tg mice and humans. As for the clearance, six CYP3A4 substrates (alprazolam, felodipine, midazolam, nifedipine, nitrendipine, and quinidine) were given intravenously to CYP3A4-Tg mice, and their hepatic intrinsic clearance (CLint,h) was evaluated. A regression analysis of the data obtained indicated that the CLint,h values of six substrates in CYP3A4-Tg mice were highly correlated with those in humans (R(2) = 0.95). This correlation could be improved by correcting the CLint,h values by the relative contribution of artificially expressed CYP3A4 to the overall metabolism in the mice. From these findings, it is reasonable to expect that the CLint,h of a particular drug in humans is predictable by applying the CLint,h obtained in CYP3A4-Tg mice to a regression line prepared in advance. The variance of the CLint,h prediction by this method was evaluated and found to be within a range of 2-fold of the regression value. These results suggest that the CYP3A4-Tg mouse model has the potential to accurately predict the human hepatic clearance of CYP3A4 substrates. PMID:25005602

  11. Comparing histone deacetylase inhibitor responses in genetically engineered mouse lung cancer models and a window of opportunity trial in patients with lung cancer.

    PubMed

    Ma, Tian; Galimberti, Fabrizio; Erkmen, Cherie P; Memoli, Vincent; Chinyengetere, Fadzai; Sempere, Lorenzo; Beumer, Jan H; Anyang, Bean N; Nugent, William; Johnstone, David; Tsongalis, Gregory J; Kurie, Jonathan M; Li, Hua; Direnzo, James; Guo, Yongli; Freemantle, Sarah J; Dragnev, Konstantin H; Dmitrovsky, Ethan

    2013-08-01

    Histone deacetylase inhibitor (HDACi; vorinostat) responses were studied in murine and human lung cancer cell lines and genetically engineered mouse lung cancer models. Findings were compared with a window of opportunity trial in aerodigestive tract cancers. In human (HOP62, H522, and H23) and murine transgenic (ED-1, ED-2, LKR-13, and 393P, driven, respectively, by cyclin E, degradation-resistant cyclin E, KRAS, or KRAS/p53) lung cancer cell lines, vorinostat reduced growth, cyclin D1, and cyclin E levels, but induced p27, histone acetylation, and apoptosis. Other biomarkers also changed. Findings from transgenic murine lung cancer models were integrated with those from a window of opportunity trial that measured vorinostat pharmacodynamic responses in pre- versus posttreatment tumor biopsies. Vorinostat repressed cyclin D1 and cyclin E expression in murine transgenic lung cancers and significantly reduced lung cancers in syngeneic mice. Vorinostat also reduced cyclin D1 and cyclin E expression, but increased p27 levels in post- versus pretreatment human lung cancer biopsies. Notably, necrotic and inflammatory responses appeared in posttreatment biopsies. These depended on intratumoral HDACi levels. Therefore, HDACi treatments of murine genetically engineered lung cancer models exert similar responses (growth inhibition and changes in gene expression) as observed in lung cancer cell lines. Moreover, enhanced pharmacodynamic responses occurred in the window of opportunity trial, providing additional markers of response that can be evaluated in subsequent HDACi trials. Thus, combining murine and human HDACi trials is a strategy to translate preclinical HDACi treatment outcomes into the clinic. This study uncovered clinically tractable mechanisms to engage in future HDACi trials. PMID:23686769

  12. 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. PMID:25777770

  13. Corticosteroids prevent acute lung dysfunction caused by thoracic irradiation in unanesthetized sheep

    SciTech Connect

    Loyd, J.E.; Bolds, J.M.; Wickersham, N.; Malcolm, A.W.; Brigham, K.L.

    1988-11-01

    We sought to determine the effect of corticosteroid therapy in a new acute model of oxidant lung injury, thoracic irradiation in awake sheep. Sheep were irradiated with 1,500 rads to the whole chest except for blocking the heart and adjacent ventral lung. Seven experimental sheep were given methylprednisolone (1 g intravenously every 6 h for four doses) and thoracic irradiation; control sheep received only irradiation. In irradiated control sheep, lung lymph flow increased from baseline (7.6 ml/h) to peak at 3 h (13.2), and lung lymph protein clearance increased from 5.1 to 9.7 ml/h. Mean pulmonary artery pressure increased in the irradiated control sheep from 19 to 32.4 cm H/sub 2/O, whereas the lung lymph thromboxane concentration increased from 0.09 to 6.51 ng/ml at 3 h. Arterial oxygen tension in irradiated control sheep fell gradually from 86 mm Hg at baseline to 65 mm Hg at 8 h. Methylprednisolone administration significantly prevented the increase in lung lymph protein clearance, mean pulmonary artery pressure, and lung lymph thromboxane concentration. Methylprednisolone also prevented the fall in arterial oxygen tension after thoracic irradiation, but did not prevent a further decrease in lymphocytes in blood or lung lymph after radiation. We conclude that corticosteroid therapy prevents most of the acute physiologic changes caused by thoracic irradiation in awake sheep.

  14. 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. PMID:26089976

  15. Characterization of free breathing patterns with 5D lung motion model

    SciTech Connect

    Zhao Tianyu; Lu Wei; Yang Deshan; Mutic, Sasa; Noel, Camille E.; Parikh, Parag J.; Bradley, Jeffrey D.; Low, Daniel A.

    2009-11-15

    Purpose: To determine the quiet respiration breathing motion model parameters for lung cancer and nonlung cancer patients. Methods: 49 free breathing patient 4DCT image datasets (25 scans, cine mode) were collected with simultaneous quantitative spirometry. A cross-correlation registration technique was employed to track the lung tissue motion between scans. The registration results were applied to a lung motion model: X-vector=X-vector{sub 0}+{alpha}-vector{beta}-vector f, where X-vector is the position of a piece of tissue located at reference position X-vector{sub 0} during a reference breathing phase (zero tidal volume v, zero airflow f). {alpha}-vector is a parameter that characterizes the motion due to air filling (motion as a function of tidal volume v) and {beta}-vector is the parameter that accounts for the motion due to the imbalance of dynamical stress distributions during inspiration and exhalation that causes lung motion hysteresis (motion as a function of airflow f). The parameters {alpha}-vector and {beta}-vector together provide a quantitative characterization of breathing motion that inherently includes the complex hysteresis interplay. The {alpha}-vector and {beta}-vector distributions were examined for each patient to determine overall general patterns and interpatient pattern variations. Results: For 44 patients, the greatest values of |{alpha}-vector| were observed in the inferior and posterior lungs. For the rest of the patients, |{alpha}-vector| reached its maximum in the anterior lung in three patients and the lateral lung in two patients. The hysteresis motion {beta}-vector had greater variability, but for the majority of patients, |{beta}-vector| was largest in the lateral lungs. Conclusions: This is the first report of the three-dimensional breathing motion model parameters for a large cohort of patients. The model has the potential for noninvasively predicting lung motion. The majority of patients exhibited similar |{alpha}-vector| maps

  16. Immunomodulatory Effects of Mixed Hematopoietic Chimerism: Immune Tolerance in Canine Model of Lung Transplantation

    PubMed Central

    Nash;, Richard A.; Yunosov;, Murad; Abrams;, Kraig; Hwang;, Billanna; Castilla-Llorente;, Cristina; Chen;, Peter; Farivar;, Alexander S.; Georges;, George E.; Hackman;, Robert C.; Lamm;, Wayne J.E.; Lesnikova;, Marina; Ochs;, Hans D.; Randolph-Habecker;, Julie; Ziegler;, Stephen F.; Storb;, Rainer; Storer;, Barry; Madtes;, David K.; Glenny;, Robb; Mulligan, Michael S.

    2010-01-01

    Long-term survival after lung transplantation is limited by acute and chronic graft rejection. Induction of immune tolerance by first establishing mixed hematopoietic chimerism (MC) is a promising strategy to improve outcomes. In a preclinical canine model, stable MC was established in recipients after reduced-intensity conditioning and hematopoietic cell transplantation from a DLA-identical donor. Delayed lung transplantation was performed from the stem cell donor without pharmacological immunosuppression. Lung graft survival without loss of function was prolonged in chimeric (n=5) vs. nonchimeric (n=7) recipients (p≤0.05, Fisher’s test). There were histological changes consistent with low grade rejection in 3/5 of the lung grafts in chimeric recipients at ≥1 year. Chimeric recipients after lung transplantation had a normal immune response to a T-dependent antigen. Compared to normal dogs, there were significant increases of CD4+INFγ+, CD4+IL-4+ and CD8+ INFγ+ T-cell subsets in the blood (p <0.0001 for each of the 3 T-cell subsets). Markers for regulatory T-cell subsets including foxP3, IL10 and TGFβ were also increased in CD3+ T cells from the blood and peripheral tissues of chimeric recipients after lung transplantation. Establishing MC is immunomodulatory and observed changes were consistent with activation of both the effector and regulatory immune response. PMID:19422333

  17. 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

  18. 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

  19. 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

  20. Method of isolated ex vivo lung perfusion in a rat model: lessons learned from developing a rat EVLP program.

    PubMed

    Nelson, Kevin; Bobba, Christopher; Eren, Emre; Spata, Tyler; Tadres, Malak; Hayes, Don; Black, Sylvester M; Ghadiali, Samir; Whitson, Bryan A

    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. The need for a new animal model for chronic rejection after lung transplantation.

    PubMed

    De Vleeschauwer, S; Vanaudenaerde, B; Vos, R; Meers, C; Wauters, S; Dupont, L; Van Raemdonck, D; Verleden, G

    2011-11-01

    The single most important cause of late mortality after lung transplantation is obliterative bronchiolitis (OB), clinically characterized by a decrease in lung function and morphologically by characteristic changes. Recently, new insights into its pathogenesis have been acquired: risk factors have been identified and the use of azithromycin showed a dichotomy with at least 2 different phenotypes of bronchiolitis obliterans syndrome (BOS). It is clear that a good animal model is indispensable to further dissect and unravel the pathogenesis of BOS. Many animal models have been developed to study BOS but, so far, none of these models truly mimics the human situation. Looking at the definition of BOS, a good animal model implies histological OB lesions, possibility to measure lung function, and airway inflammation. This review sought to discuss, including pros and cons, all potential animal models that have been developed to study OB/BOS. It has become clear that a new animal model is needed; recent developments using an orthotopic mouse lung transplantation model may offer the answer because it mimics the human situation. The genetic variants among this species may open new perspectives for research into the pathogenesis of OB/BOS. PMID:22099823

  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. A model for treating avian aspergillosis: serum and lung tissue kinetics for Japanese quail (Coturnix japonica) following single and multiple aerosol exposures of a nanoparticulate itraconazole suspension.

    PubMed

    Rundfeldt, Chris; Wyska, Elżbieta; Steckel, Hartwig; Witkowski, Andrzej; Jeżewska-Witkowska, Grażyna; Wlaź, Piotr

    2013-11-01

    Aspergillosis is frequently reported in parrots, falcons and other birds held in captivity. Inhalation is the main route of infection for Aspergillus fumigatus, resulting in both acute and chronic disease conditions. Itraconazole (ITRA) is an antifungal commonly used in birds, but administration requires repeated oral dosing and the safety margin is narrow. We describe lung tissue and serum pharmacokinetics of a nanoparticulate ITRA suspension administered to Japanese quail by aerosol exposure. Aerosolized ITRA (1 and 10% suspension) administered over 30 min did not induce adverse clinical reactions in quail upon single or 5-day repeated doses. High lung concentrations, well above the inhibitory levels for A. fumigatus, of 4.14 ± 0.19 μg/g and 27.5 ± 4.58 μg/g (mean ± SEM, n = 3), were achieved following single-dose inhalation of 1% and 10% suspension, respectively. Upon multiple dose administration of 10% suspension, mean lung concentrations reached 104.9 ± 10.1 μg/g. Drug clearance from the lungs was slow with terminal half-lives of 19.7 h and 35.8 h following inhalation of 1% and 10% suspension, respectively. Data suggest that lung clearance is solubility driven. Lung concentrations of hydroxy-itraconazole reached 1-2% of the ITRA lung tissue concentration indicating metabolism in lung tissue. Steady, but low, serum concentrations of ITRA could be measured after multiple dose administration, reaching less than 0.1% of the lung tissue concentration. This formulation may represent a novel, easy to administer treatment modality for fungal lung infection, preventing high systemic exposure. It may also be useful as metaphylaxis to prevent the outbreak of aspergillosis in colonized animals. PMID:23815436

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

    PubMed

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

    2014-06-01

    Our objective was to model the cost-effectiveness and economic value of routine peri-operative Staphylococcus aureus screening and decolonization of lung and heart-lung transplant recipients from hospital and third-party payer perspectives. We used clinical data from 596 lung and heart-lung transplant recipients to develop a model in TreeAge Pro 2009 (Williamsport, MA, USA). Sensitivity analyses varied S. aureus colonization rate (5-15 %), probability of infection if colonized (10-30 %), and decolonization efficacy (25-90 %). Data were collected from the Cardiothoracic Transplant Program at the University of Pittsburgh Medical Center. Consecutive lung and heart-lung transplant recipients from January 2006 to December 2010 were enrolled retrospectively. Baseline rates of S. aureus colonization, infection and decolonization efficacy were 9.6 %, 36.7 %, and 31.9 %, respectively. Screening and decolonization was economically dominant for all scenarios tested, providing more cost savings and health benefits than no screening. Savings per case averted (2012 $US) ranged from $73,567 to $133,157 (hospital perspective) and $10,748 to $16,723 (third party payer perspective), varying with the probability of colonization, infection, and decolonization efficacy. Using our clinical data, screening and decolonization led to cost savings per case averted of $240,602 (hospital perspective) and averted 6.7 S. aureus infections (4.3 MRSA and 2.4 MSSA); 89 patients needed to be screened to prevent one S. aureus infection. Our data support routine S. aureus screening and decolonization of lung and heart-lung transplant patients. The economic value of screening and decolonization was greater than in previous models of other surgical populations. PMID:24500598

  5. Turbomachinery Clearance Control

    NASA Technical Reports Server (NTRS)

    Chupp, Raymond E.; Hendricks, Robert C.; Lattime, Scott B.; Steinetz, Bruce M.; Aksit, Mahmut F.

    2007-01-01

    Controlling interface clearances is the most cost effective method of enhancing turbomachinery performance. Seals control turbomachinery leakages, coolant flows and contribute to overall system rotordynamic stability. In many instances, sealing interfaces and coatings are sacrificial, like lubricants, giving up their integrity for the benefit of the component. They are subjected to abrasion, erosion, oxidation, incursive rubs, foreign object damage (FOD) and deposits as well as extremes in thermal, mechanical, aerodynamic and impact loadings. Tribological pairing of materials control how well and how long these interfaces will be effective in controlling flow. A variety of seal types and materials are required to satisfy turbomachinery sealing demands. These seals must be properly designed to maintain the interface clearances. In some cases, this will mean machining adjacent surfaces, yet in many other applications, coatings are employed for optimum performance. Many seals are coating composites fabricated on superstructures or substrates that are coated with sacrificial materials which can be refurbished either in situ or by removal, stripping, recoating and replacing until substrate life is exceeded. For blade and knife tip sealing an important class of materials known as abradables permit blade or knife rubbing without significant damage or wear to the rotating element while maintaining an effective sealing interface. Most such tip interfaces are passive, yet some, as for the high-pressure turbine (HPT) case or shroud, are actively controlled. This work presents an overview of turbomachinery sealing. Areas covered include: characteristics of gas and steam turbine sealing applications and environments, benefits of sealing, types of standard static and dynamics seals, advanced seal designs, as well as life and limitations issues.

  6. Intermittent hypoxia inhibits clearance of triglyceride-rich lipoproteins and inactivates adipose lipoprotein lipase in a mouse model of sleep apnoea

    PubMed Central

    Drager, Luciano F.; Li, Jianguo; Shin, Mi-Kyung; Reinke, Christian; Aggarwal, Neil R.; Jun, Jonathan C.; Bevans-Fonti, Shannon; Sztalryd, Carole; O'Byrne, Sheila M.; Kroupa, Olessia; Olivecrona, Gunilla; Blaner, William S.; Polotsky, Vsevolod Y.

    2012-01-01

    Aims Delayed lipoprotein clearance is associated with atherosclerosis. This study examined whether chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnoea (OSA), can lead to hyperlipidaemia by inhibiting clearance of triglyceride rich lipoproteins (TRLP). Methods and results Male C57BL/6J mice on high-cholesterol diet were exposed to 4 weeks of CIH or chronic intermittent air (control). FIO2 was decreased to 6.5% once per minute during the 12 h light phase in the CIH group. After the exposure, we measured fasting lipid profile. TRLP clearance was assessed by oral gavage of retinyl palmitate followed by serum retinyl esters (REs) measurements at 0, 1, 2, 4, 10, and 24 h. Activity of lipoprotein lipase (LpL), a key enzyme of lipoprotein clearance, and levels of angiopoietin-like protein 4 (Angptl4), a potent inhibitor of the LpL activity, were determined in the epididymal fat pads, skeletal muscles, and heart. Chronic intermittent hypoxia induced significant increases in levels of total cholesterol and triglycerides, which occurred in TRLP and LDL fractions (P< 0.05 for each comparison). Compared with control mice, animals exposed to CIH showed increases in REs throughout first 10 h after oral gavage of retinyl palmitate (P< 0.05), indicating that CIH inhibited TRLP clearance. CIH induced a >5-fold decrease in LpL activity (P< 0.01) and an 80% increase in Angptl4 mRNA and protein levels in the epididymal fat, but not in the skeletal muscle or heart. Conclusions CIH decreases TRLP clearance and inhibits LpL activity in adipose tissue, which may contribute to atherogenesis observed in OSA. PMID:21478490

  7. Mechanistic evaluation of virus clearance by depth filtration.

    PubMed

    Venkiteshwaran, Adith; Fogle, Jace; Patnaik, Purbasa; Kowle, Ron; Chen, Dayue

    2015-01-01

    Virus clearance by depth filtration has not been well-understood mechanistically due to lack of quantitative data on filter charge characteristics and absence of systematic studies. It is generally believed that both electrostatic interactions and sized based mechanical entrapment contribute to virus clearance by depth filtration. In order to establish whether the effectiveness of virus clearance correlates with the charge characteristics of a given depth filter, a counter-ion displacement technique was employed to determine the ionic capacity for several depth filters. Two depth filters (Millipore B1HC and X0HC) with significant differences in ionic capacities were selected and evaluated for their ability to eliminate viruses. The high ionic capacity X0HC filter showed complete porcine parvovirus (PPV) clearance (eliminating the spiked viruses to below the limit of detection) under low conductivity conditions (≤2.5 mS/cm), achieving a log10 reduction factor (LRF) of > 4.8. On the other hand, the low ionic capacity B1HC filter achieved only ∼2.1-3.0 LRF of PPV clearance under the same conditions. These results indicate that parvovirus clearance by these two depth filters are mainly achieved via electrostatic interactions between the filters and PPV. When much larger xenotropic murine leukemia virus (XMuLV) was used as the model virus, complete retrovirus clearance was obtained under all conditions evaluated for both depth filters, suggesting the involvement of mechanisms other than just electrostatic interactions in XMuLV clearance. PMID:25683459

  8. A Novel Telomerase Activator Suppresses Lung Damage in a Murine Model of Idiopathic Pulmonary Fibrosis

    PubMed Central

    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. PMID:23516479

  9. 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. PMID:23516479

  10. 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.

  11. 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. PMID:21186893

  12. 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

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

    PubMed

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

    2015-06-01

    Electrical impedance tomography (EIT) has shown significant promise for lung imaging. One key challenge for EIT in this application is the movement of electrodes during breathing, which introduces artefacts in reconstructed images. Various approaches have been proposed to compensate for electrode movement, but no comparison of these approaches is available. This paper analyses boundary model mismatch and electrode movement in lung EIT. The aim is to evaluate the extent to which various algorithms tolerate movement, and to determine if a patient specific model is required for EIT lung imaging. Movement data are simulated from a CT-based model, and image analysis is performed using quantitative figures of merit. The electrode movement is modelled based on expected values of chest movement and an extended Jacobian method is proposed to make use of exterior boundary tracking. Results show that a dynamical boundary tracking is the most robust method against any movement, but is computationally more expensive. Simultaneous electrode movement and conductivity reconstruction algorithms show increased robustness compared to only conductivity reconstruction. The results of this comparative study can help develop a better understanding of the impact of shape model mismatch and electrode movement in lung EIT. PMID:26007150

  14. Computational Multiscale Toxicodynamic Modeling of Silver and Carbon Nanoparticle Effects on Mouse Lung Function

    PubMed Central

    Mukherjee, Dwaipayan; Botelho, Danielle; Gow, Andrew J.; Zhang, Junfeng; Georgopoulos, Panos G.

    2013-01-01

    A computational, multiscale toxicodynamic model has been developed to quantify and predict pulmonary effects due to uptake of engineered nanomaterials (ENMs) in mice. The model consists of a collection of coupled toxicodynamic modules, that were independently developed and tested using information obtained from the literature. The modules were developed to describe the dynamics of tissue with explicit focus on the cells and the surfactant chemicals that regulate the process of breathing, as well as the response of the pulmonary system to xenobiotics. Alveolar type I and type II cells, and alveolar macrophages were included in the model, along with surfactant phospholipids and surfactant proteins, to account for processes occurring at multiple biological scales, coupling cellular and surfactant dynamics affected by nanoparticle exposure, and linking the effects to tissue-level lung function changes. Nanoparticle properties such as size, surface chemistry, and zeta potential were explicitly considered in modeling the interactions of these particles with biological media. The model predictions were compared with in vivo lung function response measurements in mice and analysis of mice lung lavage fluid following exposures to silver and carbon nanoparticles. The predictions were found to follow the trends of observed changes in mouse surfactant composition over 7 days post dosing, and are in good agreement with the observed changes in mouse lung function over the same period of time. PMID:24312506

  15. Bioengineering Lungs for Transplantation.

    PubMed

    Gilpin, Sarah E; Charest, Jonathan M; Ren, Xi; Ott, Harald C

    2016-05-01

    Whole lung extracellular matrix scaffolds can be created by perfusion of cadaveric organs with decellularizing detergents, providing a platform for organ regeneration. Lung epithelial engineering must address both the proximal airway cells that function to metabolize toxins and aid mucociliary clearance and the distal pneumocytes that facilitate gas exchange. Engineered pulmonary vasculature must support in vivo blood perfusion with low resistance and intact barrier function and be antithrombotic. Repopulating the native lung matrix with sufficient cell numbers in appropriate anatomic locations is required to enable organ function. PMID:27112255

  16. 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

  17. Development of ferret as a human lung cancer model by injecting4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  18. Transthyretin stabilization by iododiflunisal promotes amyloid-β peptide clearance, decreases its deposition, and ameliorates cognitive deficits in an Alzheimer's disease mouse model.

    PubMed

    Ribeiro, Carlos A; Oliveira, Sandra Marisa; Guido, Luis F; Magalhães, Ana; Valencia, Gregorio; Arsequell, Gemma; Saraiva, Maria João; Cardoso, Isabel

    2014-01-01

    Alzheimer's disease (AD) is the most common form of dementia and now represents 50-70% of total dementia cases. Over the last two decades, transthyretin (TTR) has been associated with AD and, very recently, a novel concept of TTR stability has been established in vitro as a key factor in TTR/amyloid-β (Aβ) interaction. Small compounds, TTR stabilizers (usually non-steroid anti-inflammatory drugs), bind to the thyroxine (T4) central binding channel, increasing TTR tetrameric stability and TTR/Aβ interaction. In this work, we evaluated in vivo the effects of one of the TTR stabilizers identified as improving TTR/Aβ interaction, iododiflunisal (IDIF), in Aβ deposition and other AD features, using AβPPswe/PS1A246E transgenic mice, either carrying two or just one copy of the TTR gene (AD/TTR+/+ or AD/TTR+/-, respectively), available and characterized in our laboratory. The results showed that IDIF administered orally bound TTR in plasma and stabilized the protein, as assessed by T4 displacement assays, and was able to enter the brain as revealed by mass spectrometry analysis of cerebrospinal fluid. TTR levels, both in plasma and cerebrospinal fluid, were not altered. In AD/TTR+/- mice, IDIF administration resulted not only in decreased brain Aβ levels and deposition but also in improved cognitive function associated with the AD-like neuropathology in this mouse model, although no improvements were detectable in the AD/TTR+/+ animals. Further, in AD/TTR+/- mice, Aβ levels were reduced in plasma suggesting TTR promoted Aβ clearance from the brain and from the periphery. Taken together, these results strengthen the importance of TTR stability in the design of therapeutic drugs, highlighting the capacity of IDIF to be used in AD treatment to prevent and to slow the progression of the disease. PMID:24169237

  19. Low-dose benznidazole treatment results in parasite clearance and attenuates heart inflammatory reaction in an experimental model of infection with a highly virulent Trypanosoma cruzi strain.

    PubMed

    Cevey, Ágata Carolina; Mirkin, Gerardo Ariel; Penas, Federico Nicolás; Goren, Nora Beatriz

    2016-04-01

    Chagas disease, caused by Trypanosoma cruzi, is the main cause of dilated cardiomyopathy in the Americas. Antiparasitic treatment mostly relies on benznidazole (Bzl) due to Nifurtimox shortage or unavailability. Both induce adverse drug effects (ADE) of varied severity in many patients, leading to treatment discontinuation or abandonment. Since dosage may influence ADE, we aimed to assess Bzl efficacy in terms of parasiticidal and anti-inflammatory activity, using doses lower than those previously reported. BALB/c mice infected with the T. cruzi RA strain were treated with different doses of Bzl. Parasitaemia, mortality and weight change were assessed. Parasite load, tissue infiltrates and inflammatory mediators were studied in the heart. Serum creatine kinase (CK) activity was determined as a marker of heart damage. The infection-independent anti-inflammatory properties of Bzl were studied in an in vitro model of LPS-treated cardiomyocyte culture. Treatment with 25 mg/kg/day Bzl turned negative the parasitological parameters, induced a significant decrease in IL-1β, IL-6 and NOS2 in the heart and CK activity in serum, to normal levels. No mortality was observed in infected treated mice. Primary cultured cardiomyocytes treated with Bzl showed that inflammatory mediators were reduced via inhibition of the NF-κB pathway. A Bzl dose lower than that previously reported for treatment of experimental Chagas disease exerts adequate antiparasitic and anti-inflammatory effects leading to parasite clearance and tissue healing. This may be relevant to reassess the dose currently used for the treatment of human Chagas disease, aiming to minimize ADE. PMID:26862474

  20. Low-dose benznidazole treatment results in parasite clearance and attenuates heart inflammatory reaction in an experimental model of infection with a highly virulent Trypanosoma cruzi strain

    PubMed Central

    Cevey, Ágata Carolina; Mirkin, Gerardo Ariel; Penas, Federico Nicolás; Goren, Nora Beatriz

    2015-01-01

    Chagas disease, caused by Trypanosoma cruzi, is the main cause of dilated cardiomyopathy in the Americas. Antiparasitic treatment mostly relies on benznidazole (Bzl) due to Nifurtimox shortage or unavailability. Both induce adverse drug effects (ADE) of varied severity in many patients, leading to treatment discontinuation or abandonment. Since dosage may influence ADE, we aimed to assess Bzl efficacy in terms of parasiticidal and anti-inflammatory activity, using doses lower than those previously reported. BALB/c mice infected with the T. cruzi RA strain were treated with different doses of Bzl. Parasitaemia, mortality and weight change were assessed. Parasite load, tissue infiltrates and inflammatory mediators were studied in the heart. Serum creatine kinase (CK) activity was determined as a marker of heart damage. The infection-independent anti-inflammatory properties of Bzl were studied in an in vitro model of LPS-treated cardiomyocyte culture. Treatment with 25 mg/kg/day Bzl turned negative the parasitological parameters, induced a significant decrease in IL-1β, IL-6 and NOS2 in the heart and CK activity in serum, to normal levels. No mortality was observed in infected treated mice. Primary cultured cardiomyocytes treated with Bzl showed that inflammatory mediators were reduced via inhibition of the NF-κB pathway. A Bzl dose lower than that previously reported for treatment of experimental Chagas disease exerts adequate antiparasitic and anti-inflammatory effects leading to parasite clearance and tissue healing. This may be relevant to reassess the dose currently used for the treatment of human Chagas disease, aiming to minimize ADE. PMID:26862474

  1. Vaccination with Brucella abortus recombinant in vivo-induced antigens reduces bacterial load and promotes clearance in a mouse model for infection.

    PubMed

    Lowry, Jake E; Isaak, Dale D; Leonhardt, Jack A; Vernati, Giulia; Pate, Jessie C; Andrews, Gerard P

    2011-01-01

    Current vaccines used for the prevention of brucellosis are ineffective in inducing protective immunity in animals that are chronically infected with Brucella abortus, such as elk. Using a gene discovery approach, in vivo-induced antigen technology (IVIAT) on B. abortus, we previously identified ten loci that encode products up-regulated during infection in elk and consequently may play a role in virulence. In our present study, five of the loci (D15, 0187, VirJ, Mdh, AfuA) were selected for further characterization and compared with three additional antigens with virulence potential (Hia, PrpA, MltA). All eight genes were PCR-amplified from B. abortus and cloned into E. coli. The recombinant products were then expressed, purified, adjuvanted, and delivered subcutaneously to BALB/c mice. After primary immunization and two boosts, mice were challenged i.p. with 5 x 10⁴ CFU of B. abortus strain 19. Spleens from challenged animals were harvested and bacterial loads determined by colony count at various time points. While vaccination with four of the eight individual proteins appeared to have some effect on clearance kinetics, mice vaccinated with recombinant Mdh displayed the most significant reduction in bacterial colonization. Furthermore, mice immunized with Mdh maintained higher levels of IFN-γ in spleens compared to other treatment groups. Collectively, our in vivo data gathered from the S19 murine colonization model suggest that vaccination with at least three of the IVIAT antigens conferred an enhanced ability of the host to respond to infection, reinforcing the utility of this methodology for the identification of potential vaccine candidates against brucellosis. Mechanisms for immunity to one protein, Mdh, require further in vitro exploration and evaluation against wild-type B. abortus challenge in mice, as well as other hosts. Additional studies are being undertaken to clarify the role of Mdh and other IVI antigens in B. abortus virulence and induction of

  2. Optimizing principal component models for representing interfraction variation in lung cancer radiotherapy

    SciTech Connect

    Badawi, Ahmed M.; Weiss, Elisabeth; Sleeman, William C. IV; Yan Chenyu; Hugo, Geoffrey D.

    2010-09-15

    Purpose: To optimize modeling of interfractional anatomical variation during active breath-hold radiotherapy in lung cancer using principal component analysis (PCA). Methods: In 12 patients analyzed, weekly CT sessions consisting of three repeat intrafraction scans were acquired with active breathing control at the end of normal inspiration. The gross tumor volume (GTV) and lungs were delineated and reviewed on the first week image by physicians and propagated to all other images using deformable image registration. PCA was used to model the target and lung variability during treatment. Four PCA models were generated for each specific patient: (1) Individual models for the GTV and each lung from one image per week (week to week, W2W); (2) a W2W composite model of all structures; (3) individual models using all images (weekly plus repeat intrafraction images, allscans); and (4) composite model with all images. Models were reconstructed retrospectively (using all available images acquired) and prospectively (using only data acquired up to a time point during treatment). Dominant modes representing at least 95% of the total variability were used to reconstruct the observed anatomy. Residual reconstruction error between the model-reconstructed and observed anatomy was calculated to compare the accuracy of the models. Results: An average of 3.4 and 4.9 modes was required for the allscans models, for the GTV and composite models, respectively. The W2W model required one less mode in 40% of the patients. For the retrospective composite W2W model, the average reconstruction error was 0.7{+-}0.2 mm, which increased to 1.1{+-}0.5 mm when the allscans model was used. Individual and composite models did not have significantly different errors (p=0.15, paired t-test). The average reconstruction error for the prospective models of the GTV stabilized after four measurements at 1.2{+-}0.5 mm and for the composite model after five measurements at 0.8{+-}0.4 mm. Conclusions

  3. Redistribution of pulmonary blood flow impacts thermodilution-based extravascular lung water measurements in a model of acute lung injury

    PubMed Central

    Easley, R. Blaine; Mulreany, Daniel G.; Lancaster, Christopher T.; Custer, Jason W.; Fernandez-Bustamante, Ana; Colantuoni, Elizabeth; Simon, Brett A.

    2009-01-01

    Background Studies using transthoracic thermodilution have demonstrated increased extravascular lung water (EVLW) measurements attributed to progression of edema and flooding during sepsis and acute lung injury. We hypothesize that redistribution of pulmonary blood flow can cause increased apparent EVLW secondary to increased perfusion of thermally silent tissue, not increased lung edema. Methods Anesthetized, mechanically ventilated canines were instrumented with PiCCO® (Pulsion Medical, Munich, Germany) catheters and underwent lung injury by repetitive saline lavage. Hemodynamic and respiratory physiologic data were recorded. After stabilized lung injury, endotoxin was administered to inactivate hypoxic pulmonary vasoconstriction. Computerized tomographic imaging was performed to quantify in vivo lung volume, total tissue (fluid) and air content, and regional distribution of blood flow. Results Lavage injury caused an increase in airway pressures and decreased arterial oxygen content with minimal hemodynamic effects. EVLW and shunt fraction increased after injury and then markedly following endotoxin administration. Computerized tomographic measurements quantified an endotoxin-induced increase in pulmonary blood flow to poorly aerated regions with no change in total lung tissue volume. Conclusions The abrupt increase in EVLW and shunt fraction after endotoxin administration is consistent with inactivation of hypoxic pulmonary vasoconstriction and increased perfusion to already flooded lung regions that were previously thermally silent. Computerized tomographic studies further demonstrate in vivo alterations in regional blood flow (but not lung water) and account for these alterations in shunt fraction and EVLW. PMID:19809280

  4. Establishment of a Rat Adjuvant Arthritis-Interstitial Lung Disease Model

    PubMed Central

    Song, Liu-nan; Kong, Xiao-dan; Wang, Hong-jiang; Zhan, Li-bin

    2016-01-01

    Introduction. Development of an animal model of rheumatoid arthritis-interstitial lung disease (RA-ILD) and improved knowledge of the pathogenesis of RA-ILD may facilitate earlier diagnosis and the development of more effective targeted therapies. Methods. Adult male Wistar rats were studied in an adjuvant arthritis (AA) model induced by the injection of Freund's complete adjuvant (FCA). Rats were sacrificed on days 7, 14, 21, and 28 after FCA injection. Lung tissue was obtained for histopathological examination and evaluation of Caveolin-1 (Cav-1) and transforming growth factor-β (TGF-β1) protein expression levels. Results. Pulmonary inflammation was evident in lung tissue from day 21 after FCA injection. Inflammation and mild fibrosis were observed in lung tissue on day 28 after FCA injection. Cav-1 protein expression was significantly decreased from day 7 through day 28 and TGF-β1 protein expression was significantly increased on day 28 after FCA injection compared to control (P < 0.05). Conclusion. We established an AA rat model that exhibited the extra-articular complication of RA-ILD. We identified Cav-1 and TGF-β1 as protein biomarkers of RA-ILD in this model and propose their signaling pathway as a possible target for therapeutic intervention. PMID:26881215

  5. 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.

  6. 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

  7. Novel electrospun gelatin/oxycellulose nanofibers as a suitable platform for lung disease modeling.

    PubMed

    Švachová, Veronika; Vojtová, Lucy; Pavliňák, David; Vojtek, Libor; Sedláková, Veronika; Hyršl, Pavel; Alberti, Milan; Jaroš, Josef; Hampl, Aleš; Jančář, Josef

    2016-10-01

    Novel hydrolytically stable gelatin nanofibers modified with sodium or calcium salt of oxycellulose were prepared by electrospinning method. The unique inhibitory effect of these nanofibers against Escherichia coli bacteria was examined by luminometric method. Biocompatibility of these gelatin/oxycellulose nanofibers with eukaryotic cells was tested using human lung adenocarcinoma cell line NCI-H441. Cells firmly adhered to nanofiber surface, as determined by scanning electron microscopy, and no signs of cell dying were detected by fluorescent live/dead assay. We propose that the newly developed gelatin/oxycellulose nanofibers could be used as promising scaffold for lung disease modeling and anti-cancer drug testing. PMID:27287147

  8. The Rabbit as a Model for Studying Lung Disease and Stem Cell Therapy

    PubMed Central

    Kamaruzaman, Nurfatin Asyikhin; Kamaldin, Nurulain ‘Atikah; Latahir, Ahmad Zaeri; Yahaya, Badrul Hisham

    2013-01-01

    No single animal model can reproduce all of the human features of both acute and chronic lung diseases. However, the rabbit is a reliable model and clinically relevant facsimile of human disease. The similarities between rabbits and humans in terms of airway anatomy and responses to inflammatory mediators highlight the value of this species in the investigation of lung disease pathophysiology and in the development of therapeutic agents. The inflammatory responses shown by the rabbit model, especially in the case of asthma, are comparable with those that occur in humans. The allergic rabbit model has been used extensively in drug screening tests, and this model and humans appear to be sensitive to similar drugs. In addition, recent studies have shown that the rabbit serves as a good platform for cell delivery for the purpose of stem-cell-based therapy. PMID:23653896

  9. Unsupervised segmentation of lung fields in chest radiographs using multiresolution fractal feature vector and deformable models.

    PubMed

    Lee, Wen-Li; Chang, Koyin; Hsieh, Kai-Sheng

    2016-09-01

    Segmenting lung fields in a chest radiograph is essential for automatically analyzing an image. We present an unsupervised method based on multiresolution fractal feature vector. The feature vector characterizes the lung field region effectively. A fuzzy c-means clustering algorithm is then applied to obtain a satisfactory initial contour. The final contour is obtained by deformable models. The results show the feasibility and high performance of the proposed method. Furthermore, based on the segmentation of lung fields, the cardiothoracic ratio (CTR) can be measured. The CTR is a simple index for evaluating cardiac hypertrophy. After identifying a suspicious symptom based on the estimated CTR, a physician can suggest that the patient undergoes additional extensive tests before a treatment plan is finalized. PMID:26530048

  10. Stimulation of lung maturity: investigation of ambroxol in various animal models.

    PubMed

    von Seefeld, H; Weiss, J M; Eberhardt, H

    1985-01-01

    The surfactant or phospholipid lining of the alveolar surface is essential for lung function and airway stability. In premature neonates, the idiopathic respiratory distress syndrome (IRDS) is usually due to a prenatal deficiency in pulmonary surfactant. Experimental and clinical investigations with corticosteroids and other drugs were conducted to study various aspects of lung maturation. The present study of Ambroxol, a new compound with surfactant stimulating properties, was carried out on adult and foetal animals. In adult experimental animals an increase in the activity of Type II pneumocytes was shown by measuring various biochemical parameters. In models of premature animals comparable to clinical IRDS conditions, the antenatal treatment of foetal lambs and rabbits with Ambroxol enhanced lung maturation. PMID:3839344

  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. PMID:25997262

  12. Airway clearance in neuromuscular weakness.

    PubMed

    Gauld, Leanne Maree

    2009-05-01

    Impaired airway clearance leads to recurrent chest infections and respiratory deterioration in neuromuscular weakness. It is frequently the cause of death. Cough is the major mechanism of airway clearance. Cough has several components, and assessment tools are available to measure the different components of cough. These include measuring peak cough flow, respiratory muscle strength, and inspiratory capacity. Each is useful in assessing the ability to generate an effective cough, and can be used to guide when techniques of assisting airway clearance may be effective for the individual and which are most effective. Techniques to assist airway clearance include augmenting inspiration by air stacking, augmenting expiration by assisting the cough, and augmenting both inspiration and expiration with the mechanical insufflator-exsufflator or by direct suctioning via a tracheostomy. Physiotherapists are invaluable in assisting airway clearance, and in teaching patients and their families how to use these techniques. Use of the mechanical insufflator-exsufflator has gained popularity in recent times, but several simpler, more economical methods are available to assist airway clearance that can be used effectively alone or in combination. This review examines the literature available on the assessment and management of impaired airway clearance in neuromuscular weakness. PMID:19379290

  13. Ibuprofen modifies the inflammatory response of the murine lung to Pseudomonas aeruginosa.

    PubMed

    Sordelli, D O; Cerquetti, M C; el-Tawil, G; Ramwell, P W; Hooke, A M; Bellanti, J A

    1985-08-01

    In chronic P. aeruginosa infection, lung tissue damage is induced by either the microorganism or the inflammatory response. We investigated, in an animal model, whether a non-steroidal anti-inflammatory drug, ibuprofen, reduced lung inflammation produced by P. aeruginosa. Lung lavages, pulmonary clearance of P. aeruginosa and lung pathology were studied in CD-1 mice injected with sodium ibuprofenate. A single dose of the drug, injected immediately after 30 min exposure to the P. aeruginosa aerosol, decreased the recruitment of granulocytes into airways in a dose-dependent manner. Pretreatment with 2 doses of the drug 18 and 6 h before the P. aeruginosa challenge was even more effective. The kinetics of changes in prostaglandin E2, 6-keto-prostaglandin F1 alpha and thromboxane B2 concentrations in lung lavage fluids after P. aeruginosa aerosol were also modified by ibuprofen. Moreover, ibuprofen treatment did not impair lung clearance of the challenge microorganisms, and the animals had less inflammation of the lungs. PMID:3863757

  14. Particle deposition and clearance of atmospheric particles in the human respiratory tract during LACE 98

    NASA Astrophysics Data System (ADS)

    Bundke, U.; Hänel, G.

    2003-04-01

    During the LACE 98footnote{Lindenberg Aerosol Characterization Experiment, (Germany) 1998} experiment microphysical, chemical and optical properties of atmospheric particles were measured by several groups. (Bundke et al.). The particle deposition and clearance of the particles in the human respiratory tract was calculated using the ICRP (International Commission on Radiological Protection) deposition and clearance model (ICRP 1994). Particle growth as function of relative humidity outside the body was calculated from measurement data using the model introduced by Bundke et al.. Particle growth inside the body was added using a non-equilibrium particle growth model. As a result of the calculations, time series of the total dry particle mass and -size distribution were obtained for all compartments of the human respiratory tract defined by ICRP 1994. The combined ICRP deposition and clearance model was initialized for different probationers like man, woman, children of different ages and several circumstances like light work, sitting, sleeping etc. Keeping the conditions observed during LACE 98 constant a approximation of the aerosol burdens of the different compartments was calculated up to 4 years of exposure and compared to the results from Snipes et al. for the "Phoenix" and "Philadelphia" aerosol. References: footnotesize{ Bundke, U. et al.,it{Aerosol Optical Properties during the Lindenberg Aerosol Characterization Experiment (LACE 98)} ,10.1029/2000JD000188, JGR, 2002 ICRP,it{Human Respiratory Tract Model for Radiological Protection, Bd. ICRP Publication 66}, Annals of the ICRP, 24,1-3, Elsevier Science, Ocford, 1994 Snipes et al. ,it{The 1994 ICRP66 Human Respiratory Tract Model as a Tool for predicting Lung Burdens from Exposure to Environmental Aerosols}, Appl. Occup. Environ. Hyg., 12, 547-553,1997}

  15. SN50, a Cell-Permeable Inhibitor of Nuclear Factor-κB, Attenuates Ventilator-Induced Lung Injury in an Isolated and Perfused Rat Lung Model.

    PubMed

    Chian, Chih-Feng; Chiang, Chi-Huei; Chuang, Chiao-Hui; Liu, Shiou-Ling; Tsai, Chen-Liang

    2016-08-01

    High tidal volume (VT) ventilation causes the release of various mediators and results in ventilator-induced lung injury (VILI). SN50, a cell-permeable nuclear factor-κB (NF-κB) inhibitory peptide, attenuates inflammation and acute respiratory distress syndrome. However, the mechanisms associated with the effects of SN50 in VILI have not been fully elucidated. We investigated the cellular and molecular mechanisms for the effects of SN50 treatment in VILI. An isolated and perfused rat lung model was exposed to low (5 mL/kg) or high (15 mL/kg) VT ventilation for 6 h. SN50 was administered in the perfusate at the onset of the high-stretch mechanical ventilation. The hemodynamics, lung histological changes, inflammatory responses, and activation of apoptotic pathways were evaluated. VILI was demonstrated by increased pulmonary vascular permeability and lung weight gain, as well as by increased levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, myeloperoxidase (MPO), hydrogen peroxide, and macrophage inflammatory protein-2 in the bronchoalveolar lavage fluid. The lung tissue expression of TNF-α, IL-1β, mitogen-activated protein kinases (MAPKs), caspase-3, and phosphorylation of serine/threonine-specific protein kinase (p-AKT) was greater in the high VT group than in the low VT group. Upregulation and activation of NF-κB was associated with increased lung injury in VILI. SN50 attenuated the inflammatory responses, including the expression of IL-1β, TNF-α, MPO, MAPKs, and NF-κB. In addition, the downregulation of apoptosis was evaluated using caspase-3 and p-AKT expression. Furthermore, SN50 mitigated the increases in the lung weights, pulmonary vascular permeability, and lung injury. In conclusion, VILI is associated with inflammatory responses and activation of NF-κB. SN50 inhibits the activation of NF-κB and attenuates VILI. PMID:26780513

  16. Mechanisms of viral clearance and persistence.

    PubMed

    Borrow, P

    1997-01-01

    Using examples predominantly drawn from study of the lymphocytic choriomeningitis virus (LCMV) model system, this review describes the mechanisms involved in control of virus infections by the cell-mediated immune response, and some of the different strategies viruses have evolved to evade such immune clearance so that they can persist in their hosts. The important role played by the CD8+ cytotoxic lymphocyte (CTL) response in clearance of many systemic virus infections is discussed; and it is emphasized that although CD8+ CTL are classically thought of as lymphocytes which mediate lysis of virus-infected target cells, the principal mechanism by which CD8+ T cells effect clearance of persistent and many acute virus infections via production of antiviral cytokines such as tumour necrosis factor-alpha and interferon-gamma, not via destruction of virus-producing cells. To avoid immune-mediated clearance, viruses frequently use a combination of several different strategies. These can be grouped into mechanisms for avoiding recognition by the immune response (such as establishing latent infections, replicating in immune-privileged sites, down-regulating the expression of immune recognition signals on the surface of infected cells, or undergoing antigenic variation); and mechanisms for suppressing the immune response. The latter include generalized immune suppression mechanisms, and strategies for more precisely disabling the specific immune response such as inducing tolerance or exhaustion of virus-specific CTL. The value of understanding both immune clearance mechanisms and viral evasion strategies in the rational design of immune-based therapies to combat persistent virus infections is discussed. PMID:9429206

  17. Incorporating epistasis interaction of genetic susceptibility single nucleotide polymorphisms in a lung cancer risk prediction model.

    PubMed

    Marcus, Michael W; Raji, Olaide Y; Duffy, Stephen W; Young, Robert P; Hopkins, Raewyn J; Field, John K

    2016-07-01

    Incorporation of genetic variants such as single nucleotide polymorphisms (SNPs) into risk prediction models may account for a substantial fraction of attributable disease risk. Genetic data, from 2385 subjects recruited into the Liverpool Lung Project (LLP) between 2000 and 2008, consisting of 20 SNPs independently validated in a candidate-gene discovery study was used. Multifactor dimensionality reduction (MDR) and random forest (RF) were used to explore evidence of epistasis among 20 replicated SNPs. Multivariable logistic regression was used to identify similar risk predictors for lung cancer in the LLP risk model for the epidemiological model and extended model with SNPs. Both models were internally validated using the bootstrap method and model performance was assessed using area under the curve (AUC) and net reclassification improvement (NRI). Using MDR and RF, the overall best classifier of lung cancer status were SNPs rs1799732 (DRD2), rs5744256 (IL-18), rs2306022 (ITGA11) with training accuracy of 0.6592 and a testing accuracy of 0.6572 and a cross-validation consistency of 10/10 with permutation testing P<0.0001. The apparent AUC of the epidemiological model was 0.75 (95% CI 0.73-0.77). When epistatic data were incorporated in the extended model, the AUC increased to 0.81 (95% CI 0.79-0.83) which corresponds to 8% increase in AUC (DeLong's test P=2.2e-16); 17.5% by NRI. After correction for optimism, the AUC was 0.73 for the epidemiological model and 0.79 for the extended model. Our results showed modest improvement in lung cancer risk prediction when the SNP epistasis factor was added. PMID:27121382

  18. Incorporating epistasis interaction of genetic susceptibility single nucleotide polymorphisms in a lung cancer risk prediction model

    PubMed Central

    MARCUS, MICHAEL W.; RAJI, OLAIDE Y.; DUFFY, STEPHEN W.; YOUNG, ROBERT P.; HOPKINS, RAEWYN J.; FIELD, JOHN K.

    2016-01-01

    Incorporation of genetic variants such as single nucleotide polymorphisms (SNPs) into risk prediction models may account for a substantial fraction of attributable disease risk. Genetic data, from 2385 subjects recruited into the Liverpool Lung Project (LLP) between 2000 and 2008, consisting of 20 SNPs independently validated in a candidate-gene discovery study was used. Multifactor dimensionality reduction (MDR) and random forest (RF) were used to explore evidence of epistasis among 20 replicated SNPs. Multivariable logistic regression was used to identify similar risk predictors for lung cancer in the LLP risk model for the epidemiological model and extended model with SNPs. Both models were internally validated using the bootstrap method and model performance was assessed using area under the curve (AUC) and net reclassification improvement (NRI). Using MDR and RF, the overall best classifier of lung cancer status were SNPs rs1799732 (DRD2), rs5744256 (IL-18), rs2306022 (ITGA11) with training accuracy of 0.6592 and a testing accuracy of 0.6572 and a cross-validation consistency of 10/10 with permutation testing P<0.0001. The apparent AUC of the epidemiological model was 0.75 (95% CI 0.73–0.77). When epistatic data were incorporated in the extended model, the AUC increased to 0.81 (95% CI 0.79–0.83) which corresponds to 8% increase in AUC (DeLong's test P=2.2e-16); 17.5% by NRI. After correction for optimism, the AUC was 0.73 for the epidemiological model and 0.79 for the extended model. Our results showed modest improvement in lung cancer risk prediction when the SNP epistasis factor was added. PMID:27121382

  19. 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.

  20. Lung Tumorigenesis in a Conditional Cul4A Transgenic Mouse Model

    PubMed Central

    Yang, Yi-Lin; Hung, Ming-Szu; Wang, Yang; Ni, Jian; Mao, Jian-Hua; Hsieh, David; Au, Alfred; Kumar, Atul; Quigley, David; Fang, Li Tai; Yeh, Che-Chung; Xu, Zhidong; Jablons, David M.; You, Liang

    2014-01-01

    Cullin4A (Cul4A) is a scaffold protein that assembles cullin-RING ubiquitin ligase (E3) complexes and regulates many cellular events, including cell survival, development, growth, and cell cycle control. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied. Here, we used a Cul4A transgenic mouse model to study the potential oncogenic role of Cul4A in lung tumor development. After Cul4A overexpression was induced in the lungs for 32 weeks, atypical epithelial cells were observed. After 40 weeks, lung tumors were visible and were characterized as Grade I or II adenocarcinomas. Immunohistochemistry (IHC) revealed decreased levels of Cul4A associated proteins p21CIP1 and tumor suppressor p19ARF in the lung tumors, suggesting Cul4A regulated their expression in these tumors. Increased levels of p27KIP1 and p16INK4a were also detected in these tumors. Moreover, protein level of DNA replication licensing factor CDT1 was decreased. Genomic instability in the lung tumors was further analyzed by the results from pericentrin protein expression and array Comparative Genomic Hybridization analysis. Furthermore, knocking down Cul4A expression in lung cancer H2170 cells increased their sensitivity to the chemotherapy drug cisplatin in vitro, suggesting that Cul4A overexpression is associated with cisplatin resistance in the cancer cells. Our findings indicate that Cul4A is oncogenic in vivo, and this Cul4A mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A. PMID:24648314

  1. A Human-Mouse Chimeric Model of Obliterative Bronchiolitis after Lung Transplantation

    PubMed Central

    Xue, Jianmin; Zhu, Xuehai; George, M. Patricia; Myerburg, Michael M.; Stoner, Michael W.; Pilewski, Joseph W.; Duncan, Steven R.

    2011-01-01

    Obliterative bronchiolitis is a frequent, morbid, and usually refractory complication of lung transplantation. Mechanistic study of obliterative bronchiolitis would be aided by development of a relevant model that uses human immune effector cells and airway targets. Our objective was to develop a murine chimera model that mimics obliterative bronchiolitis of lung allograft recipients in human airways in vivo. Human peripheral blood mononuclear cells were adoptively transferred to immunodeficient mice lacking activity of T, B, and NK cells, with and without concurrent transplantations of human small airways dissected from allogeneic cadaveric lungs. Chimerism with human T cells occurred in the majority of recipient animals. The chimeric T cells became highly activated, rapidly infiltrated into the small human airway grafts, and caused obliterative bronchiolitis. In contrast, airways implanted into control mice that did not also receive human peripheral blood mononuclear cell transfers remained intact. In vitro proliferation assays indicated that the chimeric T cells had enhanced specific proliferative responses to donor airway alloantigens. This model confirms the critical role of T cells in development of obliterative bronchiolitis among human lung allograft recipients and provides a novel and easily implemented mechanism for detailed, reductionist in vivo studies of human T-cell responses to allogeneic human small airways. PMID:21801868

  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. PMID:26578021

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

    NASA Astrophysics Data System (ADS)

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

    2012-11-01

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

  4. Calculation of Tip Clearance Effects in a Transonic Compressor Rotor

    NASA Technical Reports Server (NTRS)

    Chima, R. V.

    1998-01-01

    The flow through the tip clearance region of a transonic compressor rotor (NASA rotor 37) was computed and compared to aerodynamic probe and laser anemometer data. Tip clearance effects were modeled both by gridding the clearance gap and by using a simple periodicity model across the ungridded gap. The simple model was run with both the full gap height, and with half the gap height to simulate a vena-contracta effect. Comparisons between computed and measured performance maps and downstream profiles were used to validate the models and to assess the effects of gap height on the simple clearance model. Recommendations were made concern- ing the use of the simple clearance model Detailed comparisons were made between the gridded clearance gap solution and the laser anemometer data near the tip at two operating points. The computed results agreed fairly well with the data but overpredicted the extent of the casing separation and underpredicted the wake decay rate. The computations were then used to describe the interaction of the tip vortex, the passage shock, and the casing boundary layer.

  5. Calculation of tip clearance effects in a transonic compressor rotor

    NASA Technical Reports Server (NTRS)

    Chima, R. V.

    1996-01-01

    The flow through the tip clearance region of a transonic compressor rotor (NASA rotor 37) was computed and compared to aerodynamic probe and laser anemometer data. Tip clearance effects were modeled both by gridding the clearance gap and by using a simple periodicity model across the ungridded gap. The simple model was run with both the full gap height, and with half the gap height to simulate a vena-contracta effect. Comparisons between computed and measured performance maps and downstream profiles were used to validate the models and to assess the effects of gap height on the simple clearance model. Recommendations were made concerning the use of the simple clearance model. Detailed comparisons were made between the gridded clearance gap solution and the laser anemometer data near the tip at two operating points. The computer results agreed fairly well with the data but overpredicted the extent of the casing separation and underpredicted the wake decay rate. The computations were then used to describe the interaction of the tip vortex, the passage shock, and the casing boundary layer.

  6. [Mortality from pleural and peritoneal cancer in a cohort of asbestos workers, many years after start of the exposure: possible role of fibers clearance].

    PubMed

    Adesi, F Barone; Ferrante, D; Bertolotti, M; Todesco, A; Mirabelli, D; Terracini, B; Magnani, C

    2007-01-01

    The multistage theory of carcinogenesis assumes rates of mesothelioma increasing monotonically as a function of time since first exposure (TSFE) to asbestos. However, some authors have suggested that the increase in mesothelioma rate with TSFE might be attenuated by clearance of asbestos from the lungs. We estimated mortality time trends from pleural and peritoneal cancer in a cohort of 3443 asbestos-cement workers. The role of asbestos clearance was explored using the traditional mesothelioma multistage model, generalized to include a term representing elimination over time. We observed 139 deaths from pleural and 56 from peritoneal cancer during the period 1950-2003. The rate of pleural cancer increased during the first 40 years of TSFE and reached a plateau thereafter. In contrast, the rate of peritoneal cancer increased monotonically with TSFE. The model allowing for asbestos elimination fitted the data better than the traditional model for pleural (p = 0.02) but not for peritoneal cancer (p = 0.22). The risk for pleural cancer, rather than showing an indefinite increase, might reach a plateau when a sufficiently long time has elapsed since exposure. The different trends for pleural and peritoneal cancer might be related to clearance of the asbestos from the workers' lungs. PMID:18409718

  7. Toward a Fast-Response Active Turbine Tip Clearance Control

    NASA Technical Reports Server (NTRS)

    Melcher, Kevin J.; Kypuros, Javier A.

    2003-01-01

    This paper describes active tip clearance control research being conducted by NASA to improve turbine engine systems. The target application for this effort is commercial aircraft engines. However, technologies developed for clearance control can benefit a broad spectrum of current and future turbomachinery. The first portion of the paper addresses the research from a programmatic viewpoint. Recent studies that provide motivation for the work, identification of key technologies, and NASA's plan for addressing deficiencies in the technologies are discussed. The later portion of the paper drills down into one of the key technologies by presenting equations and results for a preliminary dynamic model of the tip clearance phenomena.

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

    PubMed Central

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

    2016-01-01

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

  9. CD36 and Proteoglycan-Mediated Pathways for (n-3) Fatty Acid–Enriched Triglyceride-Rich Particle Blood Clearance in Mouse Models In Vivo and in Peritoneal Macrophages In Vitro1,2

    PubMed Central

    Densupsoontorn, Narumon; Carpentier, Yvon A.; Racine, Radjini; Murray, Faith M.; Seo, Toru; Ramakrishnan, Rajasekhar; Deckelbaum, Richard J.

    2008-01-01

    Because the mechanisms of (n-3) fatty acid–enriched triglyceride-rich particle [(n-3)-TGRP] uptake are not well characterized, we questioned whether (n-3)-TGRP are removed via “nonclassical” pathways, e.g., pathways other than an LDL receptor and/or involving apolipoprotein E (apoE). Chylomicron-sized model (n-3)-TGRP labeled with [3H]cholesteryl ether were injected into wild-type (WT) and CD36 knockout (CD36−/−) mice at low, nonsaturating and high, saturating doses. Blood clearance of (n-3)-TGRP was determined by calculating fractional catabolic rates. At saturating doses, blood clearance of (n-3)-TGRP was slower in CD36−/− mice relative to WT mice, suggesting that in part CD36 contributes to (n-3)-TGRP uptake. To further examine the potential nonclassical clearance pathways, peritoneal-elicited macrophages from WT and CD36−/− mice were incubated with (n-3)-TGRP in the presence of apoE, lactoferrin, and/or sodium chlorate. Cellular (n-3)-TGRP uptake was measured to test the roles of apoE-mediated pathways and/or proteoglycans. ApoE-mediated pathways compensated in part for defective (n-3)-TGRP uptake in CD36−/− cells. Lactoferrin decreased (n-3)-TGRP uptake in the presence of apoE. Inhibition of cell proteoglycan synthesis by chlorate reduced (n-3)-TGRP uptake in both groups of macrophages, and chlorate effects were independent of apoE. We conclude that although CD36 is involved, it is not the primary contributor to the blood clearance of (n-3)-TGRP. The removal of (n-3)-TGRP likely relies more on nonclassical pathways, such as proteoglycan-mediated pathways. PMID:18203888

  10. Deposition and clearance of inhaled particles.

    PubMed Central

    Stuart, B O

    1976-01-01

    Theoretical models of respiratory tract deposition of inhaled particles are compared to experimental studies of deposition patterns in humans and animals, as determined principally by particle size, density, respiratory rate and flow parameters. Various models of inhaled particle deposition make use of convenient approximations of the respiratory tract to predict tractional deposition according to fundamental physical processes of impaction, sedimentation, and diffusion. These theoretical models for both total deposition and regional (nasopharyngeal, tracheobronchial, and pulmonary) deposition are compared with experimental studies of inhaled dusts in humans or experimental animals that have been performed in many laboratories over several decades. Reasonable correlation has been obtained between theoretical and experimental studies, but the behavior of very fine (less than 0.01 mum) particles requires further refinement.Properties of particle shape, charge, and hygroscopicity as well as the degree of respiratory tract pathology also influence deposition patterns and further experimental work is urgently needed in these areas. The influence upon deposition patterns of dynamic alterations in inspiratory flow profiles caused by a variety of breathing patterns also requires further study, and the use of such techniques with selected inhaled particle size holds promise in possible diagnostic aid in diagnosis of normal versus disease conditions. Mechanisms of conducting airway and alveolar clearance processes involving mucociliary clearance, dissolution, transport to systemic circulation, and translocation via regional lymphatic clearance are discussed. The roles of the pulmonary macrophage in airway and alveolar clearance are described, and the applicability of recent solubility models for translocation or deposited materials to liver, skeleton, or other systemic organs is discussed. PMID:797567

  11. High Inorganic Phosphate Intake Promotes Tumorigenesis at Early Stages in a Mouse Model of Lung Cancer.

    PubMed

    Lee, Somin; Kim, Ji-Eun; Hong, Seong-Ho; Lee, Ah-Young; Park, Eun-Jung; Seo, Hwi Won; Chae, Chanhee; Doble, Philip; Bishop, David; Cho, Myung-Haing

    2015-01-01

    Inorganic phosphate (Pi) is required by all living organisms for the development of organs such as bone, muscle, brain, and lungs, regulating the expression of several critical genes as well as signal transduction. However, little is known about the effects of prolonged dietary Pi consumption on lung cancer progression. This study investigated the effects of a high-phosphate diet (HPD) in a mouse model of adenocarcinoma. K-rasLA1 mice were fed a normal diet (0.3% Pi) or an HPD (1% Pi) for 1, 2, or 4 months. Mice were then sacrificed and subjected to inductively coupled plasma mass/optical emission spectrometry and laser ablation inductively coupled plasma mass-spectrometry analyses, western blot analysis, histopathological, immunohistochemical, and immunocytochemical analyses to evaluate tumor formation and progression (including cell proliferation, angiogenesis, and apoptosis), changes in ion levels and metabolism, autophagy, epithelial-to-mesenchymal transition, and protein translation in the lungs. An HPD accelerated tumorigenesis, as evidenced by increased adenoma and adenocarcinoma rates as well as tumor size. However, after 4 months of the HPD, cell proliferation was arrested, and marked increases in liver and lung ion levels and in energy production via the tricarboxylic acid cycle in the liver were observed, which were accompanied by increased autophagy and decreased angiogenesis and apoptosis. These results indicate that an HPD initially promotes but later inhibits lung cancer progression because of metabolic adaptation leading to tumor cell quiescence. Moreover, the results suggest that carefully regulated Pi consumption are effective in lung cancer prevention. PMID:26285136

  12. Surfactant dysfunction and lung inflammation in the female mouse model of lymphangioleiomyomatosis.

    PubMed

    Atochina-Vasserman, Elena N; Guo, Chang-Jiang; Abramova, Elena; Golden, Thea N; Sims, Michael; James, Melane L; Beers, Michael F; Gow, Andrew J; Krymskaya, Vera P

    2015-07-01

    Pulmonary lymphangioleiomyomatosis (LAM) is a rare lung disease caused by mutations of the tumor suppressor genes, tuberous sclerosis complex (TSC) 1 or TSC2. LAM affects women almost exclusively, and it is characterized by neoplastic growth of atypical smooth muscle-like TSC2-null LAM cells in the pulmonary interstitium, cystic destruction of lung parenchyma, and progressive decline in lung function. In this study, we hypothesized that TSC2-null lesions promote a proinflammatory environment, which contributes to lung parenchyma destruction. Using a TSC2-null female murine LAM model, we demonstrate that TSC2-null lesions promote alveolar macrophage accumulation, recruitment of immature multinucleated cells, an increased induction of proinflammatory genes, nitric oxide (NO) synthase 2, IL-6, chemokine (C-C motif) ligand 2 (CCL2)/monocyte chemotactic protein 1 (MCP1), chemokine (C-X-C motif) ligand 1 (CXCL1)/keratinocyte chemoattractant (KC), and up-regulation of IL-6, KC, MCP-1, and transforming growth factor-β1 levels in bronchoalveolar lavage fluid. Bronchoalveolar lavage fluid also contained an increased level of surfactant protein (SP)-D, but not SP-A, significant reduction of SP-B levels, and a resultant increase in alveolar surface tension. Consistent with the growth of TSC2-null lesions, NO levels were also increased and, in turn, modified SP-D through S-nitrosylation, forming S-nitrosylated SP-D, a known consequence of lung inflammation. Progressive growth of TSC2-null lesions was accompanied by elevated levels of matrix metalloproteinase-3 and -9. This report demonstrates a link between growth of TSC2-null lesions and inflammation-induced surfactant dysfunction that might contribute to lung destruction in LAM. PMID:25474372

  13. Surfactant Dysfunction and Lung Inflammation in the Female Mouse Model of Lymphangioleiomyomatosis

    PubMed Central

    Guo, Chang-Jiang; Abramova, Elena; Golden, Thea N.; Sims, Michael; James, Melane L.; Beers, Michael F.; Gow, Andrew J.; Krymskaya, Vera P.

    2015-01-01

    Pulmonary lymphangioleiomyomatosis (LAM) is a rare lung disease caused by mutations of the tumor suppressor genes, tuberous sclerosis complex (TSC) 1 or TSC2. LAM affects women almost exclusively, and it is characterized by neoplastic growth of atypical smooth muscle–like TSC2-null LAM cells in the pulmonary interstitium, cystic destruction of lung parenchyma, and progressive decline in lung function. In this study, we hypothesized that TSC2-null lesions promote a proinflammatory environment, which contributes to lung parenchyma destruction. Using a TSC2-null female murine LAM model, we demonstrate that TSC2-null lesions promote alveolar macrophage accumulation, recruitment of immature multinucleated cells, an increased induction of proinflammatory genes, nitric oxide (NO) synthase 2, IL-6, chemokine (C-C motif) ligand 2 (CCL2)/monocyte chemotactic protein 1 (MCP1), chemokine (C-X-C motif) ligand 1 (CXCL1)/keratinocyte chemoattractant (KC), and up-regulation of IL-6, KC, MCP-1, and transforming growth factor-β1 levels in bronchoalveolar lavage fluid. Bronchoalveolar lavage fluid also contained an increased level of surfactant protein (SP)-D, but not SP-A, significant reduction of SP-B levels, and a resultant increase in alveolar surface tension. Consistent with the growth of TSC2-null lesions, NO levels were also increased and, in turn, modified SP-D through S-nitrosylation, forming S-nitrosylated SP-D, a known consequence of lung inflammation. Progressive growth of TSC2-null lesions was accompanied by elevated levels of matrix metalloproteinase-3 and -9. This report demonstrates a link between growth of TSC2-null lesions and inflammation-induced surfactant dysfunction that might contribute to lung destruction in LAM. PMID:25474372

  14. Classification of lung cancer tumors based on structural and physicochemical properties of proteins by bioinformatics models.

    PubMed

    Hosseinzadeh, Faezeh; Ebrahimi, Mansour; Goliaei, Bahram; Shamabadi, Narges

    2012-01-01

    Rapid distinction between small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) tumors is very important in diagnosis of this disease. Furthermore sequence-derived structural and physicochemical descriptors are very useful for machine learning prediction of protein structural and functional classes, classifying proteins and the prediction performance. Herein, in this study is the classification of lung tumors based on 1497 attributes derived from structural and physicochemical properties of protein sequences (based on genes defined by microarray analysis) investigated through a combination of attribute weighting, supervised and unsupervised clustering algorithms. Eighty percent of the weighting methods selected features such as autocorrelation, dipeptide composition and distribution of hydrophobicity as the most important protein attributes in classification of SCLC, NSCLC and COMMON classes of lung tumors. The same results were observed by most tree induction algorithms while descriptors of hydrophobicity distribution were high in protein sequences COMMON in both groups and distribution of charge in these proteins was very low; showing COMMON proteins were very hydrophobic. Furthermore, compositions of polar dipeptide in SCLC proteins were higher than NSCLC proteins. Some clustering models (alone or in combination with attribute weighting algorithms) were able to nearly classify SCLC and NSCLC proteins. Random Forest tree induction algorithm, calculated on leaves one-out and 10-fold cross validation) shows more than 86% accuracy in clustering and predicting three different lung cancer tumors. Here for the first time the application of data mining tools to effectively classify three classes of lung cancer tumors regarding the importance of dipeptide composition, autocorrelation and distribution descriptor has been reported. PMID:22829872

  15. High Inorganic Phosphate Intake Promotes Tumorigenesis at Early Stages in a Mouse Model of Lung Cancer

    PubMed Central

    Lee, Somin; Kim, Ji-Eun; Hong, Seong-Ho; Lee, Ah-Young; Park, Eun-Jung; Seo, Hwi Won; Chae, Chanhee; Doble, Philip; Bishop, David; Cho, Myung-Haing

    2015-01-01

    Inorganic phosphate (Pi) is required by all living organisms for the development of organs such as bone, muscle, brain, and lungs, regulating the expression of several critical genes as well as signal transduction. However, little is known about the effects of prolonged dietary Pi consumption on lung cancer progression. This study investigated the effects of a high-phosphate diet (HPD) in a mouse model of adenocarcinoma. K-rasLA1 mice were fed a normal diet (0.3% Pi) or an HPD (1% Pi) for 1, 2, or 4 months. Mice were then sacrificed and subjected to inductively coupled plasma mass/optical emission spectrometry and laser ablation inductively coupled plasma mass-spectrometry analyses, western blot analysis, histopathological, immunohistochemical, and immunocytochemical analyses to evaluate tumor formation and progression (including cell proliferation, angiogenesis, and apoptosis), changes in ion levels and metabolism, autophagy, epithelial-to-mesenchymal transition, and protein translation in the lungs. An HPD accelerated tumorigenesis, as evidenced by increased adenoma and adenocarcinoma rates as well as tumor size. However, after 4 months of the HPD, cell proliferation was arrested, and marked increases in liver and lung ion levels and in energy production via the tricarboxylic acid cycle in the liver were observed, which were accompanied by increased autophagy and decreased angiogenesis and apoptosis. These results indicate that an HPD initially promotes but later inhibits lung cancer progression because of metabolic adaptation leading to tumor cell quiescence. Moreover, the results suggest that carefully regulated Pi consumption are effective in lung cancer prevention. PMID:26285136

  16. Resident alveolar macrophages suppress while recruited monocytes promote allergic lung inflammation in murine models of asthma

    PubMed Central

    Zasłona, Zbigniew; Przybranowski, Sally; Wilke, Carol; van Rooijen, Nico; Teitz-Tennenbaum, Seagal; Osterholzer, John J.; Wilkinson, John E.; Moore, Bethany B.; Peters-Golden, Marc

    2014-01-01

    The role and origin of alveolar macrophages (AMs) in asthma are incompletely defined. We sought to clarify these issues in the context of acute allergic lung inflammation utilizing house dust mite and ovalbumin murine models. Use of liposomal clodronate to deplete resident AMs (rAMs) resulted in increased levels of inflammatory cytokines and eosinophil numbers in lavage fluid and augmented histopathologic evidence of lung inflammation, suggesting a suppressive role of rAMs. Lung digests of asthmatic mice revealed an increased percentage of Ly6Chigh/CD11bpos inflammatory monocytes. Clodronate depletion of circulating monocytes, by contrast, resulted in an attenuation of allergic inflammation. A CD45.1/CD45.2 chimera model demonstrated that recruitment at least partially contributes to the AM pool in irradiated non-asthmatic mice, but its contribution was no greater in asthma. Ki-67 staining of AMs supported a role for local proliferation, which was increased in asthma. Our data demonstrate that rAMs dampen, while circulating monocytes promote, early events in allergic lung inflammation. Moreover, maintenance of the AM pool in the early stages of asthmatic inflammation depends on local proliferation but not recruitment. PMID:25225663

  17. Measurement and mathematical modelling of elastic and resistive lung mechanical properties studied at sinusoidal expiratory flow.

    PubMed

    Bitzén, Ulrika; Niklason, Lisbet; Göransson, Ingegerd; Jonson, Björn

    2010-11-01

    Elastic pressure/volume (P(el) /V) and elastic pressure/resistance (P(el) /R) diagrams reflect parenchymal and bronchial properties, respectively. The objective was to develop a method for determination and mathematical characterization of P(el) /V and P(el) /R relationships, simultaneously studied at sinusoidal flow-modulated vital capacity expirations in a body plethysmograph. Analysis was carried out by iterative parameter estimation based on a composite mathematical model describing a three-segment P(el) /V curve and a hyperbolic P(el) /R curve. The hypothesis was tested that the sigmoid P(el) /V curve is non-symmetric. Thirty healthy subjects were studied. The hypothesis of a non-symmetric P(el) /V curve was verified. Its upper volume asymptote was nearly equal to total lung capacity (TLC), indicating lung stiffness increasing at high lung volume as the main factor limiting TLC at health. The asymptotic minimal resistance of the hyperbolic P(el) /R relationship reflected lung size. A detailed description of both P(el) /V and P(el) /R relationships was simultaneously derived from sinusoidal flow-modulated vital capacity expirations. The nature of the P(el) /V curve merits the use of a non-symmetric P(el) /V model. PMID:20726995

  18. The Effect of Different Doses of Cigarette Smoke in a Mouse Lung Tumor Model

    PubMed Central

    Santiago, Ludmilla Nadir; de Camargo Fenley, Juliana; Braga, Lúcia Campanario; Cordeiro, José Antônio; Cury, Patrícia M.

    2009-01-01

    Few studies have used Balb/c mice as an animal model for lung carcinogenesis. In this study, we investigated the effect of different doses of cigarette smoking in the urethane-induced Balb/c mouse lung cancer model. After injection of 3mg/kg urethane intraperitoneally, the mice were then exposed to tobacco smoke once or twice a day, five times a week, in a closed chamber. The animals were randomly divided into four groups. The control group (G0) received urethane only. The experimental groups (G1, G2 and G3) received urethane and exposure to the smoke of 3 cigarettes for 10 minutes once a day, 3 cigarettes for 10 minutes twice a day, and 6 cigarettes for 10 minutes twice a day, respectively. The mice were sacrificed after 16 weeks of exposure, and the number of nodules and hyperplasia in the lungs was counted. The results showed no statistically significant difference in the mean number of nodules and hyperplasia among the different groups, suggesting that the Balb/c mice are not suitable to study the pathogenesis of tobacco smoking-induced tumor progression in the lungs. PMID:19079653

  19. Model-based assessment of lung structures: inferencing and control system

    NASA Astrophysics Data System (ADS)

    Brown, Matthew S.; Gill, Robert W.; Talhami, H. E.; Wilson, Laurie S.; Doust, Bruce D.

    1995-05-01

    A general methodology has been developed for computer interpretation of medical images, based on an explicit anatomical model. A test system for analyzing posterior- anterior (PA) chest x-rays has been implemented. The inferencing and control system identifies the major lung structures in the image, and then flags any suspected abnormalities. Image and model data are transformed into a feature space where they are represented in terms of edge descriptions. The inference engine compares the image and model in feature space to label the edges anatomically, and check for normality. The control system schedules events within the inference engine and coordinates interaction with the model and image processing routines. The control architecture is blackboard-based, with a separate data frame for each structure to be identified. The anatomical model uses fuzzy sets to provide ranges of feature values which are considered normal or indicative of a particular abnormality. This allows the inference engine to give a confidence score and linguistic description to each decision. Mediastinum, cardiac border, domes of the diaphragm, ribs and lung outline have been modeled. Their automatic identification allows diagnostic checks such as the cardiothoracic ratio, comparison of right and left lungs to identify lobular collapse and inspection of interfaces in terms of shape and clarity. The inference engine provides simple comments on its findings, making it suitable for pre- and double-checking of images.

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

    PubMed Central

    Amini, Reza; Kaczka, David W.

    2013-01-01

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

  1. Dual clearance squeeze film damper

    NASA Technical Reports Server (NTRS)

    Fleming, D. P. (Inventor)

    1985-01-01

    A dual clearance hydrodynamic liquid squeeze film damper for a gas turbine engine is described. Under normal operating conditions, the device functions as a conventional squeeze film damper, using only one of its oil films. When an unbalance reaches abusive levels, as may occur with a blade loss or foreign object damage, a second, larger clearance film becomes active, controlling vibration amplitudes in a near optimum manner until the engine can be safely shut down and repaired.

  2. Method of mucociliary clearance assessment

    NASA Astrophysics Data System (ADS)

    Danilova, Tatiana V.; Manturov, Alexey O.; Ermakov, Igor Y.; Mareev, Gleb O.; Mareev, Oleg V.

    2016-04-01

    The article is devoted to the research capabilities of mucociliary clearance in the nasal cavity and paranasal sinuses using modern techniques of digital video recording and processing. We describe the setup and software for this method and the results of our research. Using microscope and digital camera we can provide a good method to study mucociliary clearance and by usage of special software we able to measure some characteristic of nasal mucosae and its main function.

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

    PubMed Central

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

    2015-01-01

    ABSTRACT Staphylococcus aureus necrotizing pneumonia is recognized as a toxin-mediated disease, yet the tissue-destructive