Investigations of Pulmonary Epithelial Cell Damage due to Air-Liquid Interfacial Stresses in a Microgravity Environment

NASA Technical Reports Server (NTRS)

Gaver, Donald P., III; Bilek, A. M.; Kay, S.; Dee, K. C.

2004-01-01

Pulmonary airway closure is a potentially dangerous event that can occur in microgravity environments and may result in limited gas exchange for flight crew during long-term space flight. Repetitive airway collapse and reopening subjects the pulmonary epithelium to large, dynamic, and potentially injurious mechanical stresses. During ventilation at low lung volumes and pressures, airway instability leads to repetitive collapse and reopening. During reopening, air must progress through a collapsed airway, generating stresses on the airway walls, potentially damaging airway tissues. The normal lung can tolerate repetitive collapse and reopening. However, combined with insufficient or dysfunctional pulmonary surfactant, repetitive airway collapse and reopening produces severe lung injury. Particularly at risk is the pulmonary epithelium. As an important regulator of lung function and physiology, the degree of pulmonary epithelial damage influences the course and outcome of lung injury. In this paper we present experimental and computational studies to explore the hypothesis that the mechanical stresses associated with airway reopening inflict injury to the pulmonary epithelium.

Assessment of lung function in a large cohort of patients with acromegaly.

PubMed

Störmann, Sylvère; Gutt, Bodo; Roemmler-Zehrer, Josefine; Bidlingmaier, Martin; Huber, Rudolf M; Schopohl, Jochen; Angstwurm, Matthias W

2017-07-01

Acromegaly is associated with increased mortality due to respiratory disease. To date, lung function in patients with acromegaly has only been assessed in small studies, with contradicting results. We assessed lung function parameters in a large cohort of patients with acromegaly. Lung function of acromegaly patients was prospectively assessed using spirometry, blood gas analysis and body plethysmography. Biochemical indicators of acromegaly were assessed through measurement of growth hormone and IGF-I levels. This study was performed at the endocrinology outpatient clinic of a tertiary referral center in Germany. We prospectively tested lung function of 109 acromegaly patients (53 male, 56 female; aged 24-82 years; 80 with active acromegaly) without severe acute or chronic pulmonary disease. We compared lung volume, air flow, airway resistance and blood gases to normative data. Acromegaly patients had greater lung volumes (maximal vital capacity, intra-thoracic gas volume and residual volume: P  < 0.001, total lung capacity: P  = 0.006) and showed signs of small airway obstruction (reduced maximum expiratory flow when 75% of the forced vital capacity (FVC) has been exhaled: P  < 0.001, lesser peak expiratory flow: P  = 0.01). There was no significant difference between active and inactive acromegaly. Female patients had significantly altered lung function in terms of subclinical airway obstruction. In our cross-sectional analysis of lung function in 109 patients with acromegaly, lung volumes were increased compared to healthy controls. Additionally, female patients showed signs of subclinical airway obstruction. There was no difference between patients with active acromegaly compared with patients biochemically in remission. © 2017 European Society of Endocrinology.

Differential susceptibility of inbred mouse strains to chlorine-induced airway fibrosis

PubMed Central

Mo, Yiqun; Chen, Jing; Schlueter, Connie F.

2013-01-01

Chlorine is a reactive gas that is considered a chemical threat agent. Humans who develop acute lung injury from chlorine inhalation typically recover normal lung function; however, a subset can experience chronic airway disease. To examine pathological changes following chlorine-induced lung injury, mice were exposed to a single high dose of chlorine, and repair of the lung was analyzed at multiple times after exposure. In FVB/NJ mice, chlorine inhalation caused pronounced fibrosis of larger airways that developed by day 7 after exposure and was associated with airway hyperreactivity. In contrast, A/J mice had little or no airway fibrosis and had normal lung function at day 7. Unexposed FVB/NJ mice had less keratin 5 staining (basal cell marker) than A/J mice in large intrapulmonary airways where epithelial repair was poor and fibrosis developed after chlorine exposure. FVB/NJ mice had large areas devoid of epithelium on day 1 after exposure leading to fibroproliferative lesions on days 4 and 7. A/J mice had airways covered by squamous keratin 5-stained cells on day 1 that transitioned to a highly proliferative reparative epithelium by day 4 followed by the reappearance of ciliated and Clara cells by day 7. The data suggest that lack of basal cells in the large intrapulmonary airways and failure to effect epithelial repair at these sites are factors contributing to the development of airway fibrosis in FVB/NJ mice. The observed differences in susceptibility to chlorine-induced airway disease provide a model in which mechanisms and treatment of airway fibrosis can be investigated. PMID:23171502

Differential susceptibility of inbred mouse strains to chlorine-induced airway fibrosis.

PubMed

Mo, Yiqun; Chen, Jing; Schlueter, Connie F; Hoyle, Gary W

2013-01-15

Chlorine is a reactive gas that is considered a chemical threat agent. Humans who develop acute lung injury from chlorine inhalation typically recover normal lung function; however, a subset can experience chronic airway disease. To examine pathological changes following chlorine-induced lung injury, mice were exposed to a single high dose of chlorine, and repair of the lung was analyzed at multiple times after exposure. In FVB/NJ mice, chlorine inhalation caused pronounced fibrosis of larger airways that developed by day 7 after exposure and was associated with airway hyperreactivity. In contrast, A/J mice had little or no airway fibrosis and had normal lung function at day 7. Unexposed FVB/NJ mice had less keratin 5 staining (basal cell marker) than A/J mice in large intrapulmonary airways where epithelial repair was poor and fibrosis developed after chlorine exposure. FVB/NJ mice had large areas devoid of epithelium on day 1 after exposure leading to fibroproliferative lesions on days 4 and 7. A/J mice had airways covered by squamous keratin 5-stained cells on day 1 that transitioned to a highly proliferative reparative epithelium by day 4 followed by the reappearance of ciliated and Clara cells by day 7. The data suggest that lack of basal cells in the large intrapulmonary airways and failure to effect epithelial repair at these sites are factors contributing to the development of airway fibrosis in FVB/NJ mice. The observed differences in susceptibility to chlorine-induced airway disease provide a model in which mechanisms and treatment of airway fibrosis can be investigated.

Stochastic dosimetry model for radon progeny in the rat lung.

PubMed

Winkler-HeiI, R; Hofmann, W; Hussain, M

2014-07-01

The stochastic dosimetry model presented here considers the distinctly asymmetric, stochastic branching pattern reported in morphometric measurements. This monopodial structure suggests that an airway diameter is a more appropriate morphometric parameter to classify bronchial dose distributions for inhaled radon progeny than the commonly assigned airway generation numbers. Bronchial doses were calculated for the typical exposure conditions reported for the Pacific Northwest National Laboratory rat inhalation studies, yielding an average bronchial dose of 7.75 mGy WLM(-1). If plotted as functions of airway generations, the resulting dose distributions are highest in the central bronchial airways, while significantly decreasing towards peripheral generations. However, if plotted as functions of airway diameters, doses are much more uniformly distributed among bronchial airways. The comparison between rat and human lungs indicates that dose conversion coefficients for the rat lung are higher than the corresponding values for the human lung by a factor of 1.34 for the experimental PNNL exposure conditions, and of 1.25 for typical human indoor conditions. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The Association of Lung Function, Bronchial Hyperresponsiveness, and Exhaled Nitric Oxide Differs Between Atopic and Non-atopic Asthma in Children

PubMed Central

Shim, Eunhee; Lee, Eun; Yang, Song-I; Jung, Young-Ho; Park, Geun Mi; Kim, Hyung Young; Seo, Ju-Hee

2015-01-01

Purpose Although many previous studies have attempted to identify differences between atopic asthma (AA) and non-atopic asthma (NAA), they have mainly focused on the difference of each variable of lung function and airway inflammation. The aim of this study was to evaluate relationships between lung function, bronchial hyperresponsiveness (BHR), and the exhaled nitric oxide (eNO) levels in children with AA and NAA. Methods One hundred and thirty six asthmatic children aged 5-15 years and 40 normal controls were recruited. Asthma cases were classified as AA (n=100) or NAA (n=36) from skin prick test results. Lung function, BHR to methacholine and adenosine-5'-monophosphate (AMP), eNO, blood eosinophils, and serum total IgE were measured. Results The AA and NAA cases shared common features including a reduced small airway function and increased BHR to methacholine. However, children with AA showed higher BHR to AMP and eNO levels than those with NAA. When the relationships among these variables in the AA and NAA cases were evaluated, the AA group showed significant relationships between lung function, BHR to AMP or methacholine and eNO levels. However, the children in the NAA group showed an association between small airway function and BHR to methacholine only. Conclusions These findings suggest that the pathogenesis of NAA may differ from that of AA during childhood in terms of the relationship between lung function, airway inflammation and BHR. PMID:25749776

Effects of cannabis on lung function: a population-based cohort study.

PubMed

Hancox, R J; Poulton, R; Ely, M; Welch, D; Taylor, D R; McLachlan, C R; Greene, J M; Moffitt, T E; Caspi, A; Sears, M R

2010-01-01

The effects of cannabis on lung function remain unclear and may be different from those of tobacco. We compared the associations between use of these substances and lung function in a population-based cohort (n = 1,037). Cannabis and tobacco use were reported at ages 18, 21, 26 and 32 yrs. Spirometry, plethysmography and carbon monoxide transfer factor were measured at 32 yrs. Associations between lung function and exposure to each substance were adjusted for exposure to the other substance. Cumulative cannabis use was associated with higher forced vital capacity, total lung capacity, functional residual capacity and residual volume. Cannabis was also associated with higher airway resistance but not with forced expiratory volume in 1 s, forced expiratory ratio or transfer factor. These findings were similar among those who did not smoke tobacco. In contrast, tobacco use was associated with lower forced expiratory volume in 1 s, lower forced expiratory ratio, lower transfer factor and higher static lung volumes, but not with airway resistance. Cannabis appears to have different effects on lung function from those of tobacco. Cannabis use was associated with higher lung volumes, suggesting hyperinflation and increased large-airways resistance, but there was little evidence for airflow obstruction or impairment of gas transfer.

Computed Tomographic Airway Morphology in Chronic Obstructive Pulmonary Disease. Remodeling or Innate Anatomy?

PubMed

Diaz, Alejandro A; Estépar, Raul San José; Washko, George R

2016-01-01

Computed tomographic measures of central airway morphology have been used in clinical, epidemiologic, and genetic investigation as an inference of the presence and severity of small-airway disease in smokers. Although several association studies have brought us to believe that these computed tomographic measures reflect airway remodeling, a careful review of such data and more recent evidence may reveal underappreciated complexity to these measures and limitations that prompt us to question that belief. This Perspective offers a review of seminal papers and alternative explanations of their data in the light of more recent evidence. The relationships between airway morphology and lung function are observed in subjects who never smoked, implying that native airway structure indeed contributes to lung function; computed tomographic measures of central airways such as wall area, lumen area, and total bronchial area are smaller in smokers with chronic obstructive pulmonary disease versus those without chronic obstructive pulmonary disease; and the airways are smaller as disease severity increases. The observations suggest that (1) native airway morphology likely contributes to the relationships between computed tomographic measures of airways and lung function; and (2) the presence of smaller airways in those with chronic obstructive pulmonary disease versus those without chronic obstructive pulmonary disease as well as their decrease with disease severity suggests that smokers with chronic obstructive pulmonary disease may simply have smaller airways to begin with, which put them at greater risk for the development of smoking-related disease.

Reproducibility of airway luminal size in asthma measured by HRCT.

PubMed

Brown, Robert H; Henderson, Robert J; Sugar, Elizabeth A; Holbrook, Janet T; Wise, Robert A

2017-10-01

Brown RH, Henderson RJ, Sugar EA, Holbrook JT, Wise RA, on behalf of the American Lung Association Airways Clinical Research Centers. Reproducibility of airway luminal size in asthma measured by HRCT. J Appl Physiol 123: 876-883, 2017. First published July 13, 2017; doi:10.1152/japplphysiol.00307.2017.-High-resolution CT (HRCT) is a well-established imaging technology used to measure lung and airway morphology in vivo. However, there is a surprising lack of studies examining HRCT reproducibility. The CPAP Trial was a multicenter, randomized, three-parallel-arm, sham-controlled 12-wk clinical trial to assess the use of a nocturnal continuous positive airway pressure (CPAP) device on airway reactivity to methacholine. The lack of a treatment effect of CPAP on clinical or HRCT measures provided an opportunity for the current analysis. We assessed the reproducibility of HRCT imaging over 12 wk. Intraclass correlation coefficients (ICCs) were calculated for individual airway segments, individual lung lobes, both lungs, and air trapping. The ICC [95% confidence interval (CI)] for airway luminal size at total lung capacity ranged from 0.95 (0.91, 0.97) to 0.47 (0.27, 0.69). The ICC (95% CI) for airway luminal size at functional residual capacity ranged from 0.91 (0.85, 0.95) to 0.32 (0.11, 0.65). The ICC measurements for airway distensibility index and wall thickness were lower, ranging from poor (0.08) to moderate (0.63) agreement. The ICC for air trapping at functional residual capacity was 0.89 (0.81, 0.94) and varied only modestly by lobe from 0.76 (0.61, 0.87) to 0.95 (0.92, 0.97). In stable well-controlled asthmatic subjects, it is possible to reproducibly image unstimulated airway luminal areas over time, by region, and by size at total lung capacity throughout the lungs. Therefore, any changes in luminal size on repeat CT imaging are more likely due to changes in disease state and less likely due to normal variability. NEW & NOTEWORTHY There is a surprising lack of studies examining the reproducibility of high-resolution CT in asthma. The current study examined reproducibility of airway measurements. In stable well-controlled asthmatic subjects, it is possible to reproducibly image airway luminal areas over time, by region, and by size at total lung capacity throughout the lungs. Therefore, any changes in luminal size on repeat CT imaging are more likely due to changes in disease state and less likely due to normal variability. Copyright © 2017 the American Physiological Society.

Stochastic rat lung dosimetry for inhaled radon progeny: a surrogate for the human lung for lung cancer risk assessment.

PubMed

Winkler-Heil, R; Hussain, M; Hofmann, W

2015-05-01

Laboratory rats are frequently used in inhalation studies as a surrogate for human exposures. The objective of the present study was therefore to develop a stochastic dosimetry model for inhaled radon progeny in the rat lung, to predict bronchial dose distributions and to compare them with corresponding dose distributions in the human lung. The most significant difference between human and rat lungs is the branching structure of the bronchial tree, which is relatively symmetric in the human lung, but monopodial in the rat lung. Radon progeny aerosol characteristics used in the present study encompass conditions typical for PNNL and COGEMA rat inhalation studies, as well as uranium miners and human indoor exposure conditions. It is shown here that depending on exposure conditions and modeling assumptions, average bronchial doses in the rat lung ranged from 5.4 to 7.3 mGy WLM(-1). If plotted as a function of airway generation, bronchial dose distributions exhibit a significant maximum in large bronchial airways. If, however, plotted as a function of airway diameter, then bronchial doses are much more uniformly distributed throughout the bronchial tree. Comparisons between human and rat exposures indicate that rat bronchial doses are slightly higher than human bronchial doses by about a factor of 1.3, while lung doses, averaged over the bronchial (BB), bronchiolar (bb) and alveolar-interstitial (AI) regions, are higher by about a factor of about 1.6. This supports the current view that the rat lung is indeed an appropriate surrogate for the human lung in case of radon-induced lung cancers. Furthermore, airway diameter seems to be a more appropriate morphometric parameter than airway generations to relate bronchial doses to bronchial carcinomas.

Elastase-Induced Parenchymal Disruption and Airway Hyper Responsiveness in Mouse Precision Cut Lung Slices: Toward an Ex vivo COPD Model.

PubMed

Van Dijk, Eline M; Culha, Sule; Menzen, Mark H; Bidan, Cécile M; Gosens, Reinoud

2016-01-01

Background: COPD is a progressive lung disease characterized by emphysema and enhanced bronchoconstriction. Current treatments focused on bronchodilation can delay disease progression to some extent, but recovery or normalization of loss of lung function is impossible. Therefore, novel therapeutic targets are needed. The importance of the parenchyma in airway narrowing is increasingly recognized. In COPD, the parenchyma and extracellular matrix are altered, possibly affecting airway mechanics and enhancing bronchoconstriction. Our aim was to set up a comprehensive ex vivo Precision Cut Lung Slice (PCLS) model with a pathophysiology resembling that of COPD and integrate multiple readouts in order to study the relationship between parenchyma, airway functionality, and lung repair processes. Methods: Lungs of C57Bl/6J mice were sliced and treated ex vivo with elastase (2.5 μg/ml) or H 2 O 2 (200 μM) for 16 h. Following treatment, parenchymal structure, airway narrowing, and gene expression levels of alveolar Type I and II cell repair were assessed. Results: Following elastase, but not H 2 O 2 treatment, slices showed a significant increase in mean linear intercept (Lmi), reflective of emphysema. Only elastase-treated slices showed disorganization of elastin and collagen fibers. In addition, elastase treatment lowered both alveolar Type I and II marker expression, whereas H 2 O 2 stimulation lowered alveolar Type I marker expression only. Furthermore, elastase-treated slices showed enhanced methacholine-induced airway narrowing as reflected by increased pEC50 (5.87 at basal vs. 6.50 after elastase treatment) and Emax values (47.96 vs. 67.30%), and impaired chloroquine-induced airway opening. The increase in pEC50 correlated with an increase in mean Lmi. Conclusion: Using this model, we show that structural disruption of elastin fibers leads to impaired alveolar repair, disruption of the parenchymal compartment, and altered airway biomechanics, enhancing airway contraction. This finding may have implications for COPD, as the amount of elastin fiber and parenchymal tissue disruption is associated with disease severity. Therefore, we suggest that PCLS can be used to model certain aspects of COPD pathophysiology and that the parenchymal tissue damage observed in COPD contributes to lung function decline by disrupting airway biomechanics. Targeting the parenchymal compartment may therefore be a promising therapeutic target in the treatment of COPD.

Cystic Fibrosis Transmembrane Conductance Regulator in Sarcoplasmic Reticulum of Airway Smooth Muscle. Implications for Airway Contractility

PubMed Central

Cook, Daniel P.; Rector, Michael V.; Bouzek, Drake C.; Michalski, Andrew S.; Gansemer, Nicholas D.; Reznikov, Leah R.; Li, Xiaopeng; Stroik, Mallory R.; Ostedgaard, Lynda S.; Abou Alaiwa, Mahmoud H.; Thompson, Michael A.; Prakash, Y. S.; Krishnan, Ramaswamy; Meyerholz, David K.; Seow, Chun Y.

2016-01-01

Rationale: An asthma-like airway phenotype has been described in people with cystic fibrosis (CF). Whether these findings are directly caused by loss of CF transmembrane conductance regulator (CFTR) function or secondary to chronic airway infection and/or inflammation has been difficult to determine. Objectives: Airway contractility is primarily determined by airway smooth muscle. We tested the hypothesis that CFTR is expressed in airway smooth muscle and directly affects airway smooth muscle contractility. Methods: Newborn pigs, both wild type and with CF (before the onset of airway infection and inflammation), were used in this study. High-resolution immunofluorescence was used to identify the subcellular localization of CFTR in airway smooth muscle. Airway smooth muscle function was determined with tissue myography, intracellular calcium measurements, and regulatory myosin light chain phosphorylation status. Precision-cut lung slices were used to investigate the therapeutic potential of CFTR modulation on airway reactivity. Measurements and Main Results: We found that CFTR localizes to the sarcoplasmic reticulum compartment of airway smooth muscle and regulates airway smooth muscle tone. Loss of CFTR function led to delayed calcium reuptake following cholinergic stimulation and increased myosin light chain phosphorylation. CFTR potentiation with ivacaftor decreased airway reactivity in precision-cut lung slices following cholinergic stimulation. Conclusions: Loss of CFTR alters porcine airway smooth muscle function and may contribute to the airflow obstruction phenotype observed in human CF. Airway smooth muscle CFTR may represent a therapeutic target in CF and other diseases of airway narrowing. PMID:26488271

DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease

PubMed Central

Birch, Jodie; Anderson, Rhys K.; Correia-Melo, Clara; Jurk, Diana; Hewitt, Graeme; Marques, Francisco Madeira; Green, Nicola J.; Moisey, Elizabeth; Birrell, Mark A.; Belvisi, Maria G.; Black, Fiona; Taylor, John J.; Fisher, Andrew J.; De Soyza, Anthony

2015-01-01

Cellular senescence has been associated with the structural and functional decline observed during physiological lung aging and in chronic obstructive pulmonary disease (COPD). Airway epithelial cells are the first line of defense in the lungs and are important to COPD pathogenesis. However, the mechanisms underlying airway epithelial cell senescence, and particularly the role of telomere dysfunction in this process, are poorly understood. We aimed to investigate telomere dysfunction in airway epithelial cells from patients with COPD, in the aging murine lung and following cigarette smoke exposure. We evaluated colocalization of γ-histone protein 2A.X and telomeres and telomere length in small airway epithelial cells from patients with COPD, during murine lung aging, and following cigarette smoke exposure in vivo and in vitro. We found that telomere-associated DNA damage foci increase in small airway epithelial cells from patients with COPD, without significant telomere shortening detected. With age, telomere-associated foci increase in small airway epithelial cells of the murine lung, which is accelerated by cigarette smoke exposure. Moreover, telomere-associated foci predict age-dependent emphysema, and late-generation Terc null mice, which harbor dysfunctional telomeres, show early-onset emphysema. We found that cigarette smoke accelerates telomere dysfunction via reactive oxygen species in vitro and may be associated with ataxia telangiectasia mutated-dependent secretion of inflammatory cytokines interleukin-6 and -8. We propose that telomeres are highly sensitive to cigarette smoke-induced damage, and telomere dysfunction may underlie decline of lung function observed during aging and in COPD. PMID:26386121

Longitudinal changes in airway remodeling and air trapping in severe asthma

PubMed Central

Witt, Chad A.; Sheshadri, Ajay; Carlstrom, Luke; Tarsi, Jaime; Kozlowski, James; Wilson, Brad; Gierada, David; Hoffman, Eric; Fain, Sean; Cook-Granroth, Janice; Sajol, Geneline; Sierra, Oscar; Giri, Tusar; O'Neil, Michael; Zheng, Jie; Schechtman, Kenneth B.; Bacharier, Leonard B.; Jarjour, Nizar; Busse, William; Castro, Mario

2014-01-01

Rationale and Objectives Previous cross-sectional studies have demonstrated that airway wall thickness and air trapping are greater in subjects with severe asthma than in those with mild-to-moderate asthma. However, a better understanding of how airway remodeling and lung density change over time is needed. This study aims to evaluate predictors of airway wall remodeling and change in lung function and lung density over time in severe asthma. Materials and Methods Phenotypic characterization and quantitative multidetector computed tomography (MDCT) of the chest was performed at baseline and ∼2.6 years later in 38 participants with asthma (severe n=24, mild-moderate n=14) and 9 normal controls from the Severe Asthma Research Program. Results Subjects with severe asthma had a significant decline in post-bronchodilator FEV1% predicted over time (p = <0.001). Airway wall thickness measured by MDCT was increased at multiple airway generations in severe asthma compared to mild-to-moderate asthma (wall area percent (WA%): p <0.05) and normals (p <0.05) at baseline and year 2. Over time, there was an increase in WA% and wall thickness (WT%) in all subjects (p = 0.030 and 0.009 respectively) with no change in emphysema-like lung or air trapping. Baseline pre-bronchodilator FEV1% inversely correlated with WA% and WT% (both p = <0.05). In a multivariable regression model, baseline WA%, race and healthcare utilization were predictors of subsequent airway remodeling. Conclusions Severe asthma subjects have a greater decline in lung function over time than normal subjects or those with mild-to-moderate asthma. MDCT provides a noninvasive measure of airway wall thickness that may predict subsequent airway remodeling. PMID:25018070

Airway and alveolar nitric oxide production, lung function, and pulmonary blood flow in sickle cell disease.

PubMed

Lunt, Alan; Ahmed, Na'eem; Rafferty, Gerrard F; Dick, Moira; Rees, David; Height, Sue; Thein, Swee Lay; Greenough, Anne

2016-02-01

Children with sickle cell disease (SCD) often have obstructive lung function abnormalities which could be due to asthma or increased pulmonary blood volume; it is important to determine the underlying mechanism to direct appropriate treatment. In asthmatics, exhaled nitric oxide (FeNO) is elevated. FeNO, however, can also be raised due to increased alveolar production. Our aim, therefore, was to determine if airway or alveolar NO production differed between SCD children and ethnic and age-matched controls. Lung function, airway NO flux and alveolar NO production, and effective pulmonary blood flow were assessed in 18 SCD children and 18 ethnic and age-matched controls. The SCD children compared to the controls had a higher respiratory system resistance (P = 0.0008), alveolar NO production (P = 0.0224), and pulmonary blood flow (P < 0.0001), but not airway NO flux. There was no significant correlation between FeNO and respiratory system resistance in either group, but in the SCD children, there were correlations between alveolar NO production (P = 0.0006) and concentration (P < 0.0001) and pulmonary blood flow. Airway NO flux was not elevated in the SCD children nor correlated with airways obstruction, suggesting that airways obstruction, at least in some SCD children, is not due to asthma.

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

X-Ray based Lung Function measurement-a sensitive technique to quantify lung function in allergic airway inflammation mouse models

NASA Astrophysics Data System (ADS)

Dullin, C.; Markus, M. A.; Larsson, E.; Tromba, G.; Hülsmann, S.; Alves, F.

2016-11-01

In mice, along with the assessment of eosinophils, lung function measurements, most commonly carried out by plethysmography, are essential to monitor the course of allergic airway inflammation, to examine therapy efficacy and to correlate animal with patient data. To date, plethysmography techniques either use intubation and/or restraining of the mice and are thus invasive, or are limited in their sensitivity. We present a novel unrestrained lung function method based on low-dose planar cinematic x-ray imaging (X-Ray Lung Function, XLF) and demonstrate its performance in monitoring OVA induced experimental allergic airway inflammation in mice and an improved assessment of the efficacy of the common treatment dexamethasone. We further show that XLF is more sensitive than unrestrained whole body plethysmography (UWBP) and that conventional broncho-alveolar lavage and histology provide only limited information of the efficacy of a treatment when compared to XLF. Our results highlight the fact that a multi-parametric imaging approach as delivered by XLF is needed to address the combined cellular, anatomical and functional effects that occur during the course of asthma and in response to therapy.

Optimizing lung aeration at birth using a sustained inflation and positive pressure ventilation in preterm rabbits

PubMed Central

te Pas, Arjan B.; Kitchen, Marcus J.; Lee, Katie; Wallace, Megan J.; Fouras, Andreas; Lewis, Robert A.; Yagi, Naoto; Uesugi, Kentaro; Hooper, Stuart B.

2016-01-01

Background: A sustained inflation (SI) facilitates lung aeration, but the most effective pressure and duration are unknown. We investigated the effect of gestational age (GA) and airway liquid volume on the required inflation pressure and SI duration. Methods: Rabbit kittens were delivered at 27, 29, and 30 d gestation, intubated and airway liquid was aspirated. Either no liquid (control) or 30 ml/kg of liquid was returned to the airways. Lung gas volumes were measured by plethysmography and phase-contrast X-ray-imaging. Starting at 22 cmH2O, airway pressure was increased until airflow commenced and pressure was then held constant. The SI was truncated when 20 ml/kg air had entered the lung and ventilation continued with intermittent positive pressure ventilation (iPPV). Results: Higher SI pressures and longer durations were required in 27-d kittens compared to 30-d kittens. During iPPV, 27-d kittens needed higher pressures and had lower functional residual capacity (FRC) compared to 30-d kittens. Adding lung liquid increased SI duration, reduced FRC, and increased resistance and pressures during iPPV in 29- and 30-d kittens. Conclusion: Immature kittens required higher starting pressures and longer SI durations to achieve a set inflation volume. Larger airway liquid volumes adversely affected lung function during iPPV in older but not young kittens. PMID:26991259

Crosstalk between beta-2-adrenoceptor and muscarinic acetylcholine receptors in the airway.

PubMed

Pera, Tonio; Penn, Raymond B

2014-06-01

The M3 and M2 muscarinic acetylcholine receptors (mAChRs) and beta-2-adrenoceptors (β2ARs) are important regulators of airway cell function, and drugs targeting these receptors are among the first line drugs in the treatment of the obstructive lung diseases asthma and chronic obstructive lung disease (COPD). Cross-regulation or crosstalk between mAChRs and β2ARs in airway smooth muscle (ASM) helps determine the contractile state of the muscle, thus airway diameter and resistance to airflow. In this review we will detail mAChR and β2AR-signaling and crosstalk, focusing on events in the ASM cell but also addressing the function of these receptors in other cell types that impact airway physiology. We conclude by discussing how recent advances in GPCR pharmacology offer a unique opportunity to fine tune mAChR and β2AR signaling and their crosstalk, and thereby produce superior therapeutics for obstructive lung and other diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.

Exploring the context of the lung proteome within the airway mucosa following allergen challenge.

PubMed

Fehniger, Thomas E; Sato-Folatre, José-Gabriel; Malmström, Johan; Berglund, Magnus; Lindberg, Claes; Brange, Charlotte; Lindberg, Henrik; Marko-Varga, György

2004-01-01

The lung proteome is a dynamic collection of specialized proteins related to pulmonary function. Many cells of different derivations, activation states, and levels of maturity contribute to the changing environment, which produces the lung proteome. Inflammatory cells reacting to environmental challenge, for example from allergens, produce and secrete proteins which have profound effects on both resident and nonresident cells located in airways, alveoli, and the vascular tree which provides blood cells to the parenchyma alveolar bed for gas exchange. In an experimental model of allergic airway inflammation, we have compared control and allergen challenged lung compartments to determine global protein expression patterns using 2D-gel electrophoresis and subsequent spot identification by MS/MS mass spectrometry. We have then specifically isolated the epithelial mucosal layer, which lines conducting airways, from control and allergen challenged lungs, using laser capture technology and performed proteome identification on these selected cell samples. A central component of our investigations has been to contextually relate the histological features of the dynamic pulmonary environment to the changes in protein expression observed following challenge. Our results provide new information of the complexity of the submucosa/epithelium interface and the mechanisms behind the transformation of airway epithelium from normal steady states to functionally activated states.

CXCR4+ granulocytes reflect fungal cystic fibrosis lung disease.

PubMed

Carevic, Melanie; Singh, Anurag; Rieber, Nikolaus; Eickmeier, Olaf; Griese, Matthias; Hector, Andreas; Hartl, Dominik

2015-08-01

Cystic fibrosis airways are frequently colonised with fungi. However, the interaction of these fungi with immune cells and the clinical relevance in cystic fibrosis lung disease are incompletely understood.We characterised granulocytes in airway fluids and peripheral blood from cystic fibrosis patients with and without fungal colonisation, non-cystic fibrosis disease controls and healthy control subjects cross-sectionally and longitudinally and correlated these findings with lung function parameters.Cystic fibrosis patients with chronic fungal colonisation by Aspergillus fumigatus were characterised by an accumulation of a distinct granulocyte subset, expressing the HIV coreceptor CXCR4. Percentages of airway CXCR4(+) granulocytes correlated with lung disease severity in patients with cystic fibrosis.These studies demonstrate that chronic fungal colonisation with A. fumigatus in cystic fibrosis patients is associated with CXCR4(+) airway granulocytes, which may serve as a potential biomarker and therapeutic target in fungal cystic fibrosis lung disease. Copyright ©ERS 2015.

[Pulmonary rehabilitation after total laryngectomy using a heat and moisture exchanger (HME)].

PubMed

Lorenz, K J; Maier, H

2009-08-01

A complete removal of the larynx has profound consequences for a patient. Since laryngectomy involves the separation of the upper airway from the lower airway, it not only implies a loss of the voice organ but also leads to chronic lung problems such as increased coughing, mucus production and expectoration. In addition, laryngectomees complain of fatigue, sleeping problems, a reduced sense of smell and taste, and a loss of social contact. A heat and moisture exchanger (HME) cassette can replace a function of the upper airway which consists in conditioning inspired air. It can improve pulmonary symptoms in three ways. 1. An HME cassette heats and moisturises inhaled air and thus creates nearly physiological conditions in the region of the deep airway. 2. The use of an HME cassette leads to an increase in breathing resistance, thereby reducing dynamic airway compression and improving lung ventilation. 3. An HME cassette acts as a filter and removes larger particles from incoming air. This review examines the current understanding of lung physiology after laryngectomy and assesses the effects of HME cassettes on the conditioning of respiratory air, lung function and psychosocial problems. Georg Thieme Verlag KG Stuttgart, New York.

Unravelling a Clinical Paradox - Why Does Bronchial Thermoplasty Work in Asthma?

PubMed

Donovan, Graham M; Elliot, John G; Green, Francis H Y; James, Alan L; Noble, Peter B

2018-04-18

Rationale Bronchial thermoplasty is a relatively new but effective treatment in asthmatic subjects who do not respond to conventional therapy. While the favoured mechanism is ablation of the airway smooth muscle layer, because bronchial thermoplasty treats only a small number of central airways, there is ongoing debate regarding its precise method of action. Objectives Elucidate the underlying method of action behind bronchial thermoplasty. Methods We employ a combination of extensive human lung specimens and novel computational methods. Whole left lungs were acquired from the Prairie Provinces Fatal Asthma Study. Subjects were classified as control (N=31), non-fatal asthma (N=32), or fatal asthma (N=25). Simulated lungs for each group were constructed stochastically, and flow distributions and functional indicators were quantified both before and after a 70% reduction in airway smooth muscle in the thermoplasty-treated airways. Main Results Bronchial thermoplasty triggers global redistribution of clustered flow patterns, wherein structural changes to the treated central airways lead to a re-opening cascade in the small airways and significant improvement in lung function via reduced spatial heterogeneity of flow patterns. This mechanism accounts for progressively greater efficacy of thermoplasty with both severity of asthma and degree of muscle activation, consistent with existing empirical results. Conclusions We report a probable mechanism of action for bronchial thermoplasty: alteration of lung-wide flow patterns in response to structural alteration of the treated central airways. This insight could lead to improved therapy via patient-specific, tailored versions of the treatment -- as well as implications for more conventional asthma therapies.

Arsenic Compromises Conducting Airway Epithelial Barrier Properties in Primary Mouse and Immortalized Human Cell Cultures

PubMed Central

Sherwood, Cara L.; Liguori, Andrew E.; Olsen, Colin E.; Lantz, R. Clark; Burgess, Jefferey L.; Boitano, Scott

2013-01-01

Arsenic is a lung toxicant that can lead to respiratory illness through inhalation and ingestion, although the most common exposure is through contaminated drinking water. Lung effects reported from arsenic exposure include lung cancer and obstructive lung disease, as well as reductions in lung function and immune response. As part of their role in innate immune function, airway epithelial cells provide a barrier that protects underlying tissue from inhaled particulates, pathogens, and toxicants frequently found in inspired air. We evaluated the effects of a five-day exposure to environmentally relevant levels of arsenic {<4μM [~300 μg/L (ppb)] as NaAsO2} on airway epithelial barrier function and structure. In a primary mouse tracheal epithelial (MTE) cell model we found that both micromolar (3.9 μM) and submicromolar (0.8 μM) arsenic concentrations reduced transepithelial resistance, a measure of barrier function. Immunofluorescent staining of arsenic-treated MTE cells showed altered patterns of localization of the transmembrane tight junction proteins claudin (Cl) Cl-1, Cl-4, Cl-7 and occludin at cell-cell contacts when compared with untreated controls. To better quantify arsenic-induced changes in tight junction transmembrane proteins we conducted arsenic exposure experiments with an immortalized human bronchial epithelial cell line (16HBE14o-). We found that arsenic exposure significantly increased the protein expression of Cl-4 and occludin as well as the mRNA levels of Cl-4 and Cl-7 in these cells. Additionally, arsenic exposure resulted in altered phosphorylation of occludin. In summary, exposure to environmentally relevant levels of arsenic can alter both the function and structure of airway epithelial barrier constituents. These changes likely contribute to the observed arsenic-induced loss in basic innate immune defense and increased infection in the airway. PMID:24349408

Cigarette smoke–induced induction of antioxidant enzyme activities in airway leukocytes is absent in active smokers with COPD

PubMed Central

Dove, Rosamund E.; Leong-Smith, Pheneatia; Roos-Engstrand, Ester; Pourazar, Jamshid; Shah, Mittal; Behndig, Annelie F.; Mudway, Ian S.; Blomberg, Anders

2015-01-01

Background Oxidative injury to the airway has been proposed as an important underlying mechanism in the pathogenesis of chronic obstructive pulmonary disease (COPD). As the extent of oxidant-mediated damage is dependent on the endogenous antioxidant defences within the airways, we examined whether COPD was associated with deficiencies in the antioxidant network within the respiratory tract lining fluids (RTLFs) and resident airway leukocytes. We hypothesised that COPD would be associated with both basal depression of antioxidant defences and impaired adaptive antioxidant responses to cigarette smoke. Methods Low molecular weight and enzymatic antioxidants together with metal-handling proteins were quantified in bronchoalveolar lavage fluid and airway leukocytes, derived from current (n=9) and ex-smoking COPD patients (n=15), as well as from smokers with normal lung function (n=16) and healthy never smokers (n=13). Results Current cigarette smoking was associated with an increase in ascorbate and glutathione within peripheral RTLFs in both smokers with normal lung function compared with healthy never smokers and in COPD smokers compared with COPD ex-smokers. In contrast, intra-cellular antioxidant enzyme activities (glutathione peroxidase, glutathione reductase, and catalase) were only up-regulated in smokers with normal lung function compared with healthy never smokers and not in actively smoking COPD patients relative to COPD ex-smokers. Conclusions We found no evidence of impaired basal antioxidant defences, within either the RTLFs or airway leukocytes in stable ex-smoking COPD patients compared with healthy never smoking controls. Current cigarette smoking induced an up-regulation of low molecular weight antioxidants in the RTLFs of both control subjects with normal lung function and patients with COPD. Importantly, the present data demonstrated a cigarette smoke–induced increase in intra-cellular antioxidant enzyme activities only within the smokers with normal lung function, implying that patients with COPD who continue to smoke will experience enhanced oxidative stress, prompting disease progression. PMID:26557249

A Dynamic Bronchial Airway Gene Expression Signature of Chronic Obstructive Pulmonary Disease and Lung Function Impairment

PubMed Central

Steiling, Katrina; van den Berge, Maarten; Hijazi, Kahkeshan; Florido, Roberta; Campbell, Joshua; Liu, Gang; Xiao, Ji; Zhang, Xiaohui; Duclos, Grant; Drizik, Eduard; Si, Huiqing; Perdomo, Catalina; Dumont, Charles; Coxson, Harvey O.; Alekseyev, Yuriy O.; Sin, Don; Pare, Peter; Hogg, James C.; McWilliams, Annette; Hiemstra, Pieter S.; Sterk, Peter J.; Timens, Wim; Chang, Jeffrey T.; Sebastiani, Paola; O’Connor, George T.; Bild, Andrea H.; Postma, Dirkje S.; Lam, Stephen

2013-01-01

Rationale: Molecular phenotyping of chronic obstructive pulmonary disease (COPD) has been impeded in part by the difficulty in obtaining lung tissue samples from individuals with impaired lung function. Objectives: We sought to determine whether COPD-associated processes are reflected in gene expression profiles of bronchial airway epithelial cells obtained by bronchoscopy. Methods: Gene expression profiling of bronchial brushings obtained from 238 current and former smokers with and without COPD was performed using Affymetrix Human Gene 1.0 ST Arrays. Measurements and Main Results: We identified 98 genes whose expression levels were associated with COPD status, FEV1% predicted, and FEV1/FVC. In silico analysis identified activating transcription factor 4 (ATF4) as a potential transcriptional regulator of genes with COPD-associated airway expression, and ATF4 overexpression in airway epithelial cells in vitro recapitulates COPD-associated gene expression changes. Genes with COPD-associated expression in the bronchial airway epithelium had similarly altered expression profiles in prior studies performed on small-airway epithelium and lung parenchyma, suggesting that transcriptomic alterations in the bronchial airway epithelium reflect molecular events found at more distal sites of disease activity. Many of the airway COPD-associated gene expression changes revert toward baseline after therapy with the inhaled corticosteroid fluticasone in independent cohorts. Conclusions: Our findings demonstrate a molecular field of injury throughout the bronchial airway of active and former smokers with COPD that may be driven in part by ATF4 and is modifiable with therapy. Bronchial airway epithelium may ultimately serve as a relatively accessible tissue in which to measure biomarkers of disease activity for guiding clinical management of COPD. PMID:23471465

Multiple Facets of cAMP Signalling and Physiological Impact: cAMP Compartmentalization in the Lung

PubMed Central

Oldenburger, Anouk; Maarsingh, Harm; Schmidt, Martina

2012-01-01

Therapies involving elevation of the endogenous suppressor cyclic AMP (cAMP) are currently used in the treatment of several chronic inflammatory disorders, including chronic obstructive pulmonary disease (COPD). Characteristics of COPD are airway obstruction, airway inflammation and airway remodelling, processes encompassed by increased airway smooth muscle mass, epithelial changes, goblet cell and submucosal gland hyperplasia. In addition to inflammatory cells, airway smooth muscle cells and (myo)fibroblasts, epithelial cells underpin a variety of key responses in the airways such as inflammatory cytokine release, airway remodelling, mucus hypersecretion and airway barrier function. Cigarette smoke, being next to environmental pollution the main cause of COPD, is believed to cause epithelial hyperpermeability by disrupting the barrier function. Here we will focus on the most recent progress on compartmentalized signalling by cAMP. In addition to G protein-coupled receptors, adenylyl cyclases, cAMP-specific phospho-diesterases (PDEs) maintain compartmentalized cAMP signalling. Intriguingly, spatially discrete cAMP-sensing signalling complexes seem also to involve distinct members of the A-kinase anchoring (AKAP) superfamily and IQ motif containing GTPase activating protein (IQGAPs). In this review, we will highlight the interaction between cAMP and the epithelial barrier to retain proper lung function and to alleviate COPD symptoms and focus on the possible molecular mechanisms involved in this process. Future studies should include the development of cAMP-sensing multiprotein complex specific disruptors and/or stabilizers to orchestrate cellular functions. Compartmentalized cAMP signalling regulates important cellular processes in the lung and may serve as a therapeutic target. PMID:24281338

Prevention of abnormal pulmonary mechanics in the postmortem guinea pig lung.

PubMed

Reynolds, A M; McEvoy, R D

1988-04-01

Severe postmortem bronchoconstriction has been shown previously in guinea pig lungs and linked to pulmonary blood loss during exsanguination (Lai et al., J. Appl. Physiol. 56: 308-314, 1984). To reexamine this phenomenon we measured postmortem airway function in anesthetized open-chest guinea pigs after sudden circulatory arrest. Animals were divided into 4 groups of 10 and ventilated for 15 min postmortem with different gases: 1) room air, 2) conditioned air, 3) dry 5% CO2-21% O2-74% N2, and 4) conditioned 5% CO2-21% O2-74% N2. In room air-ventilated lungs there was a 50% decrease in dynamic compliance (Cdyn) by 15 min and marked gas trapping compared with control lungs. Conditioning the room air did not attenuate these changes, but when 5% CO2 was added to the conditioned postmortem inspirate, gas trapping was eliminated and the fall in Cdyn was almost abolished. Ventilation with a dry 5% CO2 gas mixture at room temperature resulted in a 31% fall in Cdyn at 15 min but no gas trapping. We conclude that marked abnormalities of airway function occur postmortem in room air-ventilated guinea pig lungs in the absence of pulmonary blood loss. The changes are mainly due to airway hypocarbia, a known cause of bronchoconstriction, but a reduction in Cdyn can also occur if there is marked airway cooling and drying. Acute postmortem airway dysfunction can be prevented in the guinea pig by maintaining normal airway gas composition.

Effects of conventional tobacco smoke and nicotine-free cigarette smoke on airway inflammation, airway remodelling and lung function in a triple allergen model of severe asthma.

PubMed

Tilp, C; Bucher, H; Haas, H; Duechs, M J; Wex, E; Erb, K J

2016-07-01

Patients with asthma who smoke have reduced lung function, increased exacerbation rates and increased steroid resistance compared to non-smoking asthmatics. In mice, cigarette smoke has been reported to have both pro- and anti-Th2 response effects. We hypothesized that combining tobacco cigarette smoke (tCS) with allergen exposure increases inflammation, airway remodelling and lung function in mice. To test this hypothesis, we combined a severe triple allergen model with tCS exposure and investigated whether effects were due to Toll-like receptor 4 signalling and/or nicotine and also observed when nicotine-free cigarettes were used. Mice were sensitized with ovalbumin, cockroach and house dust mite allergen in alum followed by intratracheal challenges with allergen twice a week for 6 weeks or additionally exposed to tCS during the allergen challenge period. Nicotine or nicotine-free herbal cigarette smoke was also applied to allergen challenged mice. tCS significantly reduced eosinophil numbers, IL-4 and IL-5 concentrations in the lung, total and allergen-specific IgE in serum, improved lung function and reduced collagen I levels. With the exception of collagen I all parameters reduced by tobacco cigarette smoke were also reduced in Toll-like receptor 4-deficient mice. Nicotine-free cigarette smoke also had significant anti-inflammatory effects on eosinophils, IL-4 and IL-5 concentrations in the lung and reduced airway hyperreactivity, albeit weaker than tobacco smoke. Applying nicotine alone also reduced Th2 cytokine levels and eosinophil numbers in the airways. Our experiments show that tCS exposure reduces allergen-induced Th2 response in the lung and associated collagen I production and development of airway hyperreactivity. With the exception on collagen I formation, these effects were not dependent on Toll-like receptor 4. The observed anti-Th2 effects of both nicotine and nicotine-free herbal cigarette smoke together suggests that tCS reduces the Th2 responses through nicotine and other products released by burning tobacco. © 2015 John Wiley & Sons Ltd.

Relation between lung function, exercise capacity, and exposure to asbestos cement.

PubMed Central

Wollmer, P; Eriksson, L; Jonson, B; Jakobsson, K; Albin, M; Skerfving, S; Welinder, H

1987-01-01

A group of 137 male workers with known exposure (mean 20 fibre years per millilitre) to asbestos cement who had symptoms or signs of pulmonary disease was studied together with a reference group of 49 healthy industrial workers with no exposure to asbestos. Lung function measurements were made at rest and during exercise. Evidence of lung fibrosis was found as well as of obstructive airways disease in the exposed group compared with the reference group. Asbestos cement exposure was related to variables reflecting lung fibrosis but not to variables reflecting airflow obstruction. Smoking was related to variables reflecting obstructive lung disease. Exercise capacity was reduced in the exposed workers and was related to smoking and to lung function variables, reflecting obstructive airways disease. There was no significant correlation between exercise capacity and exposure to asbestos cement. PMID:3651353

Conservation of small-airway function by tacrolimus/cyclosporine conversion in the management of bronchiolitis obliterans following lung transplantation.

PubMed

Revell, M P; Lewis, M E; Llewellyn-Jones, C G; Wilson, I C; Bonser, R S

2000-12-01

We studied serial lung function in 11 patients with bronchiolitis obliterans syndrome who were treated with tacrolimus conversion following lung or heart-lung transplantation. Our results show that tacrolimus conversion slows the decline of lung function in bronchiolitis obliterans syndrome. The attenuation continues for at least 1 year following conversion.

Chronic Alcohol Induces M2 Polarization Enhancing Pulmonary Disease Caused by Exposure to Particulate Air Pollution

PubMed Central

Thevenot, Paul; Saravia, Jordy; Giaimo, Joseph; Happel, Kyle I.; Dugas, Tammy R.; Cormier, Stephania A.

2013-01-01

Background Chronic alcohol consumption causes persistent oxidative stress in the lung, leading to impaired alveolar macrophage (AM) function and impaired immune responses. AMs play a critical role in protecting the lung from particulate matter (PM) inhalation by removing particulates from the airway and secreting factors which mediate airway repair. We hypothesized AM dysfunction caused by chronic alcohol consumption increases the severity of injury caused by particulate matter inhalation. Methods Age- and sex-matched C57BL6 mice were fed the Lieber-DeCarli liquid diet containing either alcohol or an iso-caloric substitution (control diet) for 8 weeks. Mice from both diet groups were exposed to combustion derived PM (CDPM) for the final 2 weeks. AM number, maturation, and polarization status were assessed by flow cytometry. Noninvasive and invasive strategies were used to assess pulmonary function and correlated with histomorphological assessments of airway structure and matrix deposition. Results Co-exposure to alcohol and CDPM decreased AM number and maturation status (CD11c expression) while increasing markers of M2 activation (IL-4Rα, Ym1, Fizz1 expression and IL-10 and TGF-β production). Changes in AM function were accompanied by decreased airway compliance and increased elastance. Altered lung function was attributable to elevated collagen content localized to the small airways and loss of alveolar integrity. Intranasal administration of neutralizing antibody to TGF-β during the CDPM exposure period improved changes in airway compliance and elastance while reducing collagen content caused by co-exposure. Conclusion CDPM inhalation causes enhanced disease severity in the alcoholic lung by stimulating the release of latent TGF-β stores in AMs. The combinatorial effect of elevated TGF-β, M2 polarization of AMs, and increased oxidative stress impairs pulmonary function by increasing airway collagen content and compromising alveolar integrity. PMID:23763452

SPONTANEOUS AIRWAY HYPERRESPONSIVENESS IN ESTROGEN RECEPTOR-A DEFICIENT MICE

EPA Science Inventory

Rationale: Airway hyperresponsiveness is a critical feature of asthma. Substantial epidemiologic evidence supports a role for female sex hormones in modulating lung function and airway hyperresponsiveness in humans. Objectives: To examine the role of estrogen receptors in modulat...

Perinatal stress and early life programming of lung structure and function

PubMed Central

Wright, Rosalind J.

2010-01-01

Exposure to environmental toxins during critical periods of prenatal and/or postnatal development may alter the normal course of lung morphogenesis and maturation, potentially resulting in changes that affect both structure and function of the respiratory system. Moreover, these early effects may persist into adult life magnifying the potential public health impact. Aberrant or excessive pro-inflammatory immune responses, occurring both locally and systemically, that result in inflammatory damage to the airway are a central determinant of lung structure-function changes throughout life. Disruption of neuroendocrine function in early development, specifically the hypothalamic-pituitary-adrenal (HPA) axis, may alter functional status of the immune system. Autonomic nervous system (ANS) function (sympathovagal imbalance) is another integral component of airway function and immunity in childhood. This overview discusses the evidence linking psychological factors to alterations in these interrelated physiological processes that may, in turn, influence childhood lung function and identifies gaps in our understanding. PMID:20080145

Airway Basal Cells. The “Smoking Gun” of Chronic Obstructive Pulmonary Disease

PubMed Central

2014-01-01

The earliest abnormality in the lung associated with smoking is hyperplasia of airway basal cells, the stem/progenitor cells of the ciliated and secretory cells that are central to pulmonary host defense. Using cell biology and ’omics technologies to assess basal cells isolated from bronchoscopic brushings of nonsmokers, smokers, and smokers with chronic obstructive pulmonary disease (COPD), compelling evidence has been provided in support of the concept that airway basal cells are central to the pathogenesis of smoking-associated lung diseases. When confronted by the chronic stress of smoking, airway basal cells become disorderly, regress to a more primitive state, behave as dictated by their inheritance, are susceptible to acquired changes in their genome, lose the capacity to regenerate the epithelium, are responsible for the major changes in the airway that characterize COPD, and, with persistent stress, can undergo malignant transformation. Together, these observations led to the conclusion that accelerated loss of lung function in susceptible individuals begins with disordered airway basal cell biology (i.e., that airway basal cells are the “smoking gun” of COPD, a potential target for the development of therapies to prevent smoking-related lung disorders). PMID:25354273

High-resolution CT assessment of the pediatric airways: structure and function

NASA Astrophysics Data System (ADS)

Kramer, Sandra S.; Hoffman, Eric A.; Amirav, Israel

1994-05-01

The airway has always been a central focus for respiratory pathology in infants and children. Imaging of the larynx, trachea, and the central bronchi can be readily accomplished by radiographic or conventional CT techniques. Newer high resolution CT (HRCT) techniques have extended our view of the bronchi peripherally to the limits of scanner resolution, i.e., to bronchial generations 7 - 9, and rapid volumetric CT data acquisitions have made it possible to follow the same lung anatomic level through the rapidly occurring changes in a series of experimental protocols. These techniques together with a custom designed computer software program for image display and analysis have enabled us to objectively study changes in airway caliber and lung density that occurred in an animal mode of airway reactivity and thereby relate structure with function in the airways.

CT Metrics of Airway Disease and Emphysema in Severe COPD

PubMed Central

Kim, Woo Jin; Silverman, Edwin K.; Hoffman, Eric; Criner, Gerard J.; Mosenifar, Zab; Sciurba, Frank C.; Make, Barry J.; Carey, Vincent; Estépar, Raúl San José; Diaz, Alejandro; Reilly, John J.; Martinez, Fernando J.; Washko, George R.

2009-01-01

Background: CT scan measures of emphysema and airway disease have been correlated with lung function in cohorts of subjects with a range of COPD severity. The contribution of CT scan-assessed airway disease to objective measures of lung function and respiratory symptoms such as dyspnea in severe emphysema is less clear. Methods: Using data from 338 subjects in the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study, densitometric measures of emphysema using a threshold of −950 Hounsfield units (%LAA-950) and airway wall phenotypes of the wall thickness (WT) and the square root of wall area (SRWA) of a 10-mm luminal perimeter airway were calculated for each subject. Linear regression analysis was performed for outcome variables FEV1 and percent predicted value of FEV1 with CT scan measures of emphysema and airway disease. Results: In univariate analysis, there were significant negative correlations between %LAA-950 and both the WT (r = −0.28, p = 0.0001) and SRWA (r = −0.19, p = 0.0008). Airway wall thickness was weakly but significantly correlated with postbronchodilator FEV1% predicted (R = −0.12, p = 0.02). Multivariate analysis showed significant associations between either WT or SRWA (β = −5.2, p = 0.009; β = −2.6, p = 0.008, respectively) and %LAA-950 (β = −10.6, p = 0.03) with the postbronchodilator FEV1% predicted. Male subjects exhibited significantly thicker airway wall phenotypes (p = 0.007 for WT and p = 0.0006 for SRWA). Conclusions: Airway disease and emphysema detected by CT scanning are inversely related in patients with severe COPD. Airway wall phenotypes were influenced by gender and associated with lung function in subjects with severe emphysema. PMID:19411295

Chronic Aspergillus fumigatus colonization of the pediatric cystic fibrosis airway is common and may be associated with a more rapid decline in lung function.

PubMed

Saunders, Rosalind V; Modha, Deborah E; Claydon, Alison; Gaillard, Erol A

2016-07-01

Filamentous fungi are commonly isolated from the respiratory tract of CF patients, but their clinical significance is uncertain and the reported incidence variable. We report on the degree of Aspergillus fumigatus airway colonization in a tertiary pediatric CF cohort, evaluate the sensitivity of routine clinical sampling at detecting A. fumigatus, and compare lung function of A. fumigatus-colonized and non-colonized children.We carried out an 8-year retrospective cohort analysis using local databases, examining 1024 respiratory microbiological specimens from 45 children. Nineteen (42%) had a positive A. fumigatus culture at least once during the 8-year period, with 10 (22%) children persistently colonized. Overall, 29% of 48 bronchoalveolar lavage (BAL) samples tested positive for A. fumigatus, compared with 14% of 976 sputum samples. Of 33 children for whom lung function data were available during the study period, seven were classed as having severe lung disease, of whom four (57%) were persistently colonized with A. fumigatus.We conclude that chronic A. fumigatus colonization of the CF airway is common, and may be associated with worse lung function. In our practice, BAL appears superior at detecting lower airway A. fumigatus compared to sputum samples. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Vitamin D deficiency causes airway hyperresponsiveness, increases airway smooth muscle mass, and reduces TGF‐β expression in the lungs of female BALB/c mice

PubMed Central

Foong, Rachel E.; Shaw, Nicole C.; Berry, Luke J.; Hart, Prue H.; Gorman, Shelley; Zosky, Graeme R.

2014-01-01

Abstract Vitamin D deficiency is associated with disease severity in asthma. We tested whether there is a causal association between vitamin D deficiency, airway smooth muscle (ASM) mass, and the development of airway hyperresponsiveness (AHR). A physiologically relevant mouse model of vitamin D deficiency was developed by raising BALB/c mice on vitamin D‐deficient or ‐replete diets. AHR was assessed by measuring lung function responses to increasing doses of inhaled methacholine. Five‐micron sections from formalin‐fixed lungs were used for ASM measurement and assessment of lung structure using stereological methods. Transforming growth factor (TGF)‐β levels were measured in bronchoalveolar lavage fluid (BALF). Lungs were dissected from embryonic day (E) 17.5 vitamin D‐deficient and ‐replete fetal mice for quantification of ASM density and relative gene expression of TGF‐β signaling pathway molecules. Eight‐week‐old adult vitamin D‐deficient female mice had significantly increased airway resistance and ASM in the large airways compared with controls. Vitamin D‐deficient female mice had a smaller lung volume, volume of parenchyma, and alveolar septa. Both vitamin D‐deficient male and female mice had reduced TGF‐β levels in BALF. Vitamin D deficiency did not have an effect on ASM density in E17.5 mice, however, expression of TGF‐β1 and TGF‐β receptor I was downregulated in vitamin D‐deficient female fetal mice. Decreased expression of TGF‐β1 and TGF‐β receptor I during early lung development in vitamin D‐deficient mice may contribute to airway remodeling and AHR in vitamin D‐deficient adult female mice. This study provides a link between vitamin D deficiency and respiratory symptoms in chronic lung disease. PMID:24760528

DEVELOPMENT OF THE SMALL AIRWAYS AND ALVEOLI FROM CHILDHOOD TO ADULT LUNG MEASURED BY AEROSOL-DERIVED AIRWAY MORPHOMETRY

EPA Science Inventory

Understanding the human development of pulmonary airspaces is important for calculating the dose from exposure to inhaled materials as a function of age. We have measured, in vivo, the airspace caliber of the small airways and alveoli by aerosol-derived airway morphometry (ADAM) ...

Foetal airway motor tone in prenatal lung development of the pig.

PubMed

Sparrow, M P; Warwick, S P; Mitchell, H W

1994-08-01

The terminal airways from embryonic lung in situ or as explants exhibit rhythmic spontaneous contractions. Our objective was to see whether narrowing responses of the airways occurred throughout the bronchial tree in the first trimester foetus and, if so, to characterize them. The bronchial tree was freed of vasculature and parenchyma from the lungs of 20-35 g pig foetuses (44-48 days gestation). The airway lumen was visualized directly with transmitted light, and narrowing was recorded in real time by video-imaging microscopy. From the main stem bronchi to the terminal regions of late generation branches (20-35 microns i.d.) strong bronchoconstrictor responses to micromolar concentrations of acetylcholine (ACh), histamine, substance P and K+ depolarizing solution were seen, whilst inhibition of narrowing with beta-adrenoceptor agonists was evidence of beta-receptors on the smooth muscle. Moreover, strong narrowing responses to electrical field stimulation, which were blocked by atropine, indicated that functional cholinergic nerves were present. A remarkable display of spontaneous narrowing in the airways of many of the bronchial tree preparations caused the movement of lung liquid to and fro. We speculate that the bronchomotor tone and associated spontaneous activity, which move the lung fluid along the airways, serve to maintain an even positive pressure in localized areas of the bronchial tree which is essential to provide the stimulus for continued growth of the lung.

Emodin mitigates diesel exhaust particles-induced increase in airway resistance, inflammation and oxidative stress in mice.

PubMed

Nemmar, Abderrahim; Al-Salam, Suhail; Yuvaraju, Priya; Beegam, Sumaya; Ali, Badreldin H

2015-08-15

Clinical and experimental studies have reported that short-term exposure to particulate air pollution is associated with inflammation, oxidative stress and impairment of lung function. Emodin (1,3,8-trihydroxy-6-methylanthraquinone) has a strong antioxidant and anti-inflammatory actions. Therefore, in the present study, we evaluated the possible ameliorative effect of emodin on diesel exhaust particles (DEP)-induced impairment of lung function, inflammation and oxidative stress in mice. Mice were intratracheally instilled with DEP (20 μg/mouse) or saline (control). Emodin was administered intraperitoneally 1h before and 7h after pulmonary exposure to DEP. Twenty-four hours following DEP exposure, we evaluated airway resistance measured by forced oscillation technique, lung inflammation and oxidative stress. Emodin treatment abated the DEP-induced increase in airway resistance, and prevented the influx of neutrophils in bronchoalveolar lavage fluid. Similarly, lung histopathology confirmed the protective effect of emodin on DEP-induced lung inflammation. DEP induced a significant increase of proinflammatory cytokines in the lung including tumor necrosis factor α, interleukin 6 and interleukin 1β. The latter effect was significantly ameliorated by emodin. DEP caused a significant increase in lung lipid peroxidation, reactive oxygen species and a significant decrease of reduced glutathione concentration. These effects were significantly mitigated by emodin. We conclude that emodin significantly mitigated DEP-induced increase of airway resistance, lung inflammation and oxidative stress. Pending further pharmacological and toxicological studies, emodin may be considered a potentially useful pulmonary protective agent against particulate air pollution-induced lung toxicity. Copyright © 2015 Elsevier B.V. All rights reserved.

The clinical utility of long-term humidification therapy in chronic airway disease.

PubMed

Rea, Harold; McAuley, Sue; Jayaram, Lata; Garrett, Jeffrey; Hockey, Hans; Storey, Louanne; O'Donnell, Glenis; Haru, Lynne; Payton, Matthew; O'Donnell, Kevin

2010-04-01

Persistent airway inflammation with mucus retention in patients with chronic airway disorders such as COPD and bronchiectasis may lead to frequent exacerbations, reduced lung function and poor quality of life. This study investigates if long-term humidification therapy with high flow fully humidified air at 37 degrees C through nasal cannulae can improve these clinical outcomes in this group of patients. 108 patients diagnosed with COPD or bronchiectasis were randomised to daily humidification therapy or usual care for 12 months over which exacerbations were recorded. Lung function, quality of life, exercise capacity, and measures of airway inflammation were also recorded at baseline, 3 and 12 months. Patients on long-term humidification therapy had significantly fewer exacerbation days (18.2 versus 33.5 days; p = 0.045), increased time to first exacerbation (median 52 versus 27 days; p = 0.0495) and reduced exacerbation frequency (2.97/patient/year versus 3.63/patient/year; p = 0.067) compared with usual care. Quality of life scores and lung function improved significantly with humidification therapy compared with usual care at 3 and 12 months. Long-term humidification therapy significantly reduced exacerbation days, increased time to first exacerbation, improved lung function and quality of life in patients with COPD and bronchiectasis. Clinical trial registered with www.actr.org.au; Number ACTRN2605000623695. Copyright 2010 Elsevier Ltd. All rights reserved.

Should regional ventilation function be considered during radiation treatment planning to prevent radiation-induced complications?

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

Lan, Fujun; Jeudy, Jean; D’Souza, Warren

Purpose: To investigate the incorporation of pretherapy regional ventilation function in predicting radiation fibrosis (RF) in stage III nonsmall cell lung cancer (NSCLC) patients treated with concurrent thoracic chemoradiotherapy. Methods: Thirty-seven patients with stage III NSCLC were retrospectively studied. Patients received one cycle of cisplatin–gemcitabine, followed by two to three cycles of cisplatin–etoposide concurrently with involved-field thoracic radiotherapy (46–66 Gy; 2 Gy/fraction). Pretherapy regional ventilation images of the lung were derived from 4D computed tomography via a density change–based algorithm with mass correction. In addition to the conventional dose–volume metrics (V{sub 20}, V{sub 30}, V{sub 40}, and mean lung dose),more » dose–function metrics (fV{sub 20}, fV{sub 30}, fV{sub 40}, and functional mean lung dose) were generated by combining regional ventilation and radiation dose. A new class of metrics was derived and referred to as dose–subvolume metrics (sV{sub 20}, sV{sub 30}, sV{sub 40}, and subvolume mean lung dose); these were defined as the conventional dose–volume metrics computed on the functional lung. Area under the receiver operating characteristic curve (AUC) values and logistic regression analyses were used to evaluate these metrics in predicting hallmark characteristics of RF (lung consolidation, volume loss, and airway dilation). Results: AUC values for the dose–volume metrics in predicting lung consolidation, volume loss, and airway dilation were 0.65–0.69, 0.57–0.70, and 0.69–0.76, respectively. The respective ranges for dose–function metrics were 0.63–0.66, 0.61–0.71, and 0.72–0.80 and for dose–subvolume metrics were 0.50–0.65, 0.65–0.75, and 0.73–0.85. Using an AUC value = 0.70 as cutoff value suggested that at least one of each type of metrics (dose–volume, dose–function, dose–subvolume) was predictive for volume loss and airway dilation, whereas lung consolidation cannot be accurately predicted by any of the metrics. Logistic regression analyses showed that dose–function and dose–subvolume metrics were significant (P values ≤ 0.02) in predicting volume airway dilation. Likelihood ratio test showed that when combining dose–function and/or dose–subvolume metrics with dose–volume metrics, the achieved improvements of prediction accuracy on volume loss and airway dilation were significant (P values ≤ 0.04). Conclusions: The authors’ results demonstrated that the inclusion of regional ventilation function improved accuracy in predicting RF. In particular, dose–subvolume metrics provided a promising method for preventing radiation-induced pulmonary complications.« less

Novel therapeutic strategies for lung disorders associated with airway remodelling and fibrosis.

PubMed

Royce, Simon G; Moodley, Yuben; Samuel, Chrishan S

2014-03-01

Inflammatory cell infiltration, cytokine release, epithelial damage, airway/lung remodelling and fibrosis are central features of inflammatory lung disorders, which include asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome and idiopathic pulmonary fibrosis. Although the lung has some ability to repair itself from acute injury, in the presence of ongoing pathological stimuli and/or insults that lead to chronic disease, it no longer retains the capacity to heal, resulting in fibrosis, the final common pathway that causes an irreversible loss of lung function. Despite inflammation, genetic predisposition/factors, epithelial-mesenchymal transition and mechanotransduction being able to independently contribute to airway remodelling and fibrosis, current therapies for inflammatory lung diseases are limited by their ability to only target the inflammatory component of the disease without having any marked effects on remodelling (epithelial damage and fibrosis) that can cause lung dysfunction independently of inflammation. Furthermore, as subsets of patients suffering from these diseases are resistant to currently available therapies (such as corticosteroids), novel therapeutic approaches are required to combat all aspects of disease pathology. This review discusses emerging therapeutic approaches, such as trefoil factors, relaxin, histone deacetylase inhibitors and stem cells, amongst others that have been able to target airway inflammation and airway remodelling while improving related lung dysfunction. A better understanding of the mode of action of these therapies and their possible combined effects may lead to the identification of their clinical potential in the setting of lung disease, either as adjunct or alternative therapies to currently available treatments. © 2013.

Gene-by-environment effect of house dust mite on purinergic receptor P2Y12 (P2RY12) and lung function in children with asthma.

PubMed

Bunyavanich, S; Boyce, J A; Raby, B A; Weiss, S T

2012-02-01

Distinct receptors likely exist for leukotriene (LT)E(4), a potent mediator of airway inflammation. Purinergic receptor P2Y12 is needed for LTE(4)-induced airways inflammation, and P2Y12 antagonism attenuates house dust mite-induced pulmonary eosinophilia in mice. Although experimental data support a role for P2Y12 in airway inflammation, its role in human asthma has never been studied. To test for association between variants in the P2Y12 gene (P2RY12) and lung function in human subjects with asthma, and to examine for gene-by-environment interaction with house dust mite exposure. Nineteen single nucleotide polymorphisms (SNPs) in P2RY12 were genotyped in 422 children with asthma and their parents (n = 1266). Using family based methods, we tested for associations between these SNPs and five lung function measures. We performed haplotype association analyses and tested for gene-by-environment interactions using house dust mite exposure. We used the false discovery rate to account for multiple comparisons. Five SNPs in P2RY12 were associated with multiple lung function measures (P-values 0.006–0.025). Haplotypes in P2RY12 were also associated with lung function (P-values 0.0055–0.046). House dust mite exposure modulated associations between P2RY12 and lung function, with minor allele homozygotes exposed to house dust mite demonstrating worse lung function than those unexposed (significant interaction P-values 0.0028–0.040). The P2RY12 variants were associated with lung function in a large family-based asthma cohort. House dust mite exposure caused significant gene-by-environment effects. Our findings add the first human evidence to experimental data supporting a role for P2Y12 in lung function. P2Y12 could represent a novel target for asthma treatment.

Neutrophilic infiltration within the airway smooth muscle in patients with COPD

PubMed Central

Baraldo, S; Turato, G; Badin, C; Bazzan, E; Beghe, B; Zuin, R; Calabrese, F; Casoni, G; Maestrelli, P; Papi, A; Fabbri, L; Saetta, M

2004-01-01

Background: COPD is an inflammatory disorder characterised by chronic airflow limitation, but the extent to which airway inflammation is related to functional abnormalities is still uncertain. The interaction between inflammatory cells and airway smooth muscle may have a crucial role. Methods: To investigate the microlocalisation of inflammatory cells within the airway smooth muscle in COPD, surgical specimens obtained from 26 subjects undergoing thoracotomy (eight smokers with COPD, 10 smokers with normal lung function, and eight non-smoking controls) were examined. Immunohistochemical analysis was used to quantify the number of neutrophils, macrophages, mast cells, CD4+ and CD8+ cells localised within the smooth muscle of peripheral airways. Results: Smokers with COPD had an increased number of neutrophils and CD8+ cells in the airway smooth muscle compared with non-smokers. Smokers with normal lung function also had a neutrophilic infiltration in the airway smooth muscle, but to a lesser extent. When all the subjects were analysed as one group, neutrophilic infiltration was inversely related to forced expiratory volume in 1 second (% predicted). Conclusions: Microlocalisation of neutrophils and CD8+ cells in the airway smooth muscle in smokers with COPD suggests a possible role for these cells in the pathogenesis of smoking induced airflow limitation. PMID:15047950

Identification of genes differentially regulated by vitamin D deficiency that alter lung pathophysiology and inflammation in allergic airways disease.

PubMed

Foong, Rachel E; Bosco, Anthony; Troy, Niamh M; Gorman, Shelley; Hart, Prue H; Kicic, Anthony; Zosky, Graeme R

2016-09-01

Vitamin D deficiency is associated with asthma risk. Vitamin D deficiency may enhance the inflammatory response, and we have previously shown that airway remodeling and airway hyperresponsiveness is increased in vitamin D-deficient mice. In this study, we hypothesize that vitamin D deficiency would exacerbate house dust mite (HDM)-induced inflammation and alterations in lung structure and function. A BALB/c mouse model of vitamin D deficiency was established by dietary manipulation. Responsiveness to methacholine, airway smooth muscle (ASM) mass, mucus cell metaplasia, lung and airway inflammation, and cytokines in bronchoalveolar lavage (BAL) fluid were assessed. Gene expression patterns in mouse lung samples were profiled by RNA-Seq. HDM exposure increased inflammation and inflammatory cytokines in BAL, baseline airway resistance, tissue elastance, and ASM mass. Vitamin D deficiency enhanced the HDM-induced influx of lymphocytes into BAL, ameliorated the HDM-induced increase in ASM mass, and protected against the HDM-induced increase in baseline airway resistance. RNA-Seq identified nine genes that were differentially regulated by vitamin D deficiency in the lungs of HDM-treated mice. Immunohistochemical staining confirmed that protein expression of midline 1 (MID1) and adrenomedullin was differentially regulated such that they promoted inflammation, while hypoxia-inducible lipid droplet-associated, which is associated with ASM remodeling, was downregulated. Protein expression studies in human bronchial epithelial cells also showed that addition of vitamin D decreased MID1 expression. Differential regulation of these genes by vitamin D deficiency could determine lung inflammation and pathophysiology and suggest that the effect of vitamin D deficiency on HDM-induced allergic airways disease is complex. Copyright © 2016 the American Physiological Society.

A mechanical design principle for tissue structure and function in the airway tree.

PubMed

LaPrad, Adam S; Lutchen, Kenneth R; Suki, Béla

2013-01-01

With every breath, the dynamically changing mechanical pressures must work in unison with the cells and soft tissue structures of the lung to permit air to efficiently traverse the airway tree and undergo gas exchange in the alveoli. The influence of mechanics on cell and tissue function is becoming apparent, raising the question: how does the airway tree co-exist within its mechanical environment to maintain normal cell function throughout its branching structure of diminishing dimensions? We introduce a new mechanical design principle for the conducting airway tree in which mechanotransduction at the level of cells is driven to orchestrate airway wall structural changes that can best maintain a preferred mechanical microenvironment. To support this principle, we report in vitro radius-transmural pressure relations for a range of airway radii obtained from healthy bovine lungs and model the data using a strain energy function together with a thick-walled cylinder description. From this framework, we estimate circumferential stresses and incremental Young's moduli throughout the airway tree. Our results indicate that the conducting airways consistently operate within a preferred mechanical homeostatic state, termed mechanical homeostasis, that is characterized by a narrow range of circumferential stresses and Young's moduli. This mechanical homeostatic state is maintained for all airways throughout the tree via airway wall dimensional and mechanical relationships. As a consequence, cells within the airway walls throughout the airway tree experience similar oscillatory strains during breathing that are much smaller than previously thought. Finally, we discuss the potential implications of how the maintenance of mechanical homeostasis, while facilitating healthy tissue-level alterations necessary for maturation, may lead to airway wall structural changes capable of chronic asthma.

A Mechanical Design Principle for Tissue Structure and Function in the Airway Tree

PubMed Central

LaPrad, Adam S.; Lutchen, Kenneth R.; Suki, Béla

2013-01-01

With every breath, the dynamically changing mechanical pressures must work in unison with the cells and soft tissue structures of the lung to permit air to efficiently traverse the airway tree and undergo gas exchange in the alveoli. The influence of mechanics on cell and tissue function is becoming apparent, raising the question: how does the airway tree co-exist within its mechanical environment to maintain normal cell function throughout its branching structure of diminishing dimensions? We introduce a new mechanical design principle for the conducting airway tree in which mechanotransduction at the level of cells is driven to orchestrate airway wall structural changes that can best maintain a preferred mechanical microenvironment. To support this principle, we report in vitro radius-transmural pressure relations for a range of airway radii obtained from healthy bovine lungs and model the data using a strain energy function together with a thick-walled cylinder description. From this framework, we estimate circumferential stresses and incremental Young's moduli throughout the airway tree. Our results indicate that the conducting airways consistently operate within a preferred mechanical homeostatic state, termed mechanical homeostasis, that is characterized by a narrow range of circumferential stresses and Young's moduli. This mechanical homeostatic state is maintained for all airways throughout the tree via airway wall dimensional and mechanical relationships. As a consequence, cells within the airway walls throughout the airway tree experience similar oscillatory strains during breathing that are much smaller than previously thought. Finally, we discuss the potential implications of how the maintenance of mechanical homeostasis, while facilitating healthy tissue-level alterations necessary for maturation, may lead to airway wall structural changes capable of chronic asthma. PMID:23737742

Recurrent milk aspiration produces changes in airway mechanics, lung eosinophilia, and goblet cell hyperplasia in a murine model.

PubMed

Janahi, I A; Elidemir, O; Shardonofsky, F R; Abu-Hassan, M N; Fan, L L; Larsen, G L; Blackburn, M R; Colasurdo, G N

2000-12-01

Recurrent aspiration of milk into the respiratory tract has been implicated in the pathogenesis of a variety of inflammatory lung disorders including asthma. However, the lack of animal models of aspiration-induced lung injury has limited our knowledge of the pathophysiological characteristics of this disorder. This study was designed to evaluate the effects of recurrent milk aspiration on airway mechanics and lung cells in a murine model. Under light anesthesia, BALB/c mice received daily intranasal instillations of whole cow's milk (n = 7) or sterile physiologic saline (n = 9) for 10 d. Respiratory system resistance (Rrs) and dynamic elastance (Edyn,rs) were measured in anesthetized, tracheotomized, paralyzed and mechanically ventilated mice 24 h after the last aspiration of milk. Rrs and Edyn,rs were derived from transrespiratory and plethysmographic pressure signals. In addition, airway responses to increasing concentrations of i.v. methacholine (Mch) were determined. Airway responses were measured in terms of PD(100) (dose of Mch causing 100% increase from baseline Rrs) and Rrs,max (% increase from baseline at the maximal plateau response) and expressed as % control (mean +/- SE). We found recurrent milk aspiration did not affect Edyn and baseline Rrs values. However, airway responses to Mch were increased after milk aspiration when compared with control mice. These changes in airway mechanics were associated with an increased percentage of lymphocytes and eosinophils in the bronchoalveolar lavage, mucus production, and lung inflammation. Our findings suggest that recurrent milk aspiration leads to alterations in airway function, lung eosinophilia, and goblet cell hyperplasia in a murine model.

The role of anaerobic bacteria in the cystic fibrosis airway.

PubMed

Sherrard, Laura J; Bell, Scott C; Tunney, Michael M

2016-11-01

Anaerobic bacteria are not only normal commensals, but are also considered opportunistic pathogens and have been identified as persistent members of the lower airway community in people with cystic fibrosis of all ages and stages of disease. Currently, the role of anaerobic bacteria in cystic fibrosis lower airway disease is not well understood. Therefore, this review describes the recent studies relating to the potential pathophysiological role(s) of anaerobes within the cystic fibrosis lungs. The most frequently identified anaerobic bacteria in the lower airways are common to both cystic fibrosis and healthy lungs. Studies have shown that in cystic fibrosis, the relative abundance of anaerobes fluctuates in the lower airways with reduced lung function and increased inflammation associated with a decreased anaerobic load. However, anaerobes found within the lower airways also produce virulence factors, may cause a host inflammatory response and interact synergistically with recognized pathogens. Anaerobic bacteria are potentially members of the airway microbiota in health but could also contribute to the pathogenesis of lower airway disease in cystic fibrosis via both direct and indirect mechanisms. A personalized treatment strategy that maintains a normal microbial community may be possible in the future.

Deleterious impact of hyperglycemia on cystic fibrosis airway ion transport and epithelial repair.

PubMed

Bilodeau, Claudia; Bardou, Olivier; Maillé, Émilie; Berthiaume, Yves; Brochiero, Emmanuelle

2016-01-01

Cystic fibrosis (CF)-related diabetes (CFRD) is associated with faster pulmonary function decline. Thus, we evaluated the impact of hyperglycemia on airway epithelial repair and transepithelial ion transport, which are critical in maintaining lung integrity and function. Non-CF and CF airway epithelial cells were exposed to low (LG) or high (HG) glucose before ion current and wound repair rate measurements. CFTR and K+ currents decreased after HG treatments. HG also reduced the wound healing rates of non-CF and CF cell monolayers. Although CFTR correction with VRT-325 accelerated the healing rates of CF cells monolayers under LG conditions, this improvement was significantly abrogated under HG conditions. Our data highlights a deleterious impact of hyperglycemia on ion transport and epithelial repair functions, which could contribute to the deterioration in lung function in CFRD patients. HG may also interfere with the beneficial effects of CFTR rescue on airway epithelial repair. Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Airway morphometry in the lungs as depicted in chest CT examinations variability of measurements

NASA Astrophysics Data System (ADS)

Leader, J. K.; Zheng, Bin; Scuirba, Frank C.; Coxson, Harvey O.; Weissfeld, Joel L.; Fuhrman, Carl R.; Maitz, Glenn S.; Gur, David

2006-03-01

The purpose of the study was to decrease the variability of computed tomographic airway measurements. We to developed and evaluated a novel computer scheme to automatically segment airways depicted on chest CT examinations at the level of the lobar and segmental bronchi and to decrease. The computer scheme begins with manual selection of a seed point within the airway from which the airway wall and lumen are automatically segmented and airway pixels were assigned full or partial membership to the lumen or wall. Airway pixels not assigned full membership to the lumen (< -900 HU) or wall (> 0 HU) were assigned partial membership to the lumen and wall. In fifteen subjects with no visible signs of emphysema and a range of pulmonary obstruction from none to severe, airway measures were compared to pulmonary function parameters in a rank order analysis to evaluate measuring a single airway versus multiple airways. The quality of the automated airway segmentation was visually acceptable. The Pearson Correlation coefficients for the ranking of FEV I versus wall area percent (percent of total airway size) and FVC versus wall area percent were 0.164 and 0.175 for a single measurement, respectively, and were 0.243 and 0.239 for multiple measurements, respectively. Our preliminary results suggest that averaging the measurements from multiple airways may improve the relation between airway measures and lung function compared to measurement from a single airway, which improve quantification of airway remodeling in COPD patients.

[K+ channels and lung epithelial physiology].

PubMed

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

2009-04-01

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

Revascularization of decellularized lung scaffolds: principles and progress

PubMed Central

Stabler, Collin T.; Lecht, Shimon; Mondrinos, Mark J.; Goulart, Ernesto; Lazarovici, Philip

2015-01-01

There is a clear unmet clinical need for novel biotechnology-based therapeutic approaches to lung repair and/or replacement, such as tissue engineering of whole bioengineered lungs. Recent studies have demonstrated the feasibility of decellularizing the whole organ by removal of all its cellular components, thus leaving behind the extracellular matrix as a complex three-dimensional (3D) biomimetic scaffold. Implantation of decellularized lung scaffolds (DLS), which were recellularized with patient-specific lung (progenitor) cells, is deemed the ultimate alternative to lung transplantation. Preclinical studies demonstrated that, upon implantation in rodent models, bioengineered lungs that were recellularized with airway and vascular cells were capable of gas exchange for up to 14 days. However, the long-term applicability of this concept is thwarted in part by the failure of current approaches to reconstruct a physiologically functional, quiescent endothelium lining the entire vascular tree of reseeded lung scaffolds, as inferred from the occurrence of hemorrhage into the airway compartment and thrombosis in the vasculature in vivo. In this review, we explore the idea that successful whole lung bioengineering will critically depend on 1) preserving and/or reestablishing the integrity of the subendothelial basement membrane, especially of the ultrathin respiratory membrane separating airways and capillaries, during and following decellularization and 2) restoring vascular physiological functionality including the barrier function and quiescence of the endothelial lining following reseeding of the vascular compartment. We posit that physiological reconstitution of the pulmonary vascular tree in its entirety will significantly promote the clinical translation of the next generation of bioengineered whole lungs. PMID:26408553

Total Airway Count on Computed Tomography and the Risk of Chronic Obstructive Pulmonary Disease Progression. Findings from a Population-based Study.

PubMed

Kirby, Miranda; Tanabe, Naoya; Tan, Wan C; Zhou, Guohai; Obeidat, Ma'en; Hague, Cameron J; Leipsic, Jonathon; Bourbeau, Jean; Sin, Don D; Hogg, James C; Coxson, Harvey O

2018-01-01

Studies of excised lungs show that significant airway attrition in the "quiet" zone occurs early in chronic obstructive pulmonary disease (COPD). To determine if the total number of airways quantified in vivo using computed tomography (CT) reflects early airway-related disease changes and is associated with lung function decline independent of emphysema in COPD. Participants in the multicenter, population-based, longitudinal CanCOLD (Canadian Chronic Obstructive Lung Disease) study underwent inspiratory/expiratory CT at visit 1; spirometry was performed at four visits over 6 years. Emphysema was quantified as the CT inspiratory low-attenuation areas below -950 Hounsfield units. CT total airway count (TAC) was measured as well as airway inner diameter and wall area using anatomically equivalent airways. Participants included never-smokers (n = 286), smokers with normal spirometry at risk for COPD (n = 298), Global Initiative for Chronic Obstructive Lung Disease (GOLD) I COPD (n = 361), and GOLD II COPD (n = 239). TAC was significantly reduced by 19% in both GOLD I and GOLD II compared with never-smokers (P < 0.0001) and by 17% in both GOLD I and GOLD II compared with at-risk participants (P < 0.0001) after adjusting for low-attenuation areas below -950 Hounsfield units. Further analysis revealed parent airways with missing daughter branches had reduced inner diameters (P < 0.0001) and thinner walls (P < 0.0001) compared with those without missing daughter branches. Among all CT measures, TAC had the greatest influence on FEV 1 (P < 0.0001), FEV 1 /FVC (P < 0.0001), and bronchodilator responsiveness (P < 0.0001). TAC was independently associated with lung function decline (FEV 1 , P = 0.02; FEV 1 /FVC, P = 0.01). TAC may reflect the airway-related disease changes that accumulate in the "quiet" zone in early/mild COPD, indicating that TAC acquired with commercially available software across various CT platforms may be a biomarker to predict accelerated COPD progression.

Cryopreserved Human Precision-Cut Lung Slices as a Bioassay for Live Tissue Banking. A Viability Study of Bronchodilation with Bitter-Taste Receptor Agonists

PubMed Central

Bai, Yan; Krishnamoorthy, Nandini; Patel, Kruti R.; Rosas, Ivan; Ai, Xingbin

2016-01-01

Human precision-cut lung slices (hPCLSs) provide a unique ex vivo model for translational research. However, the limited and unpredictable availability of human lung tissue greatly impedes their use. Here, we demonstrate that cryopreservation of hPCLSs facilitates banking of live human lung tissue for routine use. Our results show that cryopreservation had little effect on overall cell viability and vital functions of immune cells, including phagocytes and T lymphocytes. In addition, airway contraction and relaxation in response to specific agonists and antagonists, respectively, were unchanged after cryopreservation. At the subcellular level, cryopreserved hPCLSs maintained Ca2+-dependent regulatory mechanisms for the control of airway smooth muscle cell contractility. To exemplify the use of cryopreserved hPCLSs in smooth muscle research, we provide evidence that bitter-taste receptor (TAS2R) agonists relax airways by blocking Ca2+ oscillations in airway smooth muscle cells. In conclusion, the banking of cryopreserved hPCLSs provides a robust bioassay for translational research of lung physiology and disease. PMID:26550921

Cryopreserved Human Precision-Cut Lung Slices as a Bioassay for Live Tissue Banking. A Viability Study of Bronchodilation with Bitter-Taste Receptor Agonists.

PubMed

Bai, Yan; Krishnamoorthy, Nandini; Patel, Kruti R; Rosas, Ivan; Sanderson, Michael J; Ai, Xingbin

2016-05-01

Human precision-cut lung slices (hPCLSs) provide a unique ex vivo model for translational research. However, the limited and unpredictable availability of human lung tissue greatly impedes their use. Here, we demonstrate that cryopreservation of hPCLSs facilitates banking of live human lung tissue for routine use. Our results show that cryopreservation had little effect on overall cell viability and vital functions of immune cells, including phagocytes and T lymphocytes. In addition, airway contraction and relaxation in response to specific agonists and antagonists, respectively, were unchanged after cryopreservation. At the subcellular level, cryopreserved hPCLSs maintained Ca(2+)-dependent regulatory mechanisms for the control of airway smooth muscle cell contractility. To exemplify the use of cryopreserved hPCLSs in smooth muscle research, we provide evidence that bitter-taste receptor (TAS2R) agonists relax airways by blocking Ca(2+) oscillations in airway smooth muscle cells. In conclusion, the banking of cryopreserved hPCLSs provides a robust bioassay for translational research of lung physiology and disease.

Childhood-Onset Asthma in Smokers. Association between CT Measures of Airway Size, Lung Function, and Chronic Airflow Obstruction

PubMed Central

Hardin, Megan E.; Come, Carolyn E.; San José Estépar, Raúl; Ross, James C.; Kurugol, Sila; Okajima, Yuka; Han, MeiLan K.; Kim, Victor; Ramsdell, Joe; Silverman, Edwin K.; Crapo, James D.; Lynch, David A.; Make, Barry; Barr, R. Graham; Hersh, Craig P.; Washko, George R.

2014-01-01

Rationale and Objectives: Asthma is associated with chronic airflow obstruction. Our goal was to assess the association of computed tomographic measures of airway wall volume and lumen volume with the FEV1 and chronic airflow obstruction in smokers with childhood-onset asthma. Methods: We analyzed clinical, lung function, and volumetric computed tomographic airway volume data from 7,266 smokers, including 590 with childhood-onset asthma. Small wall volume and small lumen volume of segmental airways were defined as measures 1 SD below the mean. We assessed the association between small wall volume, small lumen volume, FEV1, and chronic airflow obstruction (post-bronchodilator FEV1/FVC ratio < 0.7) using linear and logistic models. Measurements and Main Results: Compared with subjects without childhood-onset asthma, those with childhood-onset asthma had smaller wall volume and lumen volume (P < 0.0001) of segmental airways. Among subjects with childhood-onset asthma, those with the smallest wall volume and lumen volume had the lowest FEV1 and greatest odds of chronic airflow obstruction. A similar tendency was seen in those without childhood-onset asthma. When comparing these two groups, both small wall volume and small lumen volume were more strongly associated with FEV1 and chronic airflow obstruction among subjects with childhood-asthma in multivariate models. Conclusion: In smokers with childhood-onset asthma, smaller airways are associated with reduced lung function and chronic airflow obstruction. Clinical trial registered with www.clinicaltrials.gov (NCT00608764). PMID:25296268

Childhood-onset asthma in smokers. association between CT measures of airway size, lung function, and chronic airflow obstruction.

PubMed

Diaz, Alejandro A; Hardin, Megan E; Come, Carolyn E; San José Estépar, Raúl; Ross, James C; Kurugol, Sila; Okajima, Yuka; Han, MeiLan K; Kim, Victor; Ramsdell, Joe; Silverman, Edwin K; Crapo, James D; Lynch, David A; Make, Barry; Barr, R Graham; Hersh, Craig P; Washko, George R

2014-11-01

Asthma is associated with chronic airflow obstruction. Our goal was to assess the association of computed tomographic measures of airway wall volume and lumen volume with the FEV1 and chronic airflow obstruction in smokers with childhood-onset asthma. We analyzed clinical, lung function, and volumetric computed tomographic airway volume data from 7,266 smokers, including 590 with childhood-onset asthma. Small wall volume and small lumen volume of segmental airways were defined as measures 1 SD below the mean. We assessed the association between small wall volume, small lumen volume, FEV1, and chronic airflow obstruction (post-bronchodilator FEV1/FVC ratio < 0.7) using linear and logistic models. Compared with subjects without childhood-onset asthma, those with childhood-onset asthma had smaller wall volume and lumen volume (P < 0.0001) of segmental airways. Among subjects with childhood-onset asthma, those with the smallest wall volume and lumen volume had the lowest FEV1 and greatest odds of chronic airflow obstruction. A similar tendency was seen in those without childhood-onset asthma. When comparing these two groups, both small wall volume and small lumen volume were more strongly associated with FEV1 and chronic airflow obstruction among subjects with childhood-asthma in multivariate models. In smokers with childhood-onset asthma, smaller airways are associated with reduced lung function and chronic airflow obstruction. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

Role of collateral paths in long-range diffusion in lungs

PubMed Central

Bartel, Seth-Emil T.; Haywood, Susan E.; Woods, Jason C.; Chang, Yulin V.; Menard, Christopher; Yablonskiy, Dmitriy A.; Gierada, David S.; Conradi, Mark S.

2010-01-01

The long-range apparent diffusion coefficient (LRADC) of 3He gas in lungs, measured over times of several seconds and distances of 1–3 cm, probes the connections between the airways. Previous work has shown the LRADC to be small in health and substantially elevated in emphysema, reflecting tissue destruction, which is known to create collateral pathways. To better understand what controls LRADC, we report computer simulations and measurements of 3He gas diffusion in healthy lungs. The lung is generated with a random algorithm using well-defined rules, yielding a three-dimensional set of nodes or junctions, each connected by airways to one parent node and two daughters; airway dimensions are taken from published values. Spin magnetization in the simulated lung is modulated sinusoidally, and the diffusion equation is solved to 1,000 s. The modulated magnetization decays with a time constant corresponding to an LRADC of ~0.001 cm2/s, which is smaller by a factor of ~20 than the values in healthy lungs measured here and previously in vivo and in explanted lungs. It appears that collateral gas pathways, not present in the simulations, are functional in healthy lungs; they provide additional and more direct routes for long-range motion than the canonical airway tree. This is surprising, inasmuch as collateral ventilation is believed to be physiologically insignificant in healthy lungs. We discuss the effect on LRADC of small collateral connections through airway walls and rule out other possible mechanisms. The role of collateral paths is supported by measurements of smaller LRADC in pigs, where collateral ventilation is known to be smaller. PMID:18292298

Aging effects on airflow dynamics and lung function in human bronchioles.

PubMed

Kim, JongWon; Heise, Rebecca L; Reynolds, Angela M; Pidaparti, Ramana M

2017-01-01

The mortality rate for patients requiring mechanical ventilation is about 35% and this rate increases to about 53% for the elderly. In general, with increasing age, the dynamic lung function and respiratory mechanics are compromised, and several experiments are being conducted to estimate these changes and understand the underlying mechanisms to better treat elderly patients. Human tracheobronchial (G1 ~ G9), bronchioles (G10 ~ G22) and alveolar sacs (G23) geometric models were developed based on reported anatomical dimensions for a 50 and an 80-year-old subject. The aged model was developed by altering the geometry and material properties of the model developed for the 50-year-old. Computational simulations using coupled fluid-solid analysis were performed for geometric models of bronchioles and alveolar sacs under mechanical ventilation to estimate the airflow and lung function characteristics. The airway mechanical characteristics decreased with aging, specifically a 38% pressure drop was observed for the 80-year-old as compared to the 50-year-old. The shear stress on airway walls increased with aging and the highest shear stress was observed in the 80-year-old during inhalation. A 50% increase in peak strain was observed for the 80-year-old as compared to the 50-year-old during exhalation. The simulation results indicate that there is a 41% increase in lung compliance and a 35%-50% change in airway mechanical characteristics for the 80-year-old in comparison to the 50-year-old. Overall, the airway mechanical characteristics as well as lung function are compromised due to aging. Our study demonstrates and quantifies the effects of aging on the airflow dynamics and lung capacity. These changes in the aging lung are important considerations for mechanical ventilation parameters in elderly patients. Realistic geometry and material properties need to be included in the computational models in future studies.

Aging effects on airflow dynamics and lung function in human bronchioles

PubMed Central

Kim, JongWon; Heise, Rebecca L.; Reynolds, Angela M.; Pidaparti, Ramana M.

2017-01-01

Background and objective The mortality rate for patients requiring mechanical ventilation is about 35% and this rate increases to about 53% for the elderly. In general, with increasing age, the dynamic lung function and respiratory mechanics are compromised, and several experiments are being conducted to estimate these changes and understand the underlying mechanisms to better treat elderly patients. Materials and methods Human tracheobronchial (G1 ~ G9), bronchioles (G10 ~ G22) and alveolar sacs (G23) geometric models were developed based on reported anatomical dimensions for a 50 and an 80-year-old subject. The aged model was developed by altering the geometry and material properties of the model developed for the 50-year-old. Computational simulations using coupled fluid-solid analysis were performed for geometric models of bronchioles and alveolar sacs under mechanical ventilation to estimate the airflow and lung function characteristics. Findings The airway mechanical characteristics decreased with aging, specifically a 38% pressure drop was observed for the 80-year-old as compared to the 50-year-old. The shear stress on airway walls increased with aging and the highest shear stress was observed in the 80-year-old during inhalation. A 50% increase in peak strain was observed for the 80-year-old as compared to the 50-year-old during exhalation. The simulation results indicate that there is a 41% increase in lung compliance and a 35%-50% change in airway mechanical characteristics for the 80-year-old in comparison to the 50-year-old. Overall, the airway mechanical characteristics as well as lung function are compromised due to aging. Conclusion Our study demonstrates and quantifies the effects of aging on the airflow dynamics and lung capacity. These changes in the aging lung are important considerations for mechanical ventilation parameters in elderly patients. Realistic geometry and material properties need to be included in the computational models in future studies. PMID:28846719

IFN-λ prevents influenza virus spread from the upper airways to the lungs and limits virus transmission

PubMed Central

Ye, Liang; Schwaderlapp, Marilena; Gad, Hans Henrik; Hartmann, Rune; Garcin, Dominique; Mahlakõiv, Tanel

2018-01-01

Host factors restricting the transmission of respiratory viruses are poorly characterized. We analyzed the contribution of type I and type III interferon (IFN) using a mouse model in which the virus is selectively administered to the upper airways, mimicking a natural respiratory virus infection. Mice lacking functional IFN-λ receptors (Ifnlr1−/−) no longer restricted virus dissemination from the upper airways to the lungs. Ifnlr1−/− mice shed significantly more infectious virus particles via the nostrils and transmitted the virus much more efficiently to naïve contacts compared with wild-type mice or mice lacking functional type I IFN receptors. Prophylactic treatment with IFN-α or IFN-λ inhibited initial virus replication in all parts of the respiratory tract, but only IFN-λ conferred long-lasting antiviral protection in the upper airways and blocked virus transmission. Thus, IFN-λ has a decisive and non-redundant function in the upper airways that greatly limits transmission of respiratory viruses to naïve contacts. PMID:29651984

Mammalian short palate lung and nasal epithelial clone 1 (SPLUNC1) in pH-dependent airway hydration✩

PubMed Central

Tarran, Robert; Redinbo, Matthew R.

2014-01-01

The epithelia that line the conducting airways are the lung’s first point of contact with inhaled pathogens and toxicants. As such, they are known to play an important role in the lung’s innate defense system, which includes (i) the production of airway surface liquid (ASL) that helps cleanse the airways through the physical removal of pathogens and toxicants on the mucociliary escalator and (ii) the secretion of anti-microbial proteins into the ASL to kill inhaled pathogens. Interestingly, the recently crystallized short palate lung and nasal epithelial clone 1 (SPLUNC1) protein appears to be a multi-functional protein. That is, it not only acts as an anti-microbial agent, but also modulates ASL homeostasis by acting as an endogenous inhibitor of the epithelial Na+ channel (ENaC). This review will focus on the latter function of SPLUNC1, and will discuss new structural and physiological data regarding SPLUNC1’s failure to function as a regulator of ASL hydration in CF airways. PMID:24631954

Prognostic Significance of Large Airway Dimensions on Computed Tomography in the General Population. The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study.

PubMed

Oelsner, Elizabeth C; Smith, Benjamin M; Hoffman, Eric A; Kalhan, Ravi; Donohue, Kathleen M; Kaufman, Joel D; Nguyen, Jennifer N; Manichaikul, Ani W; Rotter, Jerome I; Michos, Erin D; Jacobs, David R; Burke, Gregory L; Folsom, Aaron R; Schwartz, Joseph E; Watson, Karol; Barr, R Graham

2018-06-01

Large airway dimensions on computed tomography (CT) have been associated with lung function, symptoms, and exacerbations in chronic obstructive pulmonary disease (COPD), as well as with symptoms in smokers with preserved spirometry. Their prognostic significance in persons without lung disease remains undefined. To examine associations between large airway dimensions on CT and respiratory outcomes in a population-based cohort of adults without prevalent lung disease. The Multi-Ethnic Study of Atherosclerosis recruited participants ages 45-84 years without cardiovascular disease in 2000-2002; we excluded participants with prevalent chronic lower respiratory disease (CLRD). Spirometry was measured in 2004-2006 and 2010-2012. CLRD hospitalizations and deaths were classified by validated criteria through 2014. The average wall thickness for a hypothetical airway of 10-mm lumen perimeter on CT (Pi10) was calculated using measures of airway wall thickness and lumen diameter. Models were adjusted for age, sex, principal components of ancestry, body mass index, smoking, pack-years, scanner, percent emphysema, genetic risk score, and initial forced expiratory volume in 1 second (FEV 1 ) percent predicted. Greater Pi10 was associated with 9% faster FEV 1 decline (95% confidence interval [CI], 2 to 15%; P = 0.012) and increased incident COPD (odds ratio, 2.22; 95% CI, 1.43-3.45; P = 0.0004) per standard deviation among 1,830 participants. Over 78,147 person-years, higher Pi10 was associated with a 57% higher risk of first CLRD hospitalization or mortality (P = 0.0496) per standard deviation. Of Pi10's component measures, both greater airway wall thickness and narrower lumen predicted incident COPD and CLRD clinical events. In adults without CLRD, large airway dimensions on CT were prospectively associated with accelerated lung function decline and increased risks of COPD and CLRD hospitalization and mortality.

Persistent effects of chlorine inhalation on respiratory health

PubMed Central

Hoyle, Gary W.; Svendsen, Erik R.

2016-01-01

Chlorine gas is a toxic respiratory irritant that is considered a chemical threat agent because of the potential for release in industrial accidents or terrorist attacks. Chlorine inhalation damages the respiratory tract, including the airways and distal lung, and can result in acute lung injury. Some individuals exposed to chlorine experience a full recovery from acute injury, whereas others develop persistent adverse effects, such as respiratory symptoms, inflammation, and lung-function decrements. In animal models, chlorine can produce persistent inflammation, remodeling, and obstruction in large or small airways, depending on species. Airways with pseudostratified epithelium are repaired efficiently, with surviving basal epithelial cells serving as progenitor cells that repopulate the complement of differentiated cell types. Distal airways lacking basal cells are repaired less efficiently, leading to chronic inflammation and fibrosis at these sites. Persistent chlorine-induced airway disease in humans is treated with asthma medication to relieve symptoms. However, such treatment does not ameliorate the underlying disease pathogenesis, so treatments that are more effective at preventing initial development of airway disease after irritant gas exposure and at reversing established disease are needed. PMID:27385061

A Different Microbiome Gene Repertoire in the Airways of Cystic Fibrosis Patients with Severe Lung Disease

PubMed Central

Bacci, Giovanni; Fiscarelli, Ersilia; Taccetti, Giovanni; Dolce, Daniela; Paganin, Patrizia; Morelli, Patrizia; Tuccio, Vanessa; De Alessandri, Alessandra; Lucidi, Vincenzina

2017-01-01

In recent years, next-generation sequencing (NGS) was employed to decipher the structure and composition of the microbiota of the airways in cystic fibrosis (CF) patients. However, little is still known about the overall gene functions harbored by the resident microbial populations and which specific genes are associated with various stages of CF lung disease. In the present study, we aimed to identify the microbial gene repertoire of CF microbiota in twelve patients with severe and normal/mild lung disease by performing sputum shotgun metagenome sequencing. The abundance of metabolic pathways encoded by microbes inhabiting CF airways was reconstructed from the metagenome. We identified a set of metabolic pathways differently distributed in patients with different pulmonary function; namely, pathways related to bacterial chemotaxis and flagellar assembly, as well as genes encoding efflux-mediated antibiotic resistance mechanisms and virulence-related genes. The results indicated that the microbiome of CF patients with low pulmonary function is enriched in virulence-related genes and in genes encoding efflux-mediated antibiotic resistance mechanisms. Overall, the microbiome of severely affected adults with CF seems to encode different mechanisms for the facilitation of microbial colonization and persistence in the lung, consistent with the characteristics of multidrug-resistant microbial communities that are commonly observed in patients with severe lung disease. PMID:28758937

Design of a numerical model of lung by means of a special boundary condition in the truncated branches.

PubMed

Tena, Ana F; Fernández, Joaquín; Álvarez, Eduardo; Casan, Pere; Walters, D Keith

2017-06-01

The need for a better understanding of pulmonary diseases has led to increased interest in the development of realistic computational models of the human lung. To minimize computational cost, a reduced geometry model is used for a model lung airway geometry up to generation 16. Truncated airway branches require physiologically realistic boundary conditions to accurately represent the effect of the removed airway sections. A user-defined function has been developed, which applies velocities mapped from similar locations in fully resolved airway sections. The methodology can be applied in any general purpose computational fluid dynamics code, with the only limitation that the lung model must be symmetrical in each truncated branch. Unsteady simulations have been performed to verify the operation of the model. The test case simulates a spirometry because the lung is obliged to rapidly perform both inspiration and expiration. Once the simulation was completed, the obtained pressure in the lower level of the lung was used as a boundary condition. The output velocity, which is a numerical spirometry, was compared with the experimental spirometry for validation purposes. This model can be applied for a wide range of patient-specific resolution levels. If the upper airway generations have been constructed from a computed tomography scan, it would be possible to quickly obtain a complete reconstruction of the lung specific to a specific person, which would allow individualized therapies. Copyright © 2016 John Wiley & Sons, Ltd.

CPAP of 4 cm H(2)O Has no short-term benefit at term in infants with BPD.

PubMed

Sandberg, Kenneth L; Hjalmarson, Ola

2012-01-01

Lung development and function is compromised at term in infants with bronchopulmonary dysplasia (BPD), characterized by reduced functional residual capacity (FRC) and impaired gas-mixing efficiency in distal airways. To determine whether continuous positive airway pressure (CPAP) improves FRC, ventilation, distal airway function, and gas exchange in spontaneously breathing infants with BPD. Twenty-one infants with BPD (median birth weight 0.72 kg (range 0.50-1.27) and median gestational age 26 weeks (range 23-28)) were studied before and after CPAP of 4 cm H(2)O was applied by a facemask system. A multiple-breath nitrogen washout method was used to assess FRC, ventilation, and gas-mixing efficiency. Moment analysis and lung clearance index was calculated from the nitrogen-decay curve for assessment of gas-mixing efficiency. Transcutaneous (Tc) PO(2)/PCO(2) was monitored during stable infant conditions before each washout test. When CPAP was raised from 0 to 4 cm H(2)O, FRC increased significantly together with a significant increase in moment ratios (M(1)/M(0) and M(2)/M(0)). Tc PO(2) decreased significantly and the breathing pattern changed, with significantly reduced respiratory rate, minute ventilation, and alveolar ventilation. There was also an increase in tidal volume and dead space. CPAP of 4 cm H(2)O applied with a facemask at term to infants with BPD did not improve ventilation, gas-mixing efficiency in distal airways, or oxygenation despite an increase in FRC. We speculate that instead of promoting recruitment of unventilated lung volumes, increasing the end-expiratory pressure in infants with BPD may lead to an overexpansion of already ventilated parts of the lung, causing further compromise of lung function. Copyright © 2012 S. Karger AG, Basel.

Smooth muscle in human bronchi is disposed to resist airway distension.

PubMed

Gazzola, Morgan; Henry, Cyndi; Couture, Christian; Marsolais, David; King, Gregory G; Fredberg, Jeffrey J; Bossé, Ynuk

2016-07-15

Studying airway smooth muscle (ASM) in conditions that emulate the in vivo environment within which the bronchi normally operate may provide important clues regarding its elusive physiological function. The present study examines the effect of lengthening and shortening of ASM on tension development in human bronchial segments. ASM from each bronchial segment was set at a length approximating in situ length (Linsitu). Bronchial tension was then measured during a slow cyclical strain (0.004Hz, from 0.7Linsitu to 1.3Linsitu) in the relaxed state and at graded levels of activation by methacholine. In all cases, tension was greater at longer ASM lengths, and greater during lengthening than shortening. The threshold of methacholine concentration that was required for ASM to account for bronchial tension across the entire range of ASM lengths tested was on average smaller by 2.8 logs during lengthening than during shortening. The length-dependency of ASM tension, together with this lower threshold of methacholine concentration during lengthening versus shortening, suggest that ASM has a greater ability to resist airway dilation during lung inflation than to narrow the airways during lung deflation. More than serving to narrow the airway, as has long been thought, these data suggest that the main function of ASM contraction is to limit airway wall distension during lung inflation. Copyright © 2016 Elsevier B.V. All rights reserved.

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

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

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

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

The effect of methacholine-induced acute airway narrowing on lung sounds in normal and asthmatic subjects.

PubMed

Schreur, H J; Vanderschoot, J; Zwinderman, A H; Dijkman, J H; Sterk, P J

1995-02-01

The association between lung sound alterations and airways obstruction has long been recognized in clinical practice, but the precise pathophysiological mechanisms of this relationship have not been determined. Therefore, we examined the changes in lung sounds at well-defined levels of methacholine-induced airway narrowing in eight normal and nine asthmatic subjects with normal baseline lung function. All subjects underwent phonopneumography at baseline condition and at > or = 20% fall in forced expiratory volume in one second (FEV1), and in asthmatic subjects also at > or = 40% fall in FEV1. Lung sounds were recorded at three locations on the chest wall during standardized quiet breathing, and during maximal forced breathing. Airflow-dependent power spectra were computed using fast Fourier transform. For each spectrum, we determined the intensity and frequency content of lung sounds, together with the extent of wheezing. The results were analysed using analysis of variance (ANOVA). During acute airway narrowing, the intensity and frequency content of the recorded sounds, as well as the extent of wheezing, were higher than at baseline in both groups of subjects. At similar levels of obstruction, both the pitch and the change in sound intensity with airflow were higher in asthmatics than in normal subjects. Wheezing, being nondiscriminative between the subject groups at baseline, was more prominent in asthmatics than in normal subjects at 20% fall in FEV1. We conclude that, at given levels of acute airway narrowing, lung sounds differ between asthmatics and normal subjects. This suggests that airflow-standardized phonopneumography is a sensitive method for detecting abnormalities in airway dynamics in asthma.(ABSTRACT TRUNCATED AT 250 WORDS)

Mast cells in airway diseases and interstitial lung disease.

PubMed

Cruse, Glenn; Bradding, Peter

2016-05-05

Mast cells are major effector cells of inflammation and there is strong evidence that mast cells play a significant role in asthma pathophysiology. There is also a growing body of evidence that mast cells contribute to other inflammatory and fibrotic lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. This review discusses the role that mast cells play in airway diseases and highlights how mast cell microlocalisation within specific lung compartments and their cellular interactions are likely to be critical for their effector function in disease. Published by Elsevier B.V.

Small Airway Dysfunction and Abnormal Exercise Responses

PubMed Central

Petsonk, Edward L.; Stansbury, Robert C.; Beeckman-Wagner, Lu-Ann; Long, Joshua L.; Wang, Mei Lin

2016-01-01

Rationale Coal mine dust exposure can cause symptoms and loss of lung function from multiple mechanisms, but the roles of each disease process are not fully understood. Objectives We investigated the implications of small airway dysfunction for exercise physiology among a group of workers exposed to coal mine dust. Methods Twenty coal miners performed spirometry, first breathing air and then helium-oxygen, single-breath diffusing capacity, and computerized chest tomography, and then completed cardiopulmonary exercise testing. Measurements and Main Results Six participants meeting criteria for small airway dysfunction were compared with 14 coal miners who did not. At submaximal workload, miners with small airway dysfunction used a higher proportion of their maximum voluntary ventilation and had higher ventilatory equivalents for both O2 and CO2. Regression modeling indicated that inefficient ventilation was significantly related to small airway dysfunction but not to FEV1 or diffusing capacity. At the end of exercise, miners with small airway dysfunction had 27% lower O2 consumption. Conclusions Small airway abnormalities may be associated with important inefficiency of exercise ventilation. In dust-exposed individuals with only mild abnormalities on resting lung function tests or chest radiographs, cardiopulmonary exercise testing may be important in defining causes of exercise intolerance. PMID:27073987

Airway pressure release ventilation during ex vivo lung perfusion attenuates injury.

PubMed

Mehaffey, J Hunter; Charles, Eric J; Sharma, Ashish K; Money, Dustin T; Zhao, Yunge; Stoler, Mark H; Lau, Christine L; Tribble, Curtis G; Laubach, Victor E; Roeser, Mark E; Kron, Irving L

2017-01-01

Critical organ shortages have resulted in ex vivo lung perfusion gaining clinical acceptance for lung evaluation and rehabilitation to expand the use of donation after circulatory death organs for lung transplantation. We hypothesized that an innovative use of airway pressure release ventilation during ex vivo lung perfusion improves lung function after transplantation. Two groups (n = 4 animals/group) of porcine donation after circulatory death donor lungs were procured after hypoxic cardiac arrest and a 2-hour period of warm ischemia, followed by a 4-hour period of ex vivo lung perfusion rehabilitation with standard conventional volume-based ventilation or pressure-based airway pressure release ventilation. Left lungs were subsequently transplanted into recipient animals and reperfused for 4 hours. Blood gases for partial pressure of oxygen/inspired oxygen fraction ratios, airway pressures for calculation of compliance, and percent wet weight gain during ex vivo lung perfusion and reperfusion were measured. Airway pressure release ventilation during ex vivo lung perfusion significantly improved left lung oxygenation at 2 hours (561.5 ± 83.9 mm Hg vs 341.1 ± 136.1 mm Hg) and 4 hours (569.1 ± 18.3 mm Hg vs 463.5 ± 78.4 mm Hg). Likewise, compliance was significantly higher at 2 hours (26.0 ± 5.2 mL/cm H 2 O vs 15.0 ± 4.6 mL/cm H 2 O) and 4 hours (30.6 ± 1.3 mL/cm H 2 O vs 17.7 ± 5.9 mL/cm H 2 O) after transplantation. Finally, airway pressure release ventilation significantly reduced lung edema development on ex vivo lung perfusion on the basis of percentage of weight gain (36.9% ± 14.6% vs 73.9% ± 4.9%). There was no difference in additional edema accumulation 4 hours after reperfusion. Pressure-directed airway pressure release ventilation strategy during ex vivo lung perfusion improves the rehabilitation of severely injured donation after circulatory death lungs. After transplant, these lungs demonstrate superior lung-specific oxygenation and dynamic compliance compared with lungs ventilated with standard conventional ventilation. This strategy, if implemented into clinical ex vivo lung perfusion protocols, could advance the field of donation after circulatory death lung rehabilitation to expand the lung donor pool. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Matrix metalloproteinases and airway remodeling and function in primary ciliary dyskinesia.

PubMed

Pifferi, Massimo; Bush, Andrew; Caramella, Davide; Metelli, Maria Rita; Di Cicco, Maria; Piras, Martina; Gherarducci, Giulia; Capristo, Carlo; Maggi, Fabrizio; Peroni, Diego; Boner, Attilio L

2017-03-01

The balance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) is important in the regulation of airway damage. To evaluate whether they are important in the pathophysiology of primary and secondary ciliary dyskinesia (PCD, SCD). We measured sputum bacteriology, lung CT changes, MMPs, TIMPs and lung function in 86 patients (51 PCD, 35 SCD) in a cross-sectional study; the 10 controls studied did not have HRCT or sputum cultures. MMPs, TIMPs and lung function were evaluated longitudinally for up to one year in 38 PCD patients. At baseline, there were no differences in MMPs, TIMPs and MMPs/TIMPs, between PCD and SCD but lower levels were found in controls. There was an association between poorer lung function with increasing levels of MMPs in PCD, while in SCD only MMP-9/TIMP-1 values correlated with FRC z-scores. Levels of MMPs and TIMPs significantly correlated with severity HRCT changes. Longitudinally, there were significant correlations between slope of changes in spirometric parameters and slope of change in sputum MMPs in PCD patients. In conclusion, we report for the first time that increased MMPs are associated with worse airway damage in PCD and SCD, and thus are potential therapeutic targets. Copyright © 2017 Elsevier Ltd. All rights reserved.

Computer-aided pulmonary image analysis in small animal models

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

Xu, Ziyue; Mansoor, Awais; Mollura, Daniel J.

Purpose: To develop an automated pulmonary image analysis framework for infectious lung diseases in small animal models. Methods: The authors describe a novel pathological lung and airway segmentation method for small animals. The proposed framework includes identification of abnormal imaging patterns pertaining to infectious lung diseases. First, the authors’ system estimates an expected lung volume by utilizing a regression function between total lung capacity and approximated rib cage volume. A significant difference between the expected lung volume and the initial lung segmentation indicates the presence of severe pathology, and invokes a machine learning based abnormal imaging pattern detection system next.more » The final stage of the proposed framework is the automatic extraction of airway tree for which new affinity relationships within the fuzzy connectedness image segmentation framework are proposed by combining Hessian and gray-scale morphological reconstruction filters. Results: 133 CT scans were collected from four different studies encompassing a wide spectrum of pulmonary abnormalities pertaining to two commonly used small animal models (ferret and rabbit). Sensitivity and specificity were greater than 90% for pathological lung segmentation (average dice similarity coefficient > 0.9). While qualitative visual assessments of airway tree extraction were performed by the participating expert radiologists, for quantitative evaluation the authors validated the proposed airway extraction method by using publicly available EXACT’09 data set. Conclusions: The authors developed a comprehensive computer-aided pulmonary image analysis framework for preclinical research applications. The proposed framework consists of automatic pathological lung segmentation and accurate airway tree extraction. The framework has high sensitivity and specificity; therefore, it can contribute advances in preclinical research in pulmonary diseases.« less

Functional Invariant NKT Cells in Pig Lungs Regulate the Airway Hyperreactivity: A Potential Animal Model

PubMed Central

Manickam, Cordelia; Khatri, Mahesh; Rauf, Abdul; Li, Xiangming; Tsuji, Moriya; Rajashekara, Gireesh; Dwivedi, Varun

2015-01-01

Important roles played by invariant natural killer T (iNKT) cells in asthma pathogenesis have been demonstrated. We identified functional iNKT cells and CD1d molecules in pig lungs. Pig iNKT cells cultured in the presence of α-GalCer proliferated and secreted Th1 and Th2 cytokines. Like in other animal models, direct activation of pig lung iNKT cells using α-GalCer resulted in acute airway hyperreactivity (AHR). Clinically, acute AHR-induced pigs had increased respiratory rate, enhanced mucus secretion in the airways, fever, etc. In addition, we observed petechial hemorrhages, infiltration of CD4+ cells, and increased Th2 cytokines in AHR-induced pig lungs. Ex vivo proliferated iNKT cells of asthma induced pigs in the presence of C-glycoside analogs of α-GalCer had predominant Th2 phenotype and secreted more of Th2 cytokine, IL-4. Thus, baby pigs may serve as a useful animal model to study iNKT cell-mediated AHR caused by various environmental and microbial CD1d-specific glycolipid antigens. PMID:21042929

Defective parasympathetic innervation is associated with airway branching abnormalities in experimental CDH

PubMed Central

Rhodes, Julie; Saxena, Deeksha; Zhang, GuangFeng; Gittes, George K.

2015-01-01

Developmental mechanisms leading to lung hypoplasia in congenital diaphragmatic hernia (CDH) remain poorly defined. Pulmonary innervation is defective in the human disease and in the rodent models of CDH. We hypothesize that defective parasympathetic innervation may contribute to airway branching abnormalities and, therefore, lung hypoplasia, during lung development in CDH. The murine nitrofen model of CDH was utilized to study the effect of the cholinergic agonist carbachol on embryonic day 11.5 (E11.5) lung explant cultures. Airway branching and contractions were quantified. In a subset of experiments, verapamil was added to inhibit airway contractions. Sox9 immunostaining and 5-bromo-2-deoxyuridine incorporation were used to identify and quantify the number and proliferation of distal airway epithelial progenitor cells. Intra-amniotic injections were used to determine the in vivo effect of carbachol. Airway branching and airway contractions were significantly decreased in nitrofen-treated lungs compared with controls. Carbachol resulted in increased airway contractions and branching in nitrofen-treated lungs. Nitrofen-treated lungs exhibited an increased number of proliferating Sox9-positive distal epithelial progenitor cells, which were decreased and normalized by treatment with carbachol. Verapamil inhibited the carbachol-induced airway contractions in nitrofen-treated lungs but had no effect on the carbachol-induced increase in airway branching, suggesting a direct carbachol effect independent of airway contractions. In vivo treatment of nitrofen-treated embryos via amniotic injection of carbachol at E10.5 resulted in modest increases in lung size and branching at E17.5. These results suggest that defective parasympathetic innervation may contribute to airway branching abnormalities in CDH. PMID:25934671

In utero and postnatal exposure to arsenic alters pulmonary structure and function

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

Lantz, R. Clark; Southwest Environmental Health Science Center, University of Arizona, Tucson, AZ 85721; BIO5 Institute, University of Arizona, Tucson, AZ 85721

2009-02-15

In addition to cancer endpoints, arsenic exposures can also lead to non-cancerous chronic lung disease. Exposures during sensitive developmental time points can contribute to the adult disease. Using a mouse model, in utero and early postnatal exposures to arsenic (100 ppb or less in drinking water) were found to alter airway reactivity to methacholine challenge in 28 day old pups. Removal of mice from arsenic exposure 28 days after birth did not reverse the alterations in sensitivity to methacholine. In addition, adult mice exposed to similar levels of arsenic in drinking water did not show alterations. Therefore, alterations in airwaymore » reactivity were irreversible and specific to exposures during lung development. These functional changes correlated with protein and gene expression changes as well as morphological structural changes around the airways. Arsenic increased the whole lung levels of smooth muscle actin in a dose dependent manner. The level of smooth muscle mass around airways was increased with arsenic exposure, especially around airways smaller than 100 {mu}m in diameter. This increase in smooth muscle was associated with alterations in extracellular matrix (collagen, elastin) expression. This model system demonstrates that in utero and postnatal exposure to environmentally relevant levels of arsenic can irreversibly alter pulmonary structure and function in the adults.« less

Air pollution, airway inflammation and lung function in Mexico City school children

EPA Science Inventory

BACKGROUND: The biological mechanisms involved in inflammatory response to air pollution are not clearly understood. OBJECTIVE: In this study we assessed the association of short-term air pollutant exposure with inflammatory markers and lung function. METHODS: We studied a cohort...

Structural basis for pulmonary functional imaging.

PubMed

Itoh, H; Nakatsu, M; Yoxtheimer, L M; Uematsu, H; Ohno, Y; Hatabu, H

2001-03-01

An understanding of fine normal lung morphology is important for effective pulmonary functional imaging. The lung specimens must be inflated. These include (a) unfixed, inflated lung specimen, (b) formaldehyde fixed lung specimen, (c) fixed, inflated dry lung specimen, and (d) histology specimen. Photography, magnified view, radiograph, computed tomography, and histology of these specimens are demonstrated. From a standpoint of diagnostic imaging, the main normal lung structures consist of airways (bronchi and bronchioles), alveoli, pulmonary vessels, secondary pulmonary lobules, and subpleural pulmonary lymphatic channels. This review summarizes fine radiologic normal lung morphology as an aid to effective pulmonary functional imaging.

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

PubMed

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

2008-09-28

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

Impact of the CFTR-potentiator ivacaftor on airway microbiota in cystic fibrosis patients carrying a G551D mutation.

PubMed

Bernarde, Cédric; Keravec, Marlène; Mounier, Jérôme; Gouriou, Stéphanie; Rault, Gilles; Férec, Claude; Barbier, Georges; Héry-Arnaud, Geneviève

2015-01-01

Airway microbiota composition has been clearly correlated with many pulmonary diseases, and notably with cystic fibrosis (CF), an autosomal genetic disorder caused by mutation in the CF transmembrane conductance regulator (CFTR). Recently, a new molecule, ivacaftor, has been shown to re-establish the functionality of the G551D-mutated CFTR, allowing significant improvement in lung function. The purpose of this study was to follow the evolution of the airway microbiota in CF patients treated with ivacaftor, using quantitative PCR and pyrosequencing of 16S rRNA amplicons, in order to identify quantitative and qualitative changes in bacterial communities. Three G551D children were followed up longitudinally over a mean period of more than one year covering several months before and after initiation of ivacaftor treatment. 129 operational taxonomy units (OTUs), representing 64 genera, were identified. There was no significant difference in total bacterial load before and after treatment. Comparison of global community composition found no significant changes in microbiota. Two OTUs, however, showed contrasting dynamics: after initiation of ivacaftor, the relative abundance of the anaerobe Porphyromonas 1 increased (p<0.01) and that of Streptococcus 1 (S. mitis group) decreased (p<0.05), possibly in relation to the anti-Gram-positive properties of ivacaftor. The anaerobe Prevotella 2 correlated positively with the pulmonary function test FEV-1 (r=0.73, p<0.05). The study confirmed the presumed positive role of anaerobes in lung function. Several airway microbiota components, notably anaerobes (obligate or facultative anaerobes), could be valuable biomarkers of lung function improvement under ivacaftor, and could shed light on the pathophysiology of lung disease in CF patients.

Airway Tree Segmentation in Serial Block-Face Cryomicrotome Images of Rat Lungs

PubMed Central

Bauer, Christian; Krueger, Melissa A.; Lamm, Wayne J.; Smith, Brian J.; Glenny, Robb W.; Beichel, Reinhard R.

2014-01-01

A highly-automated method for the segmentation of airways in serial block-face cryomicrotome images of rat lungs is presented. First, a point inside of the trachea is manually specified. Then, a set of candidate airway centerline points is automatically identified. By utilizing a novel path extraction method, a centerline path between the root of the airway tree and each point in the set of candidate centerline points is obtained. Local disturbances are robustly handled by a novel path extraction approach, which avoids the shortcut problem of standard minimum cost path algorithms. The union of all centerline paths is utilized to generate an initial airway tree structure, and a pruning algorithm is applied to automatically remove erroneous subtrees or branches. Finally, a surface segmentation method is used to obtain the airway lumen. The method was validated on five image volumes of Sprague-Dawley rats. Based on an expert-generated independent standard, an assessment of airway identification and lumen segmentation performance was conducted. The average of airway detection sensitivity was 87.4% with a 95% confidence interval (CI) of (84.9, 88.6)%. A plot of sensitivity as a function of airway radius is provided. The combined estimate of airway detection specificity was 100% with a 95% CI of (99.4, 100)%. The average number and diameter of terminal airway branches was 1179 and 159 μm, respectively. Segmentation results include airways up to 31 generations. The regression intercept and slope of airway radius measurements derived from final segmentations were estimated to be 7.22 μm and 1.005, respectively. The developed approach enables quantitative studies of physiology and lung diseases in rats, requiring detailed geometric airway models. PMID:23955692

Efficient generation of functional CFTR-expressing airway epithelial cells from human pluripotent stem cells.

PubMed

Wong, Amy P; Chin, Stephanie; Xia, Sunny; Garner, Jodi; Bear, Christine E; Rossant, Janet

2015-03-01

Airway epithelial cells are of great interest for research on lung development, regeneration and disease modeling. This protocol describes how to generate cystic fibrosis (CF) transmembrane conductance regulator protein (CFTR)-expressing airway epithelial cells from human pluripotent stem cells (PSCs). The stepwise approach from PSC culture to differentiation into progenitors and then mature epithelia with apical CFTR activity is outlined. Human PSCs that were inefficient at endoderm differentiation using our previous lung differentiation protocol were able to generate substantial lung progenitor cell populations. Augmented CFTR activity can be observed in all cultures as early as at 35 d of differentiation, and full maturation of the cells in air-liquid interface cultures occurs in <5 weeks. This protocol can be used for drug discovery, tissue regeneration or disease modeling.

Antioxidant airway responses following experimental exposure to wood smoke in man

PubMed Central

2010-01-01

Background Biomass combustion contributes to the production of ambient particulate matter (PM) in rural environments as well as urban settings, but relatively little is known about the health effects of these emissions. The aim of this study was therefore to characterize airway responses in humans exposed to wood smoke PM under controlled conditions. Nineteen healthy volunteers were exposed to both wood smoke, at a particulate matter (PM2.5) concentration of 224 ± 22 μg/m3, and filtered air for three hours with intermittent exercise. The wood smoke was generated employing an experimental set-up with an adjustable wood pellet boiler system under incomplete combustion. Symptoms, lung function, and exhaled NO were measured over exposures, with bronchoscopy performed 24 h post-exposure for characterisation of airway inflammatory and antioxidant responses in airway lavages. Results Glutathione (GSH) concentrations were enhanced in bronchoalveolar lavage (BAL) after wood smoke exposure vs. air (p = 0.025), together with an increase in upper airway symptoms. Neither lung function, exhaled NO nor systemic nor airway inflammatory parameters in BAL and bronchial mucosal biopsies were significantly affected. Conclusions Exposure of healthy subjects to wood smoke, derived from an experimental wood pellet boiler operating under incomplete combustion conditions with PM emissions dominated by organic matter, caused an increase in mucosal symptoms and GSH in the alveolar respiratory tract lining fluids but no acute airway inflammatory responses. We contend that this response reflects a mobilisation of GSH to the air-lung interface, consistent with a protective adaptation to the investigated wood smoke exposure. PMID:20727160

Endoscopic high-resolution auto fluorescence imaging and optical coherence tomography of airways in vivo (Conference Presentation)

NASA Astrophysics Data System (ADS)

Pahlevaninezhad, Hamid; Lee, Anthony; Hohert, Geoffrey; Schwartz, Carley; Shaipanich, Tawimas; Ritchie, Alexander J.; Zhang, Wei; MacAulay, Calum E.; Lam, Stephen; Lane, Pierre M.

2016-03-01

In this work, we present multimodal imaging of peripheral airways in vivo using an endoscopic imaging system capable of co-registered optical coherence tomography and autofluorescence imaging (OCT-AFI). This system employs a 0.9 mm diameter double-clad fiber optic-based catheter for endoscopic imaging of small peripheral airways. Optical coherence tomography (OCT) can visualize detailed airway morphology in the lung periphery and autofluorescence imaging (AFI) can visualize fluorescent tissue components such as collagen and elastin, improving the detection of airway lesions. Results from in vivo imaging of 40 patients indicate that OCT and AFI offer complementary information that may increase the ability to identify pulmonary nodules in the lung periphery and improve the safety of biopsy collection by identifying large blood vessels. AFI can rapidly visualize in vivo vascular networks using fast scanning parameters resulting in vascular-sensitive imaging with less breathing/cardiac motion artifacts compared to Doppler OCT imaging. By providing complementary information about structure and function of tissue, OCT-AFI may improve site selection during biopsy collection in the lung periphery.

Survival after Lung Volume Reduction in Chronic Obstructive Pulmonary Disease

PubMed Central

Hogg, James C.; Chu, Fanny S. F.; Tan, Wan C.; Sin, Don D.; Patel, Sanjay A.; Pare, Peter D.; Martinez, Fernando J.; Rogers, Robert M.; Make, Barry J.; Criner, Gerard J.; Cherniack, Reuben M.; Sharafkhaneh, Amir; Luketich, James D.; Coxson, Harvey O.; Elliott, W. Mark; Sciurba, Frank C.

2007-01-01

Rationale: COPD is associated with reduced life expectancy. Objectives: To determine the association between small airway pathology and long-term survival after lung volume reduction in chronic obstructive pulmonary disease (COPD) and the effect of corticosteroids on this pathology. Methods: Patients with severe (GOLD-3) and very severe (GOLD-4) COPD (n = 101) were studied after lung volume reduction surgery. Respiratory symptoms, quality of life, pulmonary function, exercise tolerance, chest radiology, and corticosteroid treatment status were assessed preoperatively. The severity of luminal occlusion, wall thickening, and the presence of small airways containing lymphoid follicles were determined in resected lung tissue. Kaplan-Meier survival analysis and Cox proportional hazards models were used to determine the relationship between survival and small airway pathology. The effect of corticosteroids on this pathology was assessed by comparing treated and untreated groups. Measurements and Main Results: The quartile of subjects with the greatest luminal occlusion, adjusted for covariates, died earlier than subjects who had the least occlusion (hazard ratio, 3.28; 95% confidence interval, 1.55–6.92; P = 0.002). There was a trend toward a reduction in the number of airways containing lymphoid follicles (P = 0.051) in those receiving corticosteroids, with a statistically significant difference between the control and oral ± inhaled corticosteroid–treated groups (P = 0.019). However, corticosteroid treatment had no effect on airway wall thickening or luminal occlusion. Conclusions: Occlusion of the small airways by inflammatory exudates containing mucus is associated with early death in patients with severe emphysema treated by lung volume reduction surgery. Corticosteroid treatment dampens the host immune response in these airways by reducing lymphoid follicles without changing wall thickening and luminal occlusion. PMID:17556723

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

PubMed Central

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

2014-01-01

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

Maintenance of airway epithelium in acutely rejected orthotopic vascularized mouse lung transplants.

PubMed

Okazaki, Mikio; Gelman, Andrew E; Tietjens, Jeremy R; Ibricevic, Aida; Kornfeld, Christopher G; Huang, Howard J; Richardson, Steven B; Lai, Jiaming; Garbow, Joel R; Patterson, G Alexander; Krupnick, Alexander S; Brody, Steven L; Kreisel, Daniel

2007-12-01

Lung transplantation remains the only therapeutic option for many patients suffering from end-stage pulmonary disease. Long-term success after lung transplantation is severely limited by the development of bronchiolitis obliterans. The murine heterotopic tracheal transplantation model has been widely used for studies investigating pathogenesis of obliterative airway disease and immunosuppressive strategies to prevent its development. Despite its utility, this model employs proximal airway that lacks airflow and is not vascularized. We have developed a novel model of orthotopic vascularized lung transplantation in the mouse, which leads to severe vascular rejection in allogeneic strain combinations. Here we characterize differences in the fate of airway epithelial cells in nonimmunosuppressed heterotopic tracheal and vascularized lung allograft models over 28 days. Up-regulation of growth factors that are thought to be critical for the development of airway fibrosis and interstitial collagen deposition were similar in both models. However, while loss of airway epithelial cells occurred in the tracheal model, airway epithelium remained intact and fully differentiated in lung allografts, despite profound vascular rejection. Moreover, we demonstrate expression of the anti-apoptotic protein Bcl-2 in airway epithelial cells of acutely rejected lung allografts. These findings suggest that in addition to alloimmune responses, other stimuli may be required for the destruction of airway epithelial cells. Thus, the model of vascularized mouse lung transplantation may provide a new and more physiologic experimental tool to study the interaction between immune and nonimmune mechanisms affecting airway pathology in lung allografts.

Airway disease: anatomopathologic patterns and functional correlations.

PubMed

Mormile, F; Ciappi, G

1997-01-01

Airways represent a serial and parallel branched system, through which the alveoli are connected with the external air. They participate in the mechanical and immune defense against noxious agents, regional flow regulation to optimize the perfusion/ventilation ratio and provide lung mechanical support. Functional exploration of central airways is based on resistance measurement, flow-volume curve or spirometry, while peripheral airways influence parameters as the upstream resistance, the slope of phase III nitrogen washout and the residual volume. Bronchodynamic tests supply important information on airway reversibility and nonspecific reactivity. Anatomopathologic alterations of obstructive chronic bronchitis, pulmonary emphysema and bronchial asthma account for their specific functional and bronchodynamic alterations. There is a growing interest for bronchiolitis in the clinical, radiologic and functional field. This type of lesion, always present in COPD, asthma and interstitial disease, becomes relevant when isolated or predominant. The most useful anatomofunctional classification separates the "constrictive" forms, the cause of obstruction and hyperinflation, from "proliferative" forms where an intraluminal proliferation more or less extended to alveolar air spaces as in BOOP (bronchiolitis obliterans organizing pneumonia) results in restrictive dysfunction. Constrictive bronchiolitis obliterans represents a severe and frequent complication of lung and bone marrow transplantation. Idiopathic BOOP may occur with cough or flue-like symptoms. In other cases, constrictive and proliferative forms may have a toxic (gases or drugs), postinfective or immune etiology (rheumatoid arthritis, LES, etc). Respiratory bronchiolitis or smokers' bronchiolitis, an often asymptomatic lesion, rarely associated to an interstitial lung disease, should be considered separately. The relationships between respiratory bronchiolitis, COPD and initial centriacinar emphysema is still to be elucidated. The diagnostic combination of the more sensitive functional tests with HRCT will allow a better understanding of the natural history of the various forms of bronchiolitis.

Airway driving pressure and lung stress in ARDS patients.

PubMed

Chiumello, Davide; Carlesso, Eleonora; Brioni, Matteo; Cressoni, Massimo

2016-08-22

Lung-protective ventilation strategy suggests the use of low tidal volume, depending on ideal body weight, and adequate levels of PEEP. However, reducing tidal volume according to ideal body weight does not always prevent overstress and overstrain. On the contrary, titrating mechanical ventilation on airway driving pressure, computed as airway pressure changes from PEEP to end-inspiratory plateau pressure, equivalent to the ratio between the tidal volume and compliance of respiratory system, should better reflect lung injury. However, possible changes in chest wall elastance could affect the reliability of airway driving pressure. The aim of this study was to evaluate if airway driving pressure could accurately predict lung stress (the pressure generated into the lung due to PEEP and tidal volume). One hundred and fifty ARDS patients were enrolled. At 5 and 15 cmH2O of PEEP, lung stress, driving pressure, lung and chest wall elastance were measured. The applied tidal volume (mL/kg of ideal body weight) was not related to lung gas volume (r (2) = 0.0005 p = 0.772). Patients were divided according to an airway driving pressure lower and equal/higher than 15 cmH2O (the lower and higher airway driving pressure groups). At both PEEP levels, the higher airway driving pressure group had a significantly higher lung stress, respiratory system and lung elastance compared to the lower airway driving pressure group. Airway driving pressure was significantly related to lung stress (r (2) = 0.581 p < 0.0001 and r (2) = 0.353 p < 0.0001 at 5 and 15 cmH2O of PEEP). For a lung stress of 24 and 26 cmH2O, the optimal cutoff value for the airway driving pressure were 15.0 cmH2O (ROC AUC 0.85, 95 % CI = 0.782-0.922); and 16.7 (ROC AUC 0.84, 95 % CI = 0.742-0.936). Airway driving pressure can detect lung overstress with an acceptable accuracy. However, further studies are needed to establish if these limits could be used for ventilator settings.

Positive Rates and Factors Associated with Abnormal Lung Function of Greenhouse Workers in China: A Cross-Sectional Study.

PubMed

Zhu, Xiaojun; Gao, Panjun; Gu, Yishuo; Xiao, Pei; Liu, Mengxuan; Chen, Juan; Cen, Yacai; Ma, Wenjun; Li, Tao

2017-08-24

Since the number of greenhouse workers are increasing in China, this observational cross-sectional study was designed to evaluate lung function and discuss the potential risk factors, to provide evidence in the surveillance of greenhouse workers' health. 678 greenhouse workers in Gansu Province, China were enrolled. A questionnaire which included demographic and occupational information was used. Vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV₁), and FEV₁:FVC ratios (FEV₁/FVC), maximal expiratory flow after 50% of the FVC has not been exhaled (MEF 50 ), maximal expiratory flow after 25% of the FVC has not been exhaled (MEF 25 ) and maximal mid-expiratory flow curve (MMEF) were measured as lung function indicators. The mean values and standard deviations (SDs) of VC% predicted, FVC% predicted, FEV₁% predicted and FEV₁/FVC ratio were 106.07 ± 13.36, 107.60 ± 13.95, 97.19 ± 14.80 and 89.76 ± 10.78 respectively. The positive rates of above four and abnormal lung ventilation function were 2.9%, 2.8%, 11.2%, 4.6% and 6.5% respectively. Gender, age, BMI and number of greenhouses owned were influence factors of lung ventilation function ( p < 0.05). The mean values and SDs of MEF 50 % predicted, MEF 25 % predicted and MMEF% predicted were 69.63 ± 24.95, 54.04 ± 24.94 and 66.81 ± 24.53. The positive rates of above three and abnormal small airway function were 45.0%, 72.1%, 47.2% and 49.4% respectively. Age, education and number of greenhouses owned were influence factors for small airway function ( p < 0.05). Working in a greenhouse might influence lung function of the workers. Small airway function indicators could be used as priority indicators for the surveillance of greenhouse workers' health.

Effect on lung function of continuous positive airway pressure administered either by infant flow driver or a single nasal prong.

PubMed

Kavvadia, V; Greenough, A; Dimitriou, G

2000-04-01

The aim of this study was to assess if continuous positive airways pressure (CPAP) delivered by an infant flow driver (IFD) was a more effective method of improving lung function than delivering CPAP by a single nasal prong. A total of 36 infants (median gestational age 29 weeks, range 25-35 weeks) were studied, 12 who received CPAP via an IFD, 12 who received CPAP via a single nasal prong and 12 without CPAP. CPAP was administered post extubation if apnoeas and bradycardias or a respiratory acidosis developed or electively if the infant was of birth weight <1.0 kg. Lung function was assessed by the supplementary oxygen requirement and measurement of compliance of the respiratory system using an occlusion technique. Assessments were made immediately prior to and after 24 h of CPAP administration and at similar postnatal ages in the non-CPAP group. The infants who did not require CPAP had better lung function (non significant) than the other two groups before they received CPAP. After 24 h, lung function had improved in both CPAP groups to the level of the non CPAP infants. The supplementary oxygen requirements of all three groups decreased over the 24 h period, but this only reached significance in the single nasal prong group (P<0.05). Four infants supported by the IFD, but none with a single nasal prong, became hyperoxic. Continuous positive airways pressure administration via the infant flow driver appears to offer no short-term advantage over a single nasal prong system when used after extubation in preterm infants.

Quantification of atopy, lung function and airway hypersensitivity in adults

PubMed Central

2011-01-01

Background Studies in children have shown that concentration of specific serum IgE (sIgE) and size of skin tests to inhalant allergens better predict wheezing and reduced lung function than the information on presence or absence of atopy. However, very few studies in adults have investigated the relationship of quantitative atopy with lung function and airway hyperresponsiveness (AHR). Objective To determine the association between lung function and AHR and quantitative atopy in a large sample of adults from the UK. Methods FEV1 and FVC (% predicted) were measured using spirometry and airway responsiveness by methacholine challenge (5-breath dosimeter protocol) in 983 subjects (random sample of 800 parents of children enrolled in a population-based birth cohort enriched with 183 patients with physician-diagnosed asthma). Atopic status was assessed by skin prick tests (SPT) and measurement of sIgE (common inhalant allergens). We also measured indoor allergen exposure in subjects' homes. Results Spirometry was completed by 792 subjects and 626 underwent methacholine challenge, with 100 (16.0%) having AHR (dose-response slope>25). Using sIgE as a continuous variable in a multiple linear regression analysis, we found that increasing levels of sIgE to mite, cat and dog were significantly associated with lower FEV1 (mite p = 0.001, cat p = 0.0001, dog p = 2.95 × 10-8). Similar findings were observed when using the size of wheal on skin testing as a continuous variable, with significantly poorer lung function with increasing skin test size (mite p = 8.23 × 10-8, cat p = 3.93 × 10-10, dog p = 3.03 × 10-15, grass p = 2.95 × 10-9). The association between quantitative atopy with lung function and AHR remained unchanged when we repeated the analyses amongst subjects defined as sensitised using standard definitions (sIgE>0.35 kUa/l, SPT-3 mm>negative control). Conclusions In the studied population, lung function decreased and AHR increased with increasing sIgE levels or SPT wheal diameter to inhalant allergens, suggesting that atopy may not be a dichotomous outcome influencing lung function and AHR. PMID:22410099

Free DNA in Cystic Fibrosis Airway Fluids Correlates with Airflow Obstruction

PubMed Central

Marcos, Veronica; Zhou-Suckow, Zhe; Önder Yildirim, Ali; Bohla, Alexander; Hector, Andreas; Vitkov, Ljubomir; Krautgartner, Wolf Dietrich; Stoiber, Walter; Griese, Matthias; Eickelberg, Oliver; Mall, Marcus A.; Hartl, Dominik

2015-01-01

Chronic obstructive lung disease determines morbidity and mortality of patients with cystic fibrosis (CF). CF airways are characterized by a nonresolving neutrophilic inflammation. After pathogen contact or prolonged activation, neutrophils release DNA fibres decorated with antimicrobial proteins, forming neutrophil extracellular traps (NETs). NETs have been described to act in a beneficial way for innate host defense by bactericidal, fungicidal, and virucidal actions. On the other hand, excessive NET formation has been linked to the pathogenesis of autoinflammatory and autoimmune disease conditions. We quantified free DNA structures characteristic of NETs in airway fluids of CF patients and a mouse model with CF-like lung disease. Free DNA levels correlated with airflow obstruction, fungal colonization, and CXC chemokine levels in CF patients and CF-like mice. When viewed in combination, our results demonstrate that neutrophilic inflammation in CF airways is associated with abundant free DNA characteristic for NETosis, and suggest that free DNA may be implicated in lung function decline in patients with CF. PMID:25918476

Optical techniques in pulmonary medicine. SPIE photonics West.

PubMed

Suter, Melissa J; Lam, Stephen; Brenner, Matthew

2012-04-01

There is ongoing interest in the emerging field of pulmonary photonic-based diagnostics. Potential clinical need areas that are being actively investigated at this time include airway and peripheral lung cancer diagnostics, pulmonary parenchymal and interstitial disorders, alveolar structure function, inhalation injury, ciliary function analysis, asthma and obstructive lung diseases.

The lower airway microbiota in early cystic fibrosis lung disease: a longitudinal analysis.

PubMed

Frayman, Katherine B; Armstrong, David S; Carzino, Rosemary; Ferkol, Thomas W; Grimwood, Keith; Storch, Gregory A; Teo, Shu Mei; Wylie, Kristine M; Ranganathan, Sarath C

2017-12-01

In infants and young children with cystic fibrosis, lower airway infection and inflammation are associated with adverse respiratory outcomes. However, the role of lower airway microbiota in the pathogenesis of early cystic fibrosis lung disease remains uncertain. To assess the development of the lower airway microbiota over time in infants and young children with cystic fibrosis, and to explore its association with airway inflammation and pulmonary function at age 6 years. Serial, semi-annual bronchoscopies and bronchoalveolar lavage (BAL) procedures were performed in infants newly diagnosed with cystic fibrosis following newborn screening. Quantitative microbiological cultures and inflammatory marker (interleukin 8 and neutrophil elastase) measurements were undertaken contemporaneously. 16S ribosomal RNA gene sequencing was conducted on stored BAL samples. Spirometry results recorded at 6 years of age were extracted from medical records. Ninety-five BAL samples provided 16S ribosomal RNA gene data. These were collected from 48 subjects aged 1.2-78.3 months, including longitudinal samples from 27 subjects and 13 before age 6 months. The lower airway microbiota varied, but diversity decreased with advancing age. Detection of recognised cystic fibrosis bacterial pathogens was associated with reduced microbial diversity and greater lower airway inflammation. There was no association between the lower airway microbiota and pulmonary function at age 6 years. In infants with cystic fibrosis, the lower airway microbiota is dynamic. Dominance of the microbiota by recognised cystic fibrosis bacterial pathogens is associated with increased lower airway inflammation, however early microbial diversity is not associated with pulmonary function at 6 years of age. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Effect of MUC8 on Airway Inflammation: A Friend or a Foe?

PubMed

Cha, Hee-Jae; Song, Kyoung Seob

2018-02-06

In this review, we compile identifying molecular mechanisms of MUC8 gene expression and studies characterizing the physiological functions of MUC8 in the airway and analyzing how altered MUC8 gene expression in the lung is affected by negative regulators.

Smoking and nonsmoking asthma: differences in clinical outcome and pathogenesis.

PubMed

Fattahi, Fatemeh; Hylkema, Machteld N; Melgert, Barbro N; Timens, Wim; Postma, Dirkje S; ten Hacken, Nick H T

2011-02-01

Cigarette smoking in asthma is frequently present and is associated with worsening of symptoms, accelerated lung-function decline, a higher frequency of hospital admissions, a higher degree of asthma severity, poorer asthma control and reduced responsiveness to corticosteroids. Furthermore, it is associated with reduced numbers of eosinophils and higher numbers of mast cells in the submucosa of the airway wall. Airway remodeling is increased as evidenced by increased epithelial thickness and goblet cell hyperplasia in smoking asthmatics. The pathogenesis responsible for smoking-induced changes in airway inflammation and remodeling in asthma is complex and largely unknown. The underlying mechanism of reduced corticosteroid responsiveness is also unknown. This article discusses differences between smoking and nonsmoking asthmatics regarding the clinical expression of asthma, lung function, response to corticosteroids, airway inflammation and remodeling processes. Possible pathogenetic mechanisms that may explain the links between cigarette smoking and changes in the clinical expression of asthma will be discussed, as well as the beneficial effects of smoking cessation.

Murine lung eosinophil activation and chemokine production in allergic airway inflammation

PubMed Central

Rose, C Edward; Lannigan, Joanne A; Kim, Paul; Lee, James J; Fu, Shu Man; Sung, Sun-sang J

2010-01-01

Eosinophils play important roles in asthma and lung infections. Murine models are widely used for assessing the functional significance and mechanistic basis for eosinophil involvements in these diseases. However, little is known about tissue eosinophils in homeostasis. In addition, little data on eosinophil chemokine production during allergic airway inflammation are available. In this study, the properties and functions of homeostatic and activated eosinophils were compared. Eosinophils from normal tissues expressed costimulation and adhesion molecules B7-1, B7-2 and ICAM-1 for Ag presentation but little major histocompatibility complex (MHC) class II, and were found to be poor stimulators of T-cell proliferation. However, these eosinophils expressed high levels of chemokine mRNA including C10, macrophage inflammatory protein (MIP)-1α, MIP-1γ, MIP-2, eotaxin and monocyte chemoattractant protein-5 (MCP-5), and produced chemokine proteins. Eosinophil intracellular chemokines decreased rapidly with concomitant surface marker downregulation upon in vitro culturing consistent with piecemeal degranulation. Lung eosinophils from mice with induced allergic airway inflammation exhibited increased chemokines mRNA expression and chemokines protein production and upregulated MHC class II and CD11c expression. They were also found to be the predominant producers of the CCR1 ligands CCL6/C10 and CCL9/MIP-1γ in inflamed lungs. Eosinophil production of C10 and MIP-1γ correlated with the marked influx of CD11bhigh lung dendritic cells during allergic airway inflammation and the high expression of CCR1 on these dendritic cells (DCs). The study provided baseline information on tissue eosinophils, documented the upregulation of activation markers and chemokine production in activated eosinophils, and indicated that eosinophils were a key chemokine-producing cell type in allergic lung inflammation. PMID:20622891

Decreased expression of monocarboxylate transporter 1 and 4 in the branching airway epithelium of nitrofen-induced congenital diaphragmatic hernia.

PubMed

Takahashi, Toshiaki; Friedmacher, Florian; Zimmer, Julia; Puri, Prem

2016-06-01

Monocarboxylate transporters (MCTs) are crucial for the maintenance of intracellular pH homeostasis in developing fetal lungs. MCT1/4 is strongly expressed by epithelial airway cells throughout lung branching morphogenesis. Functional inhibition of MCT1/4 in fetal rat lung explants has been shown to result in airway defects similar to pulmonary hypoplasia (PH) in congenital diaphragmatic hernia (CDH). We hypothesized that pulmonary expression of MCT1/4 is decreased during lung branching morphogenesis in the nitrofen model of CDH-associated PH. Timed-pregnant rats received nitrofen or vehicle on gestational day 9 (D9). Fetuses were harvested on D15, D18, and D21, and divided into control and nitrofen-exposed group. Pulmonary gene expression levels of MCT1/4 were analyzed by qRT-PCR. Immunofluorescence staining for MCT1/4 was combined with E-cadherin in order to evaluate protein expression in branching airway tissue. Relative mRNA levels of MCT1/4 were significantly reduced in lungs of nitrofen-exposed fetuses on D15, D18, and D21 compared to controls. Confocal laser scanning microscopy confirmed markedly decreased immunofluorescence of MCT1/4 in distal bronchial and primitive alveolar epithelium of nitrofen-exposed fetuses on D15, D18, and D21 compared to controls. Decreased expression of MCT1/4 in distal airway epithelium may disrupt lung branching morphogenesis and thus contribute to the development of PH in the nitrofen-induced CDH model. Copyright © 2016 Elsevier Inc. All rights reserved.

A retrospective study of silicone stent placement for management of anastomotic airway complications in lung transplant recipients: short- and long-term outcomes.

PubMed

Dutau, Hervé; Cavailles, Arnaud; Sakr, Lama; Badier, Monique; Gaubert, Jean-Yves; Boniface, Stéphanie; Doddoli, Christophe; Thomas, Pascal; Reynaud-Gaubert, Martine

2010-06-01

Airway anastomotic complications remain a major cause of morbidity and mortality after lung transplantation (LT). Few data are available with regard to the use of silicone stents for these airway disorders. The aim of this retrospective study was to evaluate the clinical efficacy and safety of silicone stents for such an indication. Data of adult lung transplant recipients who had procedures performed between January 1997 and December 2007 at our institution were reviewed retrospectively. We included patients with post-transplant airway complications who required bronchoscopic intervention with a silicone stent. In 17 of 117 (14.5%) LT recipients, silicone stents were inserted at a mean time of 165 (range 5 to 360) days after surgery in order to palliate 23 anastomotic airway stenoses. Symptomatic improvement was noted in all patients, and mean forced expiratory volume in 1 second (FEV(1)) increased by 672 +/- 496 ml (p < 0.001) after stent insertion. The stent-related complication rate was 0.13/patient per month. The latter consisted of obstructive granulomas (n = 10), mucus plugging (n = 7) and migration (n = 7), which were of mild to moderate severity and were successfully managed endoscopically. Mean stent duration was 266 days (range 24 to 1,407 days). Successful stent removal was achieved in 16 of 23 cases (69.5%) without recurrence of stenosis. Overall survival was similar in patients with and without airway complications (p = 0.36). Silicone stents allow clinical and lung function improvement in patients with LT-related airway complications. Stent-related complications were of mild to moderate severity, and were appropriately managed endoscopically. Permanent resolution of airway stenosis was obtained in most patients, allowing definitive stent removal without recurrence. Copyright 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Sex differences in chronic obstructive pulmonary disease evaluated using optical coherence tomography

NASA Astrophysics Data System (ADS)

Kirby, Miranda; Zhang, Wei; Laratta, Peter K.; Sin, Don D.; Lam, Stephen; Coxson, Harvey O.

2014-03-01

Although there are more women than men dying of chronic obstructive pulmonary disease (COPD) in the United States and elsewhere, we still do not have a clear understanding of the differences in the pathophysiology of airflow obstruction between the sexes. Optical coherence tomography (OCT) is an emerging imaging technology that has the capability of imaging small bronchioles with resolution approaching histology. Therefore, our objective was to compare OCT-derived airway wall measurements between males and females matched for lung size and in anatomically matched small airways. Subjects 50-80 yrs were enrolled in the British Columbia Lung Health Study and underwent OCT and spirometry. OCT was performed using a 1.5mm diameter probe/sheath in anatomically matched airways for males and females; the right lower lobe (RB8 or RB9) or left lower lobe (LB8 or LB9) during end-expiration. OCT airway wall area (Aaw) was obtained by manual segmentation. For males and females there was no significant difference in OCT Aaw (p=0.12). Spearman correlation coefficients indicated that the forced expiratory volume in 1 second (FEV1) and Aaw were significantly correlated for males (r=-0.78, p=0.004) but not for females (r=-0.20, p=0.49) matched for lung size. These novel OCT findings demonstrate that while there were no overall sex differences in airway wall thickness, the relationship between lung function and airway wall thickness was correlated only in men. Therefore, factors other than airway remodeling may be driving COPD pathogenesis in women and OCT may provide important information for investigating airway remodeling and its relationship with COPD progression.

Rhinovirus infection of allergen-sensitized and -challenged mice induces eotaxin release from functionally polarized macrophages.

PubMed

Nagarkar, Deepti R; Bowman, Emily R; Schneider, Dina; Wang, Qiong; Shim, Jee; Zhao, Ying; Linn, Marisa J; McHenry, Christina L; Gosangi, Babina; Bentley, J Kelley; Tsai, Wan C; Sajjan, Umadevi S; Lukacs, Nicholas W; Hershenson, Marc B

2010-08-15

Human rhinovirus is responsible for the majority of virus-induced asthma exacerbations. To determine the immunologic mechanisms underlying rhinovirus (RV)-induced asthma exacerbations, we combined mouse models of allergic airways disease and human rhinovirus infection. We inoculated OVA-sensitized and challenged BALB/c mice with rhinovirus serotype 1B, a minor group strain capable of infecting mouse cells. Compared with sham-infected, OVA-treated mice, virus-infected mice showed increased lung infiltration with neutrophils, eosinophils and macrophages, airway cholinergic hyperresponsiveness, and increased lung expression of cytokines including eotaxin-1/CCL11, IL-4, IL-13, and IFN-gamma. Administration of anti-eotaxin-1 attenuated rhinovirus-induced airway eosinophilia and responsiveness. Immunohistochemical analysis showed eotaxin-1 in the lung macrophages of virus-infected, OVA-treated mice, and confocal fluorescence microscopy revealed colocalization of rhinovirus, eotaxin-1, and IL-4 in CD68-positive cells. RV inoculation of lung macrophages from OVA-treated, but not PBS-treated, mice induced expression of eotaxin-1, IL-4, and IL-13 ex vivo. Macrophages from OVA-treated mice showed increased expression of arginase-1, Ym-1, Mgl-2, and IL-10, indicating a shift in macrophage activation status. Depletion of macrophages from OVA-sensitized and -challenged mice reduced eosinophilic inflammation and airways responsiveness following RV infection. We conclude that augmented airway eosinophilic inflammation and hyperresponsiveness in RV-infected mice with allergic airways disease is directed in part by eotaxin-1. Airway macrophages from mice with allergic airways disease demonstrate a change in activation state characterized in part by altered eotaxin and IL-4 production in response to RV infection. These data provide a new paradigm to explain RV-induced asthma exacerbations.

Influenza A virus-dependent remodeling of pulmonary clock function in a mouse model of COPD

PubMed Central

Sundar, Isaac K.; Ahmad, Tanveer; Yao, Hongwei; Hwang, Jae-woong; Gerloff, Janice; Lawrence, B. Paige; Sellix, Michael T.; Rahman, Irfan

2015-01-01

Daily oscillations of pulmonary function depend on the rhythmic activity of the circadian timing system. Environmental tobacco/cigarette smoke (CS) disrupts circadian clock leading to enhanced inflammatory responses. Infection with influenza A virus (IAV) increases hospitalization rates and death in susceptible individuals, including patients with Chronic Obstructive Pulmonary Disease (COPD). We hypothesized that molecular clock disruption is enhanced by IAV infection, altering cellular and lung function, leading to severity in airway disease phenotypes. C57BL/6J mice exposed to chronic CS, BMAL1 knockout (KO) mice and wild-type littermates were infected with IAV. Following infection, we measured diurnal rhythms of clock gene expression in the lung, locomotor activity, pulmonary function, inflammatory, pro-fibrotic and emphysematous responses. Chronic CS exposure combined with IAV infection altered the timing of clock gene expression and reduced locomotor activity in parallel with increased lung inflammation, disrupted rhythms of pulmonary function, and emphysema. BMAL1 KO mice infected with IAV showed pronounced detriments in behavior and survival, and increased lung inflammatory and pro-fibrotic responses. This suggests that remodeling of lung clock function following IAV infection alters clock-dependent gene expression and normal rhythms of lung function, enhanced emphysematous and injurious responses. This may have implications for the pathobiology of respiratory virus-induced airway disease severity and exacerbations. PMID:25923474

Airway remodelling in the transplanted lung.

PubMed

Kuehnel, Mark; Maegel, Lavinia; Vogel-Claussen, Jens; Robertus, Jan Lukas; Jonigk, Danny

2017-03-01

Following lung transplantation, fibrotic remodelling of the small airways has been recognized for almost 5 decades as the main correlate of chronic graft failure and a major obstacle to long-term survival. Mainly due to airway fibrosis, pulmonary allografts currently show the highest attrition rate of all solid organ transplants, with a 5-year survival rate of 58 % on a worldwide scale. The observation that these morphological changes are not just the hallmark of chronic rejection but rather represent a manifestation of a multitude of alloimmune-dependent and -independent injuries was made more recently, as was the discovery that chronic lung allograft dysfunction manifests in different clinical phenotypes of respiratory impairment and corresponding morphological subentities. Although recent years have seen considerable advances in identifying and categorizing these subgroups on the basis of clinical, functional and histomorphological changes, as well as susceptibility to medicinal treatment, this process is far from over. Since the actual pathophysiological mechanisms governing airway remodelling are still only poorly understood, diagnosis and therapy of chronic lung allograft dysfunction presents a major challenge to clinicians, radiologists and pathologists alike. Here, we review and discuss the current state of the literature on chronic lung allograft dysfunction and shed light on classification systems, corresponding clinical and morphological changes, key cellular players and underlying molecular pathways, as well as on emerging diagnostic and therapeutic approaches.

Automated CT Scan Scores of Bronchiectasis and Air Trapping in Cystic Fibrosis

PubMed Central

Swiercz, Waldemar; Heltshe, Sonya L.; Anthony, Margaret M.; Szefler, Paul; Klein, Rebecca; Strain, John; Brody, Alan S.; Sagel, Scott D.

2014-01-01

Background: Computer analysis of high-resolution CT (HRCT) scans may improve the assessment of structural lung injury in children with cystic fibrosis (CF). The goal of this cross-sectional pilot study was to validate automated, observer-independent image analysis software to establish objective, simple criteria for bronchiectasis and air trapping. Methods: HRCT scans of the chest were performed in 35 children with CF and compared with scans from 12 disease control subjects. Automated image analysis software was developed to count visible airways on inspiratory images and to measure a low attenuation density (LAD) index on expiratory images. Among the children with CF, relationships among automated measures, Brody HRCT scanning scores, lung function, and sputum markers of inflammation were assessed. Results: The number of total, central, and peripheral airways on inspiratory images and LAD (%) on expiratory images were significantly higher in children with CF compared with control subjects. Among subjects with CF, peripheral airway counts correlated strongly with Brody bronchiectasis scores by two raters (r = 0.86, P < .0001; r = 0.91, P < .0001), correlated negatively with lung function, and were positively associated with sputum free neutrophil elastase activity. LAD (%) correlated with Brody air trapping scores (r = 0.83, P < .0001; r = 0.69, P < .0001) but did not correlate with lung function or sputum inflammatory markers. Conclusions: Quantitative airway counts and LAD (%) on HRCT scans appear to be useful surrogates for bronchiectasis and air trapping in children with CF. Our automated methodology provides objective quantitative measures of bronchiectasis and air trapping that may serve as end points in CF clinical trials. PMID:24114359

Crackle Pitch Rises Progressively during Inspiration in Pneumonia, CHF, and IPF Patients.

PubMed

Vyshedskiy, Andrey; Murphy, Raymond

2012-01-01

Objective. It is generally accepted that crackles are due to sudden opening of airways and that larger airways produce crackles of lower pitch than smaller airways do. As larger airways are likely to open earlier in inspiration than smaller airways and the reverse is likely to be true in expiration, we studied crackle pitch as a function of crackle timing in inspiration and expiration. Our goal was to see if the measurement of crackle pitch was consistent with this theory. Methods. Patients with a significant number of crackles were examined using a multichannel lung sound analyzer. These patients included 34 with pneumonia, 38 with heart failure, and 28 with interstitial fibrosis. Results. Crackle pitch progressively increased during inspirations in 79% of all patients. In these patients crackle pitch increased by approximately 40 Hz from the early to midinspiration and by another 40 Hz from mid to late-inspiration. In 10% of patients, crackle pitch did not change and in 11% of patients crackle pitch decreased. During expiration crackle pitch progressively decreased in 72% of patients and did not change in 28% of patients. Conclusion. In the majority of patients, we observed progressive crackle pitch increase during inspiration and decrease during expiration. Increased crackle pitch at larger lung volumes is likely a result of recruitment of smaller diameter airways. An alternate explanation is that crackle pitch may be influenced by airway tension that increases at greater lung volume. In any case improved understanding of the mechanism of production of these common lung sounds may help improve our understanding of pathophysiology of these disorders.

Pulmonary function test findings in patients with acute inhalation injury caused by smoke bombs

PubMed Central

Cao, Lu; Zhang, Xin-Gang; Wang, Jian-Guo; Wang, Han-Bin; Chen, Yi-Bing; Zhao, Da-Hui; Shi, Wen-Fang

2016-01-01

Background This study aimed to determine the effects of smoke bomb-induced acute inhalation injury on pulmonary function at different stages of lung injury. Methods We performed pulmonary function tests (PFTs) in 15 patients with acute inhalation injury from days 3 to 180 after smoke inhalation. We measured the trace element zinc in whole blood on days 4 and 17, and correlations of zinc levels with PFTs were performed. Results In the acute stage of lung injury (day 3), 3 of 11 patients with mild symptoms had normal pulmonary function and 8 patients with restrictive ventilatory dysfunction and reduced diffusing capacity. Some patients also had mild obstructive ventilatory dysfunction (5 patients) and a decline in small airway function (6 patients). For patients with severe symptoms, PFT results showed moderate to severe restrictive ventilatory dysfunction and reduced diffusing capacity. PaCO2 was significantly higher (P=0.047) in patients with reduced small airway function compared with those with normal small airway function. Whole blood zinc levels in the convalescence stage (day 17) were significantly lower than those in the acute stage (day 4). Zinc in the acute stage was negatively correlated with DLCO/VA on days 3, 10, and 46 (r=−0.633, −0.676, and −0.675 respectively, P<0.05). Conclusions Smoke inhalation injury mainly causes restrictive ventilatory dysfunction and reduced diffusing capacity, and causes mild obstructive ventilatory dysfunction and small airway function decline in some patients. Zinc is negatively correlated with DLCO/VA. Zinc levels may be able to predict prognosis and indicate the degree of lung injury. PMID:28066595

Identifying the heterogeneity of COPD by V/P SPECT: a new tool for improving the diagnosis of parenchymal defects and grading the severity of small airways disease.

PubMed

Bajc, M; Chen, Y; Wang, J; Li, X Y; Shen, W M; Wang, C Z; Huang, H; Lindqvist, A; He, X Y

2017-01-01

Airway obstruction and possible concomitant pulmonary diseases in COPD cannot be identified conventionally with any single diagnostic tool. We aimed to diagnose and grade COPD severity and identify pulmonary comorbidities associated with COPD with ventilation/perfusion single-photon emission computed tomography (V/P SPECT) using Technegas as the functional ventilation imaging agent. 94 COPD patients (aged 43-86 years, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I-IV) were examined with V/P SPECT and spirometry. Ventilation and perfusion defects were analyzed blindly according to the European guidelines. Penetration grade of Technegas in V SPECT measured the degree of obstructive small airways disease. Total preserved lung function and penetration grade of Technegas in V SPECT were assessed by V/P SPECT and compared to GOLD stages and spirometry. Signs of small airway obstruction in the ventilation SPECT images were found in 92 patients. Emphysema was identified in 81 patients. Two patients had no signs of COPD, but both of them had a pulmonary embolism, and in one of them we also suspected a lung tumor. The penetration grade of Technegas in V SPECT and total preserved lung function correlated significantly to GOLD stages ( r =0.63 and -0.60, respectively, P <0.0001). V/P SPECT identified pulmonary embolism in 30 patients (32%). A pattern typical for heart failure was present in 26 patients (28%). Parenchymal changes typical for pneumonia or lung tumor were present in several cases. V/P SPECT, using Technegas as the functional ventilation imaging agent, is a new tool to diagnose COPD and to grade its severity. Additionally, it revealed heterogeneity of COPD caused by pulmonary comorbidities. The characteristics of these comorbidities suggest their significant impact in clarifying symptoms, and also their influence on the prognosis.

Morphology and Three-Dimensional Inhalation Flow in Human Airways in Healthy and Diseased Subjects

NASA Astrophysics Data System (ADS)

Van de Moortele, Tristan

We investigate experimentally the relation between anatomical structure and respiratory function in healthy and diseased airways. Computed Tomography (CT) scans of human lungs are analyzed from the data base of a large multi-institution clinical study on Chronic Obstructive Pulmonary Disease (COPD). Through segmentation, the 3D volumes of the airways are determined at total lung capacity. A geometric analysis provides data on the morphometry of the airways, including the length and diameter of branches, the child-to-parent diameter ratio, and branching angles. While several geometric parameters are confirmed to match past studies for healthy subjects, previously unreported trends are reported on the length of branches. Specifically, in most dichotomous airway bifurcation, the branch of smaller diameter tends to be significantly longer than the one of larger diameter. Additionally, the branch diameter tends to be smaller in diseased airways than in healthy airways up to the 7th generation of bronchial branching. 3D fractal analysis is also performed on the airway volume. Fractal dimensions of 1.89 and 1.83 are found for healthy non-smokers and declining COPD subjects, respectively, furthering the belief that COPD (and lung disease in general) significantly affects the morphometry of the airways already in early stages of the disease. To investigate the inspiratory flow, 3D flow models of the airways are generated using Computer Aided Design (CAD) software and 3D printed. Using Magnetic Resonance Velocimetry (MRV), 3-component 3D flow fields are acquired for steady inhalation at Reynolds number Re 2000 defined at the trachea. Analysis of the flow data reveals that diseased subjects may experience greater secondary flow strength in their conducting airways, especially in deeper generations.

Airway-parenchymal interdependence

PubMed Central

Paré, Peter D; Mitzner, Wayne

2015-01-01

In this manuscript we discuss the interaction of the lung parenchyma and the airways as well as the physiological and pathophysiological significance of this interaction. These two components of the respiratory organ can be thought of as two independent elastic structures but in fact the mechanical properties of one influence the behavior of the other. Traditionally the interaction has focused on the effects of the lung on the airways but there is good evidence that the opposite is also true, i.e., that the mechanical properties of the airways influence the elastic properties of the parenchyma. The interplay between components of the respiratory system including the airways, parenchyma and vasculature is often referred to as “interdependence.” This interdependence transmits the elastic recoil of the lung to create an effective pressure that dilates the airways as transpulmonary pressure and lung volume increase. By using a continuum mechanics analysis of the lung parenchyma, it is possible to predict the effective pressure between the airways and parenchyma, and these predictions can be empirically evaluated. Normal airway caliber is maintained by this pressure in the adventitial interstitium of the airway, and it counteracts airway compression during forced expiration as well as the ability of airway smooth muscle to narrow airways. Interdependence has physiological and pathophysiological significance. Weakening of the forces of interdependence contributes to airway dysfunction and gas exchange impairment in acute and chronic airway diseases including asthma and emphysema. PMID:23723029

Quantitative analysis of airway abnormalities in CT

NASA Astrophysics Data System (ADS)

Petersen, Jens; Lo, Pechin; Nielsen, Mads; Edula, Goutham; Ashraf, Haseem; Dirksen, Asger; de Bruijne, Marleen

2010-03-01

A coupled surface graph cut algorithm for airway wall segmentation from Computed Tomography (CT) images is presented. Using cost functions that highlight both inner and outer wall borders, the method combines the search for both borders into one graph cut. The proposed method is evaluated on 173 manually segmented images extracted from 15 different subjects and shown to give accurate results, with 37% less errors than the Full Width at Half Maximum (FWHM) algorithm and 62% less than a similar graph cut method without coupled surfaces. Common measures of airway wall thickness such as the Interior Area (IA) and Wall Area percentage (WA%) was measured by the proposed method on a total of 723 CT scans from a lung cancer screening study. These measures were significantly different for participants with Chronic Obstructive Pulmonary Disease (COPD) compared to asymptomatic participants. Furthermore, reproducibility was good as confirmed by repeat scans and the measures correlated well with the outcomes of pulmonary function tests, demonstrating the use of the algorithm as a COPD diagnostic tool. Additionally, a new measure of airway wall thickness is proposed, Normalized Wall Intensity Sum (NWIS). NWIS is shown to correlate better with lung function test values and to be more reproducible than previous measures IA, WA% and airway wall thickness at a lumen perimeter of 10 mm (PI10).

Exercise-induced dehydration alters pulmonary function but does not modify airway responsiveness to dry air in athletes with mild asthma

PubMed Central

Romer, L. M.

2017-01-01

Local airway water loss is the main physiological trigger for exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effects of whole body water loss on airway responsiveness and pulmonary function in athletes with mild asthma and/or EIB. Ten recreational athletes with a medical diagnosis of mild asthma and/or EIB completed a randomized, crossover study. Pulmonary function tests, including spirometry, whole body plethysmography, and diffusing capacity of the lung for carbon monoxide (DlCO), were conducted before and after three conditions: 1) 2 h of exercise in the heat with no fluid intake (dehydration), 2) 2 h of exercise with ad libitum fluid intake (control), and 3) a time-matched rest period (rest). Airway responsiveness was assessed 2 h postexercise/rest via eucapnic voluntary hyperpnea (EVH) to dry air. Exercise in the heat with no fluid intake induced a state of mild dehydration, with a body mass loss of 2.3 ± 0.8% (SD). After EVH, airway narrowing was not different between conditions: median (interquartile range) maximum fall in forced expiratory volume in 1 s was 13 (7–15)%, 11 (9–24)%, and 12 (7–20)% in dehydration, control, and rest conditions, respectively. Dehydration caused a significant reduction in forced vital capacity (300 ± 190 ml, P = 0.001) and concomitant increases in residual volume (260 ± 180 ml, P = 0.001) and functional residual capacity (260 ± 250 ml, P = 0.011), with no change in DlCO. Mild exercise-induced dehydration does not exaggerate airway responsiveness to dry air in athletes with mild asthma/EIB but may affect small airway function. NEW & NOTEWORTHY This study is the first to investigate the effect of whole body dehydration on airway responsiveness. Our data suggest that the airway response to dry air hyperpnea in athletes with mild asthma and/or exercise-induced bronchoconstriction is not exacerbated in a state of mild dehydration. On the basis of alterations in lung volumes, however, exercise-induced dehydration appears to compromise small airway function. PMID:28280109

Exercise-induced dehydration alters pulmonary function but does not modify airway responsiveness to dry air in athletes with mild asthma.

PubMed

Simpson, A J; Romer, L M; Kippelen, P

2017-05-01

Local airway water loss is the main physiological trigger for exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effects of whole body water loss on airway responsiveness and pulmonary function in athletes with mild asthma and/or EIB. Ten recreational athletes with a medical diagnosis of mild asthma and/or EIB completed a randomized, crossover study. Pulmonary function tests, including spirometry, whole body plethysmography, and diffusing capacity of the lung for carbon monoxide (Dl CO ), were conducted before and after three conditions: 1 ) 2 h of exercise in the heat with no fluid intake (dehydration), 2 ) 2 h of exercise with ad libitum fluid intake (control), and 3 ) a time-matched rest period (rest). Airway responsiveness was assessed 2 h postexercise/rest via eucapnic voluntary hyperpnea (EVH) to dry air. Exercise in the heat with no fluid intake induced a state of mild dehydration, with a body mass loss of 2.3 ± 0.8% (SD). After EVH, airway narrowing was not different between conditions: median (interquartile range) maximum fall in forced expiratory volume in 1 s was 13 (7-15)%, 11 (9-24)%, and 12 (7-20)% in dehydration, control, and rest conditions, respectively. Dehydration caused a significant reduction in forced vital capacity (300 ± 190 ml, P = 0.001) and concomitant increases in residual volume (260 ± 180 ml, P = 0.001) and functional residual capacity (260 ± 250 ml, P = 0.011), with no change in Dl CO Mild exercise-induced dehydration does not exaggerate airway responsiveness to dry air in athletes with mild asthma/EIB but may affect small airway function. NEW & NOTEWORTHY This study is the first to investigate the effect of whole body dehydration on airway responsiveness. Our data suggest that the airway response to dry air hyperpnea in athletes with mild asthma and/or exercise-induced bronchoconstriction is not exacerbated in a state of mild dehydration. On the basis of alterations in lung volumes, however, exercise-induced dehydration appears to compromise small airway function. Copyright © 2017 the American Physiological Society.

Precision-cut vibratome slices allow functional live cell imaging of the pulmonary neuroepithelial body microenvironment in fetal mice.

PubMed

Schnorbusch, Kathy; Lembrechts, Robrecht; Brouns, Inge; Pintelon, Isabel; Timmermans, Jean-Pierre; Adriaensen, Dirk

2012-01-01

We recently developed an ex vivo lung slice model that allows for confocal live cell imaging (LCI) of neuroepithelial bodies (NEBs) in postnatal mouse lungs (postnatal days 1-21 and adult). NEBs are morphologically well-characterized, extensively innervated groups of neuroendocrine cells in the airway epithelium, which are shielded from the airway lumen by 'Clara-like' cells. The prominent presence of differentiated NEBs from early embryonic development onwards, strongly suggests that NEBs may exert important functions during late fetal and neonatal life. The main goal of the present study was to adapt the current postnatal LCI lung slice model to enable functional studies of fetal mouse lungs (gestational days 17-20).In vibratome lung slices of prenatal mice, NEBs could be unequivocally identified with the fluorescent stryryl pyridinium dye 4-Di-2-ASP. Changes in the intracellular free calcium concentration and in mitochondrial membrane potential could be monitored using appropriate functional fluorescent indicators (e.g. Fluo-4).It is clear that the described fetal mouse lung slice model is suited for LCI studies of Clara cells, ciliated cells, and the NEB microenvironment, and offers excellent possibilities to further unravel the significance of NEBs during the prenatal and perinatal period.

In vivo imaging of pulmonary nodule and vasculature using endoscopic co-registered optical coherence tomography and autofluorescence imaging (Conference Presentation)

NASA Astrophysics Data System (ADS)

Pahlevaninezhad, Hamid; Lee, Anthony; Hohert, Geoffrey; Schwartz, Carely; Shaipanich, Tawimas; Ritchie, Alexander J.; Zhang, Wei; MacAulay, Calum E.; Lam, Stephen; Lane, Pierre M.

2016-03-01

Peripheral lung nodules found by CT-scans are difficult to localize and biopsy bronchoscopically particularly for those ≤ 2 cm in diameter. In this work, we present the results of endoscopic co-registered optical coherence tomography and autofluorescence imaging (OCT-AFI) of normal and abnormal peripheral airways from 40 patients using 0.9 mm diameter fiber optic rotary pullback catheter. Optical coherence tomography (OCT) can visualize detailed airway morphology endoscopically in the lung periphery. Autofluorescence imaging (AFI) can visualize fluorescing tissue components such as collagen and elastin, enabling the detection of airway lesions with high sensitivity. Results indicate that AFI of abnormal airways is different from that of normal airways, suggesting that AFI can provide a sensitive visual presentation for rapidly identifying possible sites of pulmonary nodules. AFI can also rapidly visualize in vivo vascular networks using fast scanning parameters resulting in vascular-sensitive imaging with less breathing/cardiac motion artifacts compared to Doppler OCT imaging. It is known that tumor vasculature is structurally and functionally different from normal vessels. Thus, AFI can be potentially used for differentiating normal and abnormal lung vasculature for studying vascular remodeling.

[Physical activity and respiratory tract diseases asthma and allergy].

PubMed

Carlsen, K H

2000-11-10

This article presents a review of the relationship between physical training and airways diseases: the relationship between physical activity and the development of airways diseases, and the effect of physical training in rehabilitation after airways diseases. The article is a systematic review of exercise-induced asthma (EIA), the effect of physical training upon bronchial hyperresponsiveness and the development of asthma; how chronic lung diseases affect the ability to participate in physical activity; and the use of physical training in rehabilitation after airways diseases. Physical training may provoke EIA in asthmatic patients. Furthermore, heavy regular training over long periods of time may contribute to the development of asthma. Mastering EIA is an important goal in the management of asthma, especially in children and adolescents, in order to foster normal physical and mental development. Physical training improves fitness and the mastering of asthma, but not of bronchial hyperresponsiveness and asthma activity. In other airways disorders like cystic fibrosis or chronic obstructive lung disease, a reduced lung function may limit the ability to participate in physical activity. Training is an important tool in the rehabilitation of patients with pulmonary disorders as it improves physical fitness and quality of life.

Cleaning at Home and at Work in Relation to Lung Function Decline and Airway Obstruction.

PubMed

Svanes, Øistein; Bertelsen, Randi J; Lygre, Stein H L; Carsin, Anne E; Antó, Josep M; Forsberg, Bertil; García-García, José M; Gullón, José A; Heinrich, Joachim; Holm, Mathias; Kogevinas, Manolis; Urrutia, Isabel; Leynaert, Bénédicte; Moratalla, Jesús M; Le Moual, Nicole; Lytras, Theodore; Norbäck, Dan; Nowak, Dennis; Olivieri, Mario; Pin, Isabelle; Probst-Hensch, Nicole; Schlünssen, Vivi; Sigsgaard, Torben; Skorge, Trude D; Villani, Simona; Jarvis, Debbie; Zock, Jan P; Svanes, Cecilie

2018-05-01

Cleaning tasks may imply exposure to chemical agents with potential harmful effects to the respiratory system, and increased risk of asthma and respiratory symptoms among professional cleaners and in persons cleaning at home has been reported. Long-term consequences of cleaning agents on respiratory health are, however, not well described. This study aimed to investigate long-term effects of occupational cleaning and cleaning at home on lung function decline and airway obstruction. The European Community Respiratory Health Survey (ECRHS) investigated a multicenter population-based cohort at three time points over 20 years. A total of 6,235 participants with at least one lung function measurement from 22 study centers, who in ECRHS II responded to questionnaire modules concerning cleaning activities between ECRHS I and ECRHS II, were included. The data were analyzed with mixed linear models adjusting for potential confounders. As compared with women not engaged in cleaning (ΔFEV 1  = -18.5 ml/yr), FEV 1 declined more rapidly in women responsible for cleaning at home (-22.1; P = 0.01) and occupational cleaners (-22.4; P = 0.03). The same was found for decline in FVC (ΔFVC = -8.8 ml/yr; -13.1, P = 0.02; and -15.9, P = 0.002; respectively). Both cleaning sprays and other cleaning agents were associated with accelerated FEV 1 decline (-22.0, P = 0.04; and -22.9, P = 0.004; respectively). Cleaning was not significantly associated with lung function decline in men or with FEV 1 /FVC decline or airway obstruction. Women cleaning at home or working as occupational cleaners had accelerated decline in lung function, suggesting that exposures related to cleaning activities may constitute a risk to long-term respiratory health.

Airway Microbiota Is Associated with Up-Regulation of the PI3K Pathway in Lung Cancer.

PubMed

Tsay, Jun-Chieh J; Wu, Benjamin G; Badri, Michelle H; Clemente, Jose C; Shen, Nan; Meyn, Peter; Li, Yonghua; Yie, Ting-An; Lhakhang, Tenzin; Olsen, Evan; Murthy, Vivek; Michaud, Gaetane; Sulaiman, Imran; Tsirigos, Aristotelis; Heguy, Adriana; Pass, Harvey; Weiden, Michael D; Rom, William N; Sterman, Daniel H; Bonneau, Richard; Blaser, Martin J; Segal, Leopoldo N

2018-06-04

In lung cancer, upregulation of the PI3K pathway is an early event that contributes to cell proliferation, survival, and tissue invasion. Upregulation of this pathway was recently described as associated with enrichment of the lower airways with bacteria identified as oral commensals. We hypothesize that host-microbe interactions in the lower airways of subjects with lung cancer affect known cancer pathways. Airway brushes were collected prospectively from subjects with lung nodules at time of diagnostic bronchoscopy, including 39 subjects with final lung cancer diagnoses and 36 subjects with non-cancer diagnosis. Additionally, samples from 10 healthy control subjects were included. 16S rRNA gene amplicon sequencing and paired transcriptome sequencing (RNAseq) were performed on all airway samples. In addition, an in vitro model with airway epithelial cells exposed to bacteria/bacterial products was performed. The composition of the lower airway transcriptome in the cancer patients was significantly different from the controls, which included upregulation of ERK and PI3K signaling pathways. The lower airways of lung cancer patients were enriched for oral taxa (Streptococcus and Veillonella), which was associated with upregulation of the ERK and PI3K signaling pathways. In vitro exposure of airway epithelial cells to Veillonella, Prevotella, and Streptococcus led to upregulation of these same signaling pathways. The data presented here shows that several transcriptomic signatures previously identified as relevant to lung cancer pathogenesis are associated with enrichment of the lower airway microbiota with oral commensals.

The glutathione-S-transferase Mu 1 null genotype modulates ozone-induced airway inflammation in humans*

EPA Science Inventory

Background: The Glutathione-S-Transferase Mu 1 null genotype has been reported to be a risk factor for acute respiratory disease associated with increases in ambient air ozone. Ozone is known to cause an immediate decrease in lung function and increased airway inflammation. Howev...

The role of lung inflation and sodium transport in airway liquid clearance during lung aeration in newborn rabbits.

PubMed

Siew, Melissa L; Wallace, Megan J; Allison, Beth J; Kitchen, Marcus J; te Pas, Arjan B; Islam, M Sirajul; Lewis, Robert A; Fouras, Andreas; Yagi, Naoto; Uesugi, Kentaro; Hooper, Stuart B

2013-04-01

Recent phase-contrast X-ray imaging studies suggest that inspiration primarily drives lung aeration and airway liquid clearance at birth, which questions the role of adrenaline-induced activation of epithelial sodium channels (ENaCs). We hypothesized that pressures generated by inspiration have a greater role in airway liquid clearance than do ENaCs after birth. Rabbit pups (30 d of gestation) were delivered and sedated, and 0.1 ml of saline (S) or amiloride (Am; an ENaC inhibitor) was instilled into the lungs before mechanical ventilation. Two other groups (30 d of gestation) were treated similarly but were also given adrenaline (S/Ad and Am/Ad) before mechanical ventilation. Amiloride and adrenaline did not affect functional residual capacity (FRC) recruitment (P > 0.05). Amiloride increased the rate of FRC loss between inflations (Am: -5.2 ± 0.6 ml/kg/s), whereas adrenaline reduced the rate of FRC loss (S/Ad: -1.9 ± 0.3 ml/kg/s) as compared with saline-treated controls (S: -3.5 ± -0.6 ml/kg/s; P < 0.05). These data indicate that inspiration is a major determinant of airway liquid clearance and FRC development during positive pressure ventilation. Although ENaC inhibition and adrenaline administration had no detectable effect on FRC development, ENaC may help to prevent liquid from re-entering the airways during expiration.

Infection-induced airway fibrosis in two rat strains with differential susceptibility.

PubMed Central

McIntosh, J C; Simecka, J W; Ross, S E; Davis, J K; Miller, E J; Cassell, G H

1992-01-01

Chronic infections play a significant role in the morbidity and mortality of patients with chronic airflow limitation. By stimulating airway inflammation, persistent infection has the potential to cause airway fibrosis. However, in patient this condition is most typically found in lungs damaged by other factors, such as smoking, abnormal secretions, or barotrauma. We report the characterization of Mycoplasma pulmonis infection-induced lung fibrosis in two immunocompetent rat strains with no preexisting lung disease. The fibrosis was predominantly in the airways, as demonstrated by the findings for infected animals of increased airway inflammation, airway fibrosis, and airway wall thickness, which correlated with the collagen content of the lungs. Also, the physiological alterations were the opposite of those found in interstitial fibrosis, with a positive correlation between lung compliance and collagen content. The airway fibrosis was noted earlier and to a greater extent in Lewis rats than in Fisher rats, and this result apparently was related to regulation of the inflammatory response. Airway wall thickness, airway inflammation, and airway fibrosis are commonly reported in tissue specimens from patients with chronic airway diseases and have been shown to correlate with airflow limitation in patients with chronic obstructive pulmonary disease. Thus, this model may be useful in furthering our understanding of the role of chronic infection and airway inflammation in airflow obstruction. Images PMID:1612760

Distribution and function of the peptide transporter PEPT2 in normal and cystic fibrosis human lung.

PubMed

Groneberg, D A; Eynott, P R; Döring, F; Dinh, Q Thai; Oates, T; Barnes, P J; Chung, K F; Daniel, H; Fischer, A

2002-01-01

Aerosol administration of peptide based drugs has an important role in the treatment of various pulmonary and systemic diseases. The characterisation of pulmonary peptide transport pathways can lead to new strategies in aerosol drug treatment. Immunohistochemistry and ex vivo uptake studies were established to assess the distribution and activity of the beta-lactam transporting high affinity proton coupled peptide transporter PEPT2 in normal and cystic fibrosis human airway tissue. PEPT2 immunoreactivity in normal human airways was localised to cells of the tracheal and bronchial epithelium and the endothelium of small vessels. In peripheral lung immunoreactivity was restricted to type II pneumocytes. In sections of cystic fibrosis lung a similar pattern of distribution was obtained with signals localised to endothelial cells, airway epithelium, and type II pneumocytes. Functional ex vivo uptake studies with fresh lung specimens led to an uptake of the fluorophore conjugated dipeptide derivative D-Ala-L-Lys-AMCA into bronchial epithelial cells and type II pneumocytes. This uptake was competitively inhibited by dipeptides and cephalosporins but not ACE inhibitors, indicating a substrate specificity as described for PEPT2. These findings provide evidence for the expression and function of the peptide transporter PEPT2 in the normal and cystic fibrosis human respiratory tract and suggest that PEPT2 is likely to play a role in the transport of pulmonary peptides and peptidomimetics.

Distribution and function of the peptide transporter PEPT2 in normal and cystic fibrosis human lung

PubMed Central

Groneberg, D; Eynott, P; Doring, F; Thai, D; Oates, T; Barnes, P; Chung, K; Daniel, H; Fischer, A

2002-01-01

Background: Aerosol administration of peptide based drugs has an important role in the treatment of various pulmonary and systemic diseases. The characterisation of pulmonary peptide transport pathways can lead to new strategies in aerosol drug treatment. Methods: Immunohistochemistry and ex vivo uptake studies were established to assess the distribution and activity of the ß-lactam transporting high affinity proton coupled peptide transporter PEPT2 in normal and cystic fibrosis human airway tissue. Results: PEPT2 immunoreactivity in normal human airways was localised to cells of the tracheal and bronchial epithelium and the endothelium of small vessels. In peripheral lung immunoreactivity was restricted to type II pneumocytes. In sections of cystic fibrosis lung a similar pattern of distribution was obtained with signals localised to endothelial cells, airway epithelium, and type II pneumocytes. Functional ex vivo uptake studies with fresh lung specimens led to an uptake of the fluorophore conjugated dipeptide derivative D-Ala-L-Lys-AMCA into bronchial epithelial cells and type II pneumocytes. This uptake was competitively inhibited by dipeptides and cephalosporins but not ACE inhibitors, indicating a substrate specificity as described for PEPT2. Conclusions: These findings provide evidence for the expression and function of the peptide transporter PEPT2 in the normal and cystic fibrosis human respiratory tract and suggest that PEPT2 is likely to play a role in the transport of pulmonary peptides and peptidomimetics. PMID:11809991

Multiple exposures to swine barn air induce lung inflammation and airway hyper-responsiveness

PubMed Central

Charavaryamath, Chandrashekhar; Janardhan, Kyathanahalli S; Townsend, Hugh G; Willson, Philip; Singh, Baljit

2005-01-01

Background Swine farmers repeatedly exposed to the barn air suffer from respiratory diseases. However the mechanisms of lung dysfunction following repeated exposures to the barn air are still largely unknown. Therefore, we tested a hypothesis in a rat model that multiple interrupted exposures to the barn air will cause chronic lung inflammation and decline in lung function. Methods Rats were exposed either to swine barn (8 hours/day for either one or five or 20 days) or ambient air. After the exposure periods, airway hyper-responsiveness (AHR) to methacholine (Mch) was measured and rats were euthanized to collect bronchoalveolar lavage fluid (BALF), blood and lung tissues. Barn air was sampled to determine endotoxin levels and microbial load. Results The air in the barn used in this study had a very high concentration of endotoxin (15361.75 ± 7712.16 EU/m3). Rats exposed to barn air for one and five days showed increase in AHR compared to the 20-day exposed and controls. Lungs from the exposed groups were inflamed as indicated by recruitment of neutrophils in all three exposed groups and eosinophils and an increase in numbers of airway epithelial goblet cells in 5- and 20-day exposure groups. Rats exposed to the barn air for one day or 20 days had more total leukocytes in the BALF and 20-day exposed rats had more airway epithelial goblet cells compared to the controls and those subjected to 1 and 5 exposures (P < 0.05). Bronchus-associated lymphoid tissue (BALT) in the lungs of rats exposed for 20 days contained germinal centers and mitotic cells suggesting activation. There were no differences in the airway smooth muscle cell volume or septal macrophage recruitment among the groups. Conclusion We conclude that multiple exposures to endotoxin-containing swine barn air induce AHR, increase in mucus-containing airway epithelial cells and lung inflammation. The data also show that prolonged multiple exposures may also induce adaptation in AHR response in the exposed subjects. PMID:15932644

Airway mechanics and methods used to visualize smooth muscle dynamics in vitro.

PubMed

Cooper, P R; McParland, B E; Mitchell, H W; Noble, P B; Politi, A Z; Ressmeyer, A R; West, A R

2009-10-01

Contraction of airway smooth muscle (ASM) is regulated by the physiological, structural and mechanical environment in the lung. We review two in vitro techniques, lung slices and airway segment preparations, that enable in situ ASM contraction and airway narrowing to be visualized. Lung slices and airway segment approaches bridge a gap between cell culture and isolated ASM, and whole animal studies. Imaging techniques enable key upstream events involved in airway narrowing, such as ASM cell signalling and structural and mechanical events impinging on ASM, to be investigated.

Rejuvenating cellular respiration for optimizing respiratory function: targeting mitochondria.

PubMed

Agrawal, Anurag; Mabalirajan, Ulaganathan

2016-01-15

Altered bioenergetics with increased mitochondrial reactive oxygen species production and degradation of epithelial function are key aspects of pathogenesis in asthma and chronic obstructive pulmonary disease (COPD). This motif is not unique to obstructive airway disease, reported in related airway diseases such as bronchopulmonary dysplasia and parenchymal diseases such as pulmonary fibrosis. Similarly, mitochondrial dysfunction in vascular endothelium or skeletal muscles contributes to the development of pulmonary hypertension and systemic manifestations of lung disease. In experimental models of COPD or asthma, the use of mitochondria-targeted antioxidants, such as MitoQ, has substantially improved mitochondrial health and restored respiratory function. Modulation of noncoding RNA or protein regulators of mitochondrial biogenesis, dynamics, or degradation has been found to be effective in models of fibrosis, emphysema, asthma, and pulmonary hypertension. Transfer of healthy mitochondria to epithelial cells has been associated with remarkable therapeutic efficacy in models of acute lung injury and asthma. Together, these form a 3R model--repair, reprogramming, and replacement--for mitochondria-targeted therapies in lung disease. This review highlights the key role of mitochondrial function in lung health and disease, with a focus on asthma and COPD, and provides an overview of mitochondria-targeted strategies for rejuvenating cellular respiration and optimizing respiratory function in lung diseases. Copyright © 2016 the American Physiological Society.

No effect of elevated operating lung volumes on airway function during variable workrate exercise in asthmatic humans.

PubMed

Klansky, Andrew; Irvin, Charlie; Morrison-Taylor, Adriane; Ahlstrand, Sarah; Labrie, Danielle; Haverkamp, Hans Christian

2016-07-01

In asthmatic adults, airway caliber fluctuates during variable intensity exercise such that bronchodilation (BD) occurs with increased workrate whereas bronchoconstriction (BC) occurs with decreased workrate. We hypothesized that increased lung mechanical stretch would prevent BC during such variable workrate exercise. Ten asthmatic and ten nonasthmatic subjects completed two exercise trials on a cycle ergometer. Both trials included a 28-min exercise bout consisting of alternating four min periods at workloads equal to 40 % (Low) and 70% (High) peak power output. During one trial, subjects breathed spontaneously throughout exercise (SVT), such that tidal volume (VT) and end-inspiratory lung volume (EILV) were increased by 0.5 and 0.6 liters during the high compared with the low workload in nonasthmatic and asthmatic subjects, respectively. During the second trial (MVT), VT and EILV were maintained constant when transitioning from the high to the low workload. Forced exhalations from total lung capacity were performed during each exercise workload. In asthmatic subjects, forced expiratory volume 1.0 s (FEV1.0) increased and decreased with the increases and decreases in workrate during both SVT (Low, 3.3 ± 0.3 liters; High, 3.6 ± 0.2 liters; P < 0.05) and MVT (Low, 3.3 ± 0.3 liters; High, 3.5 ± 0.2 liters; P < 0.05). Thus increased lung stretch during MVT did not prevent decreases in airway caliber when workload was reduced. We conclude that neural factors controlling airway smooth muscle (ASM) contractile activity during whole body exercise are more robust determinants of airway caliber than the ability of lung stretch to alter ASM actin-myosin binding and contraction. Copyright © 2016 the American Physiological Society.

Abnormal lung sounds in patients with asthma during episodes with normal lung function.

PubMed

Schreur, H J; Vanderschoot, J; Zwinderman, A H; Dijkman, J H; Sterk, P J

1994-07-01

Even in patients with clinically stable asthma with normal lung function, the airways are characterized by inflammatory changes, including mucosal swelling. In order to investigate whether lung sounds can distinguish these subjects from normal subjects, we compared lung sound characteristics between eight normal and nine symptom-free subjects with mild asthma. All subjects underwent simultaneous recordings of airflow, lung volume changes, and lung sounds during standardized quiet breathing, and during forced maneuvers. Flow-dependent power spectra were computed using fast Fourier transform. For each spectrum we determined lung sound intensity (LSI), frequencies (Q25%, Q50%, Q75%) wheezing (W), and W%. The results were analyzed by ANOVA. During expiration, LSI was lower in patients with asthma than in healthy controls, in particular at relatively low airflow values. During quiet expiration, Q25% to Q75% were higher in asthmatics than in healthy controls, while the change of Q25% to Q75% with flow was greater in asthmatic than in normal subjects. The W and W% were not different between the subject groups. The results indicate that at given airflows, lung sounds are lower in intensity and higher in pitch in asthmatics as compared with controls. This suggests that the generation and/or transmission of lung sounds in symptom-free patients with stable asthma differ from that in normal subjects, even when lung function is within the normal range. Therefore, airflow standardized phonopneumography might reflect morphologic changes in airways of patients with asthma.

Respiratory physiology during early life.

PubMed

Stocks, J

1999-08-01

Despite the rapid adaptation to extrauterine life, the respiratory system of an infant is not simply a miniaturized version of that of an adult, since the rapid somatic growth that occurs during the first year of life is accompanied by major developmental changes in respiratory physiology. The highly compliant chest wall of the infant results in relatively low transpulmonary pressures at end expiration with increased tendency of the small peripheral airways to close during tidal breathing. This not only impairs gas exchange and ventilation-perfusion balance, particularly in dependent parts of the lung, but, together with the small absolute size of the airways, renders the infant and young child particularly susceptible to airway obstruction. Premature airways are highly compliant structures compared with those of mature newborns or adults. This increased compliance can cause airway collapse, resulting in increased airways resistance, flow limitation, poor gas exchange and increased work of breathing. Although there is clear evidence that airway reactivity is present from birth, its role in wheezing lower respiratory tract illnesses in young infants may be overshadowed by pre-existing abnormalities of airway geometry and lung mechanics, or by pathological changes such as airway oedema and mucus hypersecretion. Attempts to assess age-related changes in airway reactivity or response to aerosol therapy in the very young is confounded by changes in breathing patterns and the fact that infants are preferential nose breathers. There is increasing evidence that pre-existing abnormalities of respiratory function, associated with adverse events during foetal life (including maternal smoking during pregnancy), and familial predisposition to wheezing are important determinants of wheezing illnesses during the first years of life. This emphasizes the need to identify and minimize any factors that threaten the normal development of the lung during this critical period if respiratory morbidity throughout life is to be minimized.

Effects of marijuana smoking on the lung.

PubMed

Tashkin, Donald P

2013-06-01

Regular smoking of marijuana by itself causes visible and microscopic injury to the large airways that is consistently associated with an increased likelihood of symptoms of chronic bronchitis that subside after cessation of use. On the other hand, habitual use of marijuana alone does not appear to lead to significant abnormalities in lung function when assessed either cross-sectionally or longitudinally, except for possible increases in lung volumes and modest increases in airway resistance of unclear clinical significance. Therefore, no clear link to chronic obstructive pulmonary disease has been established. Although marijuana smoke contains a number of carcinogens and cocarcinogens, findings from a limited number of well-designed epidemiological studies do not suggest an increased risk for the development of either lung or upper airway cancer from light or moderate use, although evidence is mixed concerning possible carcinogenic risks of heavy, long-term use. Although regular marijuana smoking leads to bronchial epithelial ciliary loss and impairs the microbicidal function of alveolar macrophages, evidence is inconclusive regarding possible associated risks for lower respiratory tract infection. Several case reports have implicated marijuana smoking as an etiologic factor in pneumothorax/pneumomediastinum and bullous lung disease, although evidence of a possible causal link from epidemiologic studies is lacking. In summary, the accumulated weight of evidence implies far lower risks for pulmonary complications of even regular heavy use of marijuana compared with the grave pulmonary consequences of tobacco.

Postnatal airway growth in cystic fibrosis piglets.

PubMed

Adam, Ryan J; Abou Alaiwa, Mahmoud H; Bouzek, Drake C; Cook, Daniel P; Gansemer, Nicholas D; Taft, Peter J; Powers, Linda S; Stroik, Mallory R; Hoegger, Mark J; McMenimen, James D; Hoffman, Eric A; Zabner, Joseph; Welsh, Michael J; Meyerholz, David K; Stoltz, David A

2017-09-01

Mutations in the gene encoding the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) anion channel cause CF. The leading cause of death in the CF population is lung disease. Increasing evidence suggests that in utero airway development is CFTR-dependent and that developmental abnormalities may contribute to CF lung disease. However, relatively little is known about postnatal CF airway growth, largely because such studies are limited in humans. Therefore, we examined airway growth and lung volume in a porcine model of CF. We hypothesized that CF pigs would have abnormal postnatal airway growth. To test this hypothesis, we performed CT-based airway and lung volume measurements in 3-wk-old non-CF and CF pigs. We found that 3-wk-old CF pigs had tracheas of reduced caliber and irregular shape. Their bronchial lumens were reduced in size proximally but not distally, were irregularly shaped, and had reduced distensibility. Our data suggest that lack of CFTR results in aberrant postnatal airway growth and development, which could contribute to CF lung disease pathogenesis. NEW & NOTEWORTHY This CT scan-based study of airway morphometry in the cystic fibrosis (CF) postnatal period is unique, as analogous studies in humans are greatly limited for ethical and technical reasons. Findings such as reduced airway lumen area and irregular caliber suggest that airway growth and development are CF transmembrane conductance regulator-dependent and that airway growth defects may contribute to CF lung disease pathogenesis. Copyright © 2017 the American Physiological Society.

[Airway-centered interstitial fibrosis related to exposure to fumes from cleaning products].

PubMed

Serrano, Mario; Molina-Molina, María; Ramírez, José; Sánchez, Marcelo; Xaubet, Antoni

2006-10-01

Airway-centered interstitial fibrosis is a little known clinical entity that has only recently been described in the literature. Its pathology is characterized by bronchial fibrosis and localized interstitial pulmonary fibrosis around the airways. The disease has been associated with inhalation of a variety of substances, environmental or occupational, organic or inorganic. Clinical signs, radiographic manifestations, and lung function in patients with airway-centered interstitial fibrosis are similar to those of patients with idiopathic interstitial pneumonia. We describe a case of airway-centered interstitial fibrosis related to exposure to fumes from cleaning products.

Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c.

PubMed

Liu, Gang; Cooley, Marion A; Nair, Prema M; Donovan, Chantal; Hsu, Alan C; Jarnicki, Andrew G; Haw, Tatt Jhong; Hansbro, Nicole G; Ge, Qi; Brown, Alexandra C; Tay, Hock; Foster, Paul S; Wark, Peter A; Horvat, Jay C; Bourke, Jane E; Grainge, Chris L; Argraves, W Scott; Oliver, Brian G; Knight, Darryl A; Burgess, Janette K; Hansbro, Philip M

2017-12-01

Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin-1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)-induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c-deficient (Fbln1c -/- ) mice had reduced mucin (MUC) 5 AC levels, but not MUC5B levels, in the airways as compared with wild-type (WT) mice. Fbln1c interacted with fibronectin and periostin that was linked to collagen deposition around the small airways. Fbln1c -/- mice with AAD also had reduced numbers of α-smooth muscle actin-positive cells around the airways and reduced airway contractility as compared with WT mice. After HDM challenge, these mice also had fewer airway inflammatory cells, reduced interleukin (IL)-5, IL-13, IL-33, tumour necrosis factor (TNF) and CXCL1 levels in the lungs, and reduced IL-5, IL-33 and TNF levels in lung-draining lymph nodes. Therapeutic targeting of Fbln1c reduced the numbers of GATA3-positive Th2 cells in the lymph nodes and lungs after chronic HDM challenge. Treatment also reduced the secretion of IL-5 and IL-13 from co-cultured dendritic cells and T cells restimulated with HDM extract. Human epithelial cells cultured with Fbln1c peptide produced more CXCL1 mRNA than medium-treated controls. Our data show that Fbln1c may be a therapeutic target in chronic asthma. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Lung Function and Inflammatory responses in healthy young adults exposed to 0.06 ppm Ozone for 6.6 hours

EPA Science Inventory

Rationale: Exposure to ozone causes a decrease in spirometric lung function and an increase in airway inflammation in healthy young adults at concentrations as low as 0.08 ppm close to the the National Ambient Air Quality Standard for ground level ozone. Objectives: To test wheth...

Airway segmentation and analysis for the study of mouse models of lung disease using micro-CT

NASA Astrophysics Data System (ADS)

Artaechevarria, X.; Pérez-Martín, D.; Ceresa, M.; de Biurrun, G.; Blanco, D.; Montuenga, L. M.; van Ginneken, B.; Ortiz-de-Solorzano, C.; Muñoz-Barrutia, A.

2009-11-01

Animal models of lung disease are gaining importance in understanding the underlying mechanisms of diseases such as emphysema and lung cancer. Micro-CT allows in vivo imaging of these models, thus permitting the study of the progression of the disease or the effect of therapeutic drugs in longitudinal studies. Automated analysis of micro-CT images can be helpful to understand the physiology of diseased lungs, especially when combined with measurements of respiratory system input impedance. In this work, we present a fast and robust murine airway segmentation and reconstruction algorithm. The algorithm is based on a propagating fast marching wavefront that, as it grows, divides the tree into segments. We devised a number of specific rules to guarantee that the front propagates only inside the airways and to avoid leaking into the parenchyma. The algorithm was tested on normal mice, a mouse model of chronic inflammation and a mouse model of emphysema. A comparison with manual segmentations of two independent observers shows that the specificity and sensitivity values of our method are comparable to the inter-observer variability, and radius measurements of the mainstem bronchi reveal significant differences between healthy and diseased mice. Combining measurements of the automatically segmented airways with the parameters of the constant phase model provides extra information on how disease affects lung function.

Electronic cigarette liquid increases inflammation and virus infection in primary human airway epithelial cells.

PubMed

Wu, Qun; Jiang, Di; Minor, Maisha; Chu, Hong Wei

2014-01-01

The use of electronic cigarettes (e-cigarettes) is rapidly increasing in the United States, especially among young people since e-cigarettes have been perceived as a safer alternative to conventional tobacco cigarettes. However, the scientific evidence regarding the human health effects of e-cigarettes on the lung is extremely limited. The major goal of our current study is to determine if e-cigarette use alters human young subject airway epithelial functions such as inflammatory response and innate immune defense against respiratory viral (i.e., human rhinovirus, HRV) infection. We examined the effects of e-cigarette liquid (e-liquid) on pro-inflammatory cytokine (e.g., IL-6) production, HRV infection and host defense molecules (e.g., short palate, lung, and nasal epithelium clone 1, SPLUNC1) in primary human airway epithelial cells from young healthy non-smokers. Additionally, we examined the role of SPLUNC1 in lung defense against HRV infection using a SPLUNC1 knockout mouse model. We found that nicotine-free e-liquid promoted IL-6 production and HRV infection. Addition of nicotine into e-liquid further amplified the effects of nicotine-free e-liquid. Moreover, SPLUNC1 deficiency in mice significantly increased lung HRV loads. E-liquid inhibited SPLUNC1 expression in primary human airway epithelial cells. These findings strongly suggest the deleterious health effects of e-cigarettes in the airways of young people. Our data will guide future studies to evaluate the impact of e-cigarettes on lung health in human populations, and help inform the public about potential health risks of e-cigarettes.

Severe Achromobacter xylosoxidans infection and loss of sputum bacterial diversity in an adult patient with cystic fibrosis.

PubMed

Talbot, Nick P; Flight, William G

2016-08-01

Achromobacter spp. are emerging pathogens in the lungs of patients with cystic fibrosis. We report the case of an adult patient with cystic fibrosis and chronic A. xylosoxidans infection who experienced rapid, progressive clinical deterioration. Metagenomic analysis of the sputum revealed that the airway microbiota was almost entirely dominated by A. xylosoxidans. We review the impact of this organism on lung function and the airway microbiome in cystic fibrosis, and discuss the potential for cross-infection between patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Relationship between lung function and quantitative computed tomographic parameters of airway remodeling, air trapping, and emphysema in patients with asthma and chronic obstructive pulmonary disease: A single-center study.

PubMed

Hartley, Ruth A; Barker, Bethan L; Newby, Chris; Pakkal, Mini; Baldi, Simonetta; Kajekar, Radhika; Kay, Richard; Laurencin, Marie; Marshall, Richard P; Sousa, Ana R; Parmar, Harsukh; Siddiqui, Salman; Gupta, Sumit; Brightling, Chris E

2016-05-01

There is a paucity of studies comparing asthma and chronic obstructive pulmonary disease (COPD) based on thoracic quantitative computed tomographic (QCT) parameters. We sought to compare QCT parameters of airway remodeling, air trapping, and emphysema between asthmatic patients and patients with COPD and explore their relationship with airflow limitation. Asthmatic patients (n = 171), patients with COPD (n = 81), and healthy subjects (n = 49) recruited from a single center underwent QCT and clinical characterization. Proximal airway percentage wall area (%WA) was significantly increased in asthmatic patients (62.5% [SD, 2.2]) and patients with COPD (62.7% [SD, 2.3]) compared with that in healthy control subjects (60.3% [SD, 2.2], P < .001). Air trapping measured based on mean lung density expiratory/inspiratory ratio was significantly increased in patients with COPD (mean, 0.922 [SD, 0.037]) and asthmatic patients (mean, 0.852 [SD, 0.061]) compared with that in healthy subjects (mean, 0.816 [SD, 0.066], P < .001). Emphysema assessed based on lung density measured by using Hounsfield units below which 15% of the voxels lie (Perc15) was a feature of COPD only (patients with COPD: mean, -964 [SD, 19.62] vs asthmatic patients: mean, -937 [SD, 22.7] and healthy subjects: mean, -937 [SD, 17.1], P < .001). Multiple regression analyses showed that the strongest predictor of lung function impairment in asthmatic patients was %WA, whereas in the COPD and asthma subgrouped with postbronchodilator FEV1 percent predicted value of less than 80%, it was air trapping. Factor analysis of QCT parameters in asthmatic patients and patients with COPD combined determined 3 components, with %WA, air trapping, and Perc15 values being the highest loading factors. Cluster analysis identified 3 clusters with mild, moderate, or severe lung function impairment with corresponding decreased lung density (Perc15 values) and increased air trapping. In asthmatic patients and patients with COPD, lung function impairment is strongly associated with air trapping, with a contribution from proximal airway narrowing in asthmatic patients. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Modeling asthma: Pitfalls, promises, and the road ahead.

PubMed

Rosenberg, Helene F; Druey, Kirk M

2018-02-16

Asthma is a chronic, heterogeneous, and recurring inflammatory disease of the lower airways, with exacerbations that feature airway inflammation and bronchial hyperresponsiveness. Asthma has been modeled extensively via disease induction in both wild-type and genetically manipulated laboratory mice (Mus musculus). Antigen sensitization and challenge strategies have reproduced numerous important features of airway inflammation characteristic of human asthma, notably the critical roles of type 2 T helper cell cytokines. Recent models of disease induction have advanced to include physiologic aeroallergens with prolonged respiratory challenge without systemic sensitization; others incorporate tobacco, respiratory viruses, or bacteria as exacerbants. Nonetheless, differences in lung size, structure, and physiologic responses limit the degree to which airway dynamics measured in mice can be compared to human subjects. Other rodent allergic airways models, including those featuring the guinea pig (Cavia porcellus) might be considered for lung function studies. Finally, domestic cats (Feline catus) and horses (Equus caballus) develop spontaneous obstructive airway disorders with clinical and pathologic features that parallel human asthma. Information on pathogenesis and treatment of these disorders is an important resource. ©2018 Society for Leukocyte Biology.

The Effects of Hyper- and Hypocapnia on Phonatory Laryngeal Airway Resistance in Women

ERIC Educational Resources Information Center

Gillespie, Amanda I.; Slivka, William; Atwood, Charles W., Jr.; Abbott, Katherine Verdolini

2015-01-01

Purpose: The larynx has a dual role in the regulation of gas flow into and out of the lungs while also establishing resistance required for vocal fold vibration. This study assessed reciprocal relations between phonatory functions--specifically, phonatory laryngeal airway resistance (R[subscript law])--and respiratory homeostasis during states of…

Adenovirus-mediated Foxp3 expression in lung epithelial cells reduces airway inflammation in ovalbumin and cockroach-induced asthma model

PubMed Central

Park, Soojin; Chung, Hwan-Suck; Shin, Dasom; Jung, Kyung-Hwa; Lee, Hyunil; Moon, Junghee; Bae, Hyunsu

2016-01-01

Foxp3 is a master regulator of CD4+CD25+ regulatory T-cell (Treg) function and is also a suppressor of SKP2 and HER2/ErbB2. There are an increasing number of reports describing the functions of Foxp3 in cell types other than Tregs. In this context, we evaluated the functions of Foxp3 in ovalbumin- and cockroach-induced asthma models. Foxp3-EGFP-expressing adenovirus or EGFP control adenovirus was administered intratracheally (i.t.), followed by challenge with ovalbumin (OVA) or cockroach extract to induce asthma. Th2 cytokine and immune cell profiles of bronchoalveolar lavage fluid (BALF), as well as serum IgE levels, were analyzed. Histological analyses were also conducted to demonstrate the effects of Foxp3 expression on airway remodeling, goblet cell hyperplasia and inflammatory responses in the lung. Adenoviral Foxp3 was expressed only in lung epithelial cells, and not in CD4+ or CD8+ cells. BALF from Foxp3 gene-delivered mice showed significantly reduced numbers of total immune cells, eosinophils, neutrophils, macrophages and lymphocytes in response to cockroach allergen or OVA. In addition, Foxp3 expression in the lung reduced the levels of Th2 cytokines and IgE in BALF and serum, respectively. Moreover, histopathological analysis also showed that Foxp3 expression substantially inhibited eosinophil infiltration into the airways, goblet cell hyperplasia and smooth muscle cell hypertrophy. Furthermore, when Tregs were depleted by diphtheria toxin in Foxp3DTR mice, the anti-asthmatic functions of Foxp3 were not altered in OVA-challenged asthma models. In this study, our results suggest that Foxp3 expression in lung epithelial cells, and not in Tregs, inhibited OVA- and cockroach extract-induced asthma. PMID:27633092

Protective effects of valproic acid against airway hyperresponsiveness and airway remodeling in a mouse model of allergic airways disease.

PubMed

Royce, Simon G; Dang, William; Ververis, Katherine; De Sampayo, Nishika; El-Osta, Assam; Tang, Mimi L K; Karagiannis, Tom C

2011-12-01

Airway remodeling and airway hyperresponsiveness are major aspects of asthma pathology that are not targeted optimally by existing anti-inflammatory drugs. Histone deacetylase inhibitors have a wide range of effects that may potentially abrogate aspects of remodeling. One such histone deacetylase inhibitor is valproic acid (2-propylvaleric acid). Valproic acid is used clinically as an anti-epileptic drug and is a potent inhibitor of class I histone deacetylases but also inhibits class II histone deacetylases. We used valproic acid as a molecular model of histone deacetylase inhibition in vivo in chronic allergic airways disease mice with airway remodeling and airway hyperresponsiveness. Wild-type Balb/c mice with allergic airways disease were treated with valproic acid or vehicle control. Airway inflammation was assessed by bronchoalveolar lavage fluid cell counts and examination of lung tissue sections. Remodeling was assessed by morphometric analysis of histochemically stained slides and lung function was assessed by invasive plethysmography measurement of airway resistance. Valproic acid treatment did not affect inflammation parameters; however, valproic acid treatment resulted in reduced epithelial thickness as compared to vehicle treated mice (p < 0.01), reduced subepithelial collagen deposition (p < 0.05) and attenuated airway hyperresponsiveness (p < 0.05 and p < 0.01 for the two highest doses of methacholine, respectively). These findings show that treatment with valproic acid can reduce structural airway remodeling changes and hyperresponsiveness, providing further evidence for the potential use of histone deacetylase inhibitors for the treatment of asthma.

[Sputum viscosity and pulmonary function measurements during a one-week parenteral treatment with a standardized oxidation product of oil of turpentine and terpin hydrate].

PubMed

Löllgen-Horres, I; Löllgen, H

1976-01-01

In 23 patients with chronic obstructive lung diseases, viscosity, airway resistance, arterial blood gases and acid-base balance, and sputum aspect were measured before and after one-week treatment with Ozothin, a substance from oxidation products of ol. terebinth. and terpinum hydratum. Within this time, viscosity of the sputum was reduced, airway resistance decreased, and arterial oxygen pressure slightly increased, whereas arterial carbon dioxide tension obvious change of sputum aspect could be observed. Correlation calculations revealed no significant relations between viscosity and the above cited lung function values. The results indicate that administration of Ozothin may liquefy viscous secretion and reduce sputum viscosity.

An iterative method for airway segmentation using multiscale leakage detection

NASA Astrophysics Data System (ADS)

Nadeem, Syed Ahmed; Jin, Dakai; Hoffman, Eric A.; Saha, Punam K.

2017-02-01

There are growing applications of quantitative computed tomography for assessment of pulmonary diseases by characterizing lung parenchyma as well as the bronchial tree. Many large multi-center studies incorporating lung imaging as a study component are interested in phenotypes relating airway branching patterns, wall-thickness, and other morphological measures. To our knowledge, there are no fully automated airway tree segmentation methods, free of the need for user review. Even when there are failures in a small fraction of segmentation results, the airway tree masks must be manually reviewed for all results which is laborious considering that several thousands of image data sets are evaluated in large studies. In this paper, we present a CT-based novel airway tree segmentation algorithm using iterative multi-scale leakage detection, freezing, and active seed detection. The method is fully automated requiring no manual inputs or post-segmentation editing. It uses simple intensity based connectivity and a new leakage detection algorithm to iteratively grow an airway tree starting from an initial seed inside the trachea. It begins with a conservative threshold and then, iteratively shifts toward generous values. The method was applied on chest CT scans of ten non-smoking subjects at total lung capacity and ten at functional residual capacity. Airway segmentation results were compared to an expert's manually edited segmentations. Branch level accuracy of the new segmentation method was examined along five standardized segmental airway paths (RB1, RB4, RB10, LB1, LB10) and two generations beyond these branches. The method successfully detected all branches up to two generations beyond these segmental bronchi with no visual leakages.

The prevalence of reversible airway obstruction in professional football players.

PubMed

Ross, R G

2000-12-01

To determine the prevalence of reversible airway obstruction in a group of professional football training camp participants. All attendees at a Canadian Football League team rookie preseason training camp were invited to participate in a protocol designed to elicit symptoms and signs of reversible airway obstruction (asthma) during the initial preparticipation examination. Those agreeing to the protocol completed a questionnaire containing standardized inquiries about a past history of asthma and the presence of symptoms. Participants then underwent spirometry testing to determine lung function before and after receiving a standardized dose of bronchodilator medication. Players showing evidence of airway obstruction during initial testing and still on the team roster underwent repeat spirometry testing and formal pulmonary function testing during the football season. The follow-up pulmonary function tests were performed to determine those that might benefit from treatment for asthma. Nineteen of 34 (56%) players agreeing to participate had significant reversible airway obstruction as defined by a 12% or greater reversibility in forced expiratory volume in one second (FEV1), peak expiratory flow rate (PEFR), and/or forced expiratory flow rate between 25 and 75% of forced vital capacity (FEF 25-75). In most participants, the diagnosis was made on the basis of spirometry alone. Of those testing positive during initial inquiry, 88% remained positive on repeat spirometry, and 73% had reversible airway obstruction during more stringently controlled hospital-based pulmonary function testing. Those players treated for previously undiagnosed asthma noted an improvement in subjective athletic performance during the football season. Based on the remarkably high prevalence of undiagnosed asthma in this group, it may prove worthwhile to test elite football players using lung function parameters.

Cystic fibrosis: a mucosal immunodeficiency syndrome

PubMed Central

Cohen, Taylor Sitarik; Prince, Alice

2013-01-01

Cystic fibrosis transmembrane conductance regulator (CFTR) functions as a channel that regulates the transport of ions and the movement of water across the epithelial barrier. Mutations in CFTR, which form the basis for the clinical manifestations of cystic fibrosis, affect the epithelial innate immune function in the lung, resulting in exaggerated and ineffective airway inflammation that fails to eradicate pulmonary pathogens. Compounding the effects of excessive neutrophil recruitment, the mutant CFTR channel does not transport antioxidants to counteract neutrophil-associated oxidative stress. Whereas mutant CFTR expression in leukocytes outside of the lung does not markedly impair their function, the expected regulation of inflammation in the airways is clearly deficient in cystic fibrosis. The resulting bacterial infections, which are caused by organisms that have substantial genetic and metabolic flexibility, can resist multiple classes of antibiotics and evade phagocytic clearance. The development of animal models that approximate the human pulmonary phenotypes—airway inflammation and spontaneous infection—may provide the much-needed tools to establish how CFTR regulates mucosal immunity and to test directly the effect of pharmacologic potentiation and correction of mutant CFTR function on bacterial clearance. PMID:22481418

Epithelial organic cation transporters ensure pH-dependent drug absorption in the airway.

PubMed

Horvath, Gabor; Schmid, Nathalie; Fragoso, Miryam A; Schmid, Andreas; Conner, Gregory E; Salathe, Matthias; Wanner, Adam

2007-01-01

Most inhaled beta(2)-adrenergic agonist and anticholinergic bronchodilators have low lipid solubility because of their transient or permanent positive net charge at physiologic pH. Airway absorption of these cationic drugs is incompletely understood. We examined carrier-mediated mechanisms of cationic drug uptake by human airway epithelia. Airway tissues and epithelial cells, obtained from lung donors without preexisting lung disease, were evaluated for organic cation transporter expression by quantitative RT-PCR and immunofluorescence. For in vitro functional studies on primary airway epithelial cells, uptake of the cationic fluorophore 4-[4-(dimethylamino)-styryl]-N-methylpyridinium (ASP+) was characterized. Quantitative RT-PCR analysis demonstrated high mRNA levels for two polyspecific organic cation/carnitine transporters, OCTN1 and OCTN2, in human airway epithelia. Immunofluorescence of human airway sections confirmed OCTN1/2 protein expression, with a predominant localization to the apical portion of epithelial cells. Primary airway epithelial cells showed a carrier-mediated, temperature-sensitive and saturable uptake of ASP(+). Seventy-five to eighty percent of ASP(+) uptake was inhibited by L-carnitine, an OCTN2-carried zwitterion. The uptake was pH dependent, with approximately 3-fold lower rates at acidic (pH 5.7) than at alkaline (pH 8.2) extracellular pH. Albuterol and formoterol inhibited ASP(+) uptake, suggesting that all these molecules are carried by the same transport mechanism. These findings demonstrate the existence and functional role of a pH-dependent organic cation uptake machinery, namely OCTN1 and OCTN2, in human airway epithelia. We suggest that epithelial OCTN1/2 are involved in the delivery of inhaled cationic bronchodilators to the airway tissue.

Club Cell Protein 16 (CC16) Augmentation: A Potential Disease-modifying Approach for Chronic Obstructive Pulmonary Disease (COPD).

PubMed

Laucho-Contreras, Maria E; Polverino, Francesca; Tesfaigzi, Yohannes; Pilon, Aprile; Celli, Bartolome R; Owen, Caroline A

2016-07-01

Club cell protein 16 (CC16) is the most abundant protein in bronchoalveolar lavage fluid. CC16 has anti-inflammatory properties in smoke-exposed lungs, and chronic obstructive pulmonary disease (COPD) is associated with CC16 deficiency. Herein, we explored whether CC16 is a therapeutic target for COPD. We reviewed the literature on the factors that regulate airway CC16 expression, its biologic functions and its protective activities in smoke-exposed lungs using PUBMED searches. We generated hypotheses on the mechanisms by which CC16 limits COPD development, and discuss its potential as a new therapeutic approach for COPD. CC16 plasma and lung levels are reduced in smokers without airflow obstruction and COPD patients. In COPD patients, airway CC16 expression is inversely correlated with severity of airflow obstruction. CC16 deficiency increases smoke-induced lung pathologies in mice by its effects on epithelial cells, leukocytes, and fibroblasts. Experimental augmentation of CC16 levels using recombinant CC16 in cell culture systems, plasmid and adenoviral-mediated over-expression of CC16 in epithelial cells or smoke-exposed murine airways reduces inflammation and cellular injury. Additional studies are necessary to assess the efficacy of therapies aimed at restoring airway CC16 levels as a new disease-modifying therapy for COPD patients.

Transplant Pulmonary Interventions: Translating Lung Transplant Interventions to Nontransplant Patients.

PubMed

Sinha, Neeraj

2016-01-01

Roughly 10% of lung transplant recipients experience airway complications. Although the incidence has decreased dramatically since the first lung transplants were performed in the 1960s, airway complications have continued to adversely affect outcomes. Bronchoscopic interventions such as balloon dilation, airway stenting, and endobronchial electrocautery play an important role in ameliorating the morbidity and mortality associated with these complications. This review describes the array of bronchoscopic interventions used to treat airway complications after lung transplant and how these techniques can be used in nontransplant settings as well.

Lung parenchyma remodeling in a murine model of chronic allergic inflammation.

PubMed

Xisto, Debora G; Farias, Luciana L; Ferreira, Halina C; Picanço, Miguel R; Amitrano, Daniel; Lapa E Silva, Jose R; Negri, Elnara M; Mauad, Thais; Carnielli, Denise; Silva, Luiz Fernando F; Capelozzi, Vera L; Faffe, Debora S; Zin, Walter A; Rocco, Patricia R M

2005-04-15

This study tested the hypotheses that chronic allergic inflammation induces not only bronchial but also lung parenchyma remodeling, and that these histologic changes are associated with concurrent changes in respiratory mechanics. For this purpose, airway and lung parenchyma remodeling were evaluated by quantitative analysis of collagen and elastin, immunohistochemistry (smooth-muscle actin expression, eosinophil, and dendritic cell densities), and electron microscopy. In vivo (airway resistance, viscoelastic pressure, and static elastance) and in vitro (tissue elastance, resistance, and hysteresivity) respiratory mechanics were also analyzed. BALB/c mice were sensitized with ovalbumin and exposed to repeated ovalbumin challenges. A marked eosinophilic infiltration was seen in lung parenchyma and in large and distal airways. Neutrophils, lymphocytes, and dendritic cells also infiltrated the lungs. There was subepithelial fibrosis, myocyte hypertrophy and hyperplasia, elastic fiber fragmentation, and increased numbers of myofibroblasts in airways and lung parenchyma. Collagen fiber content was increased in the alveolar walls. The volume proportion of smooth muscle-specific actin was augmented in distal airways and alveolar duct walls. Airway resistance, viscoelastic pressure, static elastance, and tissue elastance and resistance were significantly increased. In conclusion, prolonged allergen exposure induced remodeling not only of the airway wall but also of the lung parenchyma, leading to in vivo and in vitro mechanical changes.

Imaging Phenotype of Occupational Endotoxin-Related Lung Function Decline.

PubMed

Lai, Peggy S; Hang, Jing-Qing; Zhang, Feng-Ying; Sun, J; Zheng, Bu-Yong; Su, Li; Washko, George R; Christiani, David C

2016-09-01

Although occupational exposures contribute to a significant proportion of obstructive lung disease, the phenotype of obstructive lung disease associated with work-related organic dust exposure independent of smoking remains poorly defined. We identified the relative contributions of smoking and occupational endotoxin exposure to parenchymal and airway remodeling as defined by quantitative computed tomography (CT). The Shanghai Textile Worker Study is a longitudinal study of endotoxin-exposed cotton workers and endotoxin-unexposed silk workers that was initiated in 1981. Spirometry, occupational endotoxin exposure, and smoking habits were assessed at 5-year intervals. High-resolution computed tomography (CT) was performed in 464 retired workers in 2011, along with quantitative lung densitometric and airway analysis. Significant differences in all CT measures were noted across exposure groups. Occupational endotoxin exposure was associated with a decrease (-1.3%) in percent emphysema (LAAI-950), a 3.3-Hounsfield unit increase in 15th percentile density, an 18.1-g increase in lung mass, and a 2.3% increase in wall area percent. Current but not former smoking was associated with a similar CT phenotype. Changes in LAAI-950 were highly correlated with 15th percentile density (correlation -1.0). Lung mass was the only measure associated with forced expiratory volume in 1 sec (FEV1) decline, with each 10-g increase in lung mass associated with an additional loss (-6.1 mL) of FEV1 (p = 0.001) between 1981 and 2011. There are many similarities between the effects of occupational endotoxin exposure and those of tobacco smoke exposure on lung parenchyma and airway remodeling. The effects of occupational endotoxin exposure appear to persist even after the cessation of exposure. LAAI-950 may not be a reliable indicator of emphysema in subjects without spirometric impairment. Lung mass is a CT-based biomarker of accelerated lung function decline. Lai PS, Hang J, Zhang F, Sun J, Zheng BY, Su L, Washko GR, Christiani DC. 2016. Imaging phenotype of occupational endotoxin-related lung function decline. Environ Health Perspect 124:1436-1442; http://dx.doi.org/10.1289/EHP195.

PAI-1 gain-of-function genotype, factors increasing PAI-1 levels, and airway obstruction: The GALA II Cohort.

PubMed

Sherenian, M G; Cho, S H; Levin, A; Min, J-Y; Oh, S S; Hu, D; Galanter, J; Sen, S; Huntsman, S; Eng, C; Rodriguez-Santana, J R; Serebrisky, D; Avila, P C; Kalhan, R; Smith, L J; Borrell, L N; Seibold, M A; Keoki Williams, L; Burchard, E G; Kumar, R

2017-09-01

PAI-1 gain-of-function variants promote airway fibrosis and are associated with asthma and with worse lung function in subjects with asthma. We sought to determine whether the association of a gain-of-function polymorphism in plasminogen activator inhibitor-1 (PAI-1) with airway obstruction is modified by asthma status, and whether any genotype effect persists after accounting for common exposures that increase PAI-1 level. We studied 2070 Latino children (8-21y) with genotypic and pulmonary function data from the GALA II cohort. We estimated the relationship of the PAI-1 risk allele with FEV1/FVC by multivariate linear regression, stratified by asthma status. We examined the association of the polymorphism with asthma and airway obstruction within asthmatics via multivariate logistic regression. We replicated associations in the SAPPHIRE cohort of African Americans (n=1056). Secondary analysis included the effect of the at-risk polymorphism on postbronchodilator lung function. There was an interaction between asthma status and the PAI-1 polymorphism on FEV 1 /FVC (P=.03). The gain-of-function variants, genotypes (AA/AG), were associated with lower FEV 1 /FVC in subjects with asthma (β=-1.25, CI: -2.14,-0.35, P=.006), but not in controls. Subjects with asthma and the AA/AG genotypes had a 5% decrease in FEV 1 /FVC (P<.001). In asthmatics, the risk genotype (AA/AG) was associated with a 39% increase in risk of clinically relevant airway obstruction (OR=1.39, CI: 1.01, 1.92, P=.04). These associations persisted after exclusion of factors that increase PAI-1 including tobacco exposure and obesity. The decrease in the FEV 1 /FVC ratio associated with the risk genotype was modified by asthma status. The genotype increased the odds of airway obstruction by 75% within asthmatics only. As exposures known to increase PAI-1 levels did not mitigate this association, PAI-1 may contribute to airway obstruction in the context of chronic asthmatic airway inflammation. © 2017 John Wiley & Sons Ltd.

Predictive role of arterial carboxyhemoglobin concentrations in ovine burn and smoke inhalation-induced lung injury.

PubMed

Lange, Matthias; Cox, Robert A; Enkhbaatar, Perenlei; Whorton, Elbert B; Nakano, Yoshimitsu; Hamahata, Atsumori; Jonkam, Collette; Esechie, Aimalohi; von Borzyskowski, Sanna; Traber, Lillian D; Traber, Daniel L

2011-05-01

Inhalation injury frequently occurs in burn patients and contributes to the morbidity and mortality of these injuries. Arterial carboxyhemoglobin has been proposed as an indicator of the severity of inhalation injury; however, the interrelation between arterial carboxyhemoglobin and histological alterations has not yet been investigated. Chronically instrumented sheep were subjected to a third degree burn of 40% of the total body surface area and inhalation of 48 breaths of cotton smoke. Carboxyhemoglobin was measured immediately after injury and correlated to clinical parameters of pulmonary function as well as histopathology scores from lung tissue harvested 24 hours after the injury. The injury was associated with a significant decline in pulmonary oxygenation and increases in pulmonary shunting, lung lymph flow, wet/dry weight ratio, congestion score, edema score, inflammation score, and airway obstruction scores. Carboxyhemoglobin was negatively correlated to pulmonary oxygenation and positively correlated to pulmonary shunting, lung lymph flow, and lung wet/dry weight ratio. No significant correlations could be detected between carboxyhemoglobin and histopathology scores and airway obstruction scores. Arterial carboxyhemoglobin in sheep with combined burn and inhalation injury are correlated with the degree of pulmonary failure and edema formation, but not with certain histological alterations including airway obstruction scores.

Use of body plethysmography to measure effect of bimaxillary orthognathic surgery on airway resistance and lung volumes.

PubMed

Rezaeetalab, Fariba; Kazemian, Mozhgan; Vaezi, Touraj; Shaban, Barratollah

2015-12-01

Bimaxillary orthognathic surgery can cause changes to respiration and the airways. We used body plethysmography to evaluate its effect on airway resistance and lung volumes in 20 patients with class III malocclusions (8 men and 12 women, aged 17 - 32 years). Lung volumes (forced vital capacity; forced inspiratory volume/one second; forced expiratory volume/one second: forced vital capacity; peak expiratory flow; maximum expiratory flow 25-75; maximum inspiratory flow; total lung capacity; residual volume; residual volume:total lung capacity), and airway resistance were evaluated one week before, and six months after, operation. Bimaxillary operations to correct class III malocclusions significantly increased airway resistance, residual volume, total lung capacity, and residual volume:total lung capacity. Other variables also changed after operation but not significantly so. Orthognathic operations should be done with caution in patients who have pre-existing respiratory diseases. Copyright © 2015 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Fas activity mediates airway inflammation during mouse adenovirus type 1 respiratory infection.

PubMed

Adkins, Laura J; Molloy, Caitlyn T; Weinberg, Jason B

2018-06-13

CD8 T cells play a key role in clearance of mouse adenovirus type 1 (MAV-1) from the lung and contribute to virus-induced airway inflammation. We tested the hypothesis that interactions between Fas ligand (FasL) and Fas mediate the antiviral and proinflammatory effects of CD8 T cells. FasL and Fas expression were increased in the lungs of C57BL/6 (B6) mice during MAV-1 respiratory infection. Viral replication and weight loss were similar in B6 and Fas-deficient (lpr) mice. Histological evidence of pulmonary inflammation was similar in B6 and lpr mice, but lung mRNA levels and airway proinflammatory cytokine concentrations were lower in MAV-1-infected lpr mice compared to infected B6 mice. Virus-induced apoptosis in lungs was not affected by Fas deficiency. Our results suggest that the proinflammatory effects of CD8 T cells during MAV-1 infection are mediated in part by Fas activation and are distinct from CD8 T cell antiviral functions. Copyright © 2018 Elsevier Inc. All rights reserved.

In Vitro Microfluidic Models of Mucus-Like Obstructions in Small Airways

NASA Astrophysics Data System (ADS)

Mulligan, Molly K.; Grotberg, James B.; Sznitman, Josué

2012-11-01

Liquid plugs can form in the lungs as a result of a host of different diseases, including cystic fibrosis and chronic obstructive pulmonary disease. The existence of such fluid obstructions have been found as far down in the bronchiole tree as the sixteenth generation, where bronchiole openings have diameters on the order of a hundred to a few hundred microns. Understanding the propagation of liquid plugs within the bifurcating branches of bronchiole airways is important because their presence in the lungs, and their rupture and break-up, can cause injury to the epithelial cells lining the airway walls as a result of high wall shear stresses. In particular, liquid plug rupture and break-up frequently occurs at airway bifurcations. Until present, however, experimental studies of liquid plugs have generally been restricted to Newtonian fluids that do not reflect the actual pseudoplastic properties of lung mucus. The present work attempts to uncover the propagation, rupture and break-up of mucus-like liquid plugs in the lower generations of the airway tree using microfluidic models. Our approach allows the dynamics of mucus-like plug break-up to be studied in real-time, in a one-to-one in vitro model, as a function of mucus rheology and bronchial tree geometry.

Cluster-guided imaging-based CFD analysis of airflow and particle deposition in asthmatic human lungs

NASA Astrophysics Data System (ADS)

Choi, Jiwoong; Leblanc, Lawrence; Choi, Sanghun; Haghighi, Babak; Hoffman, Eric; Lin, Ching-Long

2017-11-01

The goal of this study is to assess inter-subject variability in delivery of orally inhaled drug products to small airways in asthmatic lungs. A recent multiscale imaging-based cluster analysis (MICA) of computed tomography (CT) lung images in an asthmatic cohort identified four clusters with statistically distinct structural and functional phenotypes associating with unique clinical biomarkers. Thus, we aimed to address inter-subject variability via inter-cluster variability. We selected a representative subject from each of the 4 asthma clusters as well as 1 male and 1 female healthy controls, and performed computational fluid and particle simulations on CT-based airway models of these subjects. The results from one severe and one non-severe asthmatic cluster subjects characterized by segmental airway constriction had increased particle deposition efficiency, as compared with the other two cluster subjects (one non-severe and one severe asthmatics) without airway constriction. Constriction-induced jets impinging on distal bifurcations led to excessive particle deposition. The results emphasize the impact of airway constriction on regional particle deposition rather than disease severity, demonstrating the potential of using cluster membership to tailor drug delivery. NIH Grants U01HL114494 and S10-RR022421, and FDA Grant U01FD005837. XSEDE.

Differences of airway dimensions between patients with and without bronchiolitis obliterans syndrome after lung transplantation-Computer-assisted quantification of computed tomography.

PubMed

Doellinger, Felix; Weinheimer, Oliver; Zwiener, Isabella; Mayer, Eckhard; Buhl, Roland; Fahlenkamp, Ute Lina; Dueber, Christoph; Achenbach, Tobias

2016-08-01

The aim of our retrospective study was to determine whether a dedicated software for assessment of airway morphology can detect differences in airway dimensions between patients with and without bronchiolitis obliterans syndrome (BOS), regarded as the clinical correlate of chronic lung allograft rejection. 12 patients with and 14 patients without diagnosis of BOS were enrolled in the study. Evaluation of bronchial wall area percentage (WA%) and bronchial wall thickness (WT) in all follow-up CT scans was performed using a semiautomatic airway assessment tool. We assessed temporal changes (ΔWA%, ΔWT) and compared these morphological parameters with forced expiratory volume in one second (ΔFEV1). In patients with and without BOS, the temporal changes over the entire follow-up were 26.6% versus 16.2% for ΔFEV1 (p=0.034), 14.2% versus 5.4% for ΔWA% (p=0.003) and 0.212mm versus 0.064mm for ΔWT (p=0.011). We detected significant differences of the temporal changes of airway dimensions (ΔWA%, ΔWT) between lung transplant recipients with and without BOS. We conclude that computer-assisted bronchial wall measurements in CT scans might complement the information from pulmonary function tests and establish as a non-invasive method to confirm BOS in lung transplant recipients in the future. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cyclooxygenase-2-dependent bronchoconstriction in perfused rat lungs exposed to endotoxin.

PubMed

Uhlig, S; Nüsing, R; von Bethmann, A; Featherstone, R L; Klein, T; Brasch, F; Müller, K M; Ullrich, V; Wendel, A

1996-05-01

Lipopolysaccharides (LPS), widely used to study the mechanisms of gram-negative sepsis, increase airway resistance by constriction of terminal bronchioles. The role of the cyclooxygenase (COX) isoenzymes and their prostanoid metabolites in this process was studied. Pulmonary resistance, the release of thromboxane (TX) and the expression of COX-2 mRNA were measured in isolated blood-free perfused rat lungs exposed to LPS. LPS induced the release of TX and caused increased airway resistance after about 30 min. Both TX formation and LPS-induced bronchoconstriction were prevented by treatment with the unspecific COX inhibitor acetyl salicylic acid, the specific COX-2 inhibitor CGP-28238, dexamethasone, actinomycin D, or cycloheximide. LPS-induced bronchoconstriction was also inhibited by the TX receptor antagonist BM-13177. The TX-mimetic compound, U-46619, increased airway resistance predominantly by constricting terminal bronchioles. COX-2-specific mRNA in lung tissue was elevated after LPS exposure, and this increase was attenuated by addition of dexamethasone or of actinomycin D. In contrast to LPS, platelet-activating factor (PAF) induced immediate TX release and bronchoconstriction that was prevented by acetyl salicylic acid, but not by CGP-28238. LPS elicits the following biochemical and functional changes in rat lungs: (i) induction of COX-2; (ii) formation of prostaglandins and TX; (iii) activation of the TX receptor on airway smooth muscle cells; (iv) constriction of terminal bronchioles; and (v) increased airway resistance. In contrast to LPS, the PAF-induced TX release is likely to depend on COX-1.

Investigation of pulmonary acoustic simulation: comparing airway model generation techniques

NASA Astrophysics Data System (ADS)

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

2014-03-01

Alterations in the structure and function of the pulmonary system that occur in disease or injury often give rise to measurable spectral, spatial and/or temporal changes in lung sound production and transmission. These changes, if properly quantified, might provide additional information about the etiology, severity and location of trauma, injury, or pathology. With this in mind, the authors are developing a comprehensive computer simulation model of pulmonary acoustics, known as The Audible Human Project™. Its purpose is to improve our understanding of pulmonary acoustics and to aid in interpreting measurements of sound and vibration in the lungs generated by airway insonification, natural breath sounds, and external stimuli on the chest surface, such as that used in elastography. As a part of this development process, finite element (FE) models were constructed of an excised pig lung that also underwent experimental studies. Within these models, the complex airway structure was created via two methods: x-ray CT image segmentation and through an algorithmic means called Constrained Constructive Optimization (CCO). CCO was implemented to expedite the segmentation process, as airway segments can be grown digitally. These two approaches were used in FE simulations of the surface motion on the lung as a result of sound input into the trachea. Simulation results were compared to experimental measurements. By testing how close these models are to experimental measurements, we are evaluating whether CCO can be used as a means to efficiently construct physiologically relevant airway trees.

Atopic asthmatic subjects but not atopic subjects without ...

EPA Pesticide Factsheets

BACKGROUND: Asthma is a known risk factor for acute ozone-associated respiratory disease. Ozone causes an immediate decrease in lung function and increased airway inflammation. The role of atopy and asthma in modulation of ozone-induced inflammation has not been determined. OBJECTIVE: We sought to determine whether atopic status modulates ozone response phenotypes in human subjects. METHODS: Fifty volunteers (25 healthy volunteers, 14 atopic nonasthmatic subjects, and 11 atopic asthmatic subjects not requiring maintenance therapy) underwent a 0.4-ppm ozone exposure protocol. Ozone response was determined based on changes in lung function and induced sputum composition, including airway inflammatory cell concentration, cell-surface markers, and cytokine and hyaluronic acid concentrations. RESULTS: All cohorts experienced similar decreases in lung function after ozone. Atopic and atopic asthmatic subjects had increased sputum neutrophil numbers and IL-8 levels after ozone exposure; values did not significantly change in healthy volunteers. After ozone exposure, atopic asthmatic subjects had significantly increased sputum IL-6 and IL-1beta levels and airway macrophage Toll-like receptor 4, Fc(epsilon)RI, and CD23 expression; values in healthy volunteers and atopic nonasthmatic subjects showed no significant change. Atopic asthmatic subjects had significantly decreased IL-10 levels at baseline compared with healthy volunteers; IL-10 levels did not significa

[Body plethysmography (I): Standardisation and quality criteria].

PubMed

de Mir Messa, I; Sardón Prado, O; Larramona, H; Salcedo Posadas, A; Villa Asensi, J R

2015-08-01

Whole body plethysmography is used to measure lung volumes, capacities and resistances. It is a well standardised technique, and although it is widely used in paediatric chest diseases units, it requires specific equipment, specialist staff, and some cooperation by the patient. Plethysmography uses Boyle's law in order to measure the intrathoracic gas volume or functional residual capacity, and once this is determined, the residual volume and total lung capacity is extrapolated. The measurement of total lung capacity is necessary for the diagnosis of restrictive diseases. Airway resistance is a measurement of obstruction, with the total resistance being able to be measured, which includes chest wall, lung tissue and airway resistance, as well as the specific airway resistance, which is a more stable parameter that is determined by multiplying the measured values of airway resistance and functional residual capacity. The complexity of this technique, the reference equations, the differences in the equipment and their variability, and the conditions in which it is performed, has led to the need for its standardisation. Throughout this article, the practical aspects of plethysmography are analysed, specifying recommendations for performing it, its systematic calibration and the calculations that must be made, as well as the interpretation of the results obtained. The aim of this article is to provide a better understanding of the principles of whole body plethysmography with the aim of optimising the interpretation of the results, leading to improved management of the patient, as well as a consensus among the speciality. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

Transfer factor, lung volumes, resistance and ventilation distribution in healthy adults.

PubMed

Verbanck, Sylvia; Van Muylem, Alain; Schuermans, Daniel; Bautmans, Ivan; Thompson, Bruce; Vincken, Walter

2016-01-01

Monitoring of chronic lung disease requires reference values of lung function indices, including putative markers of small airway function, spanning a wide age range.We measured spirometry, transfer factor of the lung for carbon monoxide (TLCO), static lung volume, resistance and ventilation distribution in a healthy population, studying at least 20 subjects per sex and per decade between the ages of 20 and 80 years.With respect to the Global Lung Function Initiative reference data, our subjects had average z-scores for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC of -0.12, 0.04 and -0.32, respectively. Reference equations were obtained which could account for a potential dependence of index variability on age and height. This was done for (but not limited to) indices that are pertinent to asthma and chronic obstructive pulmonary disease studies: forced expired volume in 6 s, forced expiratory flow, TLCO, specific airway conductance, residual volume (RV)/total lung capacity (TLC), and ventilation heterogeneity in acinar and conductive lung zones.Deterioration in acinar ventilation heterogeneity and lung clearance index with age were more marked beyond 60 years, and conductive ventilation heterogeneity showed the greatest increase in variability with age. The most clinically relevant deviation from published reference values concerned RV/TLC values, which were considerably smaller than American Thoracic Society/European Respiratory Society-endorsed reference values. Copyright ©ERS 2016.

Corticosteroid treatment inhibits airway hyperresponsiveness and lung injury in a murine model of chemical-induced airway inflammation.

PubMed

Wigenstam, Elisabeth; Jonasson, Sofia; Koch, Bo; Bucht, Anders

2012-11-15

Exposure to toxic alkylating mustard agents causes both acute and long-term effects to the lungs as indicated by increased number of inflammatory cells in airways, lung edema and lung tissue fibrosis. We have previously demonstrated that treatment with the corticosteroid dexamethasone 1 h after lung exposure to the nitrogen mustard analog melphalan protects mice from acute and sub-acute inflammatory responses, as well as from lung tissue fibrosis. In order to address the importance of early anti-inflammatory treatment, we investigated the therapeutic effect of dexamethasone administered 1, 2 or 6 h following exposure to melphalan. C57BL/6 mice were exposed to melphalan and treated with dexamethasone 1, 2 or 6 h after exposure. Twenty hours or 14 days post exposure mice were subjected to analysis of respiratory mechanics where the effects of incremental doses of methacholine on central and peripheral lung components were measured. We also determined the amount of inflammatory cells in the bronchoalveolar lavage fluid and measured the amount of collagen content in the lungs. Melphalan exposure increased airway hyperresponsiveness in both central and peripheral airways and induced an airway inflammation dominated by infiltration of macrophages and neutrophils. Dexamethasone given 1 h after exposure to melphalan provided better protection against airway inflammation than administration 2 or 6 h after exposure. Collagen deposition 14 days after exposure was decreased due to dexamethasone treatment. Early treatment with dexamethasone is important in order to reduce the airway hyperresponsiveness and inflammation caused by toxic alkylating mustards such as melphalan. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Long-term Outcome of Short Metallic Stents for Lobar Airway Stenosis.

PubMed

Fruchter, Oren; Abed El Raouf, Bayya; Rosengarten, Dror; Kramer, Mordechai R

2017-07-01

Whereas stents are considered an excellent treatment for proximal central major airway stenosis, the value of stenting for distal lobar airway stenosis is still controversial. Our aim was to explore the short-term and long-term outcome of metallic stents placed for benign and malignant lobar airway stenosis. Between July 2007 and July 2014, 14 patients underwent small airway stent insertion. The clinical follow-up included serial semiannual physical examinations, pulmonary function tests, imaging, and bronchoscopy. The etiologies for airway stenosis were: early post-lung transplantation bronchial stenosis (N=5), sarcoidosis (N=1), amyloidosis (N=1), anthracofibrosis (N=1), right middle lobe syndrome due to external lymph node compression (N=1), lung cancer (N=4), and stenosis of the left upper lobe of unknown etiology (N=1). Stents were placed in the right upper lobe bronchus (N=2), right middle lobe bronchus (N=6), left upper lobe bronchus (N=4), linguar bronchus (N=1), and left lower lobe bronchus (N=1). The median follow-up period ranged from 2 to 72 months (median 18 mo). Immediate relief of symptoms was achieved in the vast majority of patients (13/14, 92%). Out of 10 patients with benign etiology for stenosis, 9 (90%) experienced sustained and progressive improvement in pulmonary function tests and clinical condition. We describe our positive experience with small stents for lobar airway stenosis; further prospective trials are required to evaluate the value of this novel modality of treatment.

CFTR and lung homeostasis

PubMed Central

Matalon, Sadis

2014-01-01

CFTR is a cAMP-activated chloride and bicarbonate channel that is critical for lung homeostasis. Decreases in CFTR expression have dire consequences in cystic fibrosis (CF) and have been suggested to be a component of the lung pathology in chronic obstructive pulmonary disease. Decreases or loss of channel function often lead to mucus stasis, chronic bacterial infections, and the accompanying chronic inflammatory responses that promote progressive lung destruction, and, eventually in CF, lung failure. Here we discuss CFTR's functional role airway surface liquid hydration and pH, in regulation of other channels such as the epithelial sodium channel, and in regulating inflammatory responses in the lung. PMID:25381027

Voluntary pulmonary function screening identifies high rates of undiagnosed asymptomatic chronic obstructive pulmonary disease.

PubMed

Wang, Shengyu; Gong, Wei; Tian, Yao

2016-05-01

Chronic obstructive pulmonary disease (COPD) is projected to be the third leading cause of death by 2020. Early detection and screening may alter the course and prognosis associated with lung disease. We investigated the effectiveness of a voluntary public lung function screening program and factors that had a predictive value for asymptomatic COPD in Xi'an, China. Pulmonary function testing (PFT) was conducted on volunteers recruited from four community centers in Xi'an, China, between July and August 2012. Participants underwent three forced vital capacity maneuvers. The maneuver with the best forced expiratory volume in first second was retained. Participants filled out a medical history and environmental exposure survey before undergoing the PFT. Patients who self-reported lung disease on the health survey were excluded from the analysis. Logistical regression was used to determine associations with airway obstruction. A total of 803 volunteers participated in this study, and 33 subjects were excluded as the participants did not meet the requirements of PFT. Of the 770 volunteers, 44 participants had been diagnosed with chronic respiratory diseases previously, and 144 participants (18.7%) met COPD criteria. Four hundred forty-four participants did not self-report any respiratory symptoms, and the remaining 282 participants self-reported respiratory symptoms. Of the asymptomatic participants, 98 volunteers had PFT results that were consistent with COPD and 68.1% of asymptomatic participants were undiagnosed. A greater percentage of women than men had moderate or severe airway obstruction (p = 0.004).Only smoking status (odds ratio = 2.64, 95% confidence interval 1.20-6.04) was associated with asymptomatic COPD. Voluntary public lung function screening programs in China are likely to identify a large number of undiagnosed, asymptomatic COPD. Smoking status is associated with airway obstruction and a greater percentage of women than men had moderate or severe airway obstruction. © The Author(s) 2016.

A follow-up study of airway symptoms and lung function among residents and workers 5.5 years after an oil tank explosion.

PubMed

Granslo, Jens-Tore; Bråtveit, Magne; Hollund, Bjørg Eli; Lygre, Stein Håkon Låstad; Svanes, Cecilie; Moen, Bente Elisabeth

2017-01-17

Assess if people who lived or worked in an area polluted after an oil tank explosion had persistent respiratory health impairment as compared to a non-exposed population 5.5 years after the event. A follow-up study 5.5 years after the explosion, 330 persons aged 18-67 years, compared lung function, lung function decline and airway symptoms among exposed persons (residents <6 km from the accident site or working in the industrial harbour at the time of the explosion) with a non-exposed group (residence >20 km away). Also men in the exposed group who had participated in accident related tasks (firefighting or clean-up of pollution) were compared with men who did not. Data were analysed using Poisson regression, adjusted for smoking, occupational exposure, atopy and age. Exposed men who had participated in accident related tasks had higher prevalence of lower airway symptoms after 5.5 years (n = 24 [73%]) than non-exposed men (28 [48%]), (adjusted relative risk 1.51 [95% confidence interval 1.07, 2.14]). Among men who participated in accident related tasks FEV 1 decline was 48 mL per year, and 12 mL among men who did not (adjusted difference -34 mL per year [-67 mL, -1 mL]), and at follow-up FEV 1 /FVC ratio was 71.4 and 74.2% respectively, (adjusted difference -3.0% [-6.0, 0.0%]). Residents and workers had more airway symptoms and impaired lung function 5.5 years after an oil tank explosion, most significant for a group of men engaged in firefighting and clean-up of pollution after the accident. Public health authorities should be aware of long-term consequences after such accidents.

Prolonged Injury and Altered Lung Function after Ozone Inhalation in Mice with Chronic Lung Inflammation

PubMed Central

Groves, Angela M.; Gow, Andrew J.; Massa, Christopher B.; Laskin, Jeffrey D.

2012-01-01

Surfactant protein–D (Sftpd) is a pulmonary collectin important in down-regulating macrophage inflammatory responses. In these experiments, we analyzed the effects of chronic macrophage inflammation attributable to loss of Sftpd on the persistence of ozone-induced injury, macrophage activation, and altered functioning in the lung. Wild-type (Sftpd+/+) and Sftpd−/− mice (aged 8 wk) were exposed to air or ozone (0.8 parts per million, 3 h). Bronchoalveolar lavage (BAL) fluid and tissue were collected 72 hours later. In Sftpd−/− mice, but not Sftpd+/+ mice, increased BAL protein and nitrogen oxides were observed after ozone inhalation, indicating prolonged lung injury and oxidative stress. Increased numbers of macrophages were also present in BAL fluid and in histologic sections from Sftpd−/− mice. These cells were enlarged and foamy, suggesting that they were activated. This conclusion was supported by findings of increased BAL chemotactic activity, and increased expression of inducible nitric oxide synthase in lung macrophages. In both Sftpd+/+ and Sftpd−/− mice, inhalation of ozone was associated with functional alterations in the lung. Although these alterations were limited to central airway mechanics in Sftpd+/+ mice, both central airway and parenchymal mechanics were modified by ozone exposure in Sftpd−/− mice. The most notable changes were evident in resistance and elastance spectra and baseline lung function, and in lung responsiveness to changes in positive end-expiratory pressure. These data demonstrate that a loss of Sftpd is associated with prolonged lung injury, oxidative stress, and macrophage accumulation and activation in response to ozone, and with more extensive functional changes consistent with the loss of parenchymal integrity. PMID:22878412

Acute Exacerbations of COPD Are Associated With Increased Expression of Heparan Sulfate and Chondroitin Sulfate in BAL.

PubMed

Papakonstantinou, Eleni; Klagas, Ioannis; Roth, Michael; Tamm, Michael; Stolz, Daiana

2016-03-01

Acute exacerbations of COPD (AECOPDs) are associated with accelerated aggravation of clinical symptoms and deterioration of pulmonary function. The mechanisms by which exacerbations may contribute to airway remodeling and declined lung function are poorly understood. We investigated whether AECOPDs are associated with differential expression of glycosaminoglycans in BAL in a cohort of 97 patients with COPD. Patients with COPD with either stable disease (n = 53) or AECOPD (n = 44) and undergoing diagnostic bronchoscopy were matched for demographics and lung function parameters. Levels of heparan sulfate, chondroitin sulfate, dermatan sulfate, and matrix metalloproteinases (MMPs) in BAL were measured by enzyme-linked immunosorbent assay. Heparan sulfate and chondroitin sulfate were significantly increased in BAL of patients during exacerbations. Levels of heparan sulfate were higher in the BAL of patients with microbial infections. Chondroitin sulfate was negatively correlated with FEV1 % predicted but not with diffusing capacity of lung for carbon monoxide % predicted, indicating that chondroitin sulfate is associated with airway remodeling, leading to obstruction rather than to emphysema. Furthermore, heparan sulfate and chondroitin sulfate were significantly correlated with MMP-9, MMP-2, and MMP-12 in BAL, indicating that they were cleaved from their respective proteoglycans by MMPs and subsequently washed out in BAL. During AECOPD, there is increased expression of heparan sulfate and chondroitin sulfate in BAL. These molecules are significantly correlated with MMPs in BAL, indicating that they may be associated with airway remodeling and may lead to lung function decline during exacerbations of COPD. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Development of a rhesus monkey lung geometry model and application to particle deposition in comparison to humans

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

Asgharian, Bahman; Price, Owen; McClellan, Gene

2012-11-01

The exposure-dose-response characterization of an inhalation hazard established in an animal species needs to be translated to an equivalent characterization in humans relative to comparable doses or exposure scenarios. Here, the first geometry model of the conducting airways for rhesus monkeys is developed based upon CT images of the conducting airways of a 6-month-old male, rhesus monkey. An algorithm was developed for adding the alveolar region airways using published rhesus morphometric data. The resultant lung geometry model can be used in mechanistic particle or gaseous dosimetry models. Such dosimetry models require estimates of the upper respiratory tract volume of themore » animal and the functional residual capacity, as well as of the tidal volume and breathing frequency of the animal. The relationship of these variables to rhesus monkeys of differing body weights was established by synthesizing and modeling published data as well as modeling pulmonary function measurements on 121 rhesus control animals. Deposition patterns of particles up to 10 µm in size were examined for endotracheal and and up to 5 µm for spontaneous breathing in infant and young adult monkeys and compared to those for humans. Deposition fraction of respirable size particles was found to be higher in the conducting airways of infant and young adult rhesus monkeys compared to humans. Due to the filtering effect of the conducting airways, pulmonary deposition in rhesus monkeys was lower than that in humans. Finally, future research areas are identified that would either allow replacing assumptions or improving the newly developed lung model.« less

Development of a rhesus monkey lung geometry model and application to particle deposition in comparison to humans

PubMed Central

Asgharian, Bahman; Price, Owen; McClellan, Gene; Corley, Rick; Einstein, Daniel R.; Jacob, Richard E.; Harkema, Jack; Carey, Stephan A.; Schelegle, Edward; Hyde, Dallas; Kimbell, Julia S.; Miller, Frederick J.

2016-01-01

The exposure-dose-response characterization of an inhalation hazard established in an animal species needs to be translated to an equivalent characterization in humans relative to comparable doses or exposure scenarios. Here, the first geometry model of the conducting airways for rhesus monkeys is developed based upon CT images of the conducting airways of a 6-month-old male, rhesus monkey. An algorithm was developed for adding the alveolar region airways using published rhesus morphometric data. The resultant lung geometry model can be used in mechanistic particle or gaseous dosimetry models. Such dosimetry models require estimates of the upper respiratory tract volume of the animal and the functional residual capacity, as well as of the tidal volume and breathing frequency of the animal. The relationship of these variables to rhesus monkeys of differing body weights was established by synthesizing and modeling published data as well as modeling pulmonary function measurements on 121 rhesus control animals. Deposition patterns of particles up to 10 μm in size were examined for endotracheal and and up to 5 μm for spontaneous breathing in infant and young adult monkeys and compared to those for humans. Deposition fraction of respirable size particles was found to be higher in the conducting airways of infant and young adult rhesus monkeys compared to humans. Due to the filtering effect of the conducting airways, pulmonary deposition in rhesus monkeys was lower than that in humans. Future research areas are identified that would either allow replacing assumptions or improving the newly developed lung model. PMID:23121298

Alpha-1 Antitrypsin Mitigates the Inhibition of Airway Epithelial Cell Repair by Neutrophil Elastase.

PubMed

Garratt, Luke W; Sutanto, Erika N; Ling, Kak-Ming; Looi, Kevin; Iosifidis, Thomas; Martinovich, Kelly M; Shaw, Nicole C; Buckley, Alysia G; Kicic-Starcevich, Elizabeth; Lannigan, Francis J; Knight, Darryl A; Stick, Stephen M; Kicic, Anthony

2016-03-01

Neutrophil elastase (NE) activity is associated with many destructive lung diseases and is a predictor for structural lung damage in early cystic fibrosis (CF), which suggests normal maintenance of airway epithelium is prevented by uninhibited NE. However, limited data exist on how the NE activity in airways of very young children with CF affects function of the epithelia. The aim of this study was to determine if NE activity could inhibit epithelial homeostasis and repair and whether any functional effect was reversible by antiprotease alpha-1 antitrypsin (α1AT) treatment. Viability, inflammation, apoptosis, and proliferation were assessed in healthy non-CF and CF pediatric primary airway epithelial cells (pAECnon-CF and pAECCF, respectively) during exposure to physiologically relevant NE. The effect of NE activity on pAECCF wound repair was also assessed. We report that viability after 48 hours was significantly decreased by 100 nM NE in pAECnon-CF and pAECCF owing to rapid cellular detachment that was accompanied by inflammatory cytokine release. Furthermore, both phenotypes initiated an apoptotic response to 100 nM NE, whereas ≥ 50 nM NE activity significantly inhibited the proliferative capacity of cultures. Similar concentrations of NE also significantly inhibited wound repair of pAECCF, but this effect was reversed by the addition of α1AT. Collectively, our results demonstrate free NE activity is deleterious for epithelial homeostasis and support the hypothesis that proteases in the airway contribute directly to CF structural lung disease. Our results also highlight the need to investigate antiprotease therapies in early CF disease in more detail.

Airway mucus, inflammation and remodeling: emerging links in the pathogenesis of chronic lung diseases.

PubMed

Zhou-Suckow, Zhe; Duerr, Julia; Hagner, Matthias; Agrawal, Raman; Mall, Marcus A

2017-03-01

Airway mucus obstruction is a hallmark of many chronic lung diseases including rare genetic disorders such as cystic fibrosis (CF) and primary ciliary dyskinesia, as well as common lung diseases such as asthma and chronic obstructive pulmonary disease (COPD), which have emerged as a leading cause of morbidity and mortality worldwide. However, the role of excess airway mucus in the in vivo pathogenesis of these diseases remains poorly understood. The generation of mice with airway-specific overexpression of epithelial Na + channels (ENaC), exhibiting airway surface dehydration (mucus hyperconcentration), impaired mucociliary clearance (MCC) and mucus plugging, led to a model of muco-obstructive lung disease that shares key features of CF and COPD. In this review, we summarize recent progress in the understanding of causes of impaired MCC and in vivo consequences of airway mucus obstruction that can be inferred from studies in βENaC-overexpressing mice. These studies confirm that mucus hyperconcentration on airway surfaces plays a critical role in the pathophysiology of impaired MCC, mucus adhesion and airway plugging that cause airflow obstruction and provide a nidus for bacterial infection. In addition, these studies support the emerging concept that excess airway mucus per se, probably via several mechanisms including hypoxic epithelial necrosis, retention of inhaled irritants or allergens, and potential immunomodulatory effects, is a potent trigger of chronic airway inflammation and associated lung damage, even in the absence of bacterial infection. Finally, these studies suggest that improvement of mucus clearance may be a promising therapeutic strategy for a spectrum of muco-obstructive lung diseases.

Magnetomotive optical coherence elastography for relating lung structure and function in cystic fibrosis

NASA Astrophysics Data System (ADS)

Chhetri, Raghav K.; Carpenter, Jerome; Superfine, Richard; Randell, Scott H.; Oldenburg, Amy L.

2010-02-01

Cystic fibrosis (CF) is a genetic defect in the cystic fibrosis transmembrane conductance regulator protein and is the most common life-limiting genetic condition affecting the Caucasian population. It is an autosomal recessive, monogenic inherited disorder characterized by failure of airway host defense against bacterial infection, which results in bronchiectasis, the breakdown of airway wall extracellular matrix (ECM). In this study, we show that the in vitro models consisting of human tracheo-bronchial-epithelial (hBE) cells grown on porous supports with embedded magnetic nanoparticles (MNPs) at an air-liquid interface are suitable for long term, non-invasive assessment of ECM remodeling using magnetomotive optical coherence elastography (MMOCE). The morphology of ex vivo CF and normal lung tissues using OCT and correlative study with histology is also examined. We also demonstrate a quantitative measure of normal and CF airway elasticity using MMOCE. The improved understanding of pathologic changes in CF lung structure and function and the novel method of longitudinal in vitro ECM assessment demonstrated in this study may lead to new in vivo imaging and elastography methods to monitor disease progression and treatment in cystic fibrosis.

Evaluation of respiratory system mechanics in mice using the forced oscillation technique.

PubMed

McGovern, Toby K; Robichaud, Annette; Fereydoonzad, Liah; Schuessler, Thomas F; Martin, James G

2013-05-15

The forced oscillation technique (FOT) is a powerful, integrative and translational tool permitting the experimental assessment of lung function in mice in a comprehensive, detailed, precise and reproducible manner. It provides measurements of respiratory system mechanics through the analysis of pressure and volume signals acquired in reaction to predefined, small amplitude, oscillatory airflow waveforms, which are typically applied at the subject's airway opening. The present protocol details the steps required to adequately execute forced oscillation measurements in mice using a computer-controlled piston ventilator (flexiVent; SCIREQ Inc, Montreal, Qc, Canada). The description is divided into four parts: preparatory steps, mechanical ventilation, lung function measurements, and data analysis. It also includes details of how to assess airway responsiveness to inhaled methacholine in anesthetized mice, a common application of this technique which also extends to other outcomes and various lung pathologies. Measurements obtained in naïve mice as well as from an oxidative-stress driven model of airway damage are presented to illustrate how this tool can contribute to a better characterization and understanding of studied physiological changes or disease models as well as to applications in new research areas.

Secretoglobin Superfamily Protein SCGB3A2 Alleviates House Dust Mite-Induced Allergic Airway Inflammation in Mice.

PubMed

Yoneda, Mitsuhiro; Xu, Lei; Kajiyama, Hiroaki; Kawabe, Shuko; Paiz, Jorge; Ward, Jerrold M; Kimura, Shioko

2016-01-01

Secretoglobin (SCGB) 3A2, a novel, lung-enriched, cytokine-like, secreted protein of small molecular weight, was demonstrated to exhibit various biological functions including anti-inflammatory, antifibrotic and growth-factor activities. Anti-inflammatory activity was uncovered using the ovalbumin-induced allergic airway inflammation model. However, further validation of this activity using knockout mice in a different allergic inflammation model is necessary in order to establish the antiallergic inflammatory role for this protein. Scgb3a2-null (Scgb3a2-/-) mice were subjected to nasal inhalation of Dermatophagoides pteronyssinus extract for 5 days/week for 5 consecutive weeks; control mice received nasal inhalation of saline as a comparator. Airway inflammation was assessed by histological analysis, the number of inflammatory cells and various Th2-type cytokine levels in the lungs and bronchoalveolar lavage fluids by qRT-PCR and ELISA, respectively. Exacerbated inflammation was found in the airway of Scgb3a2-/- mice subjected to house dust mite (HDM)-induced allergic airway inflammation compared with saline-treated control groups. All the inflammation end points were increased in the Scgb3a2-/- mice. The Ccr4 and Ccl17 mRNA levels were higher in HDM-treated lungs of Scgb3a2-/- mice than wild-type mice or saline-treated Scgb3a2-/- mice, whereas no changes were observed for Ccr3 and Ccl11 mRNA levels. These results demonstrate that SCGB3A2 has an anti-inflammatory activity in the HDM-induced allergic airway inflammation model, in which SCGB3A2 may modulate the CCR4-CCL17 pathway. SCGB3A2 may provide a useful tool to treat allergic airway inflammation, and further studies on the levels and function of SCGB3A2 in asthmatic patients are warranted. © 2016 S. Karger AG, Basel.

Expression and function of human hemokinin-1 in human and guinea pig airways.

PubMed

Grassin-Delyle, Stanislas; Naline, Emmanuel; Buenestado, Amparo; Risse, Paul-André; Sage, Edouard; Advenier, Charles; Devillier, Philippe

2010-10-07

Human hemokinin-1 (hHK-1) and endokinins are peptides of the tachykinin family encoded by the TAC4 gene. TAC4 and hHK-1 expression as well as effects of hHK-1 in the lung and airways remain however unknown and were explored in this study. RT-PCR analysis was performed on human bronchi to assess expression of tachykinin and tachykinin receptors genes. Enzyme immunoassay was used to quantify hHK-1, and effects of hHK-1 and endokinins on contraction of human and guinea pig airways were then evaluated, as well as the role of hHK-1 on cytokines production by human lung parenchyma or bronchi explants and by lung macrophages. In human bronchi, expression of the genes that encode for hHK-1, tachykinin NK1-and NK2-receptors was demonstrated. hHK-1 protein was found in supernatants from explants of human bronchi, lung parenchyma and lung macrophages. Exogenous hHK-1 caused a contractile response in human bronchi mainly through the activation of NK2-receptors, which blockade unmasked a NK1-receptor involvement, subject to a rapid desensitization. In the guinea pig trachea, hHK-1 caused a concentration-dependant contraction mainly mediated through the activation of NK1-receptors. Endokinin A/B exerted similar effects to hHK-1 on both human bronchi and guinea pig trachea, whereas endokinins C and D were inactive. hHK-1 had no impact on the production of cytokines by explants of human bronchi or lung parenchyma, or by human lung macrophages. We demonstrate endogenous expression of TAC4 in human bronchi, the encoded peptide hHK-1 being expressed and involved in contraction of human and guinea pig airways.

Lung penetration and patient adherence considerations in the management of asthma: role of extra-fine formulations

PubMed Central

Scichilone, Nicola; Spatafora, Mario; Battaglia, Salvatore; Arrigo, Rita; Benfante, Alida; Bellia, Vincenzo

2013-01-01

The mainstay of management in asthma is inhalation therapy at the target site, with direct delivery of the aerosolized drug into the airways to treat inflammation and relieve obstruction. Abundant evidence is available to support the concept that inflammatory and functional changes at the level of the most peripheral airways strongly contribute to the complexity and heterogeneous manifestations of asthma. It is now largely accepted that there is a wide range of clinical phenotypes of the disease, characterized primarily by small airways involvement. Thus, an appropriate diagnostic algorithm cannot exclude biological and functional assessment of the peripheral airways. Similarly, achievement of optimal control of the disease and appropriate management of specific phenotypes of asthma should be based on drugs (and delivery options) able to distribute uniformly along the bronchial tree and to reach the most peripheral airways. Products developed with the Modulite® technology platform have been demonstrated to meet these aims. Recent real-life studies have shown clearly that extra-fine fixed-combination inhaled therapy provides better asthma control than non-extra-fine formulations, thus translating the activity of the drugs into greater effectiveness in clinical practice. We suggest that in patients with incomplete asthma control despite good lung function, involvement of the peripheral airways should always be suspected. When this is the case, treatments targeting both the large and small airways should be used to improve asthma control. Above all, it is emphasized that patient adherence with prescribed medications can contribute to clinical success, and clinicians should always be aware of the role played by patients themselves in determining the success or failure of treatment. PMID:23378776

Decrease of Airway Allergies After Lung Transplantation Is Associated With Reduced Basophils and Eosinophils.

PubMed

Niedzwiecki, M; Yamada, Y; Inci, I; Weder, W; Jungraithmayr, W

2016-01-01

Allergies are hypersensitive reactions of the immune system on antigen exposure similar to immune reactions after transplantation (Tx). Their activity can change after Tx. The lung as a transplantable organ is challenged two-fold, by antigens from the blood and the air environment. Herein we analyzed if airway allergies change after lung Tx. We systematically reviewed patients' airway allergies before and after lung Tx between 1992 and 2014. The course of lymphocytes, thrombocytes, and leukocytes, among them neutrophils, eosinophils, and basophils, was analyzed in patients in whom airway allergies have changed and in whom they did not change. From 362 lung transplanted patients, 44 patients had suffered from allergies before Tx (12.2%). In 20 of these patients (45.5%), airway allergies disappeared completely within 1 year after lung Tx and were persistently absent thereafter. In these patients, basophils and eosinophils decreased significantly (P < .0012); in contrast, cells did not decrease in patients whose allergies did not disappear. Leukocytes overall, and in particular, neutrophils, decreased significantly in patients whose allergy disappeared (P < .014, P < .012, respectively). Airway allergies disappeared in almost half of cases after lung Tx. Along with this reduction, basophils and eosinophils decreased as potentially responsible cells for this phenomenon. These findings may stimulate intensified research on basophils and eosinophils as major drivers of airway allergies. Copyright © 2016 Elsevier Inc. All rights reserved.

Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents

PubMed Central

Szabo, Eva; Miller, Mark Steven; Lubet, Ronald A.; You, Ming; Wang, Yian

2017-01-01

Due to exposure to environmental toxicants, a “field cancerization” effect occurs in the lung resulting in the development of a field of initiated but morphologically normal appearing cells in the damaged epithelium of bronchial airways with dysregulated gene expression patterns. Using a mouse model of lung squamous cell carcinoma (SCC), we performed transcriptome sequencing (RNA-Seq) to profile bronchial airway gene expression and found activation of the PI3K and Myc signaling networks in cytologically normal bronchial airway epithelial cells of mice with preneopastic lung SCC lesions, which was reversed by treatment with the PI3K Inhibitor XL-147 and pioglitazone, respectively. Activated MYC signaling was also present in premalignant and tumor tissues from human lung SCC patients. In addition, we identified a key microRNA, mmu-miR-449c-5p, whose suppression significantly up-regulated Myc expression in the normal bronchial airway epithelial cells of mice with early stage SCC lesions. We developed a novel bronchial genomic classifier in mice and validated it in humans. In the classifier, Ppbp (pro-platelet basic protein) was overexpressed 115 fold in the bronchial airways of mice with preneoplastic lung SCC lesions. This is the first report that demonstrates Ppbp as a novel biomarker in the bronchial airway for lung cancer diagnosis. PMID:27935865

Circadian molecular clock in lung pathophysiology

PubMed Central

Sundar, Isaac K.; Yao, Hongwei; Sellix, Michael T.

2015-01-01

Disrupted daily or circadian rhythms of lung function and inflammatory responses are common features of chronic airway diseases. At the molecular level these circadian rhythms depend on the activity of an autoregulatory feedback loop oscillator of clock gene transcription factors, including the BMAL1:CLOCK activator complex and the repressors PERIOD and CRYPTOCHROME. The key nuclear receptors and transcription factors REV-ERBα and RORα regulate Bmal1 expression and provide stability to the oscillator. Circadian clock dysfunction is implicated in both immune and inflammatory responses to environmental, inflammatory, and infectious agents. Molecular clock function is altered by exposomes, tobacco smoke, lipopolysaccharide, hyperoxia, allergens, bleomycin, as well as bacterial and viral infections. The deacetylase Sirtuin 1 (SIRT1) regulates the timing of the clock through acetylation of BMAL1 and PER2 and controls the clock-dependent functions, which can also be affected by environmental stressors. Environmental agents and redox modulation may alter the levels of REV-ERBα and RORα in lung tissue in association with a heightened DNA damage response, cellular senescence, and inflammation. A reciprocal relationship exists between the molecular clock and immune/inflammatory responses in the lungs. Molecular clock function in lung cells may be used as a biomarker of disease severity and exacerbations or for assessing the efficacy of chronotherapy for disease management. Here, we provide a comprehensive overview of clock-controlled cellular and molecular functions in the lungs and highlight the repercussions of clock disruption on the pathophysiology of chronic airway diseases and their exacerbations. Furthermore, we highlight the potential for the molecular clock as a novel chronopharmacological target for the management of lung pathophysiology. PMID:26361874

Quantitative 3D reconstruction of airway and pulmonary vascular trees using HRCT

NASA Astrophysics Data System (ADS)

Wood, Susan A.; Hoford, John D.; Hoffman, Eric A.; Zerhouni, Elias A.; Mitzner, Wayne A.

1993-07-01

Accurate quantitative measurements of airway and vascular dimensions are essential to evaluate function in the normal and diseased lung. In this report, a novel method is described for three-dimensional extraction and analysis of pulmonary tree structures using data from High Resolution Computed Tomography (HRCT). Serially scanned two-dimensional slices of the lower left lobe of isolated dog lungs were stacked to create a volume of data. Airway and vascular trees were three-dimensionally extracted using a three dimensional seeded region growing algorithm based on difference in CT number between wall and lumen. To obtain quantitative data, we reduced each tree to its central axis. From the central axis, branch length is measured as the distance between two successive branch points, branch angle is measured as the angle produced by two daughter branches, and cross sectional area is measured from a plane perpendicular to the central axis point. Data derived from these methods can be used to localize and quantify structural differences both during changing physiologic conditions and in pathologic lungs.

A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids.

PubMed

Dye, Briana R; Dedhia, Priya H; Miller, Alyssa J; Nagy, Melinda S; White, Eric S; Shea, Lonnie D; Spence, Jason R

2016-09-28

Human pluripotent stem cell (hPSC) derived tissues often remain developmentally immature in vitro, and become more adult-like in their structure, cellular diversity and function following transplantation into immunocompromised mice. Previously we have demonstrated that hPSC-derived human lung organoids (HLOs) resembled human fetal lung tissue in vitro (Dye et al., 2015). Here we show that HLOs required a bioartificial microporous poly(lactide-co-glycolide) (PLG) scaffold niche for successful engraftment, long-term survival, and maturation of lung epithelium in vivo. Analysis of scaffold-grown transplanted tissue showed airway-like tissue with enhanced epithelial structure and organization compared to HLOs grown in vitro. By further comparing in vitro and in vivo grown HLOs with fetal and adult human lung tissue, we found that in vivo transplanted HLOs had improved cellular differentiation of secretory lineages that is reflective of differences between fetal and adult tissue, resulting in airway-like structures that were remarkably similar to the native adult human lung.

Impulse activity in afferent vagal C-fibres with endings in the intrapulmonary airways of dogs.

PubMed

Coleridge, H M; Coleridge, J C

1977-04-01

We recorded impulses from afferent vagal C-fibres (conduction velocities 0.8-2.4 m/sec) arising from endings in the lungs of anesthetized dogs with open chest. Endings were of two types ('pulmonary' and 'bronchial') distinguished by their response and accessibility to capsaicin and phenyl diguanide injected into the right or left atrium. 'Pulmonary' endings, stimulated only by capsaicin and accessible through the pulmonary circulation, have been described previously. 'Bronchial' endings were stimulated by both capsicin and phenyl diguanide and were accessible through the bronchial circulation. Eight of 28 'bronchial' endings were located in large airways within 4 cm of the hilum, and two were in small airways near the edge of the lung. The precise location of the remaining 'bronchial' endings was not determined but we think that many were in the airways. 'Bronchial' endings had a sparse and irregular spontaneous discharge. They were stimulated by the inhalation of 5% histamine aerosol, the evoked discharge having no obvious relation to the phase of ventilation. A few were weakly stimulated by hyperinflating the lungs; deflation was without effect. The function of these endings is unknown.

Low-Dose Intestinal Trichuris muris Infection Alters the Lung Immune Microenvironment and Can Suppress Allergic Airway Inflammation.

PubMed

Chenery, Alistair L; Antignano, Frann; Burrows, Kyle; Scheer, Sebastian; Perona-Wright, Georgia; Zaph, Colby

2016-02-01

Immunological cross talk between mucosal tissues such as the intestine and the lung is poorly defined during homeostasis and disease. Here, we show that a low-dose infection with the intestinally restricted helminth parasite Trichuris muris results in the production of Th1 cell-dependent gamma interferon (IFN-γ) and myeloid cell-derived interleukin-10 (IL-10) in the lung without causing overt airway pathology. This cross-mucosal immune response in the lung inhibits the development of papain-induced allergic airway inflammation, an innate cell-mediated type 2 airway inflammatory disease. Thus, we identify convergent and nonredundant roles of adaptive and innate immunity in mediating cross-mucosal suppression of type 2 airway inflammation during low-dose helminth-induced intestinal inflammation. These results provide further insight in identifying novel intersecting immune pathways elicited by gut-to-lung mucosal cross talk. Copyright © 2016 Chenery et al.

Timing of dornase alfa inhalation for cystic fibrosis.

PubMed

Dentice, Ruth; Elkins, Mark

2016-07-26

Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane review. To determine the effect of timing of dornase alfa inhalation on measures of clinical efficacy in people with cystic fibrosis (in relation to airway clearance techniques or time of day). Relevant randomised and quasi-randomised controlled trials were identified from the Cochrane Cystic Fibrosis Trials Register, Physiotherapy Evidence Database (PEDro), and international cystic fibrosis conference proceedings.Date of the most recent search: 25 April 2016. Any trial of dornase alfa in people with cystic fibrosis where timing of inhalation was the randomised element in the study with either: inhalation before compared to after airway clearance techniques; or morning compared to evening inhalation. Both authors independently selected trials, assessed risk of bias and extracted data with disagreements resolved by discussion. Relevant data were extracted and, where possible, meta-analysed. We identified 115 trial reports representing 55 studies, of which five studies (providing data on 122 participants) met our inclusion criteria. All five studies used a cross-over design. Intervention periods ranged from two to eight weeks. Four trials compared dornase alfa inhalation before versus after airway clearance techniques. Inhalation after instead of before airway clearance did not significantly change forced expiratory volume at one second. Similarly, forced vital capacity and quality of life were not significantly affected; forced expiratory flow at 25% was significantly worse with dornase alfa inhalation after airway clearance, mean difference -0.17 litres (95% confidence interval -0.28 to -0.05), based on the pooled data from two small studies in children (seven to 19 years) with well-preserved lung function. All other secondary outcomes were statistically non-significant.In one trial, morning versus evening inhalation had no impact on lung function or symptoms. The current evidence derived from a small number of participants does not indicate that inhalation of dornase alfa after airway clearance techniques is more or less effective than the traditional recommendation to inhale nebulised dornase alfa 30 minutes prior to airway clearance techniques, for most outcomes. For children with well-preserved lung function, inhalation before airway clearance may be more beneficial for small airway function than inhalation after. However, this result relied on a measure with high variability and studies with variable follow up. In the absence of strong evidence to indicate that one timing regimen is better than another, the timing of dornase alpha inhalation can be largely based on pragmatic reasons or individual preference with respect to the time of airway clearance and time of day. Further research is warranted.

Defective innate immunity and hyperinflammation in newborn cystic fibrosis transmembrane conductance regulator-knockout ferret lungs.

PubMed

Keiser, Nicholas W; Birket, Susan E; Evans, Idil A; Tyler, Scott R; Crooke, Adrianne K; Sun, Xingshen; Zhou, Weihong; Nellis, Joseph R; Stroebele, Elizabeth K; Chu, Kengyeh K; Tearney, Guillermo J; Stevens, Mark J; Harris, J Kirk; Rowe, Steven M; Engelhardt, John F

2015-06-01

Mucociliary clearance (MCC) and submucosal glands are major components of airway innate immunity that have impaired function in cystic fibrosis (CF). Although both of these defense systems develop postnatally in the ferret, the lungs of newborn ferrets remain sterile in the presence of a functioning cystic fibrosis transmembrane conductance regulator gene. We evaluated several components of airway innate immunity and inflammation in the early CF ferret lung. At birth, the rates of MCC did not differ between CF and non-CF animals, but the height of the airway surface liquid was significantly reduced in CF newborn ferrets. CF ferrets had impaired MCC after 7 days of age, despite normal rates of ciliogenesis. Only non-CF ferrets eradicated Pseudomonas directly introduced into the lung after birth, whereas both genotypes could eradicate Staphylococcus. CF bronchoalveolar lavage fluid (BALF) had significantly lower antimicrobial activity selectively against Pseudomonas than non-CF BALF, which was insensitive to changes in pH and bicarbonate. Liquid chromatography-tandem mass spectrometry and cytokine analysis of BALF from sterile Caesarean-sectioned and nonsterile naturally born animals demonstrated CF-associated disturbances in IL-8, TNF-α, and IL-β, and pathways that control immunity and inflammation, including the complement system, macrophage functions, mammalian target of rapamycin signaling, and eukaryotic initiation factor 2 signaling. Interestingly, during the birth transition, IL-8 was selectively induced in CF BALF, despite no genotypic difference in bacterial load shortly after birth. These results suggest that newborn CF ferrets have defects in both innate immunity and inflammatory signaling that may be important in the early onset and progression of lung disease in these animals.

Defective Innate Immunity and Hyperinflammation in Newborn Cystic Fibrosis Transmembrane Conductance Regulator–Knockout Ferret Lungs

PubMed Central

Keiser, Nicholas W.; Birket, Susan E.; Evans, Idil A.; Tyler, Scott R.; Crooke, Adrianne K.; Sun, Xingshen; Zhou, Weihong; Nellis, Joseph R.; Stroebele, Elizabeth K.; Chu, Kengyeh K.; Tearney, Guillermo J.; Stevens, Mark J.; Harris, J. Kirk; Rowe, Steven M.

2015-01-01

Mucociliary clearance (MCC) and submucosal glands are major components of airway innate immunity that have impaired function in cystic fibrosis (CF). Although both of these defense systems develop postnatally in the ferret, the lungs of newborn ferrets remain sterile in the presence of a functioning cystic fibrosis transmembrane conductance regulator gene. We evaluated several components of airway innate immunity and inflammation in the early CF ferret lung. At birth, the rates of MCC did not differ between CF and non-CF animals, but the height of the airway surface liquid was significantly reduced in CF newborn ferrets. CF ferrets had impaired MCC after 7 days of age, despite normal rates of ciliogenesis. Only non-CF ferrets eradicated Pseudomonas directly introduced into the lung after birth, whereas both genotypes could eradicate Staphylococcus. CF bronchoalveolar lavage fluid (BALF) had significantly lower antimicrobial activity selectively against Pseudomonas than non-CF BALF, which was insensitive to changes in pH and bicarbonate. Liquid chromatography–tandem mass spectrometry and cytokine analysis of BALF from sterile Caesarean-sectioned and nonsterile naturally born animals demonstrated CF-associated disturbances in IL-8, TNF-α, and IL-β, and pathways that control immunity and inflammation, including the complement system, macrophage functions, mammalian target of rapamycin signaling, and eukaryotic initiation factor 2 signaling. Interestingly, during the birth transition, IL-8 was selectively induced in CF BALF, despite no genotypic difference in bacterial load shortly after birth. These results suggest that newborn CF ferrets have defects in both innate immunity and inflammatory signaling that may be important in the early onset and progression of lung disease in these animals. PMID:25317669

HIV Impairs Lung Epithelial Integrity and Enters the Epithelium to Promote Chronic Lung Inflammation.

PubMed

Brune, Kieran A; Ferreira, Fernanda; Mandke, Pooja; Chau, Eric; Aggarwal, Neil R; D'Alessio, Franco R; Lambert, Allison A; Kirk, Gregory; Blankson, Joel; Drummond, M Bradley; Tsibris, Athe M; Sidhaye, Venkataramana K

2016-01-01

Several clinical studies show that individuals with HIV are at an increased risk for worsened lung function and for the development of COPD, although the mechanism underlying this increased susceptibility is poorly understood. The airway epithelium, situated at the interface between the external environment and the lung parenchyma, acts as a physical and immunological barrier that secretes mucins and cytokines in response to noxious stimuli which can contribute to the pathobiology of chronic obstructive pulmonary disease (COPD). We sought to determine the effects of HIV on the lung epithelium. We grew primary normal human bronchial epithelial (NHBE) cells and primary lung epithelial cells isolated from bronchial brushings of patients to confluence and allowed them to differentiate at an air- liquid interface (ALI) to assess the effects of HIV on the lung epithelium. We assessed changes in monolayer permeability as well as the expression of E-cadherin and inflammatory modulators to determine the effect of HIV on the lung epithelium. We measured E-cadherin protein abundance in patients with HIV compared to normal controls. Cell associated HIV RNA and DNA were quantified and the p24 viral antigen was measured in culture supernatant. Surprisingly, X4, not R5, tropic virus decreased expression of E-cadherin and increased monolayer permeability. While there was some transcriptional regulation of E-cadherin, there was significant increase in lysosome-mediated protein degradation in cells exposed to X4 tropic HIV. Interaction with CXCR4 and viral fusion with the epithelial cell were required to induce the epithelial changes. X4 tropic virus was able to enter the airway epithelial cells but not replicate in these cells, while R5 tropic viruses did not enter the epithelial cells. Significantly, X4 tropic HIV induced the expression of intercellular adhesion molecule-1 (ICAM-1) and activated extracellular signal-regulated kinase (ERK). We demonstrate that HIV can enter airway epithelial cells and alter their function by impairing cell-cell adhesion and increasing the expression of inflammatory mediators. These observed changes may contribute local inflammation, which can lead to lung function decline and increased susceptibility to COPD in HIV patients.

CD10/neutral endopeptidase 24.11 in developing human fetal lung. Patterns of expression and modulation of peptide-mediated proliferation.

PubMed

Sunday, M E; Hua, J; Torday, J S; Reyes, B; Shipp, M A

1992-12-01

The cell membrane-associated enzyme CD10/neutral endopeptidase 24.11 (CD10/NEP) functions in multiple organ systems to downregulate responses to peptide hormones. Recently, CD10/NEP was found to hydrolyze bombesin-like peptides (BLP), which are mitogens for normal bronchial epithelial cells and small cell lung carcinomas. Growth of BLP-responsive small cell lung carcinomas was potentiated by CD10/NEP inhibition, implicating CD10/NEP in regulation of BLP-mediated tumor growth. BLP are also likely to participate in normal lung development because high BLP levels are found in fetal lung, and bombesin induces proliferation and maturation of human fetal lung in organ cultures and murine fetal lung in utero. To explore potential roles for CD10/NEP in regulating peptide-mediated human fetal lung development, we have characterized temporal and cellular patterns of CD10/NEP expression and effects of CD10/NEP inhibition in organ cultures. Peak CD10/NEP transcript levels are identified at 11-13 wk gestation by Northern blots and localized to epithelial cells and mesenchyme of developing airways by in situ hybridization. CD10/NEP immunostaining is most intense in undifferentiated airway epithelium. In human fetal lung organ cultures, inhibition of CD10/NEP with either phosphoramidon or SCH32615 increases thymidine incorporation by 166-182% (P < 0.025). The specific BLP receptor antagonist, [Leu13-psi(CH2NH)Leu14]bombesin abolishes these effects on fetal lung growth, suggesting that CD10/NEP modulates BLP-mediated proliferation. CD10/NEP expression in the growing front of airway epithelium and the effects of CD10/NEP inhibitors in lung explants implicate the enzyme in the regulation of peptide-mediated fetal lung growth.

Long-term gas exchange characteristics as markers of deterioration in patients with cystic fibrosis

PubMed Central

2009-01-01

Background and Aim In patients with cystic fibrosis (CF) the architecture of the developing lungs and the ventilation of lung units are progressively affected, influencing intrapulmonary gas mixing and gas exchange. We examined the long-term course of blood gas measurements in relation to characteristics of lung function and the influence of different CFTR genotype upon this process. Methods Serial annual measurements of PaO2 and PaCO2 assessed in relation to lung function, providing functional residual capacity (FRCpleth), lung clearance index (LCI), trapped gas (VTG), airway resistance (sReff), and forced expiratory indices (FEV1, FEF50), were collected in 178 children (88 males; 90 females) with CF, over an age range of 5 to 18 years. Linear mixed model analysis and binary logistic regression analysis were used to define predominant lung function parameters influencing oxygenation and carbon dioxide elimination. Results PaO2 decreased linearly from age 5 to 18 years, and was mainly associated with FRCpleth, (p < 0.0001), FEV1 (p < 0.001), FEF50 (p < 0.002), and LCI (p < 0.002), indicating that oxygenation was associated with the degree of pulmonary hyperinflation, ventilation inhomogeneities and impeded airway function. PaCO2 showed a transitory phase of low PaCO2 values, mainly during the age range of 5 to 12 years. Both PaO2 and PaCO2 presented with different progression slopes within specific CFTR genotypes. Conclusion In the long-term evaluation of gas exchange characteristics, an association with different lung function patterns was found and was closely related to specific genotypes. Early examination of blood gases may reveal hypocarbia, presumably reflecting compensatory mechanisms to improve oxygenation. PMID:19909502

Regulated overexpression of interleukin 11 in the lung. Use to dissociate development-dependent and -independent phenotypes.

PubMed Central

Ray, P; Tang, W; Wang, P; Homer, R; Kuhn, C; Flavell, R A; Elias, J A

1997-01-01

Standard overexpression transgenic approaches are limited in their ability to model waxing and waning diseases and frequently superimpose development-dependent and -independent phenotypic manifestations. We used the clara cell 10-kD protein (CC10) promoter and the reverse tetracycline transactivator (rtTA) to create a lung-specific, externally regulatable, overexpression transgenic system and used this system to express human interleukin 11 (IL-11) in respiratory structures. Gene induction could be achieved in utero, in neonates and in adult animals. Moreover, gene expression could be turned off by removal of the inducing stimulus. When gene activation was initiated in utero and continued into adulthood, subepithelial airway fibrosis, peribronchiolar mononuclear nodules, and alveolar enlargement (emphysema) were noted. Induction in the mature lung caused airway remodeling and peribronchiolar nodules, but alveolar enlargement was not appreciated. In contrast, induction in utero and during the first 14 d of life caused alveolar enlargement without airway remodeling or peribronchiolar nodules. Thus, IL-11 overexpression causes abnormalities that are dependent (large alveoli) and independent (airway remodeling, peribronchiolar nodules) of lung growth and development, and the CC10-rtTA system can be used to differentiate among these effector functions. The CC10-rtTA transgenic system can be used to model waxing and waning, childhood and growth and development-related biologic processes with enhanced fidelity. PMID:9366564

Club Cell Protein 16 (CC16) Augmentation: A Potential Disease-modifying Approach for Chronic Obstructive Pulmonary Disease (COPD)

PubMed Central

Laucho-Contreras, Maria E.; Polverino, Francesca; Tesfaigzi, Yohannes; Pilon, Aprile; Celli, Bartolome R.; Owen, Caroline A.

2016-01-01

Introduction Club cell protein 16 (CC16) is the most abundant protein in bronchoalveolar lavage fluid. CC16 has anti-inflammatory properties in smoke-exposed lungs, and chronic obstructive pulmonary disease (COPD) is associated with CC16 deficiency. Herein, we explored whether CC16 is a therapeutic target for COPD. Areas Covered We reviewed the literature on the factors that regulate airway CC16 expression, its biologic functions and its protective activities in smoke-exposed lungs using PUBMED searches. We generated hypotheses on the mechanisms by which CC16 limits COPD development, and discuss its potential as a new therapeutic approach for COPD. Expert Opinion CC16 plasma and lung levels are reduced in smokers without airflow obstruction and COPD patients. In COPD patients, airway CC16 expression is inversely correlated with severity of airflow obstruction. CC16 deficiency increases smoke-induced lung pathologies in mice by its effects on epithelial cells, leukocytes, and fibroblasts. Experimental augmentation of CC16 levels using recombinant CC16 in cell culture systems, plasmid and adenoviral-mediated over-expression of CC16 in epithelial cells or smoke-exposed murine airways reduces inflammation and cellular injury. Additional studies are necessary to assess the efficacy of therapies aimed at restoring airway CC16 levels as a new disease-modifying therapy for COPD patients. PMID:26781659

Lipopolysaccharide does not alter small airway reactivity in mouse lung slices.

PubMed

Donovan, Chantal; Royce, Simon G; Vlahos, Ross; Bourke, Jane E

2015-01-01

The bacterial endotoxin, lipopolysaccharide (LPS) has been associated with occupational airway diseases with asthma-like symptoms and in acute exacerbations of COPD. The direct and indirect effects of LPS on small airway reactivity have not been fully elucidated. We tested the hypothesis that both in vitro and in vivo LPS treatment would increase contraction and impair relaxation of mouse small airways. Lung slices were prepared from naïve Balb/C mice and cultured in the absence or presence of LPS (10 μg/ml) for up to 48 h for measurement of TNFα levels in conditioned media. Alternatively, mice were challenged with PBS or LPS in vivo once a day for 4 days for preparation of lung slices or for harvest of lungs for Q-PCR analysis of gene expression of pro-inflammatory cytokines and receptors involved in airway contraction. Reactivity of small airways to contractile agonists, methacholine and serotonin, and bronchodilator agents, salbutamol, isoprenaline and rosiglitazone, were assessed using phase-contrast microscopy. In vitro LPS treatment of slices increased TNFα release 6-fold but did not alter contraction or relaxation to any agonists tested. In vivo LPS treatment increased lung gene expression of TNFα, IL-1β and ryanodine receptor isoform 2 more than 5-fold. However there were no changes in reactivity in lung slices from these mice, even when also incubated with LPS ex vivo. Despite evidence of LPS-induced inflammation, neither airway hyperresponsiveness or impaired dilator reactivity were evident. The increase in ryanodine receptor isoform 2, known to regulate calcium signaling in vascular smooth muscle, warrants investigation. Since LPS failed to elicit changes in small airway reactivity in mouse lung slices following in vitro or in vivo treatment, alternative approaches are required to define the potential contribution of this endotoxin to altered small airway reactivity in human lung diseases.

Lipopolysaccharide Does Not Alter Small Airway Reactivity in Mouse Lung Slices

PubMed Central

Donovan, Chantal; Royce, Simon G.; Vlahos, Ross; Bourke, Jane E.

2015-01-01

The bacterial endotoxin, lipopolysaccharide (LPS) has been associated with occupational airway diseases with asthma-like symptoms and in acute exacerbations of COPD. The direct and indirect effects of LPS on small airway reactivity have not been fully elucidated. We tested the hypothesis that both in vitro and in vivo LPS treatment would increase contraction and impair relaxation of mouse small airways. Lung slices were prepared from naïve Balb/C mice and cultured in the absence or presence of LPS (10 μg/ml) for up to 48 h for measurement of TNFα levels in conditioned media. Alternatively, mice were challenged with PBS or LPS in vivo once a day for 4 days for preparation of lung slices or for harvest of lungs for Q-PCR analysis of gene expression of pro-inflammatory cytokines and receptors involved in airway contraction. Reactivity of small airways to contractile agonists, methacholine and serotonin, and bronchodilator agents, salbutamol, isoprenaline and rosiglitazone, were assessed using phase-contrast microscopy. In vitro LPS treatment of slices increased TNFα release 6-fold but did not alter contraction or relaxation to any agonists tested. In vivo LPS treatment increased lung gene expression of TNFα, IL-1β and ryanodine receptor isoform 2 more than 5-fold. However there were no changes in reactivity in lung slices from these mice, even when also incubated with LPS ex vivo. Despite evidence of LPS-induced inflammation, neither airway hyperresponsiveness or impaired dilator reactivity were evident. The increase in ryanodine receptor isoform 2, known to regulate calcium signaling in vascular smooth muscle, warrants investigation. Since LPS failed to elicit changes in small airway reactivity in mouse lung slices following in vitro or in vivo treatment, alternative approaches are required to define the potential contribution of this endotoxin to altered small airway reactivity in human lung diseases. PMID:25822969

Differential roles of endothelin-1 ETA and ETB receptors and vasoactive intestinal polypeptide in regulation of the airways and the pulmonary vasculature in isolated rat lung.

PubMed

Janosi, Tibor; Peták, Ferenc; Fontao, Fabienne; Morel, Denis R; Beghetti, Maurice; Habre, Walid

2008-11-01

The available treatment strategies against pulmonary hypertension include the administration of endothelin-1 (ET-1) receptor subtype blockers (ET(A) and ET(B) antagonists); vasoactive intestinal polypeptide (VIP) has recently been suggested as a potential new therapeutic agent. We set out to investigate the ability of these agents to protect against the vasoconstriction and impairment of lung function commonly observed in patients with pulmonary hypertension. An ET(A) blocker (BQ123), ET(B) blocker (BQ788), a combination of these selective blockers (ET(A) + ET(B) blockers) or VIP (V6130) was administered into the pulmonary circulation in four groups of perfused normal rat lungs. Pulmonary vascular resistance (PVR) and forced oscillatory lung input impedance (Z(L)) were measured in all groups under baseline conditions and at 1 min intervals following ET-1 administrations. The airway resistance, inertance, tissue damping and elastance were extracted from the Z(L) spectra. While VIP, ET(A) blocker and combined ET(A) and ET(B) blockers significantly prevented the pulmonary vasoconstriction induced by ET-1, ET(B) blockade enhanced the ET-1-induced increases in PVR. In contrast, the ET(A) and ET(B) blockers markedly elevated the ET-1-induced increases in airway resistance, while VIP blunted this constrictor response. Our results suggest that VIP potently acts against the airway and pulmonary vascular constriction mediated by endothelin-1, while the ET(A) and ET(B) blockers exert a differential effect between airway resistance and PVR.

Ion Transport by Pulmonary Epithelia

PubMed Central

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

2011-01-01

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

Early diagnosis of asthma in young children by using non-invasive biomarkers of airway inflammation and early lung function measurements: study protocol of a case-control study

PubMed Central

van de Kant, Kim DG; Klaassen, Ester MM; Jöbsis, Quirijn; Nijhuis, Annedien J; van Schayck, Onno CP; Dompeling, Edward

2009-01-01

Background Asthma is the most common chronic disease in childhood, characterized by chronic airway inflammation. There are problems with the diagnosis of asthma in young children since the majority of the children with recurrent asthma-like symptoms is symptom free at 6 years, and does not have asthma. With the conventional diagnostic tools it is not possible to differentiate between preschool children with transient symptoms and children with asthma. The analysis of biomarkers of airway inflammation in exhaled breath is a non-invasive and promising technique to diagnose asthma and monitor inflammation in young children. Moreover, relatively new lung function tests (airway resistance using the interrupter technique) have become available for young children. The primary objective of the ADEM study (Asthma DEtection and Monitoring study), is to develop a non-invasive instrument for an early asthma diagnosis in young children, using exhaled inflammatory markers and early lung function measurements. In addition, aetiological factors, including gene polymorphisms and gene expression profiles, in relation to the development of asthma are studied. Methods/design A prospective case-control study is started in 200 children with recurrent respiratory symptoms and 50 control subjects without respiratory symptoms. At 6 years, a definite diagnosis of asthma is made (primary outcome measure) on basis of lung function assessments and current respiratory symptoms ('golden standard'). From inclusion until the definite asthma diagnosis, repeated measurements of lung function tests and inflammatory markers in exhaled breath (condensate), blood and faeces are performed. The study is registered and ethically approved. Discussion This article describes the study protocol of the ADEM study. The new diagnostic techniques applied in this study could make an early diagnosis of asthma possible. An early and reliable asthma diagnosis at 2–3 years will have consequences for the management of the large group of young children with asthma-like symptoms. It will avoid both over-treatment of children with transient wheeze and under-treatment of children with asthma. This might have a beneficial influence on the prognosis of asthma in these young children. Besides, insight into the pathophysiology and aetiology of asthma will be obtained. TRIAL REGISTRATION This study is registered by clinicaltrials.gov (NCT00422747). PMID:19563637

The long-term programming effect of maternal 25-hydroxyvitamin D in pregnancy on allergic airway disease and lung function in offspring after 20 to 25 years of follow-up.

PubMed

Hansen, Susanne; Maslova, Ekaterina; Strøm, Marin; Linneberg, Allan; Halldorsson, Thorhallur I; Granström, Charlotta; Dahl, Ronald; Hoffmann, Hans Jürgen; Olsen, Sjurdur F

2015-07-01

High prenatal vitamin D status has been linked to decreased risk of atopic diseases in early childhood, but whether such relations persist until adulthood has not been explored. We sought to examine the association between maternal 25-hydryxovitamin D (25[OH]D) concentrations and outcomes of allergic airway disease and lung function in offspring with 20 to 25 years of follow-up. In a prospective birth cohort with 965 pregnant women enrolled in 1988-1989, maternal 25(OH)D concentrations were quantified in serum from gestational week 30 (n = 850 [88%]). Offspring were followed in nationwide registries with complete follow-up to the age of 25 years (n = 850 [100%]). Additionally, at age 20 years, outcomes of allergic airway disease and lung function were assessed in a subset of offspring by using blood samples and spirometry (n = 410 [45%]) and a questionnaire (n = 641 [70%]). Exposure to a high maternal 25(OH)D concentration (≥125 nmol/L) was associated with an increased risk of asthma hospitalizations in offspring (hazard ratio [HR], 1.81; 95% CI, 0.78-4.16) during 25 years of follow-up compared with the reference group (75-<125 nmol/L). Furthermore, there were lower risks of asthma hospitalizations (HR, 0.29; 95% CI, 0.08-1.02) and asthma medication use (HR, 0.58; 95% CI, 0.35-0.95) in those exposed to a low maternal 25(OH)D concentration (<50 nmol/L). In a reduced set of participants, we found no associations between maternal 25(OH)D concentrations and offspring allergen-specific IgE, total IgE, and eosinophil cationic protein levels; self-reported doctor's diagnosis of asthma or hay fever; or lung function at 20 years of age. Our study does not provide support for a protective effect of a high maternal 25(OH)D concentration on outcomes of allergic airway disease and lung function at 20 to 25 years of age. In contrast, a high maternal 25(OH)D concentration might be associated with an increased risk of allergic diseases in offspring. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Reference database of lung volumes and capacities in wistar rats from 2 to 24 months.

PubMed

Filho, Wilson Jacob; Fontinele, Renata Gabriel; de Souza, Romeu Rodrigues

2014-01-01

This study determines the effects of growing and aging on lung physiological volumes and capacities and the incidence of inflammation in the small airways with age in rats. A reference database comprising of body weight gain, lung physiological volumes and capacities and an anatomopathological study of lung lesions over 240 Wistar rats from two to 24 -mo, is described. Tidal volume (TV), minute respiratory volume (MRV), and forced vital capacity (FVC) decreased during the first six months of life and then remain constant until 24 -mo of age. The respiratory frequency (Rf) and dynamical compliance (Cdyn) maintain at constant values from 2 to 24- mo of age; the functional residual capacity (FRC) increases in the first 6 -mo and then remains constant up to 24 -mo. It was verified a less intensive inflammation in the small airways with age, when compared with the median and large airways. This study showed the normal parameters for lung volumes and capacities and the incidence of infections for growing and aging male and female rats. The age-related data on these main respiratory parameters in rats would be useful in studies of aging-related disorders using this model and for safety pharmacology studies necessary for the development of drugs.

Pulmonary FGF-18 gene expression is downregulated during the canalicular-saccular stages in nitrofen-induced hypoplastic lungs.

PubMed

Takahashi, Hiromizu; Friedmacher, Florian; Fujiwara, Naho; Hofmann, Alejandro; Kutasy, Balazs; Gosemann, Jan-Hendrik; Puri, Prem

2013-11-01

Pulmonary hypoplasia (PH) associated with congenital diaphragmatic hernia (CDH) represents one of the major challenges in neonatal intensive care. However, the molecular pathogenesis of PH is still poorly understood. In developing fetal lungs, fibroblast growth factor 18 (FGF-18) plays a crucial role in distal airway maturation. FGF-18 knockouts show smaller lung sizes with reduced alveolar spaces and thicker interstitial mesenchymal compartments, highlighting its important function for fetal lung growth and differentiation. We hypothesized that pulmonary FGF-18 gene expression is downregulated during late gestation in nitrofen-induced hypoplastic lungs. Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). Fetuses were harvested on D18 and D21, and lungs were divided into three groups: controls, hypoplastic lungs without CDH [CDH(-)], and hypoplastic lungs with CDH [CDH(+)] (n = 24 at each time-point). Pulmonary FGF-18 gene expression levels were analyzed by qRT-PCR. Immunohistochemistry was performed to investigate FGF-18 protein expression/distribution. Relative mRNA levels of pulmonary FGF-18 gene expression were significantly decreased in CDH(-) and CDH(+) on D18 and D21 compared to controls (p < 0.05 and p < 0.01, respectively). Immunoreactivity of FGF-18 was markedly diminished in mesenchymal cells surrounding the airway epithelium on D18 and D21 compared to controls. Downregulation of FGF-18 gene expression in nitrofen-induced hypoplastic lungs suggests that decreased FGF-18 expression during the canalicular-saccular stages may interfere with saccular-alveolar differentiation and distal airway maturation resulting in PH.

Early cystic fibrosis lung disease: Role of airway surface dehydration and lessons from preventive rehydration therapies in mice.

PubMed

Mall, Marcus A; Graeber, Simon Y; Stahl, Mirjam; Zhou-Suckow, Zhe

2014-07-01

Cystic fibrosis (CF) lung disease starts in the first months of life and remains one of the most common fatal hereditary diseases. Early therapeutic interventions may provide an opportunity to prevent irreversible lung damage and improve outcome. Airway surface dehydration is a key disease mechanism in CF, however, its role in the in vivo pathogenesis and as therapeutic target in early lung disease remains poorly understood. Mice with airway-specific overexpression of the epithelial Na(+) channel (βENaC-Tg) recapitulate airway surface dehydration and phenocopy CF lung disease. Recent studies in neonatal βENaC-Tg mice demonstrated that airway surface dehydration produces early mucus plugging in the absence of mucus hypersecretion, which triggers airway inflammation, promotes bacterial infection and causes early mortality. Preventive rehydration therapy with hypertonic saline or amiloride effectively reduced mucus plugging and mortality in neonatal βENaC-Tg mice. These results support clinical testing of preventive/early rehydration strategies in infants and young children with CF. Copyright © 2014 Elsevier Ltd. All rights reserved.

Nociceptin/orphanin FQ (N/OFQ) modulates immunopathology and airway hyperresponsiveness representing a novel target for the treatment of asthma.

PubMed

Singh, Shailendra R; Sullo, Nikol; Matteis, Maria; Spaziano, Giuseppe; McDonald, John; Saunders, Ruth; Woodman, Lucy; Urbanek, Konrad; De Angelis, Antonella; De Palma, Raffaele; Berair, Rachid; Pancholi, Mitesh; Mistry, Vijay; Rossi, Francesco; Guerrini, Remo; Calò, Girolamo; D'Agostino, Bruno; Brightling, Christopher E; Lambert, David G

2016-04-01

There is evidence supporting a role for the nociceptin/orphanin FQ (N/OFQ; NOP) receptor and its endogenous ligand N/OFQ in the modulation of neurogenic inflammation, airway tone and calibre. We hypothesized that NOP receptor activation has beneficial effects upon asthma immunopathology and airway hyperresponsiveness. Therefore, the expression and function of N/OFQ and the NOP receptor were examined in healthy and asthmatic human airway tissues. The concept was further addressed in an animal model of allergic asthma. NOP receptor expression was investigated by quantitative real-time PCR. Sputum N/OFQ was determined by RIA. N/OFQ function was tested using several assays including proliferation, migration, collagen gel contraction and wound healing. The effects of N/OFQ administration in vivo were studied in ovalbumin (OVA)-sensitized and challenged mice. NOP receptors were expressed on a wide range of human and mouse immune and airway cells. Eosinophils expressed N/OFQ-precursor mRNA and their number correlated with N/OFQ concentration. N/OFQ was found in human sputum and increased in asthma. Additionally, in asthmatic human lungs N/OFQ immunoreactivity was elevated. NOP receptor activation inhibited migration of immunocytes and increased wound healing in airway structural cells. Furthermore, N/OFQ relaxed spasmogen-stimulated gel contraction. Remarkably, these findings were mirrored in OVA-mice where N/OFQ treatment before or during sensitization substantially reduced airway constriction and immunocyte trafficking to the lung, in particular eosinophils. N/OFQ also reduced inflammatory mediators and mucin production. We demonstrated a novel dual airway immunomodulator/bronchodilator role for N/OFQ and suggest targeting this system as an innovative treatment for asthma. © 2016 The British Pharmacological Society.

Tensiometric and Phase Domain Behavior of Lung Surfactant on Mucus-like Viscoelastic Hydrogels.

PubMed

Schenck, Daniel M; Fiegel, Jennifer

2016-03-09

Lung surfactant has been observed at all surfaces of the airway lining fluids and is an important contributor to normal lung function. In the conducting airways, the surfactant film lies atop a viscoelastic mucus gel. In this work, we report on the characterization of the tensiometric and phase domain behavior of lung surfactant at the air-liquid interface of mucus-like viscoelastic gels. Poly(acrylic acid) hydrogels were formulated to serve as a model mucus with bulk rheological properties that matched those of tracheobronchial mucus secretions. Infasurf (Calfactant), a commercially available pulmonary surfactant derived from calf lung extract, was spread onto the hydrogel surface. The surface tension lowering ability and relaxation of Infasurf films on the hydrogels was quantified and compared to Infasurf behavior on an aqueous subphase. Infasurf phase domains during surface compression were characterized by fluorescence microscopy and phase shifting interferometry. We observed that increasing the bulk viscoelastic properties of the model mucus hydrogels reduced the ability of Infasurf films to lower surface tension and inhibited film relaxation. A shift in the formation of Infasurf condensed phase domains from smaller, more spherical domains to large, agglomerated, multilayer structures was observed with increasing viscoelastic properties of the subphase. These studies demonstrate that the surface behavior of lung surfactant on viscoelastic surfaces, such as those found in the conducting airways, differs significantly from aqueous, surfactant-laden systems.

Active cycle of breathing technique for cystic fibrosis.

PubMed

Mckoy, Naomi A; Wilson, Lisa M; Saldanha, Ian J; Odelola, Olaide A; Robinson, Karen A

2016-07-05

People with cystic fibrosis experience chronic airway infections as a result of mucus build up within the lungs. Repeated infections often cause lung damage and disease. Airway clearance therapies aim to improve mucus clearance, increase sputum production, and improve airway function. The active cycle of breathing technique (also known as ACBT) is an airway clearance method that uses a cycle of techniques to loosen airway secretions including breathing control, thoracic expansion exercises, and the forced expiration technique. This is an update of a previously published review. To compare the clinical effectiveness of the active cycle of breathing technique with other airway clearance therapies in cystic fibrosis. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.Date of last search: 25 April 2016. Randomised or quasi-randomised controlled clinical studies, including cross-over studies, comparing the active cycle of breathing technique with other airway clearance therapies in cystic fibrosis. Two review authors independently screened each article, abstracted data and assessed the risk of bias of each study. Our search identified 62 studies, of which 19 (440 participants) met the inclusion criteria. Five randomised controlled studies (192 participants) were included in the meta-analysis; three were of cross-over design. The 14 remaining studies were cross-over studies with inadequate reports for complete assessment. The study size ranged from seven to 65 participants. The age of the participants ranged from six to 63 years (mean age 22.33 years). In 13 studies, follow up lasted a single day. However, there were two long-term randomised controlled studies with follow up of one to three years. Most of the studies did not report on key quality items, and therefore, have an unclear risk of bias in terms of random sequence generation, allocation concealment, and outcome assessor blinding. Due to the nature of the intervention, none of the studies blinded participants or the personnel applying the interventions. However, most of the studies reported on all planned outcomes, had adequate follow up, assessed compliance, and used an intention-to-treat analysis.Included studies compared the active cycle of breathing technique with autogenic drainage, airway oscillating devices, high frequency chest compression devices, conventional chest physiotherapy, and positive expiratory pressure. Preference of technique varied: more participants preferred autogenic drainage over the active cycle of breathing technique; more preferred the active cycle of breathing technique over airway oscillating devices; and more were comfortable with the active cycle of breathing technique versus high frequency chest compression. No significant difference was seen in quality of life, sputum weight, exercise tolerance, lung function, or oxygen saturation between the active cycle of breathing technique and autogenic drainage or between the active cycle of breathing technique and airway oscillating devices. There was no significant difference in lung function and the number of pulmonary exacerbations between the active cycle of breathing technique alone or in conjunction with conventional chest physiotherapy. All other outcomes were either not measured or had insufficient data for analysis. There is insufficient evidence to support or reject the use of the active cycle of breathing technique over any other airway clearance therapy. Five studies, with data from eight different comparators, found that the active cycle of breathing technique was comparable with other therapies in outcomes such as participant preference, quality of life, exercise tolerance, lung function, sputum weight, oxygen saturation, and number of pulmonary exacerbations. Longer-term studies are needed to more adequately assess the effects of the active cycle of breathing technique on outcomes important for people with cystic fibrosis such as quality of life and preference.

Respiratory symptoms and lung function in relation to wood dust and monoterpene exposure in the wood pellet industry.

PubMed

Löfstedt, Håkan; Hagström, Katja; Bryngelsson, Ing-Liss; Holmström, Mats; Rask-Andersen, Anna

2017-06-01

Wood pellets are used as a source of renewable energy for heating purposes. Common exposures are wood dust and monoterpenes, which are known to be hazardous for the airways. The purpose of this study was to study the effect of occupational exposure on respiratory health in wood pellet workers. Thirty-nine men working with wood pellet production at six plants were investigated with a questionnaire, medical examination, allergy screening, spirometry, and nasal peak expiratory flow (nasal PEF). Exposure to wood dust and monoterpenes was measured. The wood pellet workers reported a higher frequency of nasal symptoms, dry cough, and asthma medication compared to controls from the general population. There were no differences in nasal PEF between work and leisure time. A lower lung function than expected (vital capacity [VC], 95%; forced vital capacity in 1 second [FEV 1 ], 96% of predicted) was noted, but no changes were noted during shifts. There was no correlation between lung function and years working in pellet production. Personal measurements of wood dust at work showed high concentrations (0.16-19 mg/m 3 ), and exposure peaks when performing certain work tasks. Levels of monoterpenes were low (0.64-28 mg/m 3 ). There was no association between exposure and acute lung function effects. In this study of wood pellet workers, high levels of wood dust were observed, and that may have influenced the airways negatively as the study group reported upper airway symptoms and dry cough more frequently than expected. The wood pellet workers had both a lower VC and FEV 1 than expected. No cross-shift changes were found.

Respiratory symptoms and lung function in relation to wood dust and monoterpene exposure in the wood pellet industry

PubMed Central

Löfstedt, Håkan; Hagström, Katja; Bryngelsson, Ing-Liss; Holmström, Mats; Rask-Andersen, Anna

2017-01-01

Introduction Wood pellets are used as a source of renewable energy for heating purposes. Common exposures are wood dust and monoterpenes, which are known to be hazardous for the airways. The purpose of this study was to study the effect of occupational exposure on respiratory health in wood pellet workers. Materials and methods Thirty-nine men working with wood pellet production at six plants were investigated with a questionnaire, medical examination, allergy screening, spirometry, and nasal peak expiratory flow (nasal PEF). Exposure to wood dust and monoterpenes was measured. Results The wood pellet workers reported a higher frequency of nasal symptoms, dry cough, and asthma medication compared to controls from the general population. There were no differences in nasal PEF between work and leisure time. A lower lung function than expected (vital capacity [VC], 95%; forced vital capacity in 1 second [FEV1], 96% of predicted) was noted, but no changes were noted during shifts. There was no correlation between lung function and years working in pellet production. Personal measurements of wood dust at work showed high concentrations (0.16–19 mg/m3), and exposure peaks when performing certain work tasks. Levels of monoterpenes were low (0.64–28 mg/m3). There was no association between exposure and acute lung function effects. Conclusions In this study of wood pellet workers, high levels of wood dust were observed, and that may have influenced the airways negatively as the study group reported upper airway symptoms and dry cough more frequently than expected. The wood pellet workers had both a lower VC and FEV1 than expected. No cross-shift changes were found. PMID:28276782

3He Lung Morphometry Technique: Accuracy Analysis and Pulse Sequence Optimization

PubMed Central

Sukstanskii, A.L.; Conradi, M.S.; Yablonskiy, D.A.

2010-01-01

The 3He lung morphometry technique (Yablonskiy et al, JAP, 2009), based on MRI measurements of hyperpolarized gas diffusion in lung airspaces, provides unique information on the lung microstructure at the alveolar level. 3D tomographic images of standard morphological parameters (mean airspace chord length, lung parenchyma surface-to-volume ratio, and the number of alveoli per unit lung volume) can be created from a rather short (several seconds) MRI scan. These parameters are most commonly used to characterize lung morphometry but were not previously available from in vivo studies. A background of the 3He lung morphometry technique is based on a previously proposed model of lung acinar airways, treated as cylindrical passages of external radius R covered by alveolar sleeves of depth h, and on a theory of gas diffusion in these airways. The initial works approximated the acinar airways as very long cylinders, all with the same R and h. The present work aims at analyzing effects of realistic acinar airway structures, incorporating airway branching, physiological airway lengths, a physiological ratio of airway ducts and sacs, and distributions of R and h. By means of Monte Carlo computer simulations, we demonstrate that our technique allows rather accurate measurements of geometrical and morphological parameters of acinar airways. In particular, the accuracy of determining one of the most important physiological parameter of acinar airways – surface-to-volume ratio – does not exceed several percent. Second, we analyze the effect of the susceptibility induced inhomogeneous magnetic field on the parameter estimate and demonstrate that this effect is rather negligible at B0 ≤ 3T and becomes substantial only at higher B0 Third, we theoretically derive an optimal choice of MR pulse sequence parameters, which should be used to acquire a series of diffusion attenuated MR signals, allowing a substantial decrease in the acquisition time and improvement in accuracy of the results. It is demonstrated that the optimal choice represents three not equidistant b-values: b1 = 0, b2 ~ 2 s/cm2, b3 ~ 8 s/cm2. PMID:20937564

Pulmonary function in men after short-term exposure to ozone

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

Hazucha, M.; Silverman, F.; Parent, C.

1973-01-01

Volunteers were exposed to 0.37 or 0.75 ppm ozone for 2 hr in environmental chamber while doing light exercise and resting intermittently. Slight discomfort resulted: dry throat, cough, chest tightness. Reduction in flow rates, FVC, and FEV at 1 and 2 hr was noted. Thus, ozone reached terminal bronchioles and impaired their function. Reduction in pulmonary measurements of maximum flow results were probably due to decreased lung elastic recoil, increased airway resistence, and small airway obstruction.

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

NASA Astrophysics Data System (ADS)

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

2018-03-01

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

Dual-energy micro-CT imaging of pulmonary airway obstruction: correlation with micro-SPECT

NASA Astrophysics Data System (ADS)

Badea, C. T.; Befera, N.; Clark, D.; Qi, Y.; Johnson, G. A.

2014-03-01

To match recent clinical dual energy (DE) CT studies focusing on the lung, similar developments for DE micro-CT of the rodent lung are required. Our group has been actively engaged in designing pulmonary gating techniques for micro- CT, and has also introduced the first DE micro-CT imaging method of the rodent lung. The aim of this study was to assess the feasibility of DE micro-CT imaging for the evaluation of airway obstruction in mice, and to compare the method with micro single photon emission computed tomography (micro-SPECT) using technetium-99m labeled macroaggregated albumin (99mTc-MAA). The results suggest that the induced pulmonary airway obstruction causes either atelectasis, or air-trapping similar to asthma or chronic bronchitis. Atelectasis could only be detected at early time points in DE micro-CT images, and is associated with a large increase in blood fraction and decrease in air fraction. Air trapping had an opposite effect with larger air fraction and decreased blood fraction shown by DE micro-CT. The decrease in perfusion to the hypoventilated lung (hypoxic vasoconstriction) is also seen in micro-SPECT. The proposed DE micro-CT technique for imaging localized airway obstruction performed well in our evaluation, and provides a higher resolution compared to micro-SPECT. Both DE micro-CT and micro-SPECT provide critical, quantitative lung biomarkers for image-based anatomical and functional information in the small animal. The methods are readily linked to clinical methods allowing direct comparison of preclinical and clinical results.

RGS4 Overexpression in Lung Attenuates Airway Hyperresponsiveness in Mice.

PubMed

Madigan, Laura A; Wong, Gordon S; Gordon, Elizabeth M; Chen, Wei-Sheng; Balenga, Nariman; Koziol-White, Cynthia J; Panettieri, Reynold A; Levine, Stewart J; Druey, Kirk M

2018-01-01

A cardinal feature of asthma is airway hyperresponsiveness (AHR) to spasmogens, many of which activate G protein-coupled receptors (GPCRs) on airway smooth muscle (ASM) cells. Asthma subtypes associated with allergy are characterized by eosinophilic inflammation in the lung due to the type 2 immune response to allergens and proinflammatory mediators that promote AHR. The degree to which intrinsic abnormalities of ASM contribute to this phenotype remains unknown. The regulators of G protein signaling (RGS) proteins are a large group of intracellular proteins that inhibit GPCR signaling pathways. RGS2- and RGS5-deficient mice develop AHR spontaneously. Although RGS4 is upregulated in ASM from patients with severe asthma, the effects of increased RGS4 expression on AHR in vivo are unknown. Here, we examined the impact of forced RGS4 overexpression in lung on AHR using transgenic (Tg) mice. Tg RGS4 was expressed in bronchial epithelium and ASM in vivo, and protein expression in lung was increased at least 4-fold in Tg mice compared with wild-type (WT) mice. Lung slices from Tg mice contracted less in response to the m3 muscarinic receptor agonist methacholine compared with the WT, although airway resistance in live, unchallenged mice of both strains was similar. Tg mice were partially protected against AHR induced by fungal allergen challenge due to weakened contraction signaling in ASM and reduced type 2 cytokine (IL-5 and IL-13) levels in Tg mice compared with the WT. These results provide support for the hypothesis that increasing RGS4 expression and/or function could be a viable therapeutic strategy for asthma.

Airway remodeling in murine asthma correlates with a defect in PGE2 synthesis by lung fibroblasts

PubMed Central

Stumm, Camila Leindecker; Wettlaufer, Scott H.; Jancar, Sonia

2011-01-01

Asthma is a chronic lung disease characterized by local inflammation that can result in structural alterations termed airway remodeling. One component of airway remodeling involves fibroblast accumulation and activation, resulting in deposition of collagen I around small bronchi. Prostaglandin E2 (PGE2) is the main eicosanoid lipid mediator produced by lung fibroblasts, and it exerts diverse anti-fibrotic actions. Dysregulation of the PGE2 synthesis/response axis has been identified in human pulmonary fibrotic diseases and implicated in the pathogenesis of animal models of lung parenchymal fibrosis. Here we investigated the relationship between the fibroblast PGE2 axis and airway fibrosis in an animal model of chronic allergic asthma. Airway fibrosis increased progressively as the number of airway challenges with antigen increased from 3 to 7 to 12. Compared with cells from control lungs, fibroblasts grown from the lungs of asthmatic animals, regardless of challenge number, exhibited no defect in the ability of PGE2 or its analogs to inhibit cellular proliferation and collagen I expression. This correlated with intact expression of the EP2 receptor, which is pivotal for PGE2 responsiveness. However, cytokine-induced upregulation of PGE2 biosynthesis as well as expression of cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 declined with increasing numbers of antigen challenges. In addition, treatment with the COX-2-selective inhibitor nimesulide potentiated the degree of airway fibrosis following repeated allergen challenge. Because endogenous COX-2-derived PGE2 acts as a brake on airway fibrosis, the inability of fibroblasts to upregulate PGE2 generation in the inflammatory milieu presented by repeated allergen exposure could contribute to the airway remodeling and fibrosis observed in chronic asthma. PMID:21873451

Modulation of Haemophilus influenzae interaction with hydrophobic molecules by the VacJ/MlaA lipoprotein impacts strongly on its interplay with the airways.

PubMed

Fernández-Calvet, Ariadna; Rodríguez-Arce, Irene; Almagro, Goizeder; Moleres, Javier; Euba, Begoña; Caballero, Lucía; Martí, Sara; Ramos-Vivas, José; Bartholomew, Toby Leigh; Morales, Xabier; Ortíz-de-Solórzano, Carlos; Yuste, José Enrique; Bengoechea, José Antonio; Conde-Álvarez, Raquel; Garmendia, Junkal

2018-05-02

Airway infection by nontypeable Haemophilus influenzae (NTHi) associates to chronic obstructive pulmonary disease (COPD) exacerbation and asthma neutrophilic airway inflammation. Lipids are key inflammatory mediators in these disease conditions and consequently, NTHi may encounter free fatty acids during airway persistence. However, molecular information on the interplay NTHi-free fatty acids is limited, and we lack evidence on the importance of such interaction to infection. Maintenance of the outer membrane lipid asymmetry may play an essential role in NTHi barrier function and interaction with hydrophobic molecules. VacJ/MlaA-MlaBCDEF prevents phospholipid accumulation at the bacterial surface, being the only system involved in maintaining membrane asymmetry identified in NTHi. We assessed the relationship among the NTHi VacJ/MlaA outer membrane lipoprotein, bacterial and exogenous fatty acids, and respiratory infection. The vacJ/mlaA gene inactivation increased NTHi fatty acid and phospholipid global content and fatty acyl specific species, which in turn increased bacterial susceptibility to hydrophobic antimicrobials, decreased NTHi epithelial infection, and increased clearance during pulmonary infection in mice with both normal lung function and emphysema, maybe related to their shared lung fatty acid profiles. Altogether, we provide evidence for VacJ/MlaA as a key bacterial factor modulating NTHi survival at the human airway upon exposure to hydrophobic molecules.

The Contribution of Small Airway Obstruction to the Pathogenesis of Chronic Obstructive Pulmonary Disease.

PubMed

Hogg, James C; Paré, Peter D; Hackett, Tillie-Louise

2017-04-01

The hypothesis that the small conducting airways were the major site of obstruction to airflow in normal lungs was introduced by Rohrer in 1915 and prevailed until Weibel introduced a quantitative method of studying lung anatomy in 1963. Green repeated Rohrer's calculations using Weibels new data in 1965 and found that the smaller conducting airways offered very little resistance to airflow. This conflict was resolved by seminal experiments conducted by Macklem and Mead in 1967, which confirmed that a small proportion of the total lower airways resistance is attributable to small airways <2 mm in diameter. Shortly thereafter, Hogg, Macklem, and Thurlbeck used this technique to show that small airways become the major site of obstruction in lungs affected by emphysema. These and other observations led Mead to write a seminal editorial in 1970 that postulated the small airways are a silent zone within normal lungs where disease can accumulate over many years without being noticed. This review provides a progress report since the 1970s on methods for detecting chronic obstructive pulmonary disease, the structural nature of small airways' disease, and the cellular and molecular mechanisms that are thought to underlie its pathogenesis. Copyright © 2017 the American Physiological Society.

S-Nitrosoglutathione Reductase Inhibition Regulates Allergen-Induced Lung Inflammation and Airway Hyperreactivity

PubMed Central

Bassett, David J. P.; Bradley, Matthews O.; Jaffar, Zeina

2013-01-01

Allergic asthma is characterized by Th2 type inflammation, leading to airway hyperresponsivenes, mucus hypersecretion and tissue remodeling. S-Nitrosoglutathione reductase (GSNOR) is an alcohol dehydrogenase involved in the regulation of intracellular levels of S-nitrosothiols. GSNOR activity has been shown to be elevated in human asthmatic lungs, resulting in diminished S-nitrosothiols and thus contributing to increased airway hyperreactivity. Using a mouse model of allergic airway inflammation, we report that intranasal administration of a new selective inhibitor of GSNOR, SPL-334, caused a marked reduction in airway hyperreactivity, allergen-specific T cells and eosinophil accumulation, and mucus production in the lungs in response to allergen inhalation. Moreover, SPL-334 treatment resulted in a significant decrease in the production of the Th2 cytokines IL-5 and IL-13 and the level of the chemokine CCL11 (eotaxin-1) in the airways. Collectively, these observations reveal that GSNOR inhibitors are effective not only in reducing airway hyperresponsiveness but also in limiting lung inflammatory responses mediated by CD4+ Th2 cells. These findings suggest that the inhibition of GSNOR may provide a novel therapeutic approach for the treatment of allergic airway inflammation. PMID:23936192

Allergic inflammation induces a persistent mechanistic switch in thromboxane-mediated airway constriction in the mouse

PubMed Central

Cyphert, Jaime M.; Allen, Irving C.; Church, Rachel J.; Latour, Anne M.; Snouwaert, John N.; Coffman, Thomas M.

2012-01-01

Actions of thromboxane (TXA2) to alter airway resistance were first identified over 25 years ago. However, the mechanism underlying this physiological response has remained largely undefined. Here we address this question using a novel panel of mice in which expression of the thromboxane receptor (TP) has been genetically manipulated. We show that the response of the airways to TXA2 is complex: it depends on expression of other G protein-coupled receptors but also on the physiological context of the signal. In the healthy airway, TXA2-mediated airway constriction depends on expression of TP receptors by smooth muscle cells. In contrast, in the inflamed lung, the direct actions of TXA2 on smooth muscle cell TP receptors no longer contribute to bronchoconstriction. Instead, in allergic lung disease, TXA2-mediated airway constriction depends on neuronal TP receptors. Furthermore, this mechanistic switch persists long after resolution of pulmonary inflammation. Our findings demonstrate the powerful ability of lung inflammation to modify pathways leading to airway constriction, resulting in persistent changes in mechanisms of airway reactivity to key bronchoconstrictors. Such alterations are likely to shape the pathogenesis of asthmatic lung disease. PMID:21984570

Central Airway Obstruction: Benign Strictures, Tracheobronchomalacia, and Malignancy-related Obstruction.

PubMed

Murgu, Septimiu Dan; Egressy, Katarine; Laxmanan, Balaji; Doblare, Guillermo; Ortiz-Comino, Rosamaria; Hogarth, D Kyle

2016-08-01

The purpose of this article is to provide an update on methods for palliating symptoms in patients with histologically benign and malignant central airway obstruction. We review the published literature within the past decade on postintubation, posttracheostomy, and TB- and transplant-related airway strictures; tracheobronchomalacia; and malignant airway obstruction. We review terminology, classification systems, and parameters that impact treatment decisions. The focus is on how airway stent insertion fits into the best algorithm of care. Several case series and cohort studies demonstrate that airway stents improve dyspnea, lung function, and quality of life in patients with airway obstruction. Airway stenting, however, is associated with high rates of adverse events and should be used only when curative open surgical interventions are not feasible or are contraindicated. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

The Short-Term Effect of Breathing Tasks Via an Incentive Spirometer on Lung Function Compared With Autogenic Drainage in Subjects With Cystic Fibrosis.

PubMed

Sokol, Gil; Vilozni, Daphna; Hakimi, Ran; Lavie, Moran; Sarouk, Ifat; Bat-El Bar; Dagan, Adi; Ofek, Miryam; Efrati, Ori

2015-12-01

Forced expiration may assist secretion movement by manipulating airway dynamics in patients with cystic fibrosis (CF). Expiratory resistive breathing via a handheld incentive spirometer has the potential to control the expiratory flow via chosen resistances (1-8 mm) and thereby mobilize secretions and improve lung function. Our objective was to explore the short-term effect of using a resistive-breathing incentive spirometer on lung function in subjects with CF compared with the autogenic drainage technique. This was a retrospective study. Subjects with CF performed 30-45 min of either the resistive-breathing incentive spirometer (n = 40) or autogenic drainage (n = 32) technique on separate days. The spirometer encourages the patient to exhale as long as possible while maintaining a low lung volume. The autogenic drainage technique includes repetitive inspiratory and expiratory maneuvers at various tidal breathing magnitudes while exhalation is performed in a sighing manner. Spirometry was performed before and 20-30 min after the therapy. Use of a resistive-breathing incentive spirometer improved FVC and FEV1 by 5-42% in 26 subjects. The forced expiratory flow during the middle half of the FVC maneuver (FEF25-75%) improved by >20% in 9 (22%) subjects. FVC improved the most in subjects with an FEV1 of 40-60% of predicted. Improvements negatively correlated with baseline percent-of-predicted FVC values provided improvements were above 10% (r(2) = 0.28). Values improved in a single subjects using the autogenic drainage technique. These 2 techniques may allow lower thoracic pressures and assist in the prevention of central airway collapse. The resistive-breathing incentive spirometer is a self-administered simple method that may aid airway clearance and has the potential to improve lung function as measured by FVC, FEV1, and FEF25-75% in patients with CF. Copyright © 2015 by Daedalus Enterprises.

The role of high airway pressure and dynamic strain on ventilator-induced lung injury in a heterogeneous acute lung injury model.

PubMed

Jain, Sumeet V; Kollisch-Singule, Michaela; Satalin, Joshua; Searles, Quinn; Dombert, Luke; Abdel-Razek, Osama; Yepuri, Natesh; Leonard, Antony; Gruessner, Angelika; Andrews, Penny; Fazal, Fabeha; Meng, Qinghe; Wang, Guirong; Gatto, Louis A; Habashi, Nader M; Nieman, Gary F

2017-12-01

Acute respiratory distress syndrome causes a heterogeneous lung injury with normal and acutely injured lung tissue in the same lung. Improperly adjusted mechanical ventilation can exacerbate ARDS causing a secondary ventilator-induced lung injury (VILI). We hypothesized that a peak airway pressure of 40 cmH 2 O (static strain) alone would not cause additional injury in either the normal or acutely injured lung tissue unless combined with high tidal volume (dynamic strain). Pigs were anesthetized, and heterogeneous acute lung injury (ALI) was created by Tween instillation via a bronchoscope to both diaphragmatic lung lobes. Tissue in all other lobes was normal. Airway pressure release ventilation was used to precisely regulate time and pressure at both inspiration and expiration. Animals were separated into two groups: (1) over-distension + high dynamic strain (OD + H DS , n = 6) and (2) over-distension + low dynamic strain (OD + L DS , n = 6). OD was caused by setting the inspiratory pressure at 40 cmH 2 O and dynamic strain was modified by changing the expiratory duration, which varied the tidal volume. Animals were ventilated for 6 h recording hemodynamics, lung function, and inflammatory mediators followed by an extensive necropsy. In normal tissue (N T ), OD + L DS caused minimal histologic damage and a significant reduction in BALF total protein (p < 0.05) and MMP-9 activity (p < 0.05), as compared with OD + H DS . In acutely injured tissue (ALI T ), OD + L DS resulted in reduced histologic injury and pulmonary edema (p < 0.05), as compared with OD + H DS . Both N T and ALI T are resistant to VILI caused by OD alone, but when combined with a H DS , significant tissue injury develops.

Computer simulation of airflow through a multi-generation tracheobronchial conducting airway

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

Fan, B.; Cheng, Yung-Sung; Yeh, Hsu-Chi

1995-12-01

Knowledge of airflow patterns in the human lung is important for an analysis of lung diseases and drug delivery of aerosolized medicine for medical treatment. However, very little systematic information is available on the pattern of airflow in the lung and on how this pattern affects the deposition of toxicants in the lung, and the efficacy of aerosol drug therapy. Most previous studies have only considered the airflow through a single bifurcating airway. However, the flow in a network of more than one bifurcation is more complicated due to the effect of interrelated lung generations. Because of the variation ofmore » airway geometry and flow condition from generation to generation, a single bifurcating airway cannot be taken as a representative for the others in different generations. The flow in the network varies significantly with airway generations because of a redistribution of axial momentum by the secondary flow motions. The influence of the redistribution of flow is expected in every generation. Therefore, a systematic information of the airflow through a multi-generation tracheobronchial conducting airway is needed, and it becomes the purpose of this study. This study has provided information on airflow in a lung model which is necessary to the study of the deposition of toxicants and therapeutic aerosols.« less

Elevated Expression of IL-33 and TSLP in the Airways of Human Asthmatics In Vivo: A Potential Biomarker of Severe Refractory Disease.

PubMed

Li, Yan; Wang, Wei; Lv, Zhe; Li, Yun; Chen, Yan; Huang, Kewu; Corrigan, Chris J; Ying, Sun

2018-04-01

The epithelial cytokines IL-33, thymic stromal lymphopoietin (TSLP), and IL-25 have been implicated in asthma pathogenesis because they promote Th2-type cytokine synthesis, but their expression is relatively poorly documented in "real-life" human asthma. Using bronchoalveolar lavage fluid (BALF), we measured airway concentrations of these mediators and compared them with those of Th1- and Th2-type cytokines, airway infiltration of neutrophils and eosinophils, and lung function in a large group of asthmatic patients with a range of disease severity ( n = 70) and control subjects ( n = 30). The median BALF concentrations of IL-33, TSLP, IL-4, IL-5, IL-13, and IL-12p70, but not IL-25, IL-2, or IFN-γ, were significantly elevated in asthmatics compared with controls ( p < 0.05). The concentrations of IL-33 and TSLP, but not IL-25, correlated inversely with the lung function (forced expiratory volume in the first second) of asthmatics (IL-33: r = -0.488, p < 0.0001; TSLP: r = -0.565, p < 0.0001) independently of corticosteroid therapy. When divided according to disease severity and corticosteroid therapy, all subgroups of asthmatics had elevated median numbers of eosinophils in BALF, whereas the patients with more severe disease who were treated with corticosteroids had higher numbers of neutrophils compared with milder asthmatics not so treated and control subjects ( p < 0.05). The data implicate TSLP and IL-33 in the pathogenesis of asthma that is characterized by persistent airway inflammation and impaired lung function despite intensive corticosteroid therapy, highlighting them as potential molecular targets. Copyright © 2018 by The American Association of Immunologists, Inc.

Scaling laws for oxygen transport across the space-filling system of respiratory membranes in the human lung

NASA Astrophysics Data System (ADS)

Hou, Chen

Space-filling fractal surfaces play a fundamental role in how organisms function at various levels and in how structure determines function at different levels. In this thesis, we develop a quantitative theory of oxygen transport to and across the surface of the highly branched, space-filling system of alveoli, the fundamental gas exchange unit (acinar airways), in the human lung. Oxygen transport in the acinar airways is by diffusion, and we treat the two steps---diffusion through the branched airways, and transfer across the alveolar membranes---as a stationary diffusion-reaction problem, taking into account that there may be steep concentration gradients between the entrance and remote alveoli (screening). We develop a renormalization treatment of this screening effect and derive an analytic formula for the oxygen current across the cumulative alveolar membrane surface, modeled as a fractal, space-filling surface. The formula predicts the current from a minimum of morphological data of the acinus and appropriate values of the transport parameters, through a number of power laws (scaling laws). We find that the lung at rest operates near the borderline between partial screening and no screening; that it switches to no screening under exercise; and that the computed currents agree with measured values within experimental uncertainties. From an analysis of the computed current as a function of membrane permeability, we find that the space-filling structure of the gas exchanger is simultaneously optimal with respect to five criteria. The exchanger (i) generates a maximum oxygen current at minimum permeability; (ii) 'wastes' a minimum of surface area; (iii) maintains a minimum residence time of oxygen in the acinar airways; (iv) has a maximum fault tolerance to loss of permeability; and (v) generates a maximum current increase when switching from rest to exercise.

Obesity in children with poorly controlled asthma: Sex differences.

PubMed

Lang, Jason E; Holbrook, Janet T; Wise, Robert A; Dixon, Anne E; Teague, W Gerald; Wei, Christine Y; Irvin, Charles G; Shade, David; Lima, John J

2013-09-01

Obesity increases asthma risk, and may alter asthma severity. In adults, sex appears to modify the effect of obesity on asthma. Among children, the effect of sex on the relationship between obesity and asthma severity remains less clear, particularly when considering race. To determine how obesity affects disease characteristics in a diverse cohort of children with poorly controlled asthma, and if obesity effects are altered by sex. We analyzed 306 children between 6 and 17 years of age with poorly controlled asthma enrolled in a 6-month trial assessing lansoprazole for asthma control. In this secondary analysis, we determined associations between obesity and symptom severity, spirometry, exacerbation risk, airway biomarkers, bronchial reactivity, and airflow perception. We used both a multivariate linear regression and longitudinal mixed-effect model to determine if obesity interacted with sex to affect asthma severity. Regardless of sex, BMI >95th percentile did not affect asthma control, exacerbation risk or airway biomarkers. Sex changed the effect of obesity on lung function (sex × obesity FEV1%, interaction P-value < 0.01, sex × obesity FEV1/FVC, interaction P-value = 0.03). Obese males had significantly worse airflow obstruction compared to non-obese males, while in females there was no obesity effect on airflow obstruction. In females, obesity was associated with significantly greater FEV1 and FVC, and a trend toward reduced airway reactivity. Obesity did not affect asthma control, airway markers or disease stability; however obesity did affect lung function in a sex-dependent manner. In males, obesity associated with reduced FEV1/FVC, and in females, obesity associated with substantially improved lung function. Copyright © 2012 Wiley Periodicals, Inc.

Cystic fibrosis gene modifier SLC26A9 modulates airway response to CFTR-directed therapeutics.

PubMed

Strug, Lisa J; Gonska, Tanja; He, Gengming; Keenan, Katherine; Ip, Wan; Boëlle, Pierre-Yves; Lin, Fan; Panjwani, Naim; Gong, Jiafen; Li, Weili; Soave, David; Xiao, Bowei; Tullis, Elizabeth; Rabin, Harvey; Parkins, Michael D; Price, April; Zuberbuhler, Peter C; Corvol, Harriet; Ratjen, Felix; Sun, Lei; Bear, Christine E; Rommens, Johanna M

2016-10-15

Cystic fibrosis is realizing the promise of personalized medicine. Recent advances in drug development that target the causal CFTR directly result in lung function improvement, but variability in response is demanding better prediction of outcomes to improve management decisions. The genetic modifier SLC26A9 contributes to disease severity in the CF pancreas and intestine at birth and here we assess its relationship with disease severity and therapeutic response in the airways. SLC26A9 association with lung disease was assessed in individuals from the Canadian and French CF Gene Modifier consortia with CFTR-gating mutations and in those homozygous for the common Phe508del mutation. Variability in response to a CFTR-directed therapy attributed to SLC26A9 genotype was assessed in Canadian patients with gating mutations. A primary airway model system determined if SLC26A9 shows modification of Phe508del CFTR function upon treatment with a CFTR corrector. In those with gating mutations that retain cell surface-localized CFTR we show that SLC26A9 modifies lung function while this is not the case in individuals homozygous for Phe508del where cell surface expression is lacking. Treatment response to ivacaftor, which aims to improve CFTR-channel opening probability in patients with gating mutations, shows substantial variability in response, 28% of which can be explained by rs7512462 in SLC26A9 (P = 0.0006). When homozygous Phe508del primary bronchial cells are treated to restore surface CFTR, SLC26A9 likewise modifies treatment response (P = 0.02). Our findings indicate that SLC26A9 airway modification requires CFTR at the cell surface, and that a common variant in SLC26A9 may predict response to CFTR-directed therapeutics.

In vivo lung morphometry with hyperpolarized 3He diffusion MRI: Theoretical background

NASA Astrophysics Data System (ADS)

Sukstanskii, A. L.; Yablonskiy, D. A.

2008-02-01

MRI-based study of 3He gas diffusion in lungs may provide important information on lung microstructure. Lung acinar airways can be described in terms of cylinders covered with alveolar sleeve [Haefeli-Bleuer, Weibel, Anat. Rec. 220 (1988) 401]. For relatively short diffusion times (on the order of a few ms) this geometry allows description of the 3He diffusion attenuated MR signal in lungs in terms of two diffusion coefficients—longitudinal (D) and transverse (D) with respect to the individual acinar airway axis [Yablonskiy et al., PNAS 99 (2002) 3111]. In this paper, empirical relationships between D and D and the geometrical parameters of airways and alveoli are found by means of computer Monte Carlo simulations. The effects of non-Gaussian signal behavior (dependence of D and D on b-value) are also taken into account. The results obtained are quantitatively valid in the physiologically important range of airway parameters characteristic of healthy lungs and lungs with mild emphysema. In lungs with advanced emphysema, the results provide only "apparent" characteristics but still could potentially be used to evaluate emphysema progression. This creates a basis for in vivo lung morphometry—evaluation of the geometrical parameters of acinar airways from hyperpolarized 3He diffusion MRI, despite the airways being too small to be resolved by direct imaging. These results also predict a rather substantial dependence of 3He ADC on the experimentally-controllable diffusion time, Δ. If Δ is decreased from 3 ms to 1 ms, the ADC in normal human lungs may increase by almost 50%. This effect should be taken into account when comparing experimental data obtained with different pulse sequences.

Chronic obstructive pulmonary disease: knowing what we mean, meaning what we say.

PubMed

Joshi, J M

2008-01-01

Chronic obstructive pulmonary disease (COPD) is defined in several different ways using different criteria based on symptoms, physiological impairment and pathological abnormalities. While some use COPD to mean smoking related chronic airway disease, others include all disorders causing chronic airway obstruction. When COPD is used as a broad descriptive term, specific disorders that cause chronic airway obstruction remain under-diagnosed and the prevalence estimates vary considerably. The lack of agreement over the precise terminology and classification of COPD has resulted in widespread confusion. Terminology includes definition, diagnostic criteria, and a system for staging severity. Recently, COPD is defined more clearly and diagnosed using precise criteria that include tobacco smoking greater than 10 pack years, symptoms and airway obstruction on spirometry. A multi-dimensional severity grading system, the BODE (body mass index, obstruction, dyspnoea, and exercise tolerance) index has been designed to assess the respiratory and systemic expressions of COPD. This review proposes that the broad group of chronic disorders of the airways (with or without airway obstruction) be called chronic airway disease (CAD). The term COPD should be used exclusively for tobacco smoking related chronic airway disease. Chronic airway obstruction or obstructive lung disease may be used to define those conditions with airways obstruction caused by factors other than tobacco smoking. The aetiology may be appended to the label, for example, chronic airway obstruction/obstructive lung disease associated with bronchiectasis, chronic airway obstruction/obstructive lung disease associated with obliterative bronchiolitis or chronic airway obstruction/obstructive lung disease due to biomass fuel/occupational exposure.

Airway Pressure Release Ventilation During Ex Vivo Lung Perfusion Attenuates Injury

PubMed Central

Mehaffey, J. Hunter; Charles, Eric J.; Sharma, Ashish K.; Money, Dustin; Zhao, Yunge; Stoler, Mark H; Lau, Christine L; Tribble, Curtis G.; Laubach, Victor E.; Roeser, Mark E.; Kron, Irving L.

2016-01-01

Objective Critical organ shortages have resulted in Ex Vivo Lung Perfusion (EVLP) gaining clinical acceptance for lung evaluation and rehabilitation to expand the use of Donation after Circulatory Death (DCD) organs for lung transplantation. We hypothesized that an innovative use of airway pressure release ventilation (APRV) during EVLP improves lung function after transplantation. Methods Two groups (n=4 animals/group) of porcine DCD donor lungs were procured after hypoxic cardiac arrest and a 2-hour period of warm ischemia, followed by a 4-hour period of EVLP rehabilitation with either standard conventional volume-based ventilation or pressure-based APRV. Left lungs were subsequently transplanted into recipient animals and reperfused for 4 hours. Blood gases for PaO2/FiO2 ratios, airway pressures for calculation of compliance, and percent wet weight gain during EVLP and reperfusion were measured. Results APRV during EVLP significantly improved left-lung oxygenation at 2-hours (561.5±83.9 vs 341.1±136.1 mmHg) and 4-hours (569.1±18.3 vs 463.5±78.4 mmHg). Similarly, compliance was significantly higher at 2-hours (26.0±5.2 vs 15.0±4.6 mL/cmH2O) and 4-hours (30.6±1.3 vs 17.7±5.9 mL/cmH2O) after transplantation. Finally, APRV significantly reduced lung edema development on EVLP based on percentage weight gain (36.9±14.6 vs 73.9±4.9%). There was no difference in additional edema accumulation 4 hours after reperfusion. Conclusions Pressure-directed APRV ventilation strategy during EVLP improves rehabilitation of severely injured DCD lungs. After transplant these lungs demonstrate superior lung-specific oxygenation and dynamic compliance compared to lungs ventilated with standard conventional ventilation. This strategy, if implemented into clinical EVLP protocols, could advance the field of DCD lung rehabilitation to expand the lung donor pool. PMID:27742245

Novel analysis of 4DCT imaging quantifies progressive increases in anatomic dead space during mechanical ventilation in mice.

PubMed

Kim, Elizabeth H; Preissner, Melissa; Carnibella, Richard P; Samarage, Chaminda R; Bennett, Ellen; Diniz, Marcio A; Fouras, Andreas; Zosky, Graeme R; Jones, Heather D

2017-09-01

Increased dead space is an important prognostic marker in early acute respiratory distress syndrome (ARDS) that correlates with mortality. The cause of increased dead space in ARDS has largely been attributed to increased alveolar dead space due to ventilation/perfusion mismatching and shunt. We sought to determine whether anatomic dead space also increases in response to mechanical ventilation. Mice received intratracheal lipopolysaccharide (LPS) or saline and mechanical ventilation (MV). Four-dimensional computed tomography (4DCT) scans were performed at onset of MV and after 5 h of MV. Detailed measurements of airway volumes and lung tidal volumes were performed using image analysis software. The forced oscillation technique was used to obtain measures of airway resistance, tissue damping, and tissue elastance. The ratio of airway volumes to total tidal volume increased significantly in response to 5 h of mechanical ventilation, regardless of LPS exposure, and airways demonstrated significant variation in volumes over the respiratory cycle. These findings were associated with an increase in tissue elastance (decreased lung compliance) but without changes in tidal volumes. Airway volumes increased over time with exposure to mechanical ventilation without a concomitant increase in tidal volumes. These findings suggest that anatomic dead space fraction increases progressively with exposure to positive pressure ventilation and may represent a pathological process. NEW & NOTEWORTHY We demonstrate that anatomic dead space ventilation increases significantly over time in mice in response to mechanical ventilation. The novel functional lung-imaging techniques applied here yield sensitive measures of airway volumes that may have wide applications. Copyright © 2017 the American Physiological Society.

Activation of neurokinin-1 receptors during ozone inhalation contributes to epithelial injury and repair.

PubMed

Oslund, Karen L; Hyde, Dallas M; Putney, Leialoha F; Alfaro, Mario F; Walby, William F; Tyler, Nancy K; Schelegle, Edward S

2008-09-01

We investigated the importance of neurokinin (NK)-1 receptors in epithelial injury and repair and neutrophil function. Conscious Wistar rats were exposed to 1 ppm ozone or filtered air for 8 hours, followed by an 8-hour postexposure period. Before exposure, we administered either the NK-1 receptor antagonist, SR140333, or saline as a control. Ethidium homodimer was instilled into lungs as a marker of necrotic airway epithelial cells. After fixation, whole mounts of airway dissected lung lobes were immunostained for 5-bromo-2'-deoxyuridine, a marker of epithelial proliferation. Both ethidium homodimer and 5-bromo-2'-deoxyuridine-positive epithelial cells were quantified in specific airway generations. Rats treated with the NK-1 receptor antagonist had significantly reduced epithelial injury and epithelial proliferation compared with control rats. Sections of terminal bronchioles showed no significant difference in the number of neutrophils in airways between groups. In addition, staining ozone-exposed lung sections for active caspase 3 showed no apoptotic cells, but ethidium-positive cells colocalized with the orphan nuclear receptor, Nur77, a marker of nonapoptotic, programmed cell death mediated by the NK-1 receptor. An immortalized human airway epithelial cell line, human bronchial epithelial-1, showed no significant difference in the number of oxidant stress-positive cells during exposure to hydrogen peroxide and a range of SR140333 doses, demonstrating no antioxidant effect of the receptor antagonist. We conclude that activation of the NK-1 receptor during acute ozone inhalation contributes to epithelial injury and subsequent epithelial proliferation, a critical component of repair, but does not influence neutrophil emigration into airways.

Impact of obstructive sleep apnea on lung volumes and mechanical properties of the respiratory system in overweight and obese individuals.

PubMed

Abdeyrim, Arikin; Zhang, Yongping; Li, Nanfang; Zhao, Minghua; Wang, Yinchun; Yao, Xiaoguang; Keyoumu, Youledusi; Yin, Ting

2015-07-25

Even through narrowing of the upper-airway plays an important role in the generation of obstructive sleep apnea (OSA), the peripheral airways is implicated in pre-obese and obese OSA patients, as a result of decreased lung volume and increased lung elastic recoil pressure, which, in turn, may aggravate upper-airway collapsibility. A total of 263 male (n = 193) and female (n = 70) subjects who were obese to various degrees without a history of lung diseases and an expiratory flow limitation, but troubled with snoring or suspicion of OSA were included in this cross-sectional study. According to nocturnal-polysomnography the subjects were distributed into OSA and non-OSA groups, and were further sub-grouped by gender because of differences between males and females, in term of, lung volume size, airway resistance, and the prevalence of OSA among genders. Lung volume and respiratory mechanical properties at different-frequencies were evaluated by plethysmograph and an impulse oscillation system, respectively. Functional residual capacity (FRC) and expiratory reserve volume were significantly decreased in the OSA group compared to the non-OSA group among males and females. As weight and BMI in males in the OSA group were greater than in the non-OSA group (90 ± 14.8 kg vs. 82 ± 10.4 kg, p < 0.001; 30.5 ± 4.2 kg/m(2) vs. 28.0 ± 3.0 kg/m(2), p < 0.001), multiple regression analysis was required to adjust for BMI or weight and demonstrated that these lung volumes decreases were independent from BMI and associated with the severity of OSA. This result was further confirmed by the female cohort. Significant increases in total respiratory resistance and decreases in respiratory conductance (Grs) were observed with increasing severity of OSA, as defined by the apnea-hypopnea index (AHI) in both genders. The specific Grs (sGrs) stayed relatively constant between the two groups in woman, and there was only a weak association between AHI and sGrs among man. Multiple-stepwise-regression showed that reactance at 5 Hz was highly correlated with AHI in males and females or hypopnea index in females, independently-highly correlated with peripheral-airway resistance and significantly associated with decreasing FRC. Total respiratory resistance and peripheral airway resistance significantly increase, and its inverse Grs decrease, in obese patients with OSA in comparison with those without OSA, and are independently associated with OSA severity. These results might be attributed to the abnormally increased lung elasticity recoil pressure on exhalation, due to increase in lung elasticity and decreased lung volume in obese OSA.

Human adipose tissue mesenchymal stromal cells and their extracellular vesicles act differentially on lung mechanics and inflammation in experimental allergic asthma.

PubMed

de Castro, Ligia Lins; Xisto, Debora Gonçalves; Kitoko, Jamil Zola; Cruz, Fernanda Ferreira; Olsen, Priscilla Christina; Redondo, Patricia Albuquerque Garcia; Ferreira, Tatiana Paula Teixeira; Weiss, Daniel Jay; Martins, Marco Aurélio; Morales, Marcelo Marcos; Rocco, Patricia Rieken Macedo

2017-06-24

Asthma is a chronic inflammatory disease that can be difficult to treat due to its complex pathophysiology. Most current drugs focus on controlling the inflammatory process, but are unable to revert the changes of tissue remodeling. Human mesenchymal stromal cells (MSCs) are effective at reducing inflammation and tissue remodeling; nevertheless, no study has evaluated the therapeutic effects of extracellular vesicles (EVs) obtained from human adipose tissue-derived MSCs (AD-MSC) on established airway remodeling in experimental allergic asthma. C57BL/6 female mice were sensitized and challenged with ovalbumin (OVA). Control (CTRL) animals received saline solution using the same protocol. One day after the last challenge, each group received saline, 10 5 human AD-MSCs, or EVs (released by 10 5  AD-MSCs). Seven days after treatment, animals were anesthetized for lung function assessment and subsequently euthanized. Bronchoalveolar lavage fluid (BALF), lungs, thymus, and mediastinal lymph nodes were harvested for analysis of inflammation. Collagen fiber content of airways and lung parenchyma were also evaluated. In OVA animals, AD-MSCs and EVs acted differently on static lung elastance and on BALF regulatory T cells, CD3 + CD4 + T cells, and pro-inflammatory mediators (interleukin [IL]-4, IL-5, IL-13, and eotaxin), but similarly reduced eosinophils in lung tissue, collagen fiber content in airways and lung parenchyma, levels of transforming growth factor-β in lung tissue, and CD3 + CD4 + T cell counts in the thymus. No significant changes were observed in total cell count or percentage of CD3 + CD4 + T cells in the mediastinal lymph nodes. In this immunocompetent mouse model of allergic asthma, human AD-MSCs and EVs effectively reduced eosinophil counts in lung tissue and BALF and modulated airway remodeling, but their effects on T cells differed in lung and thymus. EVs may hold promise for asthma; however, further studies are required to elucidate the different mechanisms of action of AD-MSCs versus their EVs.

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

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

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

Mitran, Sorin, E-mail: mitran@unc.edu

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,more » 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.« less

Chitin elicits CCL2 from airway epithelial cells and induces CCR2-dependent innate allergic inflammation in the lung

PubMed Central

Roy, René M.; Wüthrich, Marcel; Klein, Bruce S.

2012-01-01

Chitin exposure in the lung induces eosinophilia and alternative activation of macrophages, and is correlated with allergic airway disease. However, the mechanism underlying chitin-induced polarization of macrophages is poorly understood. Here, we show that chitin induces alternative activation of macrophages in vivo, but does not do so directly in vitro. We further show that airway epithelial cells bind chitin in vitro and produce CCL2 in response to chitin both in vitro and in vivo. Supernatants of chitin exposed epithelial cells promoted alternative activation of macrophages in vitro, whereas antibody neutralization of CCL2 in the supernate abolished the alternative activation of macrophages. CCL2 acted redundantly in vivo, but mice lacking the CCL2 receptor, CCR2, showed impaired alternative activation of macrophages in response to chitin, as measured by arginase I, CCL17 and CCL22 expression. Furthermore, CCR2KO mice exposed to chitin had diminished ROS products in the lung, blunted eosinophil and monocyte recruitment, and impaired eosinophil functions as measured by expression of CCL5, IL13 and CCL11. Thus, airway epithelial cells secrete CCL2 in response to chitin and CCR2 signaling mediates chitin-induced alternative activation of macrophages and allergic inflammation in vivo. PMID:22851704

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.

A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids

PubMed Central

Dye, Briana R; Dedhia, Priya H; Miller, Alyssa J; Nagy, Melinda S; White, Eric S; Shea, Lonnie D; Spence, Jason R

2016-01-01

Human pluripotent stem cell (hPSC) derived tissues often remain developmentally immature in vitro, and become more adult-like in their structure, cellular diversity and function following transplantation into immunocompromised mice. Previously we have demonstrated that hPSC-derived human lung organoids (HLOs) resembled human fetal lung tissue in vitro (Dye et al., 2015). Here we show that HLOs required a bioartificial microporous poly(lactide-co-glycolide) (PLG) scaffold niche for successful engraftment, long-term survival, and maturation of lung epithelium in vivo. Analysis of scaffold-grown transplanted tissue showed airway-like tissue with enhanced epithelial structure and organization compared to HLOs grown in vitro. By further comparing in vitro and in vivo grown HLOs with fetal and adult human lung tissue, we found that in vivo transplanted HLOs had improved cellular differentiation of secretory lineages that is reflective of differences between fetal and adult tissue, resulting in airway-like structures that were remarkably similar to the native adult human lung. DOI: http://dx.doi.org/10.7554/eLife.19732.001 PMID:27677847

[Regulation of airway stem cell proliferation in idiopathic pulmonary fibrosis].

PubMed

Yang, S X; Wu, Q; Sun, X; Li, X; Li, K; Xu, L; Li, Y; Zhang, Q Y; Zhang, Y C; Chen, H Y

2016-09-01

To investigate the effect of fibroblasts on regulating airway stem cell proliferation in idiopathic pulmonary fibrosis. Lung cell suspension was prepared from β-actin-GFP mice. Airway stem cells were obtained by fluorescence activated cell sorting and co-cultured with lung fibroblasts. The fibroblasts were treated with TGF-β inhibitor SB43142. The expression of growth factors FGF1/2 and the effect of FGF1/2 on stem cell proliferation were observed. The cloning efficiency of airway stem cells, when co-cultured with normal lung fibroblast cells for 8 days, was (3.5±1.1)%, while the cloning efficiency was reduced to (0.04±0.04)% when co-cultured with lung fibroblasts from idiopathic pulmonary fibrosis patients. The difference between the 2 groups was statistically significant(P=0.002 5). TGF-β receptor inhibitor SB431542 increased lung fibroblast growth factors FGF1/2 expression.FGF1 mRNA expression was increased to the experimental group 0.005 5 from 0.000 2 in the control group.FGF2 mRNA expression of the amount raised to the experimental group 0.000 15 from 0.000 8 in the control group.FGF1/2 promoted the growth of airway stem cells. After FGF1/2 was co-cultured with normal lung fibroblast cells for 8 days, the cloning efficiency of airway stem cells was (0.3±0.1)%. During the development of idiopathic pulmonary fibrosis, fibroblast secreted FGF1/2 regulate airway stem cell proliferation.

Receptor for advanced glycation end-products and World Trade Center particulate induced lung function loss: A case-cohort study and murine model of acute particulate exposure

PubMed Central

Haider, Syed H.; Crowley, George; Lee, Audrey; Ebrahim, Minah; Zhang, Liqun; Chen, Lung-Chi; Gordon, Terry; Liu, Mengling; Prezant, David J.; Schmidt, Ann Marie

2017-01-01

World Trade Center-particulate matter(WTC-PM) exposure and metabolic-risk are associated with WTC-Lung Injury(WTC-LI). The receptor for advanced glycation end-products (RAGE) is most highly expressed in the lung, mediates metabolic risk, and single-nucleotide polymorphisms at the AGER-locus predict forced expiratory volume(FEV). Our objectives were to test the hypotheses that RAGE is a biomarker of WTC-LI in the FDNY-cohort and that loss of RAGE in a murine model would protect against acute PM-induced lung disease. We know from previous work that early intense exposure at the time of the WTC collapse was most predictive of WTC-LI therefore we utilized a murine model of intense acute PM-exposure to determine if loss of RAGE is protective and to identify signaling/cytokine intermediates. This study builds on a continuing effort to identify serum biomarkers that predict the development of WTC-LI. A case-cohort design was used to analyze a focused cohort of male never-smokers with normal pre-9/11 lung function. Odds of developing WTC-LI increased by 1.2, 1.8 and 1.0 in firefighters with soluble RAGE (sRAGE)≥97pg/mL, CRP≥2.4mg/L, and MMP-9≤397ng/mL, respectively, assessed in a multivariate logistic regression model (ROCAUC of 0.72). Wild type(WT) and RAGE-deficient(Ager-/-) mice were exposed to PM or PBS-control by oropharyngeal aspiration. Lung function, airway hyperreactivity, bronchoalveolar lavage, histology, transcription factors and plasma/BAL cytokines were quantified. WT-PM mice had decreased FEV and compliance, and increased airway resistance and methacholine reactivity after 24-hours. Decreased IFN-γ and increased LPA were observed in WT-PM mice; similar findings have been reported for firefighters who eventually develop WTC-LI. In the murine model, lack of RAGE was protective from loss of lung function and airway hyperreactivity and was associated with modulation of MAP kinases. We conclude that in a multivariate adjusted model increased sRAGE is associated with WTC-LI. In our murine model, absence of RAGE mitigated acute deleterious effects of PM and may be a biologically plausible mediator of PM-related lung disease. PMID:28926576

Airway symptoms and lung function in the local population after the oil tank explosion in Gulen, Norway.

PubMed

Granslo, Jens-Tore; Bråtveit, Magne; Hollund, Bjørg Eli; Irgens, Ågot; Svanes, Cecilie; Magerøy, Nils; Moen, Bente Elisabeth

2012-12-12

Oil tanks containing a mixture of hydrocarbons, including sulphuric compounds, exploded and caught fire in an industrial harbour. This study assesses airway symptoms and lung function in the nearby population 1½ years after the explosion. A cross-sectional study included individuals ≥18 years old. Individuals living <6 km (sub-groups <3km and 3-6 km) from the accident site formed the exposed group, individuals living >20 km away formed a control group. A questionnaire and spirometry tests were completed by 223 exposed individuals (response rate men 70%, women 75%) and 179 control individuals (response rate men 51%, women 65%). Regression analyses included adjustment for smoking, occupational exposure, atopy, infection in the preceding month and age. Analyses of symptoms were also adjusted for stress reactions related to the accident. Exposed individuals experienced significantly more blocked nose (odds ratio 1.7 [95% confidence interval 1.0, 2.8]), rhinorrhoea (1.6 [1.1, 3.3]), nose irritation (3.4 [2.0, 5.9]), sore throat (3.1 [1.8, 5.5]), morning cough (3.5 [2.0, 5.5]), daily cough (2.2 [1.4, 3.7]), cough >3 months a year (2.9 [1.5, 5.3]) and cough with phlegm (1.9 [1.2, 3.1]) than control individuals. A significantly increasing trend was found for nose symptoms and cough, depending on the proximity of home address to explosion site (daily cough, 3-6km 1.8 [1.0, 3.1], <3km 3.0 [1.7, 6.4]). Lung function measurements were significantly lower in the exposed group than in the control group, FEV1 adjusted mean difference -123 mL [95% confidence interval -232, -14]), FEV1% predicted -2.5 [-5.5, 0.5], FVC -173 mL [- 297, -50], FVC% predicted -3.1 [- 5.9, -0.4], and airway obstruction (GOLD II/III). Based on cross sectional analyses, individuals living in an area with air pollution from an oil tank explosion had more airway symptoms and lower lung function than a control group 1½ years after the incident.

Endogenous osteopontin promotes ozone-induced neutrophil recruitment to the lungs and airway hyperresponsiveness to methacholine

PubMed Central

Barreno, Ramon X.; Richards, Jeremy B.; Schneider, Daniel J.; Cromar, Kevin R.; Nadas, Arthur J.; Hernandez, Christopher B.; Hallberg, Lance M.; Price, Roger E.; Hashmi, Syed S.; Blackburn, Michael R.; Haque, Ikram U.

2013-01-01

Inhalation of ozone (O3), a common environmental pollutant, causes pulmonary injury, pulmonary inflammation, and airway hyperresponsiveness (AHR) in healthy individuals and exacerbates many of these same sequelae in individuals with preexisting lung disease. However, the mechanisms underlying these phenomena are poorly understood. Consequently, we sought to determine the contribution of osteopontin (OPN), a hormone and a pleiotropic cytokine, to the development of O3-induced pulmonary injury, pulmonary inflammation, and AHR. To that end, we examined indices of these aforementioned sequelae in mice genetically deficient in OPN and in wild-type, C57BL/6 mice 24 h following the cessation of an acute (3 h) exposure to filtered room air (air) or O3 (2 parts/million). In wild-type mice, O3 exposure increased bronchoalveolar lavage fluid (BALF) OPN, whereas immunohistochemical analysis demonstrated that there were no differences in the number of OPN-positive alveolar macrophages between air- and O3-exposed wild-type mice. O3 exposure also increased BALF epithelial cells, protein, and neutrophils in wild-type and OPN-deficient mice compared with genotype-matched, air-exposed controls. However, following O3 exposure, BALF neutrophils were significantly reduced in OPN-deficient compared with wild-type mice. When airway responsiveness to inhaled acetyl-β-methylcholine chloride (methacholine) was assessed using the forced oscillation technique, O3 exposure caused hyperresponsiveness to methacholine in the airways and lung parenchyma of wild-type mice, but not OPN-deficient mice. These results demonstrate that OPN is increased in the air spaces following acute exposure to O3 and functionally contributes to the development of O3-induced pulmonary inflammation and airway and lung parenchymal hyperresponsiveness to methacholine. PMID:23666750

Genetic deletion of apolipoprotein A-I increases airway hyperresponsiveness, inflammation, and collagen deposition in the lung

PubMed Central

Wang, Weiling; Xu, Hao; Shi, Yang; Nandedkar, Sandhya; Zhang, Hao; Gao, Haiqing; Feroah, Thom; Weihrauch, Dorothee; Schulte, Marie L.; Jones, Deron W.; Jarzembowski, Jason; Sorci-Thomas, Mary; Pritchard, Kirkwood A.

2010-01-01

The relationship between high-density lipoprotein and pulmonary function is unclear. To determine mechanistic relationships we investigated the effects of genetic deletion of apolipoprotein A-I (apoA-I) on plasma lipids, paraoxonase (PON1), pro-inflammatory HDL (p-HDL), vasodilatation, airway hyperresponsiveness and pulmonary oxidative stress, and inflammation. ApoA-I null (apoA-I−/−) mice had reduced total and HDL cholesterol but increased pro-inflammatory HDL compared with C57BL/6J mice. Although PON1 protein was increased in apoA-I−/− mice, PON1 activity was decreased. ApoA-I deficiency did not alter vasodilatation of facialis arteries, but it did alter relaxation responses of pulmonary arteries. Central airway resistance was unaltered. However, airway resistance mediated by tissue dampening and elastance were increased in apoA-I−/− mice, a finding also confirmed by positive end-expiratory pressure (PEEP) studies. Inflammatory cells, collagen deposition, 3-nitrotyrosine, and 4-hydroxy-2-nonenal were increased in apoA-I−/− lungs but not oxidized phospholipids. Colocalization of 4-hydroxy-2-nonenal with transforming growth factor β-1 (TGFβ-1 was increased in apoA-I−/− lungs. Xanthine oxidase, myeloperoxidase and endothelial nitric oxide synthase were increased in apoA-I−/− lungs. Dichlorodihydrofluorescein-detectable oxidants were increased in bronchoalveolar lavage fluid (BALF) in apoA-I−/− mice. In contrast, BALF nitrite+nitrate levels were decreased in apoA-I−/− mice. These data demonstrate that apoA-I plays important roles in limiting pulmonary inflammation and oxidative stress, which if not prevented, will decrease pulmonary artery vasodilatation and increase airway hyperresponsiveness. PMID:20498409

Sound transmission in porcine thorax through airway insonification.

PubMed

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

2016-04-01

Many pulmonary injuries and pathologies may lead to structural and functional changes in the lungs resulting in measurable sound transmission changes on the chest surface. Additionally, noninvasive imaging of externally driven mechanical wave motion in the chest (e.g., using magnetic resonance elastography) can provide information about lung structural property changes and, hence, may be of diagnostic value. In the present study, a comprehensive computational simulation (in silico) model was developed to simulate sound wave propagation in the airways, lung, and chest wall under normal and pneumothorax conditions. Experiments were carried out to validate the model. Here, sound waves with frequency content from 50 to 700 Hz were introduced into airways of five porcine subjects via an endotracheal tube, and transmitted waves were measured by scanning laser Doppler vibrometry at the chest wall surface. The computational model predictions of decreased sound transmission with pneumothorax were consistent with experimental measurements. The in silico model can also be used to visualize wave propagation inside and on the chest wall surface for other pulmonary pathologies, which may help in developing and interpreting diagnostic procedures that utilize sound and vibration.

Sound transmission in porcine thorax through airway insonification

PubMed Central

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

2015-01-01

Many pulmonary injuries and pathologies may lead to structural and functional changes in the lungs resulting in measurable sound transmission changes on the chest surface. Additionally, noninvasive imaging of externally driven mechanical wave motion in the chest (e.g., using magnetic resonance elastography) can provide information about lung structural property changes and, hence, may be of diagnostic value. In the present study, a comprehensive computational simulation (in silico) model was developed to simulate sound wave propagation in the airways, lung, and chest wall under normal and pneumothorax conditions. Experiments were carried out to validate the model. Here, sound waves with frequency content from 50 to 700 Hz were introduced into airways of five porcine subjects via an endotracheal tube, and transmitted waves were measured by scanning laser Doppler vibrometry at the chest wall surface. The computational model predictions of decreased sound transmission with pneumothorax were consistent with experimental measurements. The in silico model can also be used to visualize wave propagation inside and on the chest wall surface for other pulmonary pathologies, which may help in developing and interpreting diagnostic procedures that utilize sound and vibration. PMID:26280512

A Numerical Model of Viscoelastic Layer Entrainment by Airflow in Cough

NASA Astrophysics Data System (ADS)

Mitran, Sorin M.

2008-07-01

Coughing is an alternative mode of ensuring mucus clearance in the lung when normal cilia induced flow breaks down. A numerical model of this process is presented with the following aspects. (1) A portion of the airway comprising the first three bronchus generations is modeled as radially reinforced elastic tubes. Elasticity equations are solved to predict airway deformation under effect of airway pressure. (2) The compressible, turbulent flow induced by rapid lung contraction is modeled by direct numerical simulation for Reynolds numbers in the range 5,000-10,000 and by Large Eddy Simulation for Reynolds numbers in the range 5,000-40,000. (3) A two-layer model of the airway surface liquid (ASL) covering the airway epithelial layer is used. The periciliary liquid (PCL) in direct contact with the epithelial layer is considered to be a Newtonian fluid. Forces modeling cilia beating can act upon this layer. The mucus layer between the PCL and the interior airflow is modeled as an Oldroyd-B fluid. The overall computation is a fluid-structure interaction simulation that tracks changes in ASL thickness and airway diameters that result from impulsive airflow boundary conditions imposed at bronchi ends. In particular, the amount of mucus that is evacuated from the system is computed as a function of cough intensity and mucus rheological properties.

Optimal graph based segmentation using flow lines with application to airway wall segmentation.

PubMed

Petersen, Jens; Nielsen, Mads; Lo, Pechin; Saghir, Zaigham; Dirksen, Asger; de Bruijne, Marleen

2011-01-01

This paper introduces a novel optimal graph construction method that is applicable to multi-dimensional, multi-surface segmentation problems. Such problems are often solved by refining an initial coarse surface within the space given by graph columns. Conventional columns are not well suited for surfaces with high curvature or complex shapes but the proposed columns, based on properly generated flow lines, which are non-intersecting, guarantee solutions that do not self-intersect and are better able to handle such surfaces. The method is applied to segment human airway walls in computed tomography images. Comparison with manual annotations on 649 cross-sectional images from 15 different subjects shows significantly smaller contour distances and larger area of overlap than are obtained with recently published graph based methods. Airway abnormality measurements obtained with the method on 480 scan pairs from a lung cancer screening trial are reproducible and correlate significantly with lung function.

Lung function not affected by asbestos exposure in workers with normal Computed Tomography scan.

PubMed

Schikowsky, Christian; Felten, Michael K; Eisenhawer, Christian; Das, Marco; Kraus, Thomas

2017-05-01

It has been suggested that asbestos exposure affects lung function, even in the absence of asbestos-related pulmonary interstitial or pleural changes or emphysema. We analyzed associations between well-known asbestos-related risk factors, such as individual cumulative asbestos exposure, and key lung function parameters in formerly asbestos-exposed power industry workers (N = 207) with normal CT scans. For this, we excluded participants with emphysema, fibrosis, pleural changes, or any combination of these. The lung function parameters of FVC, FEV1, DLCO/VA, and airway resistance were significantly associated with the burden of smoking, BMI and years since end of exposure (only DLCO/VA). However, they were not affected by factors directly related to amount (eg, cumulative exposure) or duration of asbestos exposure. Our results confirm the well-known correlation between lung function, smoking habits, and BMI. However, we found no significant association between lung function and asbestos exposure. © 2017 Wiley Periodicals, Inc.

Chronic Hypoxia Accentuates Dysanaptic Lung Growth.

PubMed

Llapur, Conrado J; Martínez, Myriam R; Grassino, Pedro T; Stok, Ana; Altieri, Héctor H; Bonilla, Federico; Caram, María M; Krowchuk, Natasha M; Kirby, Miranda; Coxson, Harvey O; Tepper, Robert S

2016-08-01

Adults born and raised at high altitudes have larger lung volumes and greater pulmonary diffusion capacity compared with adults at low altitude; however, it remains unclear whether the air and tissue volumes have comparable increases and whether there is a difference in airway size. To assess the effect of chronic hypoxia on lung growth using in vivo high-resolution computed tomography measurements. Healthy adults born and raised at moderate altitude (2,000 m above sea level; n = 19) and at low altitude (400 m above sea level; n = 23) underwent high-resolution computed tomography. Differences in total lung, air, and tissue volume, mean lung density, as well as airway lumen and wall areas in anatomically matched airways were compared between groups. No significant differences for age, sex, weight, or height were found between the two groups (P > 0.05). In a multivariate regression model, altitude was a significant contributor for total lung volume (P = 0.02), air volume (P = 0.03), and tissue volume (P = 0.03), whereby the volumes were greater for the moderate- versus the low-altitude group. However, altitude was not a significant contributor for mean lung density (P = 0.35) or lumen and wall areas in anatomically matched segmental, subsegmental, and subsubsegmental airways. Our findings suggest that the adult lung did not increase lung volume later in life by expansion of an existing number of alveoli, but rather from increased alveolarization early in life. In addition, chronic hypoxia accentuates dysanaptic lung growth by increasing the lung parenchyma but not the airways.

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

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

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

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

Identification of Epithelial Phospholipase A2 Receptor 1 as a Potential Target in Asthma

PubMed Central

Nolin, James D.; Ogden, H. Luke; Lai, Ying; Altemeier, William A.; Frevert, Charles W.; Bollinger, James G.; Naika, Gajendra S.; Kicic, Anthony; Stick, Stephen M.; Lambeau, Gerard; Henderson, William R.; Gelb, Michael H.

2016-01-01

Secreted phospholipase A2s (sPLA2s) regulate eicosanoid formation and have been implicated in asthma. Although sPLA2s function as enzymes, some of the sPLA2s bind with high affinity to a C-type lectin receptor, called PLA2R1, which has functions in both cellular signaling and clearance of sPLA2s. We sought to examine the expression of PLA2R1 in the airway epithelium of human subjects with asthma and the function of the murine Pla2r1 gene in a model of asthma. Expression of PLA2R1 in epithelial brushings was assessed in two distinct cohorts of children with asthma by microarray and quantitative PCR, and immunostaining for PLA2R1 was conducted on endobronchial tissue and epithelial brushings from adults with asthma. C57BL/129 mice deficient in Pla2r1 (Pla2r1−/−) were characterized in an ovalbumin (OVA) model of allergic asthma. PLA2R1 was differentially overexpressed in epithelial brushings of children with atopic asthma in both cohorts. Immunostaining for PLA2R1 in endobronchial tissue localized to submucosal glandular epithelium and columnar epithelial cells. After OVA sensitization and challenge, Pla2r1−/− mice had increased airway hyperresponsiveness, as well as an increase in cellular trafficking of eosinophils to the peribronchial space and bronchoalveolar lavage fluid, and an increase in airway permeability. In addition, Pla2r1−/− mice had more dendritic cells in the lung, higher levels of OVA-specific IgG, and increased production of both type-1 and type-2 cytokines by lung leukocytes. PLA2R1 is increased in the airway epithelium in asthma, and serves as a regulator of airway hyperresponsiveness, airway permeability, antigen sensitization, and airway inflammation. PMID:27448109

Identification of Epithelial Phospholipase A2 Receptor 1 as a Potential Target in Asthma.

PubMed

Nolin, James D; Ogden, H Luke; Lai, Ying; Altemeier, William A; Frevert, Charles W; Bollinger, James G; Naika, Gajendra S; Kicic, Anthony; Stick, Stephen M; Lambeau, Gerard; Henderson, William R; Gelb, Michael H; Hallstrand, Teal S

2016-12-01

Secreted phospholipase A 2 s (sPLA 2 s) regulate eicosanoid formation and have been implicated in asthma. Although sPLA 2 s function as enzymes, some of the sPLA 2 s bind with high affinity to a C-type lectin receptor, called PLA2R1, which has functions in both cellular signaling and clearance of sPLA 2 s. We sought to examine the expression of PLA2R1 in the airway epithelium of human subjects with asthma and the function of the murine Pla2r1 gene in a model of asthma. Expression of PLA2R1 in epithelial brushings was assessed in two distinct cohorts of children with asthma by microarray and quantitative PCR, and immunostaining for PLA2R1 was conducted on endobronchial tissue and epithelial brushings from adults with asthma. C57BL/129 mice deficient in Pla2r1 (Pla2r1 -/- ) were characterized in an ovalbumin (OVA) model of allergic asthma. PLA2R1 was differentially overexpressed in epithelial brushings of children with atopic asthma in both cohorts. Immunostaining for PLA2R1 in endobronchial tissue localized to submucosal glandular epithelium and columnar epithelial cells. After OVA sensitization and challenge, Pla2r1 -/- mice had increased airway hyperresponsiveness, as well as an increase in cellular trafficking of eosinophils to the peribronchial space and bronchoalveolar lavage fluid, and an increase in airway permeability. In addition, Pla2r1 -/- mice had more dendritic cells in the lung, higher levels of OVA-specific IgG, and increased production of both type-1 and type-2 cytokines by lung leukocytes. PLA2R1 is increased in the airway epithelium in asthma, and serves as a regulator of airway hyperresponsiveness, airway permeability, antigen sensitization, and airway inflammation.

Evaluation of Allergy Effector Cell Function: Suppression of Basophils in Chronic Helminth Infections

DTIC Science & Technology

2011-01-01

cylindrical bodies, make up the largest group of helminths that parasitize humans. A 1997 World Health Organization study estimated that nearly 4 billion... eosinophilia in the lung was markedly reduced, compared to uninfected sensitized controls. Some of the protection in this model was associated with...the prevention of airway eosinophilia and reduced airway hyperreactivity after OVA challenge (38). When excretory/secretory products obtained from

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

PubMed Central

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

2016-01-01

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

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

NASA Astrophysics Data System (ADS)

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

2016-12-01

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

Physical principle of airway design in human lungs

NASA Astrophysics Data System (ADS)

Park, Keunhwan; Son, Taeho; Kim, Wonjung; Kim, Ho-Young

2014-11-01

From an engineering perspective, lungs are natural microfluidic devices that extract oxygen from air. In the bronchial tree, airways branch by dichotomy with a systematic reduction of their diameters. It is generally accepted that in conducting airways, which air passes on the way to the acinar airways from the atmosphere, the reduction ratio of diameter is closely related to the minimization of viscous dissipation. Such a principle is formulated as the Hess-Murray law. However, in acinar airways, where oxygen transfer to alveolae occurs, the diameter reduction with progressive generations is more moderate than in conducting airways. Noting that the dominant transfer mechanism in acinar airways is diffusion rather than advection, unlike conducting airways, we construct a mathematical model for oxygen transfer through a series of acinar airways. Our model allows us to predict the optimal airway reduction ratio that maximizes the oxygen transfer in a finite airway volume, thereby rationalizing the observed airway reduction ratio in acinar airways.

Inflammation Promotes Airway Epithelial ATP Release via Calcium-Dependent Vesicular Pathways

PubMed Central

Okada, Seiko F.; Ribeiro, Carla M. P.; Sesma, Juliana I.; Seminario-Vidal, Lucia; Abdullah, Lubna H.; van Heusden, Catharina; Lazarowski, Eduardo R.

2013-01-01

ATP in airway surface liquid (ASL) controls mucociliary clearance functions via the activation of airway epithelial purinergic receptors. However, abnormally elevated ATP levels have been reported in inflamed airways, suggesting that excessive ATP in ASL contributes to airway inflammation. Despite these observations, little is known about the mechanisms of ATP accumulation in the ASL covering inflamed airways. In this study, links between cystic fibrosis (CF)–associated airway inflammation and airway epithelial ATP release were investigated. Primary human bronchial epithelial (HBE) cells isolated from CF lungs exhibited enhanced IL-8 secretion after 6 to 11 days, but not 28 to 35 days, in culture, compared with normal HBE cells. Hypotonic cell swelling–promoted ATP release was increased in 6- to 11-day-old CF HBE cells compared with non-CF HBE cells, but returned to normal values after 28 to 35 days in culture. The exposure of non-CF HBE cells to airway secretions isolated from CF lungs, namely, sterile supernatants of mucopurulent material (SMM), also caused enhanced IL-8 secretion and increased ATP release. The SMM-induced increase in ATP release was sensitive to Ca2+ chelation and vesicle trafficking/exocytosis inhibitors, but not to pannexin inhibition. Transcript levels of the vesicular nucleotide transporter, but not pannexin 1, were up-regulated after SMM exposure. SMM-treated cultures displayed increased basal mucin secretion, but mucin secretion was not enhanced in response to hypotonic challenge after the exposure of cells to either vehicle or SMM. We propose that CF airway inflammation up-regulates the capacity of airway epithelia to release ATP via Ca2+-dependent vesicular mechanisms not associated with mucin granule secretion. PMID:23763446

Popcorn flavoring effects on reactivity of rat airways in vivo and in vitro.

PubMed

Zaccone, Eric J; Thompson, Janet A; Ponnoth, Dovenia S; Cumpston, Amy M; Goldsmith, W Travis; Jackson, Mark C; Kashon, Michael L; Frazer, David G; Hubbs, Ann F; Shimko, Michael J; Fedan, Jeffrey S

2013-01-01

"Popcorn workers' lung" is an obstructive pulmonary disease produced by inhalation of volatile artificial butter flavorings. In rats, inhalation of diacetyl, a major component of butter flavoring, and inhalation of a diacetyl substitute, 2,3-pentanedione, produce similar damage to airway epithelium. The effects of diacetyl and 2,3-pentanedione and mixtures of diacetyl, acetic acid, and acetoin, all components of butter flavoring, on pulmonary function and airway reactivity to methacholine (MCh) were investigated. Lung resistance (RL) and dynamic compliance (Cdyn) were negligibly changed 18 h after a 6-h inhalation exposure to diacetyl or 2,3-pentanedione (100-360 ppm). Reactivity to MCh was not markedly changed after diacetyl, but was modestly decreased after 2,3-pentanedione inhalation. Inhaled diacetyl exerted essentially no effect on reactivity to mucosally applied MCh, but 2,3-pentanedione (320 and 360 ppm) increased reactivity to MCh in the isolated, perfused trachea preparation (IPT). In IPT, diacetyl and 2,3-pentanedione (≥3 mM) applied to the serosal and mucosal surfaces of intact and epithelium-denuded tracheas initiated transient contractions followed by relaxations. Inhaled acetoin (150 ppm) exerted no effect on pulmonary function and airway reactivity in vivo; acetic acid (27 ppm) produced hyperreactivity to MCh; and exposure to diacetyl + acetoin + acetic acid (250 + 150 + 27 ppm) led to a diacetyl-like reduction in reactivity. Data suggest that the effects of 2,3-pentanedione on airway reactivity are greater than those of diacetyl, and that flavorings are airway smooth muscle relaxants and constrictors, thus indicating a complex mechanism.

PKCλ/ι regulates Th17 differentiation and house dust mite-induced allergic airway inflammation.

PubMed

Yang, Yingying; Dong, Panpan; Zhao, Jing; Zhou, Wei; Zhou, Yonghua; Xu, Yongliang; Mei, Congjin; Guo, Fukun; Zheng, Yi; Yang, Jun-Qi

2018-03-01

Asthma is a chronic airway inflammation in which Th2 and Th17 cells play critical roles in its pathogenesis. We have reported that atypical protein kinase (PKC) λ/ι is a new regulator for Th2 differentiation and function. However, the role of PKCλ/ι for Th17 cells remains elusive. In this study, we explored the effect of PKCλ/ι on Th17 cells in the context of ex vivo cell culture systems and an in vivo murine model of allergic airway inflammation with the use of activated T cell-specific conditional PKCλ/ι-deficient mice. Our findings indicate that PKCλ/ι regulates Th17 cells. The secretion of Th17 effector cytokines, including IL-17, IL-21 and IL-22, were inhibited from PKCλ/ι-deficient T cells under non-skewing or Th17-skewing culture conditions. Moreover, the impaired Th17 differentiation and function by the PKCλ/ι-deficiency was associated with the downregulation of Stat3 and Rorγt, key Th17 transcription factors. We developed a model of Th17 and neutrophil-involved allergic airway inflammation by intratracheal inoculation of house dust mites. PKCλ/ι-deficiency significantly inhibited airway inflammations. The infiltrating cells in the lungs and bronchoalveolar lavage fluids were significantly reduced in conditional PKCλ/ι-deficient mice. Th17 effector cytokines were reduced in the bronchoalveolar lavage fluids and lungs at protein and mRNA levels. Thus, PKCλ/ι emerges as a critical regulator of Th17 differentiation and allergic airway hyperresponsiveness. Copyright © 2018 Elsevier B.V. All rights reserved.

Methods for Measuring Lung Volumes: Is There a Better One?

PubMed

Tantucci, Claudio; Bottone, Damiano; Borghesi, Andrea; Guerini, Michele; Quadri, Federico; Pini, Laura

2016-01-01

Accurate measurement of lung volumes is of paramount importance to establish the presence of ventilatory defects and give insights for diagnostic and/or therapeutic purposes. It was the aim of this study to measure lung volumes in subjects with respiratory disorders and in normal controls by 3 different techniques (plethysmographic, dilutional and radiographic methods), in an attempt to clarify the role of each of them in performing such a task, without any presumptive 'a priori' superiority of one method above others. Patients andMethods: In different groups of subjects with obstructive and restrictive ventilatory defects and in a normal control group, total lung capacity, functional residual capacity (FRC) and residual volume were measured by body plethysmography, multi-breath helium (He) dilution and radiographic CT scan method with spirometric gating. The 3 methods gave comparable results in normal subjects and in patients with a restrictive defect. In patients with an obstructive defect, CT scan and plethysmography showed similar lung volumes, while on average significantly lower lung volumes were obtained with the He dilution technique. Taking into account that the He dilution technique does primarily measure FRC during tidal breathing, our data suggest that in some patients with an obstructive defect, a number of small airways can be functionally closed at end-expiratory lung volume, preventing He to reach the lung regions subserved by these airways. In all circumstances, both CT scan with spirometric gating and plethysmographic methods provide similar values of lung volumes. In contrast, the He dilution method can measure lower lung volumes in some patients with chronic airflow obstruction. © 2016 S. Karger AG, Basel.

Stress and strain in the contractile and cytoskeletal filaments of airway smooth muscle.

PubMed

Deng, Linhong; Bosse, Ynuk; Brown, Nathan; Chin, Leslie Y M; Connolly, Sarah C; Fairbank, Nigel J; King, Greg G; Maksym, Geoffrey N; Paré, Peter D; Seow, Chun Y; Stephen, Newman L

2009-10-01

Stress and strain are omnipresent in the lung due to constant lung volume fluctuation associated with respiration, and they modulate the phenotype and function of all cells residing in the airways including the airway smooth muscle (ASM) cell. There is ample evidence that the ASM cell is very sensitive to its physical environment, and can alter its structure and/or function accordingly, resulting in either desired or undesired consequences. The forces that are either conferred to the ASM cell due to external stretching or generated inside the cell must be borne and transmitted inside the cytoskeleton (CSK). Thus, maintaining appropriate levels of stress and strain within the CSK is essential for maintaining normal function. Despite the importance, the mechanisms regulating/dysregulating ASM cytoskeletal filaments in response to stress and strain remained poorly understood until only recently. For example, it is now understood that ASM length and force are dynamically regulated, and both can adapt over a wide range of length, rendering ASM one of the most malleable living tissues. The malleability reflects the CSK's dynamic mechanical properties and plasticity, both of which strongly interact with the loading on the CSK, and all together ultimately determines airway narrowing in pathology. Here we review the latest advances in our understanding of stress and strain in ASM cells, including the organization of contractile and cytoskeletal filaments, range and adaptation of functional length, structural and functional changes of the cell in response to mechanical perturbation, ASM tone as a mediator of strain-induced responses, and the novel glassy dynamic behaviors of the CSK in relation to asthma pathophysiology.

Effects of an anti-inflammatory VAP-1/SSAO inhibitor, PXS-4728A, on pulmonary neutrophil migration.

PubMed

Schilter, Heidi C; Collison, Adam; Russo, Remo C; Foot, Jonathan S; Yow, Tin T; Vieira, Angelica T; Tavares, Livia D; Mattes, Joerg; Teixeira, Mauro M; Jarolimek, Wolfgang

2015-03-20

The persistent influx of neutrophils into the lung and subsequent tissue damage are characteristics of COPD, cystic fibrosis and acute lung inflammation. VAP-1/SSAO is an endothelial bound adhesion molecule with amine oxidase activity that is reported to be involved in neutrophil egress from the microvasculature during inflammation. This study explored the role of VAP-1/SSAO in neutrophilic lung mediated diseases and examined the therapeutic potential of the selective inhibitor PXS-4728A. Mice treated with PXS-4728A underwent intra-vital microscopy visualization of the cremaster muscle upon CXCL1/KC stimulation. LPS inflammation, Klebsiella pneumoniae infection, cecal ligation and puncture as well as rhinovirus exacerbated asthma models were also assessed using PXS-4728A. Selective VAP-1/SSAO inhibition by PXS-4728A diminished leukocyte rolling and adherence induced by CXCL1/KC. Inhibition of VAP-1/SSAO also dampened the migration of neutrophils to the lungs in response to LPS, Klebsiella pneumoniae lung infection and CLP induced sepsis; whilst still allowing for normal neutrophil defense function, resulting in increased survival. The functional effects of this inhibition were demonstrated in the RV exacerbated asthma model, with a reduction in cellular infiltrate correlating with a reduction in airways hyperractivity. This study demonstrates that the endothelial cell ligand VAP-1/SSAO contributes to the migration of neutrophils during acute lung inflammation, pulmonary infection and airway hyperractivity. These results highlight the potential of inhibiting of VAP-1/SSAO enzymatic function, by PXS-4728A, as a novel therapeutic approach in lung diseases that are characterized by neutrophilic pattern of inflammation.

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

Sunil, Vasanthi R., E-mail: sunilvr@eohsi.rutgers.edu; Patel-Vayas, Kinal, E-mail: kinalv5@gmail.com; Shen, Jianliang, E-mail: jianliangs@gmail.com

Lung toxicity induced by sulfur mustard is associated with inflammation and oxidative stress. To elucidate mechanisms mediating pulmonary damage, we used 2-chloroethyl ethyl sulfide (CEES), a model sulfur mustard vesicant. Male mice (B6129) were treated intratracheally with CEES (3 or 6 mg/kg) or control. Animals were sacrificed 3, 7 or 14 days later and bronchoalveolar lavage (BAL) fluid and lung tissue collected. Treatment of mice with CEES resulted in an increase in BAL protein, an indication of alveolar epithelial damage, within 3 days. Expression of Ym1, an oxidative stress marker also increased in the lung, along with inducible nitric oxidemore » synthase, and at 14 days, cyclooxygenase-2 and monocyte chemotactic protein-1, inflammatory proteins implicated in tissue injury. These responses were attenuated in mice lacking the p55 receptor for TNF{alpha} (TNFR1-/-), demonstrating that signaling via TNFR1 is key to CEES-induced injury, oxidative stress, and inflammation. CEES-induced upregulation of CuZn-superoxide dismutase (SOD) and MnSOD was delayed or absent in TNFR1-/- mice, relative to WT mice, suggesting that TNF{alpha} mediates early antioxidant responses to lung toxicants. Treatment of WT mice with CEES also resulted in functional alterations in the lung including decreases in compliance and increases in elastance. Additionally, methacholine-induced alterations in total lung resistance and central airway resistance were dampened by CEES. Loss of TNFR1 resulted in blunted functional responses to CEES. These effects were most notable in the airways. These data suggest that targeting TNF{alpha} signaling may be useful in mitigating lung injury, inflammation and functional alterations induced by vesicants.« less

Quantitative assessment of lung ventilation and microstructure in an animal model of idiopathic pulmonary fibrosis using hyperpolarized gas MRI.

PubMed

Stephen, Michael J; Emami, Kiarash; Woodburn, John M; Chia, Elaine; Kadlecek, Stephen; Zhu, Jianliang; Pickup, Stephen; Ishii, Masaru; Rizi, Rahim R; Rossman, Milton

2010-11-01

The use of hyperpolarized (3)He magnetic resonance imaging as a quantitative lung imaging tool has progressed rapidly in the past decade, mostly in the assessment of the airway diseases chronic obstructive pulmonary disease and asthma. This technique has shown potential to assess both structural and functional information in healthy and diseased lungs. In this study, the regional measurements of structure and function were applied to a bleomycin rat model of interstitial lung disease. Male Sprague-Dawley rats (weight, 300-350 g) were administered intratracheal bleomycin. After 3 weeks, apparent diffusion coefficient and fractional ventilation were measured by (3)He magnetic resonance imaging and pulmonary function testing using a rodent-specific plethysmography chamber. Sensitized and healthy animals were then compared using threshold analysis to assess the potential sensitivity of these techniques to pulmonary abnormalities. No significant changes were observed in total lung volume and compliance between the two groups. Airway resistance elevated and forced expiratory volume significantly declined in the 3-week bleomycin rats, and fractional ventilation was significantly decreased compared to control animals (P < .0004). The apparent diffusion coefficient of (3)He showed a smaller change but still a significant decrease in 3-week bleomycin animals (P < .05). Preliminary results suggest that quantitative (3)He magnetic resonance imaging can be a sensitive and noninvasive tool to assess changes in an animal interstitial lung disease model. This technique may be useful for longitudinal animal studies and also in the investigation of human interstitial lung diseases. Copyright © 2010 AUR. Published by Elsevier Inc. All rights reserved.

Stem cells are dispensable for lung homeostasis but restore airways after injury.

PubMed

Giangreco, Adam; Arwert, Esther N; Rosewell, Ian R; Snyder, Joshua; Watt, Fiona M; Stripp, Barry R

2009-06-09

Local tissue stem cells have been described in airways of the lung but their contribution to normal epithelial maintenance is currently unknown. We therefore developed aggregation chimera mice and a whole-lung imaging method to determine the relative contributions of progenitor (Clara) and bronchiolar stem cells to epithelial maintenance and repair. In normal and moderately injured airways chimeric patches were small in size and not associated with previously described stem cell niches. This finding suggested that single, randomly distributed progenitor cells maintain normal epithelial homeostasis. In contrast we found that repair following severe lung injury resulted in the generation of rare, large clonal cell patches that were associated with stem cell niches. This study provides evidence that epithelial stem cells are dispensable for normal airway homeostasis. We also demonstrate that stem cell activation and robust clonal cellular expansion occur only during repair from severe lung injury.

AIRWAY IDENTIFICATION WITHIN PLANAR GAMMA CAMERA IMAGES USING COMPUTER MODELS OF LUNG MORPHOLOGY

EPA Science Inventory

The quantification of inhaled aerosols could be improved if a more comprehensive assessment of their spatial distribution patterns among lung airways were obtained. A common technique for quantifying particle deposition in human lungs is with planar gamma scintigraphy. However, t...

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

PubMed

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

2016-01-01

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

Spontaneous Chitin Accumulation in Airways and Age-Related Fibrotic Lung Disease.

PubMed

Van Dyken, Steven J; Liang, Hong-Erh; Naikawadi, Ram P; Woodruff, Prescott G; Wolters, Paul J; Erle, David J; Locksley, Richard M

2017-04-20

The environmentally widespread polysaccharide chitin is degraded and recycled by ubiquitous bacterial and fungal chitinases. Although vertebrates express active chitinases from evolutionarily conserved loci, their role in mammalian physiology is unclear. We show that distinct lung epithelial cells secrete acidic mammalian chitinase (AMCase), which is required for airway chitinase activity. AMCase-deficient mice exhibit premature morbidity and mortality, concomitant with accumulation of environmentally derived chitin polymers in the airways and expression of pro-fibrotic cytokines. Over time, these mice develop spontaneous pulmonary fibrosis, which is ameliorated by restoration of lung chitinase activity by genetic or therapeutic approaches. AMCase-deficient epithelial cells express fibrosis-associated gene sets linked with cell stress pathways. Mice with lung fibrosis due to telomere dysfunction and humans with interstitial lung disease also accumulate excess chitin polymers in their airways. These data suggest that altered chitin clearance could exacerbate fibrogenic pathways in the setting of lung diseases characterized by epithelial cell dysfunction. Copyright © 2017 Elsevier Inc. All rights reserved.

Expression of T-box transcription factors 2, 4 and 5 is decreased in the branching airway mesenchyme of nitrofen-induced hypoplastic lungs.

PubMed

Takahashi, Toshiaki; Friedmacher, Florian; Zimmer, Julia; Puri, Prem

2017-02-01

Pulmonary hypoplasia (PH), characterized by smaller lung size and reduced airway branching, remains a major therapeutic challenge in newborns with congenital diaphragmatic hernia (CDH). T-box transcription factors (Tbx) have been identified as key components of the gene network that regulates fetal lung development. Tbx2, Tbx4 and Tbx5 are expressed throughout the mesenchyme of the developing lung, regulating the process of lung branching morphogenesis. Furthermore, lungs of Tbx2-, Tbx4- and Tbx5-deficient mice are hypoplastic and exhibit decreased lung branching, similar to PH in human CDH. We hypothesized that the expression of Tbx2, Tbx4 and Tbx5 is decreased in the branching airway mesenchyme of hypoplastic rat lungs with nitrofen-induced CDH. Time-mated rats received either nitrofen or vehicle on gestational day 9 (D9). Fetuses were killed on D15, D18 and D21, and dissected lungs were divided into control and nitrofen-exposed specimens. Pulmonary gene expression of Tbx2, Tbx4 and Tbx5 was investigated by quantitative real-time polymerase chain reaction. Immunofluorescence double staining for Tbx2, Tbx4 and Tbx5 was combined with the mesenchymal marker Fgf10 to assess protein expression and localization in branching airway tissue. Relative mRNA levels of Tbx2, Tbx4 and Tbx5 were significantly reduced in lungs of nitrofen-exposed fetuses on D15, D18 and D21 compared to controls. Confocal laser scanning microscopy showed markedly diminished immunofluorescence of Tbx2, Tbx4 and Tbx5 in mesenchymal cells surrounding branching airways of nitrofen-exposed fetuses on D15, D18 and D21 compared to controls. Decreased expression of Tbx2, Tbx4 and Tbx5 in the pulmonary mesenchyme during fetal lung development may lead to a decrease or arrest of airway branching, thus contributing to PH in the nitrofen-induced CDH model.

The Effect of Lung Stretch during Sleep on Airway Mechanics in Overweight and Obese Asthma

PubMed Central

Campana, L.M.; Malhotra, A.; Suki, B.; Hess, L.; Israel, E.; Smales, E.; DeYoung, P.; Owens, R.L.

2012-01-01

Both obesity and sleep reduce lung volume and limit deep breaths, possibly contributing to asthma. We hypothesize that increasing lung volume dynamically during sleep would reduce airway resistance in asthma. Asthma (n=10) and control (n=10) subjects were studied during sleep at baseline and with increased lung volume via bi-level positive airway pressure (BPAP). Using forced oscillations, respiratory system resistance (Rrs) and reactance (Xrs) were measured during sleep and Rrs was partitioned to upper and lower airway resistance (Rup, Rlow) using an epiglottic pressure catheter. Rrs and Rup increased with sleep (p<0.01) and Xrs was decreased in REM (p=0.02) as compared to wake. Rrs, Rup, and Rlow, were larger (p<0.01) and Xrs was decreased (p<0.02) in asthma. On BPAP, Rrs and Rup were decreased (p<0.001) and Xrs increased (p<0.01), but Rlow was unchanged. High Rup was observed in asthma, which reduced with BPAP. We conclude that the upper airway is a major component of Rrs and larger lung volume changes may be required to alter Rlow. PMID:23041446

Enhanced alveolar growth and remodeling in Guinea pigs raised at high altitude.

PubMed

Hsia, Connie C W; Carbayo, Juan J Polo; Yan, Xiao; Bellotto, Dennis J

2005-05-12

To examine the effects of chronic high altitude (HA) exposure on lung structure during somatic maturation, we raised male weanling guinea pigs at HA (3800m) for 1, 3, or 6 months, while their respective male littermates were simultaneously raised at low altitude (LA, 1200m). Under anaesthesia, airway pressure was measured at different lung volumes. The right lung was fixed at a constant airway pressure for morphometric analysis under light and electron microscopy. In animals raised at HA for 1 month, lung volume, alveolar surface area and alveolar-capillary blood volume (V(c)) were elevated above LA control values. Following 3-6 months of HA exposure, increases in lung volume and alveolar surface area persisted while the initial increase in V(c) normalized. Additional adaptation occurred, including a higher epithelial cell volume, septal tissue volume and capillary surface area, a lower alveolar duct volume and lower harmonic mean diffusion barrier resulting in higher membrane and lung diffusing capacities. These data demonstrate enhanced alveolar septal growth and progressive acinar remodeling during chronic HA exposure with long-term augmentation of alveolar dimensions as well as functional compensation in lung compliance and diffusive gas transport.

Polymicrobial airway bacterial communities in adult bronchiectasis patients

PubMed Central

2014-01-01

Background Chronic airway infection contributes to the underlying pathogenesis of non-cystic fibrosis bronchiectasis (NCFBr). In contrast to other chronic airway infections, associated with COPD and CF bronchiectasis, where polymicrobial communities have been implicated in lung damage due to the vicious circle of recurrent bacterial infections and inflammation, there is sparse information on the composition of bacterial communities in NCFBr. Seventy consecutive patients were recruited from an outpatient adult NCFBr clinic. Bacterial communities in sputum samples were analysed by culture and pyrosequencing approaches. Bacterial sequences were analysed using partial least square discrimination analyses to investigate trends in community composition and identify those taxa that contribute most to community variation. Results The lower airway in NCFBr is dominated by three bacterial taxa Pasteurellaceae, Streptococcaceae and Pseudomonadaceae. Moreover, the bacterial community is much more diverse than indicated by culture and contains significant numbers of other genera including anaerobic Prevotellaceae, Veillonellaceae and Actinomycetaceae. We found particular taxa are correlated with different clinical states, 27 taxa were associated with acute exacerbations, whereas 11 taxa correlated with stable clinical states. We were unable to demonstrate a significant effect of antibiotic therapy, gender, or lung function on the diversity of the bacterial community. However, presence of clinically significant culturable taxa; particularly Pseudomonas aeruginosa and Haemophilus influenzae correlated with a significant change in the diversity of the bacterial community in the lung. Conclusions We have demonstrated that acute exacerbations, the frequency of exacerbation and episodes of clinical stability are correlated, in some patients, with a significantly different bacterial community structure, that are associated with a presence of particular taxa in the NCFBr lung. Moreover, there appears to be an inverse relationship between the abundance of P. aeruginosa and that of of H. influenzae within the NCFBr lung bacterial community. This interaction requires further exploration. PMID:24886473

S-nitrosothiol repletion by an inhaled gas regulates pulmonary function

NASA Astrophysics Data System (ADS)

Moya, Martin P.; Gow, Andrew J.; McMahon, Timothy J.; Toone, Eric J.; Cheifetz, Ira M.; Goldberg, Ronald N.; Stamler, Jonathan S.

2001-05-01

NO synthases are widely distributed in the lung and are extensively involved in the control of airway and vascular homeostasis. It is recognized, however, that the O2-rich environment of the lung may predispose NO toward toxicity. These Janus faces of NO are manifest in recent clinical trials with inhaled NO gas, which has shown therapeutic benefit in some patient populations but increased morbidity in others. In the airways and circulation of humans, most NO bioactivity is packaged in the form of S-nitrosothiols (SNOs), which are relatively resistant to toxic reactions with O2/O. This finding has led to the proposition that channeling of NO into SNOs may provide a natural defense against lung toxicity. The means to selectively manipulate the SNO pool, however, has not been previously possible. Here we report on a gas, O-nitrosoethanol (ENO), which does not react with O2 or release NO and which markedly increases the concentration of indigenous species of SNO within airway lining fluid. Inhalation of ENO provided immediate relief from hypoxic pulmonary vasoconstriction without affecting systemic hemodynamics. Further, in a porcine model of lung injury, there was no rebound in cardiopulmonary hemodynamics or fall in oxygenation on stopping the drug (as seen with NO gas), and additionally ENO protected against a decline in cardiac output. Our data suggest that SNOs within the lung serve in matching ventilation to perfusion, and can be manipulated for therapeutic gain. Thus, ENO may be of particular benefit to patients with pulmonary hypertension, hypoxemia, and/or right heart failure, and may offer a new therapeutic approach in disorders such as asthma and cystic fibrosis, where the airways may be depleted of SNOs.

Inhaled ENaC antisense oligonucleotide ameliorates cystic fibrosis-like lung disease in mice.

PubMed

Crosby, Jeff R; Zhao, Chenguang; Jiang, Chong; Bai, Dong; Katz, Melanie; Greenlee, Sarah; Kawabe, Hiroshi; McCaleb, Michael; Rotin, Daniela; Guo, Shuling; Monia, Brett P

2017-11-01

Epithelial sodium channel (ENaC, Scnn1) hyperactivity in the lung leads to airway surface dehydration and mucus accumulation in cystic fibrosis (CF) patients and in mice with CF-like lung disease. We identified several potent ENaC specific antisense oligonucleotides (ASOs) and tested them by inhalation in mouse models of CF-like lung disease. The inhaled ASOs distributed into lung airway epithelial cells and decreased ENaC expression by inducing RNase H1-dependent degradation of the targeted Scnn1a mRNA. Aerosol delivered ENaC ASO down-regulated mucus marker expression and ameliorated goblet cell metaplasia, inflammation, and airway hyper-responsiveness. Lack of systemic activity of ASOs delivered via the aerosol route ensures the safety of this approach. Our results demonstrate that antisense inhibition of ENaC in airway epithelial cells could be an effective and safe approach for the prevention and reversal of lung symptoms in CF and potentially other inflammatory diseases of the lung. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

WE-G-BRD-07: Investigation of Distal Lung Atelectasis Following Stereotactic Body Radiation Therapy Using Regional Lung Volume Changes Between Pre- and Post- Treatment CT Scans

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

Diot, Q; Kavanagh, B; Miften, M

2014-06-15

Purpose: To propose a quantitative method using lung deformations to differentiate between radiation-induced fibrosis and potential airway stenosis with distal atelectasis in patients treated with stereotactic body radiation therapy (SBRT) for lung tumors. Methods: Twenty-four lung patients with large radiation-induced density increases outside the high dose region had their pre- and post-treatment CT scans manually registered. They received SBRT treatments at our institution between 2002 and 2009 in 3 or 5 fractions, to a median total dose of 54Gy (range, 30–60). At least 50 anatomical landmarks inside the lung (airway branches) were paired for the pre- and post-treatment scans tomore » guide the deformable registration of the lung structure, which was then interpolated to the whole lung using splines. Local volume changes between the planning and follow-up scans were calculated using the deformation field Jacobian. Hyperdense regions were classified as atelectatic or fibrotic based on correlations between regional density increases and significant volume contractions compared to the surrounding tissues. Results: Out of 24 patients, only 7 demonstrated a volume contraction that was at least one σ larger than the remaining lung average. Because they did not receive high doses, these shrunk hyperdense regions were likely showing distal atelectasis resulting from radiation-induced airway stenosis rather than conventional fibrosis. On average, the hyperdense regions extended 9.2 cm farther than the GTV contours but not significantly more than 8.6 cm for the other patients (p>0.05), indicating that a large offset between the radiation and hyperdense region centers is not a good surrogate for atelectasis. Conclusion: A method based on the relative comparison of volume changes between different dates was developed to identify potential lung regions experiencing distal atelectasis. Such a tool is essential to study which lung structures need to be avoided to prevent atelectasis and limit lung function loss.« less

Transpleural ventilation of explanted human lungs

PubMed Central

Choong, Cliff K; Macklem, Peter T; Pierce, John A; Lefrak, Stephen S; Woods, Jason C; Conradi, Mark S; Yablonskiy, Dimitry A; Hogg, James C; Chino, Kimiaki; Cooper, Joel D

2007-01-01

Background The hypothesis that ventilation of emphysematous lungs would be enhanced by communication with the parenchyma through holes in the pleural surface was tested. Methods Fresh human lungs were obtained from patients with emphysema undergoing lung transplantation. Control human lungs were obtained from organ donors whose lungs, for technical reasons, were not considered suitable for implantation. Lungs were ventilated through the bronchial tree or transpleurally via a small hole communicating with the underlying parenchyma over which a flanged silicone tube had been cemented to the surface of the lung (spiracle). Measurements included flow‐volume‐time curves during passive deflation via each pathway; volume of trapped gas recovered from lungs via spiracles when no additional gas was obtainable passively from the airways; and magnetic resonance imaging assessment of spatial distribution of hyperpolarised helium (3He) administered through either the airways or spiracles. Results In emphysematous lungs, passively expelled volumes at 20 s were 94% greater through spiracles than via the airways. Following passive deflation from the airways, an average of 1.07 litres of trapped gas volume was recoverable via spiracles. Regions were ventilated by spiracles that were less well ventilated via bronchi. Conclusions Because of the extensive collateral ventilation present in emphysematous lungs, direct communication with the lung parenchyma through non‐anatomical pathways has the potential to improve the mechanics of breathing and hence ventilation. PMID:17412776

Aspergillus fumigatus in the cystic fibrosis lung: pros and cons of azole therapy

PubMed Central

Burgel, Pierre-Régis; Paugam, André; Hubert, Dominique; Martin, Clémence

2016-01-01

Aspergillus fumigatus is the main fungus cultured in the airways of patients with cystic fibrosis (CF). Allergic bronchopulmonary aspergillosis occurs in ~10% of CF patients and is clearly associated with airway damage and lung function decline. The effects of A. fumigatus colonization in the absence of allergic bronchopulmonary aspergillosis are less well established. Retrospective clinical studies found associations of A. fumigatus-positive cultures with computed tomography scan abnormalities, greater risk of CF exacerbations and hospitalizations, and/or lung function decline. These findings were somewhat variable among studies and provided only circumstantial evidence for a role of A. fumigatus colonization in CF lung disease progression. The availability of a growing number of oral antifungal triazole drugs, together with the results of nonrandomized case series suggesting positive effects of azole therapies, makes it tempting to treat CF patients with these antifungal drugs. However, the only randomized controlled trial that has used itraconazole in CF patients showed no significant benefit. Because triazoles may have significant adverse effects and drug interactions, and because their prolonged use has been associated with the emergence of azole-resistant A. fumigatus isolates, it remains unclear whether or not CF patients benefit from azole therapy. PMID:27703383

Aspergillus fumigatus in the cystic fibrosis lung: pros and cons of azole therapy.

PubMed

Burgel, Pierre-Régis; Paugam, André; Hubert, Dominique; Martin, Clémence

2016-01-01

Aspergillus fumigatus is the main fungus cultured in the airways of patients with cystic fibrosis (CF). Allergic bronchopulmonary aspergillosis occurs in ~10% of CF patients and is clearly associated with airway damage and lung function decline. The effects of A. fumigatus colonization in the absence of allergic bronchopulmonary aspergillosis are less well established. Retrospective clinical studies found associations of A. fumigatus -positive cultures with computed tomography scan abnormalities, greater risk of CF exacerbations and hospitalizations, and/or lung function decline. These findings were somewhat variable among studies and provided only circumstantial evidence for a role of A. fumigatus colonization in CF lung disease progression. The availability of a growing number of oral antifungal triazole drugs, together with the results of nonrandomized case series suggesting positive effects of azole therapies, makes it tempting to treat CF patients with these antifungal drugs. However, the only randomized controlled trial that has used itraconazole in CF patients showed no significant benefit. Because triazoles may have significant adverse effects and drug interactions, and because their prolonged use has been associated with the emergence of azole-resistant A. fumigatus isolates, it remains unclear whether or not CF patients benefit from azole therapy.

The Role of the Immune Response in the Pathogenesis of Bronchiectasis.

PubMed

King, Paul T

2018-01-01

Bronchiectasis is a prevalent respiratory condition characterised by permanent and abnormal dilation of the lung airways (bronchi). There are a large variety of causative factors that have been identified for bronchiectasis; all of these compromise the function of the immune response to fight infection. A triggering factor may lead to the establishment of chronic infection in the lower respiratory tract. The bacteria responsible for the lower respiratory tract infection are usually found as commensals in the upper respiratory tract microbiome. The consequent inflammatory response to infection is largely responsible for the pathology of this condition. Both innate and adaptive immune responses are activated. The literature has highlighted the central role of neutrophils in the pathogenesis of bronchiectasis. Proteases produced in the lung by the inflammatory response damage the airways and lead to the pathological dilation that is the pathognomonic feature of bronchiectasis. The small airways demonstrate infiltration with lymphoid follicles that may contribute to localised small airway obstruction. Despite aggressive treatment, most patients will have persistent disease. Manipulating the immune response in bronchiectasis may potentially have therapeutic potential.

An Interleukin-33-Mast Cell-Interleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers.

PubMed

Morita, Hideaki; Arae, Ken; Unno, Hirotoshi; Miyauchi, Kousuke; Toyama, Sumika; Nambu, Aya; Oboki, Keisuke; Ohno, Tatsukuni; Motomura, Kenichiro; Matsuda, Akira; Yamaguchi, Sachiko; Narushima, Seiko; Kajiwara, Naoki; Iikura, Motoyasu; Suto, Hajime; McKenzie, Andrew N J; Takahashi, Takao; Karasuyama, Hajime; Okumura, Ko; Azuma, Miyuki; Moro, Kazuyo; Akdis, Cezmi A; Galli, Stephen J; Koyasu, Shigeo; Kubo, Masato; Sudo, Katsuko; Saito, Hirohisa; Matsumoto, Kenji; Nakae, Susumu

2015-07-21

House dust mite-derived proteases contribute to allergic disorders in part by disrupting epithelial barrier function. Interleukin-33 (IL-33), produced by lung cells after exposure to protease allergens, can induce innate-type airway eosinophilia by activating natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2), to secrete Th2 type-cytokines. Because IL-33 also can induce mast cells (MCs) to secrete Th2 type-cytokines, MCs are thought to cooperate with NH cells in enhancing protease or IL-33-mediated innate-type airway eosinophilia. However, we found that MC-deficient Kit(W-sh/W-sh) mice exhibited exacerbated protease-induced lung inflammation associated with reduced numbers of regulatory T (Treg) cells. Moreover, IL-2 produced by IL-33-stimulated MCs promoted expansion of numbers of Treg cells, thereby suppressing development of papain- or IL-33-induced airway eosinophilia. We have thus identified a unique anti-inflammatory pathway that can limit induction of innate-type allergic airway inflammation mediated by NH cells. Copyright © 2015 Elsevier Inc. All rights reserved.

Distal airways in humans: dynamic hyperpolarized 3He MR imaging--feasibility

NASA Technical Reports Server (NTRS)

Tooker, Angela C.; Hong, Kwan Soo; McKinstry, Erin L.; Costello, Philip; Jolesz, Ferenc A.; Albert, Mitchell S.

2003-01-01

Dynamic hyperpolarized helium 3 (3He) magnetic resonance (MR) imaging of the human airways is achieved by using a fast gradient-echo pulse sequence during inhalation. The resulting dynamic images show differential contrast enhancement of both distal airways and the lung periphery, unlike static hyperpolarized 3He MR images on which only the lung periphery is seen. With this technique, up to seventh-generation airway branching can be visualized. Copyright RSNA, 2003.

Intervention effect and dose-dependent response of tanreqing injection on airway inflammation in lipopolysaccharide-induced rats.

PubMed

Dong, Shoujin; Zhong, Yunqing; Yang, Kun; Xiong, Xiaoling; Mao, Bing

2013-08-01

To assess the effect of Tanreqing injection on airway inflammation in rats. A rat model of airway inflammation was generated with lipopolysaccharide (LPS). Tanreqing injection was given by intratracheal instillation, and bronchoalveolar lavage fluid (BALF) from the right lung was collected. BALF total cell and neutrophil counts were then determined. In addition, BALF levels of inflammatory cytokines interleukin-13, cytokine-induced neutrophil chemoat-tractant-1, and tumor necrosis factor-alpha were measured using enzyme linked immunosorbent assay. The middle lobe of the right lung was stained with hematoxylin-eosin and histological changes examined. LPS increased airway inflammation, decreased BALF inflammatory cell count, inflammatory cytokine levels, and suppressed leukocyte influx of the lung. The LPS-induced airway inflammation peaked at 24 h, decreased beginning at 48 h, and had decreased markedly by 96 h. Tanreqing injection contains anti-inflammatory properties, and inhibits airway inflammation in a dose-dependent manner.

Arsenic Alters ATP-Dependent Ca2+ Signaling in Human Airway Epithelial Cell Wound Response

PubMed Central

Sherwood, Cara L.; Lantz, R. Clark; Burgess, Jefferey L.; Boitano, Scott

2011-01-01

Arsenic is a natural metalloid toxicant that is associated with occupational inhalation injury and contaminates drinking water worldwide. Both inhalation of arsenic and consumption of arsenic-tainted water are correlated with malignant and nonmalignant lung diseases. Despite strong links between arsenic and respiratory illness, underlying cell responses to arsenic remain unclear. We hypothesized that arsenic may elicit some of its detrimental effects on the airway through limitation of innate immune function and, specifically, through alteration of paracrine ATP (purinergic) Ca2+ signaling in the airway epithelium. We examined the effects of acute (24 h) exposure with environmentally relevant levels of arsenic (i.e., < 4μM as Na-arsenite) on wound-induced Ca2+ signaling pathways in human bronchial epithelial cell line (16HBE14o-). We found that arsenic reduces purinergic Ca2+ signaling in a dose-dependent manner and results in a reshaping of the Ca2+ signaling response to localized wounds. We next examined arsenic effects on two purinergic receptor types: the metabotropic P2Y and ionotropic P2X receptors. Arsenic inhibited both P2Y- and P2X-mediated Ca2+ signaling responses to ATP. Both inhaled and ingested arsenic can rapidly reach the airway epithelium where purinergic signaling is essential in innate immune functions (e.g., ciliary beat, salt and water transport, bactericide production, and wound repair). Arsenic-induced compromise of such airway defense mechanisms may be an underlying contributor to chronic lung disease. PMID:21357385

The effect of smoke inhalation on lung function and airway responsiveness in wildland fire fighters

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

Liu, D.; Tager, I.B.; Balmes, J.R.

1992-12-01

The current study was undertaken to evaluate the effect of smoke on forced expiratory volumes and airway responsiveness in wildland fire fighters during a season of active fire fighting. Sixty-three seasonal and full-time wildland fire fighters from five U.S. Department of Agriculture Forest Service (USDAFS) Hotshot crews in Northern California and Montana completed questionnaires, spirometry, and methacholine challenge testing before and after an active season of fire fighting in 1989. There were significant mean individual declines of 0.09, 0.15, and 0.44 L/s in postseason values of FVC, FEV1, and FEF25-75, respectively, compared with preseason values. There were no consistent significantmore » relationships between mean individual declines of the spirometric parameters and the covariates: sex, smoking history, history of asthma or allergies, years as a fire fighter, upper/lower respiratory symptoms, or membership in a particular Hotshot crew. There was a statistically significant increase in airway responsiveness when comparing preseason methacholine dose-response slopes (DRS) with postseason dose-response slopes (p = 0.02). The increase in airway responsiveness appeared to be greatest in fire fighters with a history of lower respiratory symptoms or asthma, but it was not related to smoking history. These data suggest that wildland fire fighting is associated with decreases in lung function and increases in airway responsiveness independent of a history of cigarette smoking. Our findings are consistent with the results of previous studies of municipal fire fighters.« less

Airway disease phenotypes in animal models of cystic fibrosis.

PubMed

McCarron, Alexandra; Donnelley, Martin; Parsons, David

2018-04-02

In humans, cystic fibrosis (CF) lung disease is characterised by chronic infection, inflammation, airway remodelling, and mucus obstruction. A lack of pulmonary manifestations in CF mouse models has hindered investigations of airway disease pathogenesis, as well as the development and testing of potential therapeutics. However, recently generated CF animal models including rat, ferret and pig models demonstrate a range of well characterised lung disease phenotypes with varying degrees of severity. This review discusses the airway phenotypes of currently available CF animal models and presents potential applications of each model in airway-related CF research.

Protection from experimental asthma by an endogenous bronchodilator.

PubMed

Que, Loretta G; Liu, Limin; Yan, Yun; Whitehead, Gregory S; Gavett, Stephen H; Schwartz, David A; Stamler, Jonathan S

2005-06-10

Mechanisms that protect against asthma remain poorly understood. S-nitrosoglutathione (GSNO), an endogenous bronchodilator, is depleted from asthmatic airways, suggesting a protective role. We report that, following allergen challenge, wild-type mice exhibiting airway hyperresponsivity have increased airway levels of the enzyme GSNO reductase (GSNOR) and are depleted of lung S-nitrosothiols (SNOs). In contrast, mice with genetic deletion of GSNOR exhibit increases in lung SNOs and are protected from airway hyperresponsivity. Our results indicate that endogenous SNOs, governed by GSNOR, are critical regulators of airway responsivity and may provide new therapeutic approaches to asthma.

The effectiveness of fish oil supplementation in asthmatic rats is limited by an inefficient action on ASM function.

PubMed

Miranda, D T S Z; Zanatta, A L; Dias, B C L; Fogaça, R T H; Maurer, J B B; Donatti, L; Calder, P C; Nishiyama, A

2013-09-01

Episodes of acute exacerbation are the major clinical feature of asthma and therefore represent an important focus for developing novel therapies for this disease. There are many reports that the n-3 fatty acids found in fish oil exert anti-inflammatory effects, but there are few studies of the action of fish oil on airway smooth muscle (ASM) function. In the present investigation, we evaluated the effect of fish oil supplementation on smooth muscle force of contraction in ovalbumin-induced asthmatic Wistar rats, and its consequences on static lung compliance, mucus production, leukocyte chemotaxis and production of proinflammatory cytokines. Fish oil supplementation suppressed the infiltration of inflammatory cells into the lung in asthmatic animals (2.04 ± 0.19 × 10(6) cells vs. 3.33 ± 0.43 × 10(6) cells in the control asthmatic group; P < 0.05). Static lung compliance increased with fish oil supplementation in asthmatic rats (0.640 ± 0.053 mL/cm H2O vs. 0.399 ± 0.043 mL/cm H2O; P < 0.05). However, fish oil did not prevent asthma-associated lung eosinophilia and did not affect the concentrations of tumor necrosis factor-α and interleukin-1β in lung tissue or the proportion of the airways obliterated with mucus. Fish oil had no effect on the force of contraction in asthmatic rats in response to acetylcholine (3.026 ± 0.274 mN vs. 2.813 ± 0.364 mN in the control asthmatic group). In conclusion, although fish oil exerts some benefits in this model of asthma, its effectiveness appears to be limited by an inefficient action on airway smooth muscle function.

Long-term clearance from small airways in subjects with ciliary dysfunction.

PubMed

Lindström, Maria; Falk, Rolf; Hjelte, Lena; Philipson, Klas; Svartengren, Magnus

2006-05-20

The objective of this study was to investigate if long-term clearance from small airways is dependent on normal ciliary function. Six young adults with primary ciliary dyskinesia (PCD) inhaled 111 Indium labelled Teflon particles of 4.2 microm geometric and 6.2 microm aerodynamic diameter with an extremely slow inhalation flow, 0.05 L/s. The inhalation method deposits particles mainly in the small conducting airways. Lung retention was measured immediately after inhalation and at four occasions up to 21 days after inhalation. Results were compared with data from ten healthy controls. For additional comparison three of the PCD subjects also inhaled the test particles with normal inhalation flow, 0.5 L/s, providing a more central deposition. The lung retention at 24 h in % of lung deposition (Ret24) was higher (p < 0.001) in the PCD subjects, 79 % (95% Confidence Interval, 67.6;90.6), compared to 49% (42.3;55.5) in the healthy controls. There was a significant clearance after 24 h both in the PCD subjects and in the healthy controls with equivalent clearance. The mean Ret24 with slow inhalation flow was 73.9 +/- 1.9% compared to 68.9 +/- 7.5% with normal inhalation flow in the three PCD subjects exposed twice. During day 7-21 the three PCD subjects exposed twice cleared 9% with normal flow, probably representing predominantly alveolar clearance, compared to 19% with slow inhalation flow, probably representing mainly small airway clearance. This study shows that despite ciliary dysfunction, clearance continues in the small airways beyond 24 h. There are apparently additional clearance mechanisms present in the small airways.

A Multi-Scale Approach to Airway Hyperresponsiveness: From Molecule to Organ

PubMed Central

Lauzon, Anne-Marie; Bates, Jason H. T.; Donovan, Graham; Tawhai, Merryn; Sneyd, James; Sanderson, Michael J.

2012-01-01

Airway hyperresponsiveness (AHR), a characteristic of asthma that involves an excessive reduction in airway caliber, is a complex mechanism reflecting multiple processes that manifest over a large range of length and time scales. At one extreme, molecular interactions determine the force generated by airway smooth muscle (ASM). At the other, the spatially distributed constriction of the branching airways leads to breathing difficulties. Similarly, asthma therapies act at the molecular scale while clinical outcomes are determined by lung function. These extremes are linked by events operating over intermediate scales of length and time. Thus, AHR is an emergent phenomenon that limits our understanding of asthma and confounds the interpretation of studies that address physiological mechanisms over a limited range of scales. A solution is a modular computational model that integrates experimental and mathematical data from multiple scales. This includes, at the molecular scale, kinetics, and force production of actin-myosin contractile proteins during cross-bridge and latch-state cycling; at the cellular scale, Ca2+ signaling mechanisms that regulate ASM force production; at the tissue scale, forces acting between contracting ASM and opposing viscoelastic tissue that determine airway narrowing; at the organ scale, the topographic distribution of ASM contraction dynamics that determine mechanical impedance of the lung. At each scale, models are constructed with iterations between theory and experimentation to identify the parameters that link adjacent scales. This modular model establishes algorithms for modeling over a wide range of scales and provides a framework for the inclusion of other responses such as inflammation or therapeutic regimes. The goal is to develop this lung model so that it can make predictions about bronchoconstriction and identify the pathophysiologic mechanisms having the greatest impact on AHR and its therapy. PMID:22701430

Activation of Neurokinin-1 Receptors during Ozone Inhalation Contributes to Epithelial Injury and Repair

PubMed Central

Oslund, Karen L.; Hyde, Dallas M.; Putney, Leialoha F.; Alfaro, Mario F.; Walby, William F.; Tyler, Nancy K.; Schelegle, Edward S.

2008-01-01

We investigated the importance of neurokinin (NK)-1 receptors in epithelial injury and repair and neutrophil function. Conscious Wistar rats were exposed to 1 ppm ozone or filtered air for 8 hours, followed by an 8-hour postexposure period. Before exposure, we administered either the NK-1 receptor antagonist, SR140333, or saline as a control. Ethidium homodimer was instilled into lungs as a marker of necrotic airway epithelial cells. After fixation, whole mounts of airway dissected lung lobes were immunostained for 5-bromo-2′-deoxyuridine, a marker of epithelial proliferation. Both ethidium homodimer and 5-bromo-2′-deoxyuridine-positive epithelial cells were quantified in specific airway generations. Rats treated with the NK-1 receptor antagonist had significantly reduced epithelial injury and epithelial proliferation compared with control rats. Sections of terminal bronchioles showed no significant difference in the number of neutrophils in airways between groups. In addition, staining ozone-exposed lung sections for active caspase 3 showed no apoptotic cells, but ethidium-positive cells colocalized with the orphan nuclear receptor, Nur77, a marker of nonapoptotic, programmed cell death mediated by the NK-1 receptor. An immortalized human airway epithelial cell line, human bronchial epithelial-1, showed no significant difference in the number of oxidant stress–positive cells during exposure to hydrogen peroxide and a range of SR140333 doses, demonstrating no antioxidant effect of the receptor antagonist. We conclude that activation of the NK-1 receptor during acute ozone inhalation contributes to epithelial injury and subsequent epithelial proliferation, a critical component of repair, but does not influence neutrophil emigration into airways. PMID:18390473

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...

Airway diffusing capacity of nitric oxide and steroid therapy in asthma.

PubMed

Shin, Hye-Won; Rose-Gottron, Christine M; Cooper, Dan M; Newcomb, Robert L; George, Steven C

2004-01-01

Exhaled nitric oxide (NO) concentration is a noninvasive index for monitoring lung inflammation in diseases such as asthma. The plateau concentration at constant flow is highly dependent on the exhalation flow rate and the use of corticosteroids and cannot distinguish airway and alveolar sources. In subjects with steroid-naive asthma (n = 8) or steroid-treated asthma (n = 12) and in healthy controls (n = 24), we measured flow-independent NO exchange parameters that partition exhaled NO into airway and alveolar regions and correlated these with symptoms and lung function. The mean (+/-SD) maximum airway flux (pl/s) and airway tissue concentration [parts/billion (ppb)] of NO were lower in steroid-treated asthmatic subjects compared with steroid-naive asthmatic subjects (1,195 +/- 836 pl/s and 143 +/- 66 ppb compared with 2,693 +/- 1,687 pl/s and 438 +/- 312 ppb, respectively). In contrast, the airway diffusing capacity for NO (pl.s-1.ppb-1) was elevated in both asthmatic groups compared with healthy controls, independent of steroid therapy (11.8 +/- 11.7, 8.71 +/- 5.74, and 3.13 +/- 1.57 pl.s-1.ppb-1 for steroid treated, steroid naive, and healthy controls, respectively). In addition, the airway diffusing capacity was inversely correlated with both forced expired volume in 1 s and forced vital capacity (%predicted), whereas the airway tissue concentration was positively correlated with forced vital capacity. Consistent with previously reported results from Silkoff et al. (Silkoff PE, Sylvester JT, Zamel N, and Permutt S, Am J Respir Crit Med 161: 1218-1228, 2000) that used an alternate technique, we conclude that the airway diffusing capacity for NO is elevated in asthma independent of steroid therapy and may reflect clinically relevant changes in airways.

A Lagrangian Approach for Calculating Microsphere Deposition in a One-Dimensional Lung-Airway Model.

PubMed

Vaish, Mayank; Kleinstreuer, Clement

2015-09-01

Using the open-source software openfoam as the solver, a novel approach to calculate microsphere transport and deposition in a 1D human lung-equivalent trumpet model (TM) is presented. Specifically, for particle deposition in a nonlinear trumpetlike configuration a new radial force has been developed which, along with the regular drag force, generates particle trajectories toward the wall. The new semi-empirical force is a function of any given inlet volumetric flow rate, micron-particle diameter, and lung volume. Particle-deposition fractions (DFs) in the size range from 2 μm to 10 μm are in agreement with experimental datasets for different laminar and turbulent inhalation flow rates as well as total volumes. Typical run times on a single processor workstation to obtain actual total deposition results at comparable accuracy are 200 times less than that for an idealized whole-lung geometry (i.e., a 3D-1D model with airways up to 23rd generation in single-path only).

Microfluidic lung airway-on-a-chip with arrayable suspended gels for studying epithelial and smooth muscle cell interactions.

PubMed

Humayun, Mouhita; Chow, Chung-Wai; Young, Edmond W K

2018-05-01

Chronic lung diseases (CLDs) are regulated by complex interactions between many different cell types residing in lung airway tissues. Specifically, interactions between airway epithelial cells (ECs) and airway smooth muscle cells (SMCs) have been shown in part to play major roles in the pathogenesis of CLDs, but the underlying molecular mechanisms are not well understood. To advance our understanding of lung pathophysiology and accelerate drug development processes, new innovative in vitro tissue models are needed that can reconstitute the complex in vivo microenvironment of human lung tissues. Organ-on-a-chip technologies have recently made significant strides in recapitulating physiological properties of in vivo lung tissue microenvironments. However, novel advancements are still needed to enable the study of airway SMC-EC communication with matrix interactions, and to provide higher throughput capabilities and manufacturability. We have developed a thermoplastic-based microfluidic lung airway-on-a-chip model that mimics the lung airway tissue microenvironment, and in particular, the interactions between SMCs, ECs, and supporting extracellular matrix (ECM). The microdevice is fabricated from acrylic using micromilling and solvent bonding techniques, and consists of three vertically stacked microfluidic compartments with a bottom media reservoir for SMC culture, a middle thin hydrogel layer, and an upper microchamber for achieving air-liquid interface (ALI) culture of the epithelium. A unique aspect of the design lies in the suspended hydrogel with upper and lower interfaces for EC and SMC culture, respectively. A mixture of type I collagen and Matrigel was found to promote EC adhesion and monolayer formation, and SMC adhesion and alignment. Optimal culturing protocols were established that enabled EC-SMC coculture for more than 31 days. Epithelial monolayers displayed common morphological markers including ZO-1 tight junctions and F-actin cell cortices, while SMCs exhibited enhanced cell alignment and expression of α-SMA. The thermoplastic device construction facilitates mass manufacturing, allows EC-SMC coculture systems to be arrayed for increased throughput, and can be disassembled to allow extraction of the suspended gel for downstream analyses. This airway-on-a-chip device has potential to significantly advance our understanding of SMC-EC-matrix interactions, and their roles in the development of CLDs.

Intratracheal instillation of pravastatin for the treatment of murine allergic asthma: a lung-targeted approach to deliver statins

PubMed Central

Zeki, Amir A; Bratt, Jennifer M; Chang, Kevin Y; Franzi, Lisa M; Ott, Sean; Silveria, Mark; Fiehn, Oliver; Last, Jerold A; Kenyon, Nicholas J

2015-01-01

Systemic treatment with statins mitigates allergic airway inflammation, TH2 cytokine production, epithelial mucus production, and airway hyperreactivity (AHR) in murine models of asthma. We hypothesized that pravastatin delivered intratracheally would be quantifiable in lung tissues using mass spectrometry, achieve high drug concentrations in the lung with minimal systemic absorption, and mitigate airway inflammation and structural changes induced by ovalbumin. Male BALB/c mice were sensitized to ovalbumin (OVA) over 4 weeks, then exposed to 1% OVA aerosol or filtered air (FA) over 2 weeks. Mice received intratracheal instillations of pravastatin before and after each OVA exposure (30 mg/kg). Ultra performance liquid chromatography – mass spectrometry was used to quantify plasma, lung, and bronchoalveolar lavage fluid (BALF) pravastatin concentration. Pravastatin was quantifiable in mouse plasma, lung tissue, and BALF (BALF > lung > plasma for OVA and FA groups). At these concentrations pravastatin inhibited airway goblet cell hyperplasia/metaplasia, and reduced BALF levels of cytokines TNFα and KC, but did not reduce BALF total leukocyte or eosinophil cell counts. While pravastatin did not mitigate AHR, it did inhibit airway hypersensitivity (AHS). In this proof-of-principle study, using novel mass spectrometry methods we show that pravastatin is quantifiable in tissues, achieves high levels in mouse lungs with minimal systemic absorption, and mitigates some pathological features of allergic asthma. Inhaled pravastatin may be beneficial for the treatment of asthma by having direct airway effects independent of a potent anti-inflammatory effect. Statins with greater lipophilicity may achieve better anti-inflammatory effects warranting further research. PMID:25969462

Advantage of impulse oscillometry over spirometry to diagnose chronic obstructive pulmonary disease and monitor pulmonary responses to bronchodilators: An observational study.

PubMed

Saadeh, Constantine; Saadeh, Charles; Cross, Blake; Gaylor, Michael; Griffith, Melissa

2015-01-01

This retrospective study was a comparative analysis of sensitivity of impulse oscillometry and spirometry techniques for use in a mixed chronic obstructive pulmonary disease group for assessing disease severity and inhalation therapy. A total of 30 patients with mild-to-moderate chronic obstructive pulmonary disease were monitored by impulse oscillometry, followed by spirometry. Lung function was measured at baseline after bronchodilation and at follow-up (3-18 months). The impulse oscillometry parameters were resistance in the small and large airways at 5 Hz (R5), resistance in the large airways at 15 Hz (R15), and lung reactance (area under the curve X; AX). After the bronchodilator therapy, forced expiratory volume in 1 second (FEV1) readings evaluated by spirometry were unaffected at baseline and at follow-up, while impulse oscillometry detected an immediate improvement in lung function, in terms of AX (p = 0.043). All impulse oscillometry parameters significantly improved at follow-up, with a decrease in AX by 37% (p = 0.0008), R5 by 20% (p = 0.0011), and R15 by 12% (p = 0.0097). Impulse oscillometry parameters demonstrated greater sensitivity compared with spirometry for monitoring reversibility of airway obstruction and the effect of maintenance therapy. Impulse oscillometry may facilitate early treatment dose optimization and personalized medicine for chronic obstructive pulmonary disease patients.

Early life rhinovirus infection exacerbates house-dust-mite induced lung disease more severely in female mice.

PubMed

Phan, Jennifer A; Kicic, Anthony; Berry, Luke J; Sly, Peter D; Larcombe, Alexander N

2016-01-01

Recent studies have employed animal models to investigate links between rhinovirus infection and allergic airways disease, however, most do not involve early life infection, and none consider the effects of sex on responses. Here, we infected male and female mice with human rhinovirus 1B (or control) on day 7 of life. Mice were then subjected to 7 weeks of exposure to house-dust-mite prior to assessment of bronchoalveolar inflammation, serum antibodies, lung function, and responsiveness to methacholine. There were significant differences in responses between males and females in most outcomes. In males, chronic house-dust-mite exposure increased bronchoalveolar inflammation, house-dust-mite specific IgG1 and responsiveness of the lung parenchyma, however, there was no additional impact of rhinovirus infection. Conversely, in females, there were additive and synergistic effects of rhinovirus infection and house-dust-mite exposure on neutrophilia, airway resistance, and responsiveness of the lung parenchyma. We conclude that early life rhinovirus infection influences the development of house-dust-mite induced lung disease in female, but not male mice.

Effect of pirfenidone on wound healing in lung transplant patients.

PubMed

Mortensen, Amber; Cherrier, Lauren; Walia, Rajat

2018-01-01

The drug pirfenidone has been shown to slow the progression and decrease mortality of idiopathic pulmonary fibrosis (IPF). Its exact mechanism is unknown, but it likely inhibits pro-fibrotic cytokine transforming growth factor beta, a known contributor to wound healing. We evaluated whether patients taking pirfenidone until lung transplantation had increased risk of impaired wound healing post-transplant. This information could determine whether pirfenidone should be discontinued prior to listing to allow for a wash-out period. We retrospectively reviewed patients who underwent lung transplantation for pulmonary fibrosis at Norton Thoracic Institute in Phoenix, Arizona, from January 2014 to December 2015. We describe 18 patients who took pirfenidone up to a month before transplant. Aside from one patient who experienced sternal dehiscence due to a surgical issue, all remaining patients did well with no evidence of airway dehiscence. Each of these 17 patients had been on pirfenidone for at least 30 days; nine patients had been on pirfenidone for over 90 days. Baseline characteristics including age, sex, body mass index, renal function, liver function, glucose level, pre-transplant corticosteroid use, and post-transplant immunosuppressant therapy were similar. In our experience, pirfenidone may be safely continued until lung transplantation. Only one patient in our series experienced impaired wound healing related to a surgical issue, even when pirfenidone was continued until lung transplantation. We found no evidence of impaired wound healing or airway complications after lung transplantation in patients who were treated with pirfenidone before lung transplantation.

Vagal Afferent Innervation of the Airways in Health and Disease

PubMed Central

Mazzone, Stuart B.

2016-01-01

Vagal sensory neurons constitute the major afferent supply to the airways and lungs. Subsets of afferents are defined by their embryological origin, molecular profile, neurochemistry, functionality, and anatomical organization, and collectively these nerves are essential for the regulation of respiratory physiology and pulmonary defense through local responses and centrally mediated neural pathways. Mechanical and chemical activation of airway afferents depends on a myriad of ionic and receptor-mediated signaling, much of which has yet to be fully explored. Alterations in the sensitivity and neurochemical phenotype of vagal afferent nerves and/or the neural pathways that they innervate occur in a wide variety of pulmonary diseases, and as such, understanding the mechanisms of vagal sensory function and dysfunction may reveal novel therapeutic targets. In this comprehensive review we discuss historical and state-of-the-art concepts in airway sensory neurobiology and explore mechanisms underlying how vagal sensory pathways become dysfunctional in pathological conditions. PMID:27279650

Substance deposition assessment in obstructed pulmonary system through numerical characterization of airflow and inhaled particles attributes.

PubMed

Lalas, Antonios; Nousias, Stavros; Kikidis, Dimitrios; Lalos, Aris; Arvanitis, Gerasimos; Sougles, Christos; Moustakas, Konstantinos; Votis, Konstantinos; Verbanck, Sylvia; Usmani, Omar; Tzovaras, Dimitrios

2017-12-20

Chronic obstructive pulmonary disease (COPD) and asthma are considered as the two most widespread obstructive lung diseases, whereas they affect more than 500 million people worldwide. Unfortunately, the requirement for detailed geometric models of the lungs in combination with the increased computational resources needed for the simulation of the breathing did not allow great progress to be made in the past for the better understanding of inflammatory diseases of the airways through detailed modelling approaches. In this context, computational fluid dynamics (CFD) simulations accompanied by fluid particle tracing (FPT) analysis of the inhaled ambient particles are deemed critical for lung function assessment. Also they enable the understanding of particle depositions on the airways of patients, since these accumulations may affect or lead to inflammations. In this direction, the current study conducts an initial investigation for the better comprehension of particle deposition within the lungs. More specifically, accurate models of the airways obstructions that relate to pulmonary disease are developed and a thorough assessment of the airflow behavior together with identification of the effects of inhaled particle properties, such as size and density, is conducted. Our approach presents a first step towards an effective personalization of pulmonary treatment in regards to the geometric characteristics of the lungs and the in depth understanding of airflows within the airways. A geometry processing technique involving contraction algorithms is established and used to employ the different respiratory arrangements associated with lung related diseases that exhibit airways obstructions. Apart from the normal lung case, two categories of obstructed cases are examined, i.e. models with obstructions in both lungs and models with narrowings in the right lung only. Precise assumptions regarding airflow and deposition fraction (DF) over various sections of the lungs are drawn by simulating these distinct incidents through the finite volume method (FVM) and particularly the CFD and FPT algorithms. Moreover, a detailed parametric analysis clarifies the effects of the particles size and density in terms of regional deposition upon several parts of the pulmonary system. In this manner, the deposition pattern of various substances can be assessed. For the specific case of the unobstructed lung model most particles are detected on the right lung (48.56% of total, when the air flowrate is 12.6 L/min), a fact that is also true when obstructions arise symmetrically in both lungs (51.45% of total, when the air flowrate is 6.06 L/min and obstructions occur after the second generation). In contrast, when narrowings are developed on the right lung only, most particles are pushed on the left section (68.22% of total, when the air flowrate is 11.2 L/min) indicating that inhaled medication is generally deposited away from the areas of inflammation. This observation is useful when designing medical treatment of lung diseases. Furthermore, particles with diameters from 1 μm to 10 μm are shown to be mainly deposited on the lower airways, whereas particles with diameters of 20 μm and 30 μm are mostly accumulated in the upper airways. As a result, the current analysis indicates increased DF levels in the upper airways when the particle diameter is enlarged. Additionally, when the particles density increases from 1000 Kg/m 3 to 2000 Kg/m 3 , the DF is enhanced on every generation and for all cases investigated herein. The results obtained by our simulations provide an accurate and quantitative estimation of all important parameters involved in lung modeling. The treatment of respiratory diseases with inhaled medical substances can be advanced by the clinical use of accurate CFD and FPT simulations and specifically by evaluating the deposition of inhaled particles in a regional oriented perspective in regards to different particle sizes and particle densities. Since a drug with specific characteristics (i.e. particle size and density) exhibits maximum deposition on particular lung areas, the current study provides initial indications to a qualified physician for proper selection of medication.

3D CFD Simulation of Plug Dynamics and Splitting through a Bifurcating Airway Model

NASA Astrophysics Data System (ADS)

Hoi, Cory; Raessi, Mehdi

2017-11-01

Respiratory distress syndrome (RDS) occurs because of pulmonary surfactant insufficiency in the lungs of preterm infants. The common medical procedure to treat RDS, called surfactant respiratory therapy (SRT), involves instilling liquid surfactant plugs into the pulmonary airways. SRT's effectiveness highly depends on the ability to deliver surfactant through the complex branching airway network. Experimental and computational efforts have been made to understand complex fluid dynamics of liquid plug motion through the lung airways in order to increase SRT's response rate. However, previous computational work used 2D airway model geometries and studied plug dynamics of a pre-split plug. In this work, we present CFD simulations of surfactant plug motion through a 3D bifurcating airway model. In our 3D y-tube geometry representing the lung airways, we are not limited by 2D or pre-split plug assumptions. The airway walls are covered with a pre-existing liquid film. Using a passive scalar marking the surfactant plug, the plug splitting and surfactant film deposition is studied under various airway orientations. Exploring the splitting process and liquid distribution in a 3D geometry will advance our understanding of surfactant delivery and will increase the effectiveness of SRT.

Comparison of capnovolumetry-derived dead space parameters with pulmonary function test in normal adults using histamine provocation.

PubMed

Sun, Xiaoli; Zhang, Yan; Yang, Wenlan; Liu, Jinming

2015-04-01

This study in healthy adults was conducted to explore the clinical application of capnovolumetric indices as compared to lung function parameters using histamine provocation. Forty healthy subjects received aerosol histamine or salbutamol in an automatic stimulation system with escalating doses of histamine. Dead space volumes of capnovolumetry and lung function parameters were examined with increased concentrations of histamine at a fixed time interval. The doses of histamine were selected from 0.0562 mg-2.2 mg and 0.1 mg salbutamol was inhaled when a maximal dose of histamine was reached. Baseline values in each group were calculated prior to histamine inhalation. Fowler dead space (VDF), Wolff dead space (VDW), threshold dead space (VDT), Bohr dead space (VDB), forced expiratory volume in 1 s (FEV1 ) and peak expiratory flow (PEF) showed a dose-dependent reduction following histamine provocation, but there were no statistical differences in the measurements at baseline and post S6 provocation. The value of dC3/DV at the maximal dose was significantly increased over its baseline value (P < 0.05). VDF, VDT and VDW were significantly increased after bronchodilator use (P < 0.05 or <0.01). The changes in capnovolumetry did not correspond with the results of lung function test. The dC3/DV and airway dead spaces of capnovolumetry in healthy adults are significantly increased compared to lung function parameters before or after bronchodilator use, suggesting that capnovolumetry is feasible in diagnostic evaluation of airway reactivity, especially for persons who are unable to undertake lung function test. © 2014 John Wiley & Sons Ltd.

[Preoperatiove Airway Bacterial Colonization: the Missing Link between Non-small Cell Lung Cancer Following Lobectomy and Postoperative Pneumonia?

PubMed

Gao, Ke; Lai, Yutian; Huang, Jian; Wang, Yifan; Wang, Xiaowei; Che, Guowei

2017-04-20

Surgical procedure is the main method of treating lung cancer. Meanwhile, postoperative pneumonia (POP) is the major cause of perioperative mortality in lung cancer surgery. The preoperative pathogenic airway bacterial colonization is an independent risk factor causing postoperative pulmonary complications (PPC). This cross-sectional study aimed to explore the relationship between preoperative pathogenic airway bacterial colonization and POP in lung cancer and to identify the high-risk factors of preoperative pathogenic airway bacterial colonization. A total of 125 patients with non-small cell lung cancer (NSCLC) underwent thoracic surgery in six hospitals of Chengdu between May 2015 and January 2016. Preoperative pathogenic airway bacterial colonization was detected in all patients via fiber bronchoscopy. Patients' PPC, high-risk factors, clinical characteristics, and the serum surfactant protein D (SP-D) level were also analyzed. The incidence of preoperative pathogenic airway bacterial colonization among NSCLC patients was 15.2% (19/125). Up to 22 strains were identified in the colonization positive group, with Gram-negative bacteria being dominant (86.36%, 19/22). High-risk factors of pathogenic airway bacterial colonization were age (≥75 yr) and smoking index (≥400 cigarettes/year). PPC incidence was significantly higher in the colonization-positive group (42.11%, 8/19) than that in the colonization-negative group (16.04%, 17/106)(P=0.021). POP incidence was significantly higher in the colonization-positive group (26.32%, 5/19) than that in the colonization-negative group (6.60%, 7/106)(P=0.019). The serum SP-D level of patients in the colonization-positive group was remarkably higher than that in the colonization-negative group [(31.25±6.09) vs (28.17±5.23)](P=0.023). The incidence of preoperative pathogenic airway bacterial colonization among NSCLC patients with POP was 41.67% (5/12). This value was 3.4 times higher than that among the patients without POP (OR=3.363, 95%CI: 1.467-7.711). An intimate correlation was observed between POP and pathogenic airway bacterial colonization in lung cancer. The high-risk factors of pathogenic airway bacterial colonization were age and smoking index.

Pulmonary Vascular Congestion: A Mechanism for Distal Lung Unit Dysfunction in Obesity.

PubMed

Oppenheimer, Beno W; Berger, Kenneth I; Ali, Saleem; Segal, Leopoldo N; Donnino, Robert; Katz, Stuart; Parikh, Manish; Goldring, Roberta M

2016-01-01

Obesity is characterized by increased systemic and pulmonary blood volumes (pulmonary vascular congestion). Concomitant abnormal alveolar membrane diffusion suggests subclinical interstitial edema. In this setting, functional abnormalities should encompass the entire distal lung including the airways. We hypothesize that in obesity: 1) pulmonary vascular congestion will affect the distal lung unit with concordant alveolar membrane and distal airway abnormalities; and 2) the degree of pulmonary congestion and membrane dysfunction will relate to the cardiac response. 54 non-smoking obese subjects underwent spirometry, impulse oscillometry (IOS), diffusion capacity (DLCO) with partition into membrane diffusion (DM) and capillary blood volume (VC), and cardiac MRI (n = 24). Alveolar-capillary membrane efficiency was assessed by calculation of DM/VC. Mean age was 45±12 years; mean BMI was 44.8±7 kg/m2. Vital capacity was 88±13% predicted with reduction in functional residual capacity (58±12% predicted). Despite normal DLCO (98±18% predicted), VC was elevated (135±31% predicted) while DM averaged 94±22% predicted. DM/VC varied from 0.4 to 1.4 with high values reflecting recruitment of alveolar membrane and low values indicating alveolar membrane dysfunction. The most abnormal IOS (R5 and X5) occurred in subjects with lowest DM/VC (r2 = 0.31, p<0.001; r2 = 0.34, p<0.001). Cardiac output and index (cardiac output / body surface area) were directly related to DM/VC (r2 = 0.41, p<0.001; r2 = 0.19, p = 0.03). Subjects with lower DM/VC demonstrated a cardiac output that remained in the normal range despite presence of obesity. Global dysfunction of the distal lung (alveolar membrane and distal airway) is associated with pulmonary vascular congestion and failure to achieve the high output state of obesity. Pulmonary vascular congestion and consequent fluid transudation and/or alterations in the structure of the alveolar capillary membrane may be considered often unrecognized causes of airway dysfunction in obesity.

Pneumomediastinum

MedlinePlus

Pneumomediastinum is uncommon. The condition can be caused by injury or disease. Most often, it occurs when air leaks from any part of the lung or airways into the mediastinum. Increased pressure in the lungs or airways may be caused ...

Leukotriene-B4 concentrations in exhaled breath condensate and lung function after thirty minutes of breathing technically dried compressed air.

PubMed

Neubauer, Birger; Struck, Niclas; Mutzbauer, Till S; Schotte, Ulrich; Langfeldt, Norbert; Tetzlaff, Kay

2002-01-01

In previous studies it had been shown that leukotriene-B4 [LTB4] concentrations in the exhaled breath mirror the inflammatory activity of the airways if the respiratory tract has been exposed to occupational hazards. In diving the respiratory tract is exposed to cold and dry air and the nasopharynx, as the site of breathing-gas warming and humidification, is bypassed. The aim of the present study was to obtain LTB4-concentrations in the exhaled breath and spirometric data of 17 healthy subjects before and after thirty minutes of technically dried air breathing at normobar ambient pressure. The exhaled breath was collected non-invasively, via a permanently cooled expiration tube. The condensate was measured by a standard enzyme immunoassay for LTB4. Lung function values (FVC, FEV1, MEF 25, MEF 50) were simultaneously obtained by spirometry. The measured pre- and post-exposure LTB4- concentrations as well as the lung function values were in the normal range. The present data gave no evidence for any inflammatory activity in the subjects' airways after thirty minutes breathing technically dried air.

Pseudomonas aeruginosa Airway Infection Recruits and Modulates Neutrophilic Myeloid-Derived Suppressor Cells

PubMed Central

Öz, Hasan H.; Zhou, Benyuan; Voss, Pina; Carevic, Melanie; Schroth, Carolin; Frey, Nina; Rieber, Nikolaus; Hector, Andreas; Hartl, Dominik

2016-01-01

Pseudomonas aeruginosa is an opportunistic pathogen that causes infections mainly in patients with cystic fibrosis (CF) lung disease. Despite innate and adaptive immune responses upon infection, P. aeruginosa is capable of efficiently escaping host defenses, but the underlying immune mechanisms remain poorly understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells that are functionally characterized by their potential to suppress T- and natural killer (NK)-cell responses. Here we demonstrate, using an airway in vivo infection model, that P. aeruginosa recruits and activates neutrophilic MDSCs, which functionally suppress T-cell responses. We further show that the CF gene defect (CF transmembrane conductance regulator, CFTR) modulates the functionality, but not the recruitment or generation of neutrophilic MDSCs. Collectively, we define a mechanism by which P. aeruginosa airway infection undermines host immunity by modulating neutrophilic MDSCs in vivo. PMID:27965936

Statistical Physics Approaches to Respiratory Dynamics and Lung Structure

NASA Astrophysics Data System (ADS)

Suki, Bela

2004-03-01

The lung consists of a branching airway tree embedded in viscoelastic tissue and provides life-sustaining gas exchange to the body. In diseases, its structure is damaged and its function is compromised. We review two recent works about lung structure and dynamics and how they change in disease. 1) We introduced a new acoustic imaging approach to study airway structure. When airways in a collapsed lung are inflated, they pop open in avalanches. A single opening emits a sound package called crackle consisting of an initial spike (s) followed by ringing. The distribution n(s) of s follows a power law and the exponent of n(s) can be used to calculate the diameter ratio d defined as the ratio of the diameters of an airway to that of its parent averaged over all bifurcations. To test this method, we measured crackles in dogs, rabbits, rats and mice by inflating collapsed isolated lungs with air or helium while recording crackles with a microphone. In each species, n(s) follows a power law with an exponent that depends on species, but not on gas in agreement with theory. Values of d from crackles compare well with those calculated from morphometric data suggesting that this approach is suitable to study airway structure in disease. 2) Using novel experiments and computer models, we studied pulmonary emphysema which is caused by cigarette smoking. In emphysema, the elastic protein fibers of the tissue are actively remodeled by lung cells due to the chemicals present in smoke. We measured the mechanical properties of tissue sheets from normal and emphysematous lungs and imaged its structure which appears as a heterogeneous hexagonal network of fibers. We found evidence that during uniaxial stretching, the collagen and elastin fibers in emphysematous tissue can fail at a critical stress generating holes of various sizes (h). We developed network models of the failure process. When the failure is governed by mechanical forces, the distribution n(h) of h is a power law which compares well with Computed Tomographic images of patients. These results suggest that the progressive nature of emphysema may be due to a complex breakdown process initiated by chemicals in the smoke and maintained by mechanical failure of the remodeled fiber network.

Disrupting actin-myosin-actin connectivity in airway smooth muscle as a treatment for asthma?

PubMed

Lavoie, Tera L; Dowell, Maria L; Lakser, Oren J; Gerthoffer, William T; Fredberg, Jeffrey J; Seow, Chun Y; Mitchell, Richard W; Solway, Julian

2009-05-01

Breathing is known to functionally antagonize bronchoconstriction caused by airway muscle contraction. During breathing, tidal lung inflation generates force fluctuations that are transmitted to the contracted airway muscle. In vitro, experimental application of force fluctuations to contracted airway smooth muscle strips causes them to relengthen. Such force fluctuation-induced relengthening (FFIR) likely represents the mechanism by which breathing antagonizes bronchoconstriction. Thus, understanding the mechanisms that regulate FFIR of contracted airway muscle could suggest novel therapeutic interventions to increase FFIR, and so to enhance the beneficial effects of breathing in suppressing bronchoconstriction. Here we propose that the connectivity between actin filaments in contracting airway myocytes is a key determinant of FFIR, and suggest that disrupting actin-myosin-actin connectivity by interfering with actin polymerization or with myosin polymerization merits further evaluation as a potential novel approach for preventing prolonged bronchoconstriction in asthma.

Fluid Mechanics of Capillary-Elastic Instabilities in Microgravity Environment

NASA Technical Reports Server (NTRS)

Grotberg, James B.

2002-01-01

The aim of this project is to investigate the closure and reopening of lung airways due to surface tension forces, coupled with airway elasticity. Airways are liquid-lined, flexible tubes and closure of airways can occur by a Rayleigh instability of the liquid lining, or an instability of the elastic support for the airway as the surface tension of the air-liquid interface pulls the tube shut, or both. Regardless of the mechanism, the airway is closed because the liquid lining has created a plug that prevents axial gas exchange. In the microgravity environment, surface tension forces dominate lung mechanics and would lead to more prevalent, and more uniformly distributed air-way closure, thereby creating a potential for respiratory problems for astronauts. Once closed the primary option for reopening an airway is by deep inspiration. This maneuver will pull the flexible airways open and force the liquid plug to flow distally by the incoming air stream. Airway reopening depends to a large extent on this plug flow and how it may lead to plug rupture to regain the continuity of gas between the environment and the alveoli. In addition to mathematical modeling of plug flows in liquid-lined, flexible tubes, this work has involved benchtop studies of propagating liquid plugs down tube networks that mimic the human airway tree. We have extended the work to involve animal models of liquid plug propagation in rat lungs. The liquid is radio-opaque and x-ray video imaging is used to ascertain the movement and distribution of the liquid plugs so that comparisons to theory may be made. This research has other uses, such as the delivery of liquids or drugs into the lung that may be used for surfactant replacement therapy or for liquid ventilation.

Hypoxic Gene Expression of Donor Bronchi Linked to Airway Complications after Lung Transplantation.

PubMed

Kraft, Bryan D; Suliman, Hagir B; Colman, Eli C; Mahmood, Kamran; Hartwig, Matthew G; Piantadosi, Claude A; Shofer, Scott L

2016-03-01

Central airway stenosis (CAS) after lung transplantation has been attributed in part to chronic airway ischemia; however, little is known about the time course or significance of large airway hypoxia early after transplantation. To evaluate large airway oxygenation and hypoxic gene expression during the first month after lung transplantation and their relation to airway complications. Subjects who underwent lung transplantation underwent endobronchial tissue oximetry of native and donor bronchi at 0, 3, and 30 days after transplantation (n = 11) and/or endobronchial biopsies (n = 14) at 30 days for real-time polymerase chain reaction of hypoxia-inducible genes. Patients were monitored for 6 months for the development of transplant-related complications. Compared with native endobronchial tissues, donor tissue oxygen saturations (Sto2) were reduced in the upper lobes (74.1 ± 1.8% vs. 68.8 ± 1.7%; P < 0.05) and lower lobes (75.6 ± 1.6% vs. 71.5 ± 1.8%; P = 0.065) at 30 days post-transplantation. Donor upper lobe and subcarina Sto2 levels were also lower than the main carina (difference of -3.9 ± 1.5 and -4.8 ± 2.1, respectively; P < 0.05) at 30 days. Up-regulation of hypoxia-inducible genes VEGFA, FLT1, VEGFC, HMOX1, and TIE2 was significant in donor airways relative to native airways (all P < 0.05). VEGFA, KDR, and HMOX1 were associated with prolonged respiratory failure, prolonged hospitalization, extensive airway necrosis, and CAS (P < 0.05). These findings implicate donor bronchial hypoxia as a driving factor for post-transplantation airway complications. Strategies to improve airway oxygenation, such as bronchial artery re-anastomosis and hyperbaric oxygen therapy merit clinical investigation.

Childhood pneumonia increases risk for chronic obstructive pulmonary disease: the COPDGene study.

PubMed

Hayden, Lystra P; Hobbs, Brian D; Cohen, Robyn T; Wise, Robert A; Checkley, William; Crapo, James D; Hersh, Craig P

2015-09-21

Development of adult respiratory disease is influenced by events in childhood. The impact of childhood pneumonia on chronic obstructive pulmonary disease (COPD) is not well defined. We hypothesize that childhood pneumonia is a risk factor for reduced lung function and COPD in adult smokers. COPD cases and control smokers between 45-80 years old from the United States COPDGene Study were included. Childhood pneumonia was defined by self-report of pneumonia at <16 years. Subjects with lung disease other than COPD or asthma were excluded. Smokers with and without childhood pneumonia were compared on measures of respiratory disease, lung function, and quantitative analysis of chest CT scans. Of 10,192 adult smokers, 854 (8.4%) reported pneumonia in childhood. Childhood pneumonia was associated with COPD (OR 1.40; 95% CI 1.17-1.66), chronic bronchitis, increased COPD exacerbations, and lower lung function: post-bronchodilator FEV1 (69.1 vs. 77.1% predicted), FVC (82.7 vs. 87.4% predicted), FEV1/FVC ratio (0.63 vs. 0.67; p < 0.001 for all comparisons). Childhood pneumonia was associated with increased airway wall thickness on CT, without significant difference in emphysema. Having both pneumonia and asthma in childhood further increased the risk of developing COPD (OR 1.85; 95% CI 1.10-3.18). Children with pneumonia are at increased risk for future smoking-related lung disease including COPD and decreased lung function. This association is supported by airway changes on chest CT scans. Childhood pneumonia may be an important factor in the early origins of COPD, and the combination of pneumonia and asthma in childhood may pose the greatest risk. ClinicalTrials.gov, NCT00608764 (Active since January 28, 2008).

The disruption of the epithelial mesenchymal trophic unit in COPD.

PubMed

Behzad, Ali R; McDonough, John E; Seyednejad, Nazgol; Hogg, James C; Walker, David C

2009-12-01

Progression of COPD is associated with a measurable increase in small airway wall thickness resulting from a repair and remodeling process that involves fibroblasts of the epithelial mesenchymal trophic unit (EMTU). The present study was designed to examine the organization of fibroblasts within the lamina propria of small airways with respect to their contacts with the epithelium and with each other in persons with COPD. Transmission electron microcopy (TEM) and three-dimensional (3D) reconstructions of serial TEM sections were used to estimate the frequency and determine the nature of the contacts between the epithelium and fibroblasts within the EMTU in small airways from 5 controls (smokers with normal lung function), from 6 persons with mild (GOLD-1) and 5 with moderate (GOLD-2) COPD. In airways from control lungs fibroblasts make frequent contact with cytoplasmic extensions of epithelial cells through apertures in the epithelial basal lamina, but the frequency of these fibroblast-epithelial contacts is reduced in both mild and moderate COPD compared to controls (p < 0.01). The 3D reconstructions showed that the cytoplasmic extensions of lamina propria fibroblasts form a reticulum with fibroblast-fibroblast contacts in an airway from a control subject but this reticulum may be reorganized in airways of COPD patients. Development of COPD is associated with significant disruption of the EMTU due to a reduction of contacts between fibroblasts and the epithelium.

The airway microbiota in early cystic fibrosis lung disease.

PubMed

Frayman, Katherine B; Armstrong, David S; Grimwood, Keith; Ranganathan, Sarath C

2017-11-01

Infection plays a critical role in the pathogenesis of cystic fibrosis (CF) lung disease. Over the past two decades, the application of molecular and extended culture-based techniques to microbial analysis has changed our understanding of the lungs in both health and disease. CF lung disease is a polymicrobial disorder, with obligate and facultative anaerobes recovered alongside traditional pathogens in varying proportions, with some differences observed to correlate with disease stage. While healthy lungs are not sterile, differences between the lower airway microbiota of individuals with CF and disease-controls are already apparent in childhood. Understanding the evolution of the CF airway microbiota, and its relationship with clinical treatments and outcome at each disease stage, will improve our understanding of the pathogenesis of CF lung disease and potentially inform clinical management. This review summarizes current knowledge of the early development of the respiratory microbiota in healthy children and then discusses what is known about the airway microbiota in individuals with CF, including how it evolves over time and where future research priorities lie. © 2017 Wiley Periodicals, Inc.

Lung function in North American Indian children: reference standards for spirometry, maximal expiratory flow volume curves, and peak expiratory flow.

PubMed

Wall, M A; Olson, D; Bonn, B A; Creelman, T; Buist, A S

1982-02-01

Reference standards of lung function was determined in 176 healthy North American Indian children (94 girls, 82 boys) 7 to 18 yr of age. Spirometry, maximal expiratory flow volume curves, and peak expiratory flow rate were measured using techniques and equipment recommended by the American Thoracic Society. Standing height was found to be an accurate predictor of lung function, and prediction equations for each lung function variable are presented using standing height as the independent variable. Lung volumes and expiratory flow rates in North American Indian children were similar to those previously reported for white and Mexican-American children but were greater than those in black children. In both boys and girls, lung function increased in a curvilinear fashion. Volume-adjusted maximal expiratory flow rates after expiring 50 or 75% of FVC tended to decrease in both sexes as age and height increased. Our maximal expiratory flow volume curve data suggest that as North American Indian children grow, lung volume increases at a slightly faster rate than airway size does.

Written Emotional Expression as an Intervention for Asthma

ERIC Educational Resources Information Center

Bray, Melissa A.; Theodore, Lea A.; Patwa, Shamim S.; Margiano, Suzanne G.; Alric, Jolie M.; Peck, Heather L.

2003-01-01

This investigation employed a multiple baseline design across five participants to examine written emotional expression as an intervention to improve lung function in high school-aged students, college students, and adults with asthma. The predicted forced expiratory volume in 1 second (FEV[subscript 1] measure of large airway functioning) and…

Constrictive Bronchiolitis in Cystic Fibrosis Adolescents with Refractory Pulmonary Decline.

PubMed

Harris, William T; Boyd, J Todd; McPhail, Gary L; Brody, Alan S; Szczesniak, Rhonda D; Korbee, Leslie L; Baker, Michael L; Clancy, John P

2016-12-01

Refractory lung function decline in association with recurrent pulmonary exacerbations is a common, yet poorly explained finding in cystic fibrosis (CF). To investigate the histopathologic mechanisms of pulmonary deterioration during adolescence and early adulthood, we reviewed clinically-indicated lung biopsy specimens obtained during a period of persistent decline. To determine if peribronchiolar remodeling is prominent in lung biopsy specimens obtained in adolescents with CF refractory to conventional therapy. Six adolescents with CF (mean age, 16.2 y; mean FEV 1 , 52% predicted at biopsy) with significant pulmonary deterioration over 12-24 months (mean FEV 1 decline of 14% predicted/year) despite aggressive intervention underwent computed tomography imaging and ultimately lung biopsy to aid clinical management. In addition to routine clinical evaluation, histopathologic investigation included staining for transforming growth factor-β (TGF-β, a genetic modifier of CF lung disease), collagen deposition (a marker of fibrosis), elastin (to evaluate for bronchiectasis), and α-smooth muscle actin (to identify myofibroblasts). All computed tomography scans demonstrated a mix of bronchiectasis and hyperinflation that was variable across lung regions and within patients. Lung biopsy revealed significant peribronchiolar remodeling, particularly in patients with more advanced disease, with near complete obliteration of the peribronchiolar lumen (constrictive bronchiolitis). Myofibroblast differentiation (a TGF-β-dependent process) was prominent in specimens with significant airway remodeling. Constrictive bronchiolitis is widely present in the lung tissue of adolescents with CF with advanced disease and may contribute to impaired lung function that is refractory to conventional therapy (antibiotics, antiinflammatories, and mucolytics). TGF-β-dependent myofibroblast differentiation is prominent in areas of active fibrogenesis and may foster small airway remodeling in CF lung disease.

Inhibitory effect of kefiran on ovalbumin-induced lung inflammation in a murine model of asthma.

PubMed

Kwon, Ok-Kyoung; Ahn, Kyung-Seop; Lee, Mee-Young; Kim, So-Young; Park, Bo-Young; Kim, Mi-Kyoung; Lee, In-Young; Oh, Sei-Ryang; Lee, Hyeong-Kyu

2008-12-01

Kefiran is a major component of kefir which is a microbial symbiont mixture that produces jelly-like grains. This study aimed to evaluate the therapeutic availability of kefiran on the ovalbumin-induced asthma mouse model in which airway inflammation and airway hyper-responsiveness were found in the lung. BALB/c mice sensitized and challenged to ovalbumin were treated intra-gastrically with kefiran 1 hour before the ovalbumin challenge. Kefiran significantly suppressed ovalbumin-induced airway hyper-responsiveness (AHR) to inhaled methacholine. Administration of kefiran significantly inhibited the release of both eosinophils and other inflammatory cells into bronchoalveolar lavage (BAL) fluid and lung tissue which was measured by Diff-Quik. Interleukin-4 (IL-4) and interleukin-5 (IL-5) were also reduced to normal levels after administration of kefiran in BAL fluid. Histological studies demonstrate that kefiran substantially inhibited ovalbumin-induced eosinophilia in lung tissue by H&E staining and goblet cell hyperplasia in the airway by PAS staining. Taken above data, kefiran may be useful for the treatment of inflammation of lung tissue and airway hyper-responsiveness in a murine model and may have therapeutic potential for the treatment of allergic bronchial asthma.

Bone Marrow Cells Expressing Clara Cell Secretory Protein Increase Epithelial Repair After Ablation of Pulmonary Clara Cells

PubMed Central

Bustos, Martha L; Mura, Marco; Marcus, Paula; Hwang, David; Ludkovski, Olga; Wong, Amy P; Waddell, Thomas K

2013-01-01

We have previously reported a subpopulation of bone marrow cells (BMC) that express Clara cell secretory protein (CCSP), generally felt to be specific to lung Clara cells. Ablation of lung Clara cells has been reported using a transgenic mouse that expresses thymidine kinase under control of the CCSP promoter. Treatment with ganciclovir results in permanent elimination of CCSP+ cells, failure of airway regeneration, and death. To determine if transtracheal delivery of wild-type bone marrow CCSP+ cells is beneficial after ablation of lung CCSP+ cells, transgenic mice were treated with ganciclovir followed by transtracheal administration of CCSP+ or CCSP− BMC. Compared with mice administered CCSP− cells, mice treated with CCSP+ cells had more donor cells lining the airway epithelium, where they expressed epithelial markers including CCSP. Although donor CCSP+ cells did not substantially repopulate the airway, their administration resulted in increased host ciliated cells, better preservation of airway epithelium, reduction of inflammatory cells, and an increase in animal survival time. Administration of CCSP+ BMC is beneficial after permanent ablation of lung Clara cells by increasing bronchial epithelial repair. Therefore, CCSP+ BMC could be important for treatment of lung diseases where airways re-epithelialization is compromised. PMID:23609017

Lung Microbiome for Clinicians. New Discoveries about Bugs in Healthy and Diseased Lungs

PubMed Central

Rom, William N.; Weiden, Michael D.

2014-01-01

Microbes are readily cultured from epithelial surfaces of the skin, mouth, and colon. In the last 10 years, culture-independent DNA-based techniques demonstrated that much more complex microbial communities reside on most epithelial surfaces; this includes the lower airways, where bacterial culture had failed to reliably demonstrate resident bacteria. Exposure to a diverse bacterial environment is important for adequate immunological development. The most common microbes found in the lower airways are also found in the upper airways. Increasing abundance of oral characteristic taxa is associated with increased inflammatory cells and exhaled nitric oxide, suggesting that the airway microbiome induces an immunological response in the lung. Furthermore, rhinovirus infection leads to outgrowth of Haemophilus in patients with chronic obstructive pulmonary disease, and human immunodeficiency virus–infected subjects have more Tropheryma whipplei in the lower airway, suggesting a bidirectional interaction in which the host immune defenses also influence the microbial niche. Quantitative and/or qualitative changes in the lung microbiome may be relevant for disease progression and exacerbations in a number of pulmonary diseases. Future investigations with longitudinal follow-up to understand the dynamics of the lung microbiome may lead to the development of new therapeutic targets. PMID:24460444

Lung function and airway obstruction: associations with circulating markers of cardiac function and incident heart failure in older men—the British Regional Heart Study

PubMed Central

Wannamethee, S Goya; Shaper, A Gerald; Papacosta, Olia; Lennon, Lucy; Welsh, Paul; Whincup, Peter H

2016-01-01

Aims The association between lung function and cardiac markers and heart failure (HF) has been little studied in the general older population. We have examined the association between lung function and airway obstruction with cardiac markers N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT) and risk of incident HF in older men. Methods and results Prospective study of 3242 men aged 60–79 years without prevalent HF or myocardial infarction followed up for an average period of 13 years, in whom 211 incident HF cases occurred. Incident HF was examined in relation to % predicted FEV1 and FVC. The Global Initiative on Obstructive Lung Diseases spirometry criteria were used to define airway obstruction. Reduced FEV1, but not FVC in the normal range, was significantly associated with increased risk of HF after adjustment for established HF risk factors including inflammation. The adjusted HRs comparing men in the 6–24th percentile with the highest quartile were 1.91 (1.24 to 2.94) and 1.30 (0.86 to 1.96) for FEV1 and FVC, respectively. FEV1 and FVC were inversely associated with NT-proBNP and cTnT, although the association between FEV1 and incident HF remained after adjustment for NT-proBNP and cTnT. Compared with normal subjects (FEV1/FVC ≥0.70 and FVC≥80%), moderate or severe (FEV1/FVC <0.70 and FEV1 <80%) airflow obstruction was independently associated with HF ((adjusted relative risk 1.59 (1.08 to 2.33)). Airflow restriction (FEV1/FVC ≥0.70 and FVC <80%) was not independently associated with HF. Conclusions Reduced FEV1 reflecting airflow obstruction is associated with cardiac dysfunction and increased risk of incident HF in older men. PMID:26811343

Perillyl alcohol suppresses antigen-induced immune responses in the lung

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

Imamura, Mitsuru; Sasaki, Oh; Okunishi, Katsuhide

Highlights: •Perillyl alcohol (POH) is an isoprenoid which inhibits the mevalonate pathway. •We examined whether POH suppresses immune responses with a mouse model of asthma. •POH treatment during sensitization suppressed Ag-induced priming of CD4{sup +} T cells. •POH suppressed airway eosinophila and cytokine production in thoracic lymph nodes. -- Abstract: Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes,more » its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4{sup +} T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects.« less

Accumulation mode particles and LPS exposure induce TLR-4 dependent and independent inflammatory responses in the lung.

PubMed

Fonceca, Angela M; Zosky, Graeme R; Bozanich, Elizabeth M; Sutanto, Erika N; Kicic, Anthony; McNamara, Paul S; Knight, Darryl A; Sly, Peter D; Turner, Debra J; Stick, Stephen M

2018-01-22

Accumulation mode particles (AMP) are formed from engine combustion and make up the inhalable vapour cloud of ambient particulate matter pollution. Their small size facilitates dispersal and subsequent exposure far from their original source, as well as the ability to penetrate alveolar spaces and capillary walls of the lung when inhaled. A significant immuno-stimulatory component of AMP is lipopolysaccharide (LPS), a product of Gram negative bacteria breakdown. As LPS is implicated in the onset and exacerbation of asthma, the presence or absence of LPS in ambient particulate matter (PM) may explain the onset of asthmatic exacerbations to PM exposure. This study aimed to delineate the effects of LPS and AMP on airway inflammation, and potential contribution to airways disease by measuring airway inflammatory responses induced via activation of the LPS cellular receptor, Toll-like receptor 4 (TLR-4). The effects of nebulized AMP, LPS and AMP administered with LPS on lung function, cellular inflammatory infiltrate and cytokine responses were compared between wildtype mice and mice not expressing TLR-4. The presence of LPS administered with AMP appeared to drive elevated airway resistance and sensitivity via TLR-4. Augmented TLR4 driven eosinophilia and greater TNF-α responses observed in AMP-LPS treated mice independent of TLR-4 expression, suggests activation of allergic responses by TLR4 and non-TLR4 pathways larger than those induced by LPS administered alone. Treatment with AMP induced macrophage recruitment independent of TLR-4 expression. These findings suggest AMP-LPS as a stronger stimulus for allergic inflammation in the airways then LPS alone.

Microfluidic chest cavities reveal that transmural pressure controls the rate of lung development.

PubMed

Nelson, Celeste M; Gleghorn, Jason P; Pang, Mei-Fong; Jaslove, Jacob M; Goodwin, Katharine; Varner, Victor D; Miller, Erin; Radisky, Derek C; Stone, Howard A

2017-12-01

Mechanical forces are increasingly recognized to regulate morphogenesis, but how this is accomplished in the context of the multiple tissue types present within a developing organ remains unclear. Here, we use bioengineered 'microfluidic chest cavities' to precisely control the mechanical environment of the fetal lung. We show that transmural pressure controls airway branching morphogenesis, the frequency of airway smooth muscle contraction, and the rate of developmental maturation of the lungs, as assessed by transcriptional analyses. Time-lapse imaging reveals that branching events are synchronized across distant locations within the lung, and are preceded by long-duration waves of airway smooth muscle contraction. Higher transmural pressure decreases the interval between systemic smooth muscle contractions and increases the rate of morphogenesis of the airway epithelium. These data reveal that the mechanical properties of the microenvironment instruct crosstalk between different tissues to control the development of the embryonic lung. © 2017. Published by The Company of Biologists Ltd.

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 coupling to the lung parenchyma; and (4) Develop improved techniques in array acoustic measurement on the torso surface of sound transmitted through the pulmonary system and torso. Tissue Viscoelasticity. Two experimental identification approaches of shear viscoelasticity were used. The first approach is to directly estimate the frequency-dependent surface wave speed and then to optimize the coefficients in an assumed viscoelastic model type. The second approach is to measure the complex-valued frequency response function (FRF) between the excitation location and points at known radial distances. The FRF has embedded in it frequency-dependent information about both surface wave phase speed and attenuation that can be used to directly estimate the complex shear modulus. The coefficients in an assumed viscoelastic tissue model type can then be optimized. Poroviscoelasticity Model for Lung Vibro-acoustics. A poroviscoelastic model based on Biot theory of wave propagation in porous media was used for compression waves in the lungs. This model predicts a fast compression wave speed close to the one predicted by the effective medium theory at low frequencies and an additional slow compression wave due to the out of phase motion of the air and the lung parenchyma. Both compression wave speeds vary with frequency. The fast compression wave speed and attenuation were measured on an excised pig lung under two different transpulmonary pressures. Good agreement was achieved between the experimental observation and theoretical predictions. Sound Transmission in Airways and Coupling to Lung Parenchyma. A computer generated airway tree was simplified to 255 segments and integrated into the lung geometry from the Visible Human Male for numerical simulations. Acoustic impedance boundary conditions were applied at the ends of the terminal segments to represent the unmodeled downstream airway segments. Experiments were also carried out on a preserved pig lung and similar trends of lung surface velocity distribution were observed between the experiments and simulations. This approach provides a feasible way of simplifying the airway tree and greatly reduces the computation time. Acoustic Measurements of Sound Transmission in Human Subjects. Scanning laser Doppler vibrometry (SLDV) was used as a gold standard for transmitted sound measurements on a human subject. A low cost piezodisk sensor array was also constructed as an alternative to SLDV. The advantages and disadvantages of each technique are discussed.

Pulmonary function abnormalities and airway irritation symptoms of metal fumes exposure on automobile spot welders.

PubMed

Luo, Jiin-Chyuan John; Hsu, Kuang-Hung; Shen, Wu-Shiun

2006-06-01

Spot or resistance welding has been considered less hazardous than other types of welding. Automobile manufacturing is a major industry in Taiwan. Spot and arc welding are common processes in this industry. The respiratory effects on automobile spot welders exposed to metal fumes are investigated. The cohort consisted of 41 male auto-body spot welders, 76 male arc welders, 71 male office workers, and 59 assemblers without welding exposure. Inductivity Coupled Plasma Mass Spectrophotometer (ICP-MS) was applied to detect metals' (zinc, copper, nickel) levels in the post-shift urine samples. Demographic data, work history, smoking status, and respiratory tract irritation symptoms were gathered by a standard self-administered questionnaire. Pulmonary function tests were also performed. There were significantly higher values for average urine metals' (zinc, copper, nickel) levels in spot welders and arc welders than in the non-welding controls. There were 4 out of 23 (17.4%) abnormal forced vital capacity (FVC) among the high-exposed spot welders, 2 out of 18 (11.1%) among the low-exposed spot welders, and 6 out of 130 (4.6%) non-welding-exposed workers. There was a significant linear trend between spot welding exposure and the prevalence of restrictive airway abnormalities (P = 0.036) after adjusting for other factors. There were 9 out of 23 (39.1%) abnormal peak expiratory flow rate (PEFR) among high-exposed spot welders, 5 out of 18 (27.8%) among the low-exposed spot welders, and 28 out of 130 (21.5%) non-welding-exposed workers. There was a borderline significant linear trend between spot welding exposure and the prevalence of obstructive lung function abnormalities (P = 0.084) after adjusting for other factors. There was also a significant dose-response relationship of airway irritation symptoms (cough, phlegm, chronic bronchitis) among the spot welders. Arc welders with high exposure status also had a significant risk of obstructive lung abnormalities (PEFR reduction). There was also a significant dose-response relationship of airway irritation symptoms (cough, phlegm, chest tightness, and chronic bronchitis) among the arc welders. These findings suggest that restrictive and obstructive lung abnormalities, and airway irritation symptoms are associated with spot and arc welding exposures.

Acute administration of ivacaftor to people with cystic fibrosis and a G551D-CFTR mutation reveals smooth muscle abnormalities

PubMed Central

Adam, Ryan J.; Hisert, Katherine B.; Dodd, Jonathan D.; Grogan, Brenda; Launspach, Janice L.; Barnes, Janel K.; Gallagher, Charles G.; Sieren, Jered P.; Gross, Thomas J.; Fischer, Anthony J.; Cavanaugh, Joseph E.; Hoffman, Eric A.; Singh, Pradeep K.; Welsh, Michael J.; McKone, Edward F.; Stoltz, David A.

2016-01-01

BACKGROUND. Airflow obstruction is common in cystic fibrosis (CF), yet the underlying pathogenesis remains incompletely understood. People with CF often exhibit airway hyperresponsiveness, CF transmembrane conductance regulator (CFTR) is present in airway smooth muscle (ASM), and ASM from newborn CF pigs has increased contractile tone, suggesting that loss of CFTR causes a primary defect in ASM function. We hypothesized that restoring CFTR activity would decrease smooth muscle tone in people with CF. METHODS. To increase or potentiate CFTR function, we administered ivacaftor to 12 adults with CF with the G551D-CFTR mutation; ivacaftor stimulates G551D-CFTR function. We studied people before and immediately after initiation of ivacaftor (48 hours) to minimize secondary consequences of CFTR restoration. We tested smooth muscle function by investigating spirometry, airway distensibility, and vascular tone. RESULTS. Ivacaftor rapidly restored CFTR function, indicated by reduced sweat chloride concentration. Airflow obstruction and air trapping also improved. Airway distensibility increased in airways less than 4.5 mm but not in larger-sized airways. To assess smooth muscle function in a tissue outside the lung, we measured vascular pulse wave velocity (PWV) and augmentation index, which both decreased following CFTR potentiation. Finally, change in distensibility of <4.5-mm airways correlated with changes in PWV. CONCLUSIONS. Acute CFTR potentiation provided a unique opportunity to investigate CFTR-dependent mechanisms of CF pathogenesis. The rapid effects of ivacaftor on airway distensibility and vascular tone suggest that CFTR dysfunction may directly cause increased smooth muscle tone in people with CF and that ivacaftor may relax smooth muscle. FUNDING. This work was funded in part from an unrestricted grant from the Vertex Investigator-Initiated Studies Program. PMID:27158673

Scaled experiments for improving diagnosis of pathological lower-airway obstruction

NASA Astrophysics Data System (ADS)

Liu, Chang; Kiger, Ken; Hariprasad, Daniel; Sul, Bora; Wallqvist, Anders; Reifman, Jaques

2017-11-01

Many lung diseases, such as asthma and chronic obstructive pulmonary disease, are characterized by obstructed airflow, particularly, in the lower airway branches in the lung. Existing diagnostic tools cannot detect some diseases due to a lack of instrumentation capable of resolving the flow in the lower airways. Recent developments in MRI techniques using hyperpolarized 3He now permit measurement of velocity profiles within the trachea. Motivated by these advances, we aim to provide a better understanding of the connection between lower-airway obstruction and velocity profiles within the trachea. Specifically, we asked whether the flow deficits created by lower-airway obstructions could be detected in the trachea to permit diagnosis of the pathology. To test this idea, we used refractive index-matched materials to construct a scaled, patient-specific, transparent lung model, and coupled it to 5 independently controlled piston pumps that could generate arbitrary flow histories (healthy or diseased) for the 5 different lung lobes. Results obtained by stereo PIV within various regions of the airway network will be presented documenting the system performance and examining the detectability of under-performing lobes within the tracheal flow profile. This work supported by the Henry M. Jackson Foundation under award #3270.

Aspergillus fumigatus generates an enhanced Th2-biased immune response in mice with defective cystic fibrosis transmembrane conductance regulator.

PubMed

Allard, Jenna B; Poynter, Matthew E; Marr, Kieren A; Cohn, Lauren; Rincon, Mercedes; Whittaker, Laurie A

2006-10-15

Cystic fibrosis (CF) lung disease is characterized by persistent airway inflammation and airway infection that ultimately leads to respiratory failure. Aspergillus sp. are present in the airways of 20-40% of CF patients and are of unclear clinical significance. In this study, we demonstrate that CF transmembrane conductance regulator (CFTR)-deficient (CFTR knockout, Cftr(tm1Unc-)TgN(fatty acid-binding protein)CFTR) and mutant (DeltaF508) mice develop profound lung inflammation in response to Aspergillus fumigatus hyphal Ag exposure. CFTR-deficient mice also develop an enhanced Th2 inflammatory response to A. fumigatus, characterized by elevated IL-4 in the lung and IgE and IgG1 in serum. In contrast, CFTR deficiency does not promote a Th1 immune response. Furthermore, we demonstrate that CD4+ T cells from naive CFTR-deficient mice produce higher levels of IL-4 in response to TCR ligation than wild-type CD4+ T cells. The Th2 bias of CD4+ T cells in the absence of functional CFTR correlates with elevated nuclear levels of NFAT. Thus, CFTR is important to maintain the Th1/Th2 balance in CD4+ T cells.

Markers of Vascular Perturbation Correlate with Airway Structural Change in Asthma

PubMed Central

Kruger, Stanley J.; Schiebler, Mark L.; Evans, Michael D.; Sorkness, Ronald L.; Denlinger, Loren C.; Busse, William W.; Jarjour, Nizar N.; Montgomery, Robert R.; Mosher, Deane F.; Fain, Sean B.

2013-01-01

Rationale: Air trapping and ventilation defects on imaging are characteristics of asthma. Airway wall thickening occurs in asthma and is associated with increased bronchial vascularity and vascular permeability. Vascular endothelial cell products have not been explored as a surrogate to mark structural airway changes in asthma. Objectives: Determine whether reporters of vascular endothelial cell perturbation correlate with airway imaging metrics in patients with asthma of varying severity. Methods: Plasma from Severe Asthma Research Program subjects was analyzed by ELISAs for soluble von Willebrand factor mature protein (VWF:Ag) and propeptide (VWFpp), P-selectin, and platelet factor 4. Additional subjects were analyzed over 48 hours after whole-lung antigen challenge. We calculated ventilation defect volume by hyperpolarized helium-3 magnetic resonance imaging and areas of low signal density by multidetector computed tomography (less than −856 Hounsfield units [HU] at functional residual capacity and −950 HU at total lung capacity [TLC]). Measurements and Main Results: VWFpp and VWFpp/Ag ratio correlated with and predicted greater percentage defect volume on hyperpolarized helium-3 magnetic resonance imaging. P-selectin correlated with and predicted greater area of low density on chest multidetector computed tomography less than −950 HU at TLC. Platelet factor 4 did not correlate. Following whole-lung antigen challenge, variation in VWFpp, VWFpp/Ag, and P-selectin among time-points was less than that among subjects, indicating stability and repeatability of the measurements. Conclusions: Plasma VWFpp and P-selectin may be useful as surrogates of functional and structural defects that are evident on imaging. The results raise important questions about why VWFpp and P-selectin are associated specifically with different imaging abnormalities. PMID:23855693

Bubble Continuous Positive Airway Pressure Enhances Lung Volume and Gas Exchange in Preterm Lambs

PubMed Central

Pillow, J. Jane; Hillman, Noah; Moss, Timothy J. M.; Polglase, Graeme; Bold, Geoff; Beaumont, Chris; Ikegami, Machiko; Jobe, Alan H.

2007-01-01

Rationale: The technique used to provide continuous positive airway pressure (CPAP) to the newborn may influence lung function and breathing efficiency. Objectives: To compare differences in gas exchange physiology and lung injury resulting from treatment of respiratory distress with either bubble or constant pressure CPAP and to determine if the applied flow influences short-term outcomes. Methods: Lambs (133 d gestation; term is 150 d) born via cesarean section were weighed, intubated, and treated with CPAP for 3 hours. Two groups were treated with 8 L/minute applied flow using the bubble (n = 12) or the constant pressure (n = 12) technique. A third group (n = 10) received the bubble method with 12 L/minute bias flow. Measurements at study completion included arterial blood gases, oxygraphy, capnography, tidal flow, multiple breath washout, lung mechanics, static pressure–volume curves, and bronchoalveolar lavage fluid protein. Measurements and Main Results: Birth weight and arterial gas variables at 15 minutes were comparable. Flow (8 or 12 L/min) did not influence the 3-hour outcomes in the bubble group. Bubble technique was associated with a higher pH, PaO2, oxygen uptake, and area under the flow–volume curve, and a decreased alveolar protein, respiratory quotient, PaCO2, and ventilation inhomogeneity compared with the constant pressure group. Conclusions: Compared with constant pressure technique, bubble CPAP promotes enhanced airway patency during treatment of acute postnatal respiratory disease in preterm lambs and may offer protection against lung injury. PMID:17431223

Delayed extubation to nasal continuous positive airway pressure in the immature baboon model of bronchopulmonary dysplasia: lung clinical and pathological findings.

PubMed

Thomson, Merran A; Yoder, Bradley A; Winter, Vicki T; Giavedoni, Luis; Chang, Ling Yi; Coalson, Jacqueline J

2006-11-01

Using the 125-day baboon model of bronchopulmonary dysplasia treated with prenatal steroid and exogenous surfactant, we hypothesized that a delay of extubation from low tidal volume positive pressure ventilation to nasal continuous positive airway pressure at 5 days (delayed nasal continuous positive airway pressure group) would not induce more lung injury when compared with baboons aggressively weaned to nasal continuous positive airway pressure at 24 hours (early nasal continuous positive airway pressure group), because both received positive pressure ventilation. After delivery by cesarean section at 125 days (term: 185 days), infants received 2 doses of Curosurf (Chiesi Farmaceutica S.p.A., Parma, Italy) and daily caffeine citrate. The delay in extubation to 5 days resulted in baboons in the delayed nasal continuous positive airway pressure group having a lower arterial to alveolar oxygen ratio, high PaCO2, and worse respiratory function. The animals in the delayed nasal continuous positive airway pressure group exhibited a poor respiratory drive that contributed to more reintubations and time on mechanical ventilation. A few animals in both groups developed necrotizing enterocolitis and/or sepsis, but infectious pneumonias were not documented. Cellular bronchiolitis and peribronchiolar alveolar wall thickening were more frequently seen in the delayed nasal continuous positive airway pressure group. Bronchoalveolar lavage levels of interleukin-6, interleukin-8, monocyte chemotactic protein-1, macrophage inflammatory protein-1 alpha, and growth-regulated oncogene-alpha were significantly increased in the delayed nasal continuous positive airway pressure group. Standard and digital morphometric analyses showed no significant differences in internal surface area and nodal measurements between the groups. Platelet endothelial cell adhesion molecule vascular staining was not significantly different between the 2 nasal continuous positive airway pressure groups. Volutrauma and/or low-grade colonization of airways secondary to increased reintubations and ventilation times are speculated to play causative roles in the delayed nasal continuous positive airway pressure group findings.

Comparison of non-invasive measures of cholinergic and allergic airway responsiveness in rats.

PubMed

Glaab, T; Hecker, H; Stephan, M; Baelder, R; Braun, A; Korolewitz, R; Krug, N; Hoymann, H G

2006-04-01

Non-invasive analysis of tidal expiratory flow parameters such as Tme/TE (time needed to reach peak expiratory flow divided by total expiratory time) or midexpiratory tidal flow (EF50) has been shown useful for phenotypic characterization of lung function in humans and animal models. In this study, we aimed to compare the utility of two non-invasive measures, EF50 and Tme/TE, to monitor bronchoconstriction to inhaled cholinergic and allergic challenges in Brown-Norway rats. Non-invasive measurements of Tme/TE and EF50 were paralleled by invasive recordings of Tme/TE, EF50 and pulmonary conductance (GL). First, dose-response studies with acetylcholine were performed in naive rats, showing that EF50 better than Tme/TE reflected the dose-related changes as observed with the classical invasive outcome parameter GL. The subsequent determination of allergen-specific early airway responsiveness (EAR) showed that ovalbumin-sensitized and -challenged rats exhibited airway inflammation and allergen-specific EAR. Again, EF50 was more sensitive than Tme/TE in detecting the allergen-specific EAR recorded with invasive and non-invasive lung function methods and agreed well with classical GL measurements. We conclude that non-invasive assessment of EF50 is significantly superior to Tme/TE and serves as a suitable and valid tool for phenotypic screening of cholinergic and allergic airway responsiveness in rats.

Small-airway obstruction and emphysema in chronic obstructive pulmonary disease.

PubMed

McDonough, John E; Yuan, Ren; Suzuki, Masaru; Seyednejad, Nazgol; Elliott, W Mark; Sanchez, Pablo G; Wright, Alexander C; Gefter, Warren B; Litzky, Leslie; Coxson, Harvey O; Paré, Peter D; Sin, Don D; Pierce, Richard A; Woods, Jason C; McWilliams, Annette M; Mayo, John R; Lam, Stephen C; Cooper, Joel D; Hogg, James C

2011-10-27

The major sites of obstruction in chronic obstructive pulmonary disease (COPD) are small airways (<2 mm in diameter). We wanted to determine whether there was a relationship between small-airway obstruction and emphysematous destruction in COPD. We used multidetector computed tomography (CT) to compare the number of airways measuring 2.0 to 2.5 mm in 78 patients who had various stages of COPD, as judged by scoring on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) scale, in isolated lungs removed from patients with COPD who underwent lung transplantation, and in donor (control) lungs. MicroCT was used to measure the extent of emphysema (mean linear intercept), the number of terminal bronchioles per milliliter of lung volume, and the minimum diameters and cross-sectional areas of terminal bronchioles. On multidetector CT, in samples from patients with COPD, as compared with control samples, the number of airways measuring 2.0 to 2.5 mm in diameter was reduced in patients with GOLD stage 1 disease (P=0.001), GOLD stage 2 disease (P=0.02), and GOLD stage 3 or 4 disease (P<0.001). MicroCT of isolated samples of lungs removed from patients with GOLD stage 4 disease showed a reduction of 81 to 99.7% in the total cross-sectional area of terminal bronchioles and a reduction of 72 to 89% in the number of terminal bronchioles (P<0.001). A comparison of the number of terminal bronchioles and dimensions at different levels of emphysematous destruction (i.e., an increasing value for the mean linear intercept) showed that the narrowing and loss of terminal bronchioles preceded emphysematous destruction in COPD (P<0.001). These results show that narrowing and disappearance of small conducting airways before the onset of emphysematous destruction can explain the increased peripheral airway resistance reported in COPD. (Funded by the National Heart, Lung, and Blood Institute and others.).

Decreased Expression of Integrin Subunits α3, α6, and α8 in the Branching Airway Mesenchyme of Nitrofen-Induced Hypoplastic Lungs.

PubMed

Takahashi, Toshiaki; Friedmacher, Florian; Zimmer, Julia; Puri, Prem

2018-02-01

 Pulmonary hypoplasia (PH), characterized by smaller lung size and reduced airway branching, remains a major cause of neonatal mortality in newborns with congenital diaphragmatic hernia (CDH). Integrin-mediated cell-matrix interactions play an essential role in the fetal lung mesenchyme by stimulating branching morphogenesis. Mice lacking integrin subunits α3 (Itga3) and α6 (Itga6) exhibit severe PH. Furthermore, Itga8-knockout mice show defective airway branching, suggesting that Itga3, Itga6, and Itga8 are crucial for fetal lung development. We hypothesized that expression of Itga3, Itga6, and Itga8 is decreased in the branching airway mesenchyme of hypoplastic rat lungs in the nitrofen-induced CDH model.  Time-mated rats received nitrofen or vehicle on gestational day 9 (D9). Fetuses were sacrificed on D15, D18, and D21, and dissected lungs were divided into control and nitrofen-exposed specimens ( n  = 12 per time-point and group, respectively). Pulmonary gene expression of Itga3, Itga6, and Itga8 was analyzed by quantitative real-time polymerase chain reaction. Immunofluorescence double-staining for Itga3, Itga6, and Itga8 was combined with the mesenchymal marker Fgf10 to evaluate protein expression and localization in branching airway tissue.  Relative mRNA expression of Itga3, Itga6, and Itga8 was significantly decreased in lungs of nitrofen-exposed fetuses on D15, D18, and D21 compared with controls. Confocal laser scanning microscopy showed markedly diminished immunofluorescence of Itga3, Itga6, and Itga8 mainly in mesenchymal cells surrounding branching airways of nitrofen-exposed fetuses on D15, D18, and D21 compared with controls.  Decreased expression of Itga3, Itga6, and Itga8 in the pulmonary mesenchyme may lead to disruptions in airway branching morphogenesis, thus contributing to PH in the nitrofen-induced CDH model. Georg Thieme Verlag KG Stuttgart · New York.

Chronic electronic cigarette exposure in mice induces features of COPD in a nicotine-dependent manner

PubMed Central

Garcia-Arcos, Itsaso; Geraghty, Patrick; Baumlin, Nathalie; Campos, Michael; Dabo, Abdoulaye Jules; Jundi, Bakr; Cummins, Neville; Eden, Edward; Grosche, Astrid; Salathe, Matthias; Foronjy, Robert

2016-01-01

Background The use of electronic (e)-cigarettes is increasing rapidly, but their lung health effects are not established. Clinical studies examining the potential long-term impact of e-cigarette use on lung health will take decades. To address this gap in knowledge, this study investigated the effects of exposure to aerosolised nicotine-free and nicotine-containing e-cigarette fluid on mouse lungs and normal human airway epithelial cells. Methods Mice were exposed to aerosolised phosphate-buffered saline, nicotine-free or nicotine-containing e-cigarette solution, 1-hour daily for 4 months. Normal human bronchial epithelial (NHBE) cells cultured at an air-liquid interface were exposed to e-cigarette vapours or nicotine solutions using a Vitrocell smoke exposure robot. Results Inhalation of nicotine-containing e-cigarettes increased airway hyper-reactivity, distal airspace enlargement, mucin production, cytokine and protease expression. Exposure to nicotine-free e-cigarettes did not affect these lung parameters. NHBE cells exposed to nicotine-containing e-cigarette vapour showed impaired ciliary beat frequency, airway surface liquid volume, cystic fibrosis transmembrane regulator and ATP-stimulated K+ ion conductance and decreased expression of FOXJ1 and KCNMA1. Exposure of NHBE cells to nicotine for 5 days increased interleukin (IL)-6 and IL-8 secretion. Conclusions Exposure to inhaled nicotine-containing e-cigarette fluids triggered effects normally associated with the development of COPD including cytokine expression, airway hyper-reactivity and lung tissue destruction. These effects were nicotine-dependent both in the mouse lung and in human airway cells, suggesting that inhaled nicotine contributes to airway and lung disease in addition to its addictive properties. Thus, these findings highlight the potential dangers of nicotine inhalation during e-cigarette use. PMID:27558745

Volumetric capnography curves as lung function test to confirm bronchoconstriction after carbachol challenge in sedated dogs.

PubMed

Scheffzek, S; Mosing, M; Hirt, R; Iff, I; Moens, Y

2012-12-01

This study investigated volumetric capnography (VC) in detecting airway responsiveness following airway challenge using carbachol in seven sedated dogs via face mask. Nebulised saline was administered, followed by increasing concentrations of nebulised carbachol until airflow limitation occurred (EP). Dead space (DS) variables and shape indices of the VC curve were calculated automatically after entering arterial carbon dioxide tension. Airway DS, airway DS to tidal volume (VT) ratio and the intercept of slope 2 of the VC curve decreased significantly at EP by 10%, 13% and 16%, respectively, minute ventilation, VT and alveolar DS increased significantly at EP by 49%, 22% and 200%, respectively. We conclude that VC and derived indices may be used to verify a reaction to airway challenge caused by carbachol in sedated dogs. Copyright © 2012 Elsevier Ltd. All rights reserved.

Lung function, diagnosis, and treatment of sleep-disordered breathing in children with achondroplasia.

PubMed

Julliand, Sébastien; Boulé, Michèle; Baujat, Geneviève; Ramirez, Adriana; Couloigner, Vincent; Beydon, Nicole; Zerah, Michel; di Rocco, Federico; Lemerrer, Martine; Cormier-Daire, Valérie; Fauroux, Brigitte

2012-08-01

Children with achondroplasia are at risk of sleep-disordered breathing. The aim of the study was to evaluate lung function and sleep-disordered breathing in children with achondroplasia. An interview, clinical examination, lung function tests with blood gases, and a polygraphic sleep study were obtained as part of routine annual evaluation in consecutive children with achondroplasia. We included 30 children (median age 3.0 years, range: 0.4-17.1) over a period of 21 months. Habitual snoring and witnessed apneas were observed in 77% and 33% of the patients, respectively. Prior to the sleep study, 10/29 (34%) patients had undergone upper airway surgery and 5/29 (17%) craniocervical decompression operation. Arterial blood gases were abnormal in two (7%) patients. Sleep findings were abnormal in 28/30 (93%) patients. Eleven (37%) patients had an apnea index≥1 event/hr and 26 (87%) had an apnea-hypopnea index≥5 events/hr. The ≥3% desaturation index was >5/hr in 22 (73%) patients. Sixteen (53%) patients had a minimal pulse oximetry<90% but only two (7%) patients had a maximal transcutaneous carbon dioxide pressure>50 mmHg during sleep. As a consequence, the following therapeutic interventions were performed: upper airway surgery in four patients and noninvasive positive pressure ventilation (NPPV) in five other patients, resulting in an improvement in sleep studies in all nine patients. Systematic sleep studies are recommended in children with achondroplasia because of the high prevalence of sleep-disordered breathing. Upper airway surgery and NPPV are effective treatments of sleep-disordered breathing. Copyright © 2012 Wiley Periodicals, Inc.

Cystic fibrosis.

PubMed

Elborn, J Stuart

2016-11-19

Cystic fibrosis is a common life-limiting autosomal recessive genetic disorder, with highest prevalence in Europe, North America, and Australia. The disease is caused by mutation of a gene that encodes a chloride-conducting transmembrane channel called the cystic fibrosis transmembrane conductance regulator (CFTR), which regulates anion transport and mucociliary clearance in the airways. Functional failure of CFTR results in mucus retention and chronic infection and subsequently in local airway inflammation that is harmful to the lungs. CFTR dysfunction mainly affects epithelial cells, although there is evidence of a role in immune cells. Cystic fibrosis affects several body systems, and morbidity and mortality is mostly caused by bronchiectasis, small airways obstruction, and progressive respiratory impairment. Important comorbidities caused by epithelial cell dysfunction occur in the pancreas (malabsorption), liver (biliary cirrhosis), sweat glands (heat shock), and vas deferens (infertility). The development and delivery of drugs that improve the clearance of mucus from the lungs and treat the consequent infection, in combination with correction of pancreatic insufficiency and undernutrition by multidisciplinary teams, have resulted in remarkable improvements in quality of life and clinical outcomes in patients with cystic fibrosis, with median life expectancy now older than 40 years. Innovative and transformational therapies that target the basic defect in cystic fibrosis have recently been developed and are effective in improving lung function and reducing pulmonary exacerbations. Further small molecule and gene-based therapies are being developed to restore CFTR function; these therapies promise to be disease modifying and to improve the lives of people with cystic fibrosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Bronchoarterial ratio in never-smokers adults: Implications for bronchial dilation definition.

PubMed

Diaz, Alejandro A; Young, Thomas P; Maselli, Diego J; Martinez, Carlos H; Maclean, Erick S; Yen, Andrew; Dass, Chandra; Simpson, Scott A; Lynch, David A; Kinney, Gregory L; Hokanson, John E; Washko, George R; San José Estépar, Raul

2017-01-01

Bronchiectasis manifests as recurrent respiratory infections and reduced lung function. Airway dilation, which is measured as the ratio of the diameters of the bronchial lumen (B) and adjacent pulmonary artery (A), is a defining radiological feature of bronchiectasis. A challenge to equating the bronchoarterial (BA) ratio to disease severity is that the diameters of airway and vessel in health are not established. We sought to explore the variability of BA ratio in never-smokers without pulmonary disease and its associations with lung function. Objective measurements of the BA ratio on volumetric computed tomography (CT) scans and pulmonary function data were collected in 106 never-smokers. The BA ratio was measured in the right upper lobe apical bronchus (RB1) and the right lower lobe basal posterior bronchus. The association between the BA ratio and forced expiratory volume in 1 s (FEV 1 ) was assessed using regression analysis. The BA ratio was 0.79 ± 0.16 and was smaller in more peripheral RB1 bronchi (P < 0.0001). The BA ratio was >1, a typical threshold for bronchiectasis, in 10 (8.5%) subjects. Subjects with a BA ratio >1 versus ≤1 had smaller artery diameters (P < 0.0001) but not significantly larger bronchial lumens. After adjusting for age, gender, race and height, the BA ratio was directly related to FEV 1 (P = 0.0007). In never-smokers, the BA ratio varies by airway generation and is associated with lung function. A BA ratio >1 is driven by small arteries. Using artery diameter as reference to define bronchial dilation seems inappropriate. © 2016 Asian Pacific Society of Respirology.

Specific airway resistance in healthy young Vietnamese and Caucasian adults.

PubMed

Le Tuan, Thanh; Nguyen, Ngoc Minh; Demoulin, Bruno; Bonabel, Claude; Nguyen-Thi, Phi Linh; Ioan, Iulia; Schweitzer, Cyril; Nguyen, H T T; Varechova, Silvia; Marchal, Francois

2015-06-01

In healthy Vietnamese children the respiratory resistance has been suggested to be similar at 110 cm height but larger at 130 cm when compared with data in Caucasians from the literature, suggesting smaller airways in older Vietnamese children (Vu et al., 2008). The hypothesis tested here is whether the difference in airway resistance remains consistent throughout growth, and if it is larger in adult Vietnamese than in Caucasians. Airway resistance and Functional Residual Capacity were measured in healthy young Caucasian and Vietnamese adults in their respective native country using identical equipment and protocols. Ninety five subjects in Vietnam (60 males) and 101 in France (41 males) were recruited. Airway resistance was significantly larger in Vietnamese than in Caucasians and in females than in males, consistent with difference in body dimensions. Specific airway resistance however was not different by ethnicity or gender. The findings do not support the hypothesis that airway size at adult age - once normalized for lung volume - differs between Vietnamese and Caucasians. Copyright © 2015 Elsevier B.V. All rights reserved.

WE-FG-206-08: Pulmonary Functional Imaging Biomarkers of NSCLC to Guide and Optimize Functional Lung Avoidance Radiotherapy

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

Sheikh, Khadija; Capaldi, Dante PI; Parraga, Grace

Purpose: Functional lung avoidance radiotherapy promises optimized therapy planning by minimizing dose to well-functioning lung and maximizing dose to the rest of the lung. Patients with NSCLC commonly present with co-morbid COPD and heterogeneously distributed ventilation abnormalities stemming from emphysema, airways disease, and tumour burden. We hypothesized that pulmonary functional imaging methods may be used to optimize radiotherapy plans to avoid regions of well-functioning lung and significantly improve outcomes like quality-of-life and survival. To ascertain the utility of functional lung avoidance therapy in clinical practice, we measured COPD phenotypes in NSCLC patients enrolled in a randomized-controlled-clinical-trial prior to curative intentmore » therapy. Methods: Thirty stage IIIA/IIIB NSCLC patients provided written informed consent to a randomized-controlled-clinical-trial ( http://clinicaltrials.gov/ct2/show/NCT02002052 ) comparing outcomes in patients randomized to standard or image-guided radiotherapy. Hyperpolarized noble gas MRI ventilation-defect-percent (VDP) (Kirby et al, Acad Radiol, 2012) as well as CT-emphysema measurements were determined. Patients were stratified based on quantitative imaging evidence of ventilation-defects and emphysema into two subgroups: 1) tumour-specific ventilation defects only (TSD), and, 2) tumour-specific and other ventilation defects with and without emphysema (TSD{sub VE}). Receiver-operating-characteristic (ROC) curves were used to characterize the performance of clinical measures as predictors of the presence of non-tumour specific ventilation defects. Results: Twenty-one out of thirty subjects (70%) had non-tumour specific ventilation defects (TSD{sub VE}) and nine subjects had ONLY tumour-specific defects (TSD). Subjects in the TSD{sub VE} group had significantly greater smoking-history (p=.006) and airflow obstruction (FEV{sub 1}/FVC) (p=.001). ROC analysis demonstrated an 87% classification rate for smoking pack-years, 90% for FEV{sub 1}/FVC, and 56% for tumour RECIST measurements for identifying patients with non-tumour and tumour-specific ventilation abnormalities. Conclusion: 70% of NSCLC patients had ventilation abnormalities stemming from emphysema, airways disease and tumour burden. Smoking-history and airflow obstruction, but not RECIST, identified NSCLC patients with ventilation abnormalities appropriate for functional lung avoidance therapy.« less

Computed Tomography Findings of Bronchiectasis in Different Respiratory Phases Correlate with Pulmonary Function Test Data in Adults.

PubMed

do Amaral, Ricardo Holderbaum; Nin, Carlos S; de Souza, Vinicius V S; Alves, Giordano R T; Marchiori, Edson; Irion, Klaus; Meirelles, Gustavo S P; Hochhegger, Bruno

2017-06-01

To investigate bronchiectasis variations in different computed tomography (CT) respiratory phases, and their correlation with pulmonary function test (PFT) data, in adults. Retrospective data analysis from 63 patients with bronchiectasis according to CT criteria selected from the institution database and for whom PFT data were also available. Bronchiectasis diameter was measured on inspiratory and expiratory phases. Its area and matched airway-vessel ratios in both phases were also calculated. Finally, PFT results were compared with radiological measurements. Bronchiectatic airways were larger on inspiration than on expiration (mean cross-sectional area, 69.44 vs. 40.84 mm 2 ; p < 0.05) as were airway-vessel ratios (2.1 vs. 1.4; p < 0.05). Cystic bronchiectasis cases showed the least variation in cross-sectional area (48%). Mean predicted values of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were 81.5 and 77.2%, respectively, in the group in which bronchiectasis could not be identified on expiratory images, and 58.3 and 56.0%, respectively, in the other group (p < 0.05). Variation in bronchiectasis area was associated with poorer lung function (r = 0.32). Bronchiectasis detection, diameter, and area varied significantly according to CT respiratory phase, with non-reducible bronchiectasis showing greater lung function impairment.

Respiratory Morbidity among Indian Tea Industry Workers.

PubMed

Moitra, S; Thapa, P; Das, P; Das, J; Debnath, S; Singh, Mahipal; Datta, A; Sen, S; Moitra, S

2016-07-01

Indian tea industry workers are exposed to various exposures at their workplace. To investigate the respiratory health of Indian tea industry workers. We administered a respiratory questionnaire to and measured lung function in workers of 34 tea gardens and 46 tea factories. We used correlation matrices to test the association between their respiratory symptoms and lung functions. The garden workers complained of shortness of breath 3 times higher than the factory workers. However, nasal allergy was more predominant among the factory workers compared to garden workers (69.6% vs 41.2%, p=0.02). The factory workers had higher total (median 107.3% vs 92.9%, p=0.05, as measured by R at 5 Hz) and peripheral airway resistance (143.8% vs 61.1%, p=0.005, as measured by R at 5-20 Hz) than the garden workers. Respiratory symptoms were inversely associated with airway obstruction as measured by the ratio between forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) and positively correlated with increased overall airway reactance among the workers. Respiratory symptoms and increased allergen susceptibility of Indian tea industry workers due to occupational exposures warrant routine systematic surveillance of their workplace air quality and health monitoring.

Effects on symptoms and lung function in humans experimentally exposed to diesel exhaust.

PubMed

Rudell, B; Ledin, M C; Hammarström, U; Stjernberg, N; Lundbäck, B; Sandström, T

1996-10-01

Diesel exhaust is a common air pollutant made up of several gases, hydrocarbons, and particles. An experimental study was carried out which was designed to evaluate if a particle trap on the tail pipe of an idling diesel engine would reduce effects on symptoms and lung function caused by the diesel exhaust, compared with exposure to unfiltered exhaust. Twelve healthy non-smoking volunteers (aged 20-37) were investigated in an exposure chamber for one hour during light work on a bicycle ergometer at 75 W. Each subject underwent three separate double blind exposures in a randomised sequence: to air and to diesel exhaust with the particle trap at the tail pipe and to unfiltered diesel exhaust. Symptoms were recorded according to the Borg scale before, every 10 minutes during, and 30 minutes after the exposure. Lung function was measured with a computerised whole body plethysmograph. The ceramic wall flow particle trap reduced the number of particles by 46%, whereas other compounds were relatively constant. It was shown that the most prominent symptoms during exposure to diesel exhaust were irritation of the eyes and nose and an unpleasant smell increasing during exposure. Both airway resistance (R(aw)) and specific airway resistance (SR(aw)) increased significantly during the exposures to diesel exhaust. Despite the 46% reduction in particle numbers by the trap effects on symptoms and lung function were not significantly attenuated. Exposure to diesel exhaust caused symptoms and bronchoconstriction which were not significantly reduced by a particle trap.

Determinants of lung function and airway hyperresponsiveness in asthmatic children.

PubMed

Bisgaard, H; Pedersen, S; Anhøj, J; Agertoft, L; Hedlin, G; Gulsvik, A; Bjermer, L; Carlsen, K H; Nordvall, L; Lundbäck, B; Wennergren, G; Werner, S; Bønnelykke, K; Weiss, S T

2007-07-01

Asthma patients exhibit an increased rate of loss of lung function. Determinants to such decline are largely unknown and the modifying effect of steroid therapy is disputed. This cross-sectional study aimed to elucidate factors contributing to such decline and the possible modifying effect of steroid treatment. We analyzed determinants of lung function and airway hyperresponsiveness (AHR) in a Scandinavian study of 2390 subjects from 550 families. Families were selected for the presence of two or more asthmatic children as part of a genetic study, Scandinavian Asthma Genetic Study (SAGA). The primary analysis studied the association between the lung function and delay of inhaled corticosteroids (ICS) after asthma diagnosis among asthmatic children and young adults with a history of regular ICS treatment (N=919). FEV(1) percent predicted (FEV(1)% pred) was 0.25% lower per year of delay from diagnosis until treatment (p=0.039). This association was significantly greater in allergy skin prick test negative children. There was no significant influence of gender, age at asthma onset, or smoking. In the secondary analysis of the whole population of 2390 asthmatics and non-asthmatics, FEV(1)% pred was inversely related to having asthmatic siblings (-7.9%; p<0.0001), asthma diagnosis (-2.7%; p=0.0007), smoking (-3.5%; p=0.0027), and positive allergy skin prick test (-0.47% per test; p=0.012), while positively related to being of female gender (1.8%; p=0.0029). Risk of AHR was higher by having asthmatic siblings (OR 2.7; p<0.0001), being of female gender (OR 2.0; p<0.0001), and having asthma (OR 2.0; p<0.0001). These data suggest that lung function is lower in asthmatics with delayed introduction of ICS therapy, smoking, and positive allergy skin prick test. Lung function is lower and AHR higher in female asthmatics and subjects with asthmatic siblings or established asthma.

[Evaluation of walk-in lung function service for smokers in Copenhagen--a 1-year study].

PubMed

Backer, Vibeke; Bolton, Sophie; Ehlers, Hanne D; Thomsen, Simon; Pedersen, Lars; Porsbjerg, Celeste; Lund, Thomas; Harmsen, Lotte; Harmse, Lotte; Fuglsang, Charlotte

2008-08-25

Early prevention of COPD and immediate consultation about tobacco cessation is a major issue in respiratory medicine. To evaluate if a community-based walk-in lung function service, either in a clinic or a shopping mall, could result in early detection of COPD. Early detection would facilitate prevention. In an area with 1.5 mill inhabitants, a walk-in lung function service opened in 2005/06 once a month for 3 hours at a clinic and on two full days in a mall. The staff consisted of two respiratory nurses and one chest physician. The nurses informed all participants about their lung function level and all received a preventive talk about tobacco consumption. Those with signs of COPD spoke with the doctor immediately. A total of 1169 subjects, 59% women, with a mean (SD) age of 60 years (15), visited the walk-in services, 602 (52%) of whom visited the walk-in service at the clinic. Among the participants, 826 (71%) were smokers (n=452) or former smokers (n=374). The mean tobacco consumption was 32 (18) packs a year. We found that more current smokers visited the walk-in service at the clinic (45% versus 33%), whereas more ex-smokers visited the lung function service at the mall (38% versus 25%) (p < 0.01). The mean tobacco consumption was 32 (18) packs a year, with a difference between those visiting the mall and the clinic (32 (20) versus 23 (16), p<0.05). Among smokers, 54% had normal lung function, 15% had signs of airway obstruction, whereas 31% had developed moderate to severe COPD. Despite free medical access, more that one thirds had signs of airway obstruction. As all were informed about tobacco cessation, a walk-in service in a clinic and not a supermarket is most cost effective.

Region-specific role for Pten in maintenance of epithelial phenotype and integrity

PubMed Central

Flodby, Per; Sunohara, Mitsuhiro; Castillo, Dan R.; McConnell, Alicia M.; Krishnaveni, Manda S.; Banfalvi, Agnes; Li, Min; Stripp, Barry; Zhou, Beiyun; Crandall, Edward D.; Minoo, Parviz

2017-01-01

Previous studies have demonstrated resistance to naphthalene-induced injury in proximal airways of mice with lung epithelial-specific deletion of the tumor-suppressor gene Pten, attributed to increased proliferation of airway progenitors. We tested effects of Pten loss following bleomycin injury, a model typically used to study distal lung epithelial injury, in conditional PtenSFTPC-cre knockout mice. Pten-deficient airway epithelium exhibited marked hyperplasia, particularly in small bronchioles and at bronchoalveolar duct junctions, with reduced E-cadherin and β-catenin expression between cells toward the luminal aspect of the hyperplastic epithelium. Bronchiolar epithelial and alveolar epithelial type II (AT2) cells in PtenSFTPC-cre mice showed decreased expression of epithelial markers and increased expression of mesenchymal markers, suggesting at least partial epithelial-mesenchymal transition at baseline. Surprisingly, and in contrast to previous studies, mutant mice were exquisitely sensitive to bleomycin, manifesting rapid weight loss, respiratory distress, increased early mortality (by day 5), and reduced dynamic lung compliance. This was accompanied by sloughing of the hyperplastic airway epithelium with occlusion of small bronchioles by cellular debris, without evidence of increased parenchymal lung injury. Increased airway epithelial cell apoptosis due to loss of antioxidant defenses, reflected by decreased expression of superoxide dismutase 3, in combination with deficient intercellular adhesion, likely predisposed to airway sloughing in knockout mice. These findings demonstrate an important role for Pten in maintenance of airway epithelial phenotype integrity and indicate that responses to Pten deletion in respiratory epithelium following acute lung injury are highly context-dependent and region-specific. PMID:27864284

Colonization with Small Conidia Aspergillus Species is associated with Bronchiolitis Obliterans Syndrome: A Two-Center Validation Study

PubMed Central

Weigt, S. Sam; Copeland, C. Ashley Finlen; Derhovanessian, Ariss; Shino, Michael Y.; Davis, W. Austin; Snyder, Laurie D.; Saggar, Rajan; Lynch, Joseph P.; Ross, David J.; Ardehali, Abbas; Elashoff, Robert M.; Palmer, Scott M.; Belperio, John A.

2012-01-01

Aspergillus colonization after lung transplantation may increase the risk for bronchiolitis obliterans syndrome (BOS), a disease of small airways. We hypothesized that colonization with small conidia Aspergillus species would be associated with a greater risk of BOS, based upon an increased likelihood of deposition in small airways. We studied adult primary lung recipients from two large centers; 298 recipients at University of California, Los Angeles and 482 recipients at Duke University Medical Center. We grouped Aspergillus species by conidia diameter ≤3.5μm. We assessed the relationship of colonization with outcomes in Cox models. Pre-BOS colonization with small conidia Aspergillus species, but not large, was a risk factor for BOS (P = 0.002, HR 1.44, 95% CI 1.14–1.82), along with acute rejection, single lung, and Pseudomonas. Colonization with small conidia species also associated with risk of death (P = 0.03, HR 1.30, 95% CI 1.03–1.64). Although other virulence traits besides conidia size may be important, we have demonstrated in two large independent cohorts that colonization with small conidia Aspergillus species increases the risk of BOS and death. Prospective evaluation of strategies to prevent Aspergillus colonization of small airways is warranted, with the goal of preserving lung allograft function as long as possible. PMID:23398785

Frontline Science: Pathological conditioning of human neutrophils recruited to the airway milieu in cystic fibrosis.

PubMed

Forrest, Osric A; Ingersoll, Sarah A; Preininger, Marcela K; Laval, Julie; Limoli, Dominique H; Brown, Milton R; Lee, Frances E; Bedi, Brahmchetna; Sadikot, Ruxana T; Goldberg, Joanna B; Tangpricha, Vin; Gaggar, Amit; Tirouvanziam, Rabindra

2018-05-09

Recruitment of neutrophils to the airways, and their pathological conditioning therein, drive tissue damage and coincide with the loss of lung function in patients with cystic fibrosis (CF). So far, these key processes have not been adequately recapitulated in models, hampering drug development. Here, we hypothesized that the migration of naïve blood neutrophils into CF airway fluid in vitro would induce similar functional adaptation to that observed in vivo, and provide a model to identify new therapies. We used multiple platforms (flow cytometry, bacteria-killing, and metabolic assays) to characterize functional properties of blood neutrophils recruited in a transepithelial migration model using airway milieu from CF subjects as an apical chemoattractant. Similarly to neutrophils recruited to CF airways in vivo, neutrophils migrated into CF airway milieu in vitro display depressed phagocytic receptor expression and bacterial killing, but enhanced granule release, immunoregulatory function (arginase-1 activation), and metabolic activities, including high Glut1 expression, glycolysis, and oxidant production. We also identify enhanced pinocytic activity as a novel feature of these cells. In vitro treatment with the leukotriene pathway inhibitor acebilustat reduces the number of transmigrating neutrophils, while the metabolic modulator metformin decreases metabolism and oxidant production, but fails to restore bacterial killing. Interestingly, we describe similar pathological conditioning of neutrophils in other inflammatory airway diseases. We successfully tested the hypothesis that recruitment of neutrophils into airway milieu from patients with CF in vitro induces similar pathological conditioning to that observed in vivo, opening new avenues for targeted therapeutic intervention. ©2018 Society for Leukocyte Biology.

Quantitative computed tomography of the lungs and airways in healthy nonsmoking adults.

PubMed

Zach, Jordan Alexander; Newell, John D; Schroeder, Joyce; Murphy, James R; Curran-Everett, Douglas; Hoffman, Eric A; Westgate, Philip M; Han, MeiLan K; Silverman, Edwin K; Crapo, James D; Lynch, David A

2012-10-01

The purposes of this study were to evaluate the reference range of quantitative computed tomography (QCT) measures of lung attenuation and airway parameter measurements in healthy nonsmoking adults and to identify sources of variation in those measures and possible means to adjust for them. Within the COPDGene study, 92 healthy non-Hispanic white nonsmokers (29 men, 63 women; mean [SD] age, 62.7 [9.0] years; mean [SD] body mass index [BMI], 28.1 [5.1] kg/m(2)) underwent volumetric computed tomography (CT) at full inspiration and at the end of a normal expiration. On QCT analysis (Pulmonary Workstation 2, VIDA Diagnostics), inspiratory low-attenuation areas were defined as lung tissue with attenuation values -950 Hounsfield units or less on inspiratory CT (LAA(I-950)). Expiratory low-attenuation areas were defined as lung tissue -856 Hounsfield units or less on expiratory CT (LAA(E-856)). We used simple linear regression to determine the impact of age and sex on QCT parameters and multiple regression to assess the additional impact of total lung capacity and functional residual capacity measured by CT (TLC(CT) and FRC(CT)), scanner type, and mean tracheal air attenuation. Airways were evaluated using measures of airway wall thickness, inner luminal area, wall area percentage (WA%), and standardized thickness of an airway with inner perimeter of 10 mm (Pi10). Mean (SD) %LAA(I-950) was 2.0% (2.7%), and mean (SD) %LAA(E-856) was 9.2% (6.8%). Mean (SD) %LAA(I-950) was 3.6% (3.2%) in men, compared with 1.3% (2.0%) in women (P < 0.001). The %LAA(I-950) did not change significantly with age (P = 0.08) or BMI (P = 0.52). %LAA(E-856) did not show any independent relationship with age (P = 0.33), sex (P = 0.70), or BMI (P = 0.32). On multivariate analysis, %LAA(I-950) showed a direct relationship to TLC(CT) (P = 0.002) and an inverse relationship to mean tracheal air attenuation (P = 0.003), and %LAA(E-856) was related to age (P = 0.001), FRC(CT) (P = 0.007), and scanner type (P < 0.001). Multivariate analysis of segmental airways showed that inner luminal area and WA% were significantly related to TLC(CT) (P < 0.001) and age (0.006). Moreover, WA% was associated with sex (P = 0.05), axial pixel size (P = 0.03), and slice interval (P = 0.04). Lastly, airway wall thickness was strongly influenced by axial pixel size (P < 0.001). Although the attenuation characteristics of normal lung differ by age and sex, these differences do not persist on multivariate analysis. Potential sources of variation in measurement of attenuation-based QCT parameters include depth of inspiration/expiration and scanner type. Tracheal air attenuation may partially correct variation because of scanner type. Sources of variation in QCT airway measurements may include age, sex, BMI, depth of inspiration, and spatial resolution.

Chronic obstructive pulmonary disease and asthma-associated Proteobacteria, but not commensal Prevotella spp., promote Toll-like receptor 2-independent lung inflammation and pathology.

PubMed

Larsen, Jeppe M; Musavian, Hanieh S; Butt, Tariq M; Ingvorsen, Camilla; Thysen, Anna H; Brix, Susanne

2015-02-01

Recent studies of healthy human airways have revealed colonization by a distinct commensal bacterial microbiota containing Gram-negative Prevotella spp. However, the immunological properties of these bacteria in the respiratory system remain unknown. Here we compare the innate respiratory immune response to three Gram-negative commensal Prevotella strains (Prevotella melaninogenica, Prevotella nanceiensis and Prevotella salivae) and three Gram-negative pathogenic Proteobacteria known to colonize lungs of patients with chronic obstructive pulmonary disease (COPD) and asthma (Haemophilus influenzae B, non-typeable Haemophilus influenzae and Moraxella catarrhalis). The commensal Prevotella spp. and pathogenic Proteobacteria were found to exhibit intrinsic differences in innate inflammatory capacities on murine lung cells in vitro. In vivo in mice, non-typeable H. influenzae induced severe Toll-like receptor 2 (TLR2)-independent COPD-like inflammation characterized by predominant airway neutrophilia, expression of a neutrophilic cytokine/chemokine profile in lung tissue, and lung immunopathology. In comparison, P. nanceiensis induced a diminished neutrophilic airway inflammation and no detectable lung pathology. Interestingly, the inflammatory airway response to the Gram-negative bacteria P. nanceiensis was completely TLR2-dependent. These findings demonstrate weak inflammatory properties of Gram-negative airway commensal Prevotella spp. that may make colonization by these bacteria tolerable by the respiratory immune system. © 2014 John Wiley & Sons Ltd.

Chronic obstructive pulmonary disease and asthma-associated Proteobacteria, but not commensal Prevotella spp., promote Toll-like receptor 2-independent lung inflammation and pathology

PubMed Central

Larsen, Jeppe M; Musavian, Hanieh S; Butt, Tariq M; Ingvorsen, Camilla; Thysen, Anna H; Brix, Susanne

2015-01-01

Recent studies of healthy human airways have revealed colonization by a distinct commensal bacterial microbiota containing Gram-negative Prevotella spp. However, the immunological properties of these bacteria in the respiratory system remain unknown. Here we compare the innate respiratory immune response to three Gram-negative commensal Prevotella strains (Prevotella melaninogenica, Prevotella nanceiensis and Prevotella salivae) and three Gram-negative pathogenic Proteobacteria known to colonize lungs of patients with chronic obstructive pulmonary disease (COPD) and asthma (Haemophilus influenzae B, non-typeable Haemophilus influenzae and Moraxella catarrhalis). The commensal Prevotella spp. and pathogenic Proteobacteria were found to exhibit intrinsic differences in innate inflammatory capacities on murine lung cells in vitro. In vivo in mice, non-typeable H. influenzae induced severe Toll-like receptor 2 (TLR2)-independent COPD-like inflammation characterized by predominant airway neutrophilia, expression of a neutrophilic cytokine/chemokine profile in lung tissue, and lung immunopathology. In comparison, P. nanceiensis induced a diminished neutrophilic airway inflammation and no detectable lung pathology. Interestingly, the inflammatory airway response to the Gram-negative bacteria P. nanceiensis was completely TLR2-dependent. These findings demonstrate weak inflammatory properties of Gram-negative airway commensal Prevotella spp. that may make colonization by these bacteria tolerable by the respiratory immune system. PMID:25179236

The microbiota in bronchoalveolar lavage from young children with chronic lung disease includes taxa present in both the oropharynx and nasopharynx.

PubMed

Marsh, R L; Kaestli, M; Chang, A B; Binks, M J; Pope, C E; Hoffman, L R; Smith-Vaughan, H C

2016-07-07

Invasive methods requiring general anaesthesia are needed to sample the lung microbiota in young children who do not expectorate. This poses substantial challenges to longitudinal study of paediatric airway microbiota. Non-invasive upper airway sampling is an alternative method for monitoring airway microbiota; however, there are limited data describing the relationship of such results with lung microbiota in young children. In this study, we compared the upper and lower airway microbiota in young children to determine whether non-invasive upper airway sampling procedures provide a reliable measure of either lung microbiota or clinically defined differences. The microbiota in oropharyngeal (OP) swabs, nasopharyngeal (NP) swabs and bronchoalveolar lavage (BAL) from 78 children (median age 2.2 years) with and without lung disease were characterised using 16S rRNA gene sequencing. Permutational multivariate analysis of variance (PERMANOVA) detected significant differences between the microbiota in BAL and those in both OP swabs (p = 0.0001, Pseudo-F = 12.2, df = 1) and NP swabs (p = 0.0001; Pseudo-F = 21.9, df = 1) with the NP and BAL microbiota more different than the OP and BAL, as indicated by a higher Pseudo-F value. The microbiota in combined OP and NP data (upper airways) provided a more comprehensive representation of BAL microbiota, but significant differences between the upper airway and BAL microbiota remained, albeit with a considerably smaller Pseudo-F (PERMANOVA p = 0.0001; Pseudo-F = 4.9, df = 1). Despite this overall difference, paired BAL and upper airway (OP and NP) microbiota were >50 % similar among 69 % of children. Furthermore, canonical analysis of principal coordinates (CAP analysis) detected significant differences between the microbiota from clinically defined groups when analysing either BAL (eigenvalues >0.8; misclassification rate 26.5 %) or the combined OP and NP data (eigenvalues >0.8; misclassification rate 12.2 %). Upper airway sampling provided an imperfect, but reliable, representation of the BAL microbiota for most children in this study. We recommend inclusion of both OP and NP specimens when non-invasive upper airway sampling is needed to assess airway microbiota in young children who do not expectorate. The results of the CAP analysis suggest lower and upper airway microbiota profiles may differentiate children with chronic suppurative lung disease from those with persistent bacterial bronchitis; however, further research is needed to confirm this observation.

Early treatment of chlorine-induced airway hyperresponsiveness and inflammation with corticosteroids

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

Jonasson, Sofia, E-mail: sofia.jonasson@foi.se; Wigenstam, Elisabeth; Department of Public Health and Clinical Medicine, Unit of Respiratory Medicine, Umeå University, Umeå

Chlorine (Cl{sub 2}) is an industrial gas that is highly toxic and irritating when inhaled causing tissue damage and an acute inflammatory response in the airways followed by a long-term airway dysfunction. The aim of this study was to evaluate whether early anti-inflammatory treatment can protect against the delayed symptoms in Cl{sub 2}-exposed mice. BALB/c mice were exposed by nose-only inhalation using 200 ppm Cl{sub 2} during 15 min. Assessment of airway hyperresponsiveness (AHR), inflammatory cell counts in bronchoalveolar lavage, occurrence of lung edema and lung fibrosis were analyzed 24 h or 14 days post-exposure. A single dose of themore » corticosteroid dexamethasone (10 or 100 mg/kg) was administered intraperitoneally 1, 3, 6, or 12 h following Cl{sub 2} exposure. High-dose of dexamethasone reduced the acute inflammation if administered within 6 h after exposure but treated animals still displayed a significant lung injury. The effect of dexamethasone administered within 1 h was dose-dependent; high-dose significantly reduced acute airway inflammation (100 mg/kg) but not treatment with the relatively low-dose (10 mg/kg). Both doses reduced AHR 14 days later, while lung fibrosis measured as collagen deposition was not significantly reduced. The results point out that the acute inflammation in the lungs due to Cl{sub 2} exposure only partly is associated with the long-term AHR. We hypothesize that additional pathogenic mechanisms apart from the inflammatory reactions contribute to the development of long-term airway dysfunction. By using this mouse model, we have validated early administration of corticosteroids in terms of efficacy to prevent acute lung injury and delayed symptoms induced by Cl{sub 2} exposure. - Highlights: • Inhalation of Cl{sub 2} may lead to a long-standing airway hyperresponsiveness. • The symptoms in Cl{sub 2}-exposed mice are similar to those described for RADS in humans. • Corticosteroids prevent delayed symptoms such as AHR in Cl{sub 2}-induced lung injury. • Early medical intervention of corticosteroids is of importance. • Treatment with corticosteroids alone is insufficient to counteract acute lung injury.« less

IN VIVO COMPARISON OF EPITHELIAL RESPONSES FOR S-8 VERSUS JP-8 JET FUELS BELOW PERMISSIBLE EXPOSURE LIMIT

PubMed Central

Wong, Simon S.; Vargas, Jason; Thomas, Alana; Fastje, Cindy; McLaughlin, Michael; Camponovo, Ryan; Lantz, R. Clark; Heys, Jeffrey; Witten, Mark L.

2010-01-01

This study was designed to characterize and compare the pulmonary effects in distal lung from a low-level exposure to jet propellant-8 fuel (JP-8) and a new synthetic-8 fuel (S-8). It is hypothesized that both fuels have different airway epithelial deposition and responses. Consequently, male C57BL/6 mice were nose-only exposed to S-8 and JP-8 at average concentrations of 53 mg/m3 for 1 hour/day for 7 days. A pulmonary function test performed 24 hr after the final exposure indicated that there was a significant increase in expiratory lung resistance in the S-8 mice, whereas JP-8 mice had significant increases in both inspiratory and expiratory lung resistance compared to control values. Neither significant S-8 nor JP-8 respiratory permeability changes were observed compared to controls, suggesting no loss of epithelial barrier integrity. Morphological examination and morphometric analysis of airway tissue demonstrated that both fuels showed different patterns of targeted epithelial cells: bronchioles in S-8 and alveoli/terminal bronchioles in JP-8. Collectively, our data suggest that both fuels may have partially different deposition patterns, which may possibly contribute to specific different adverse effects in lung ventilatory function. PMID:18930109

Characteristics of airflow and particle deposition in COPD current smokers

NASA Astrophysics Data System (ADS)

Zou, Chunrui; Choi, Jiwoong; Haghighi, Babak; Choi, Sanghun; Hoffman, Eric A.; Lin, Ching-Long

2017-11-01

A recent imaging-based cluster analysis of computed tomography (CT) lung images in a chronic obstructive pulmonary disease (COPD) cohort identified four clusters, viz. disease sub-populations. Cluster 1 had relatively normal airway structures; Cluster 2 had wall thickening; Cluster 3 exhibited decreased wall thickness and luminal narrowing; Cluster 4 had a significant decrease of luminal diameter and a significant reduction of lung deformation, thus having relatively low pulmonary functions. To better understand the characteristics of airflow and particle deposition in these clusters, we performed computational fluid and particle dynamics analyses on representative cluster patients and healthy controls using CT-based airway models and subject-specific 3D-1D coupled boundary conditions. The results show that particle deposition in central airways of cluster 4 patients was noticeably increased especially with increasing particle size despite reduced vital capacity as compared to other clusters and healthy controls. This may be attributable in part to significant airway constriction in cluster 4. This study demonstrates the potential application of cluster-guided CFD analysis in disease populations. NIH Grants U01HL114494 and S10-RR022421, and FDA Grant U01FD005837.

Manifesto on small airway involvement and management in asthma and chronic obstructive pulmonary disease: an Interasma (Global Asthma Association - GAA) and World Allergy Organization (WAO) document endorsed by Allergic Rhinitis and its Impact on Asthma (ARIA) and Global Allergy and Asthma European Network (GA2LEN).

PubMed

Braido, F; Scichilone, N; Lavorini, F; Usmani, O S; Dubuske, L; Boulet, L P; Mosges, R; Nunes, C; Sanchez-Borges, M; Ansotegui, I J; Ebisawa, M; Levi-Schaffer, F; Rosenwasser, L J; Bousquet, J; Zuberbier, T; Canonica, G Walter; Cruz, A; Yanez, A; Yorgancioglu, A; Deleanu, D; Rodrigo, G; Berstein, J; Ohta, K; Vichyanond, P; Pawankar, R; Gonzalez-Diaz, S N; Nakajima, S; Slavyanskaya, T; Fink-Wagner, A; Loyola, C Baez; Ryan, D; Passalacqua, G; Celedon, J; Ivancevich, J C; Dobashi, K; Zernotti, M; Akdis, M; Benjaponpitak, S; Bonini, S; Burks, W; Caraballo, L; El-Sayed, Z Awad; Fineman, S; Greenberger, P; Hossny, E; Ortega-Martell, J A; Saito, H; Tang, M; Zhang, L

2016-01-01

Evidence that enables us to identify, assess, and access the small airways in asthma and chronic obstructive pulmonary disease (COPD) has led INTERASMA (Global Asthma Association) and WAO to take a position on the role of the small airways in these diseases. Starting from an extensive literature review, both organizations developed, discussed, and approved the manifesto, which was subsequently approved and endorsed by the chairs of ARIA and GA 2 LEN. The manifesto describes the evidence gathered to date and defines and proposes issues on small airway involvement and management in asthma and COPD with the aim of challenging assumptions, fostering commitment, and bringing about change. The small airways (defined as those with an internal diameter <2 mm) are involved in the pathogenesis of asthma and COPD and are the major determinant of airflow obstruction in these diseases. Various tests are available for the assessment of the small airways, and their results must be integrated to confirm a diagnosis of small airway dysfunction. In asthma and COPD, the small airways play a key role in attempts to achieve disease control and better outcomes. Small-particle inhaled formulations (defined as those that, owing to their size [usually <2 μm], ensure more extensive deposition in the lung periphery than large molecules) have proved beneficial in patients with asthma and COPD, especially those in whom small airway involvement is predominant. Functional and biological tools capable of accurately assessing the lung periphery and more intensive use of currently available tools are necessary. In patients with suspected COPD or asthma, small airway involvement must be assessed using currently available tools. In patients with subotpimal disease control and/or functional or biological signs of disease activity, the role of small airway involvement should be assessed and treatment tailored. Therefore, the choice between large- and small-particle inhaled formulations must reflect the physician's considerations of disease features, phenotype, and response to previous therapy. This article is being co-published in Asthma Research and Practice and the World Allergy Organization Journal.

Bronchial blood supply after lung transplantation without bronchial artery revascularization.

PubMed

Nicolls, Mark R; Zamora, Martin R

2010-10-01

This review discusses how the bronchial artery circulation is interrupted following lung transplantation and what may be the long-term complications of compromising systemic blood flow to allograft airways. Preclinical and clinical studies have shown that the loss of airway microcirculations is highly associated with the development of airway hypoxia and an increased susceptibility to chronic rejection. The bronchial artery circulation has been highly conserved through evolution. Current evidence suggests that the failure to routinely perform bronchial artery revascularization at the time of lung transplantation may predispose patients to develop the bronchiolitis obliterans syndrome.

Nrf2 protects against airway disorders

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

Cho, Hye-Youn, E-mail: cho2@niehs.nih.go; Kleeberger, Steven R.

Nuclear factor-erythroid 2 related factor 2 (Nrf2) is a ubiquitous master transcription factor that regulates antioxidant response elements (AREs)-mediated expression of antioxidant enzyme and cytoprotective proteins. In the unstressed condition, Kelch-like ECH-associated protein 1 (Keap1) suppresses cellular Nrf2 in cytoplasm and drives its proteasomal degradation. Nrf2 can be activated by diverse stimuli including oxidants, pro-oxidants, antioxidants, and chemopreventive agents. Nrf2 induces cellular rescue pathways against oxidative injury, abnormal inflammatory and immune responses, apoptosis, and carcinogenesis. Application of Nrf2 germ-line mutant mice has identified an extensive range of protective roles for Nrf2 in experimental models of human disorders in the liver,more » gastrointestinal tract, airway, kidney, brain, circulation, and immune or nerve system. In the lung, lack of Nrf2 exacerbated toxicity caused by multiple oxidative insults including supplemental respiratory therapy (e.g., hyperoxia, mechanical ventilation), cigarette smoke, allergen, virus, bacterial endotoxin and other inflammatory agents (e.g., carrageenin), environmental pollution (e.g., particles), and a fibrotic agent bleomycin. Microarray analyses and bioinformatic studies elucidated functional AREs and Nrf2-directed genes that are critical components of signaling mechanisms in pulmonary protection by Nrf2. Association of loss of function with promoter polymorphisms in NRF2 or somatic and epigenetic mutations in KEAP1 and NRF2 has been found in cohorts of patients with acute lung injury/acute respiratory distress syndrome or lung cancer, which further supports the role for NRF2 in these lung diseases. In the current review, we address the role of Nrf2 in airways based on emerging evidence from experimental oxidative disease models and human studies.« less

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

PubMed

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

2017-01-01

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

Regulatory T-Cell Distribution within Lung Compartments in COPD.

PubMed

Sales, Davi S; Ito, Juliana T; Zanchetta, Ivy A; Annoni, Raquel; Aun, Marcelo V; Ferraz, Luiz Fernando S; Cervilha, Daniela A B; Negri, Elnara; Mauad, Thais; Martins, Mílton A; Lopes, Fernanda D T Q S

2017-10-01

The importance of the adaptive immune response, specifically the role of regulatory T (Treg) cells in controlling the obstruction progression in smokers, has been highlighted. To quantify the adaptive immune cells in different lung compartments, we used lung tissues from 21 never-smokers without lung disease, 22 current and/or ex-smokers without lung disease (NOS) and 13 current and/or ex-smokers with chronic obstructive pulmonary disease (COPD) for histological analysis. We observed increased T, B, IL-17 and BAFF + cells in small and large airways of COPD individuals; however, in the NOS, we only observed increase in T and IL-17 + cells only in small airways. A decrease in the density of Treg + , TGF-β + and IL-10 + in small and large airways was observed only in COPD individuals. In the lymphoid tissues, Treg, T,B-cells and BAFF + cells were also increased in COPD; however, changes in Treg inhibitory associated cytokines were not observed in this compartment. Therefore, our results suggest that difference in Treg + cell distributions in lung compartments and the decrease in TGF-β + and IL-10 + cells in the airways may lead to the obstruction in smokers.

Effects of multi-walled carbon nanotubes on a murine allergic airway inflammation model

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

Inoue, Ken-ichiro; Koike, Eiko; Yanagisawa, Rie

The development of nanotechnology has increased the risk of exposure to types of particles other than combustion-derived particles in the environment, namely, industrial nanomaterials. On the other hand, patients with bronchial asthma are sensitive to inhaled substances including particulate matters. This study examined the effects of pulmonary exposure to a type of nano-sized carbon nanotube (multi-walled nanotubes: MWCNT) on allergic airway inflammation in vivo and their cellular mechanisms in vitro. In vivo, ICR mice were divided into 4 experimental groups. Vehicle, MWCNT (50 {mu}g/animal), ovalbumin (OVA), and OVA + MWCNT were repeatedly administered intratracheally. Bronchoalveolar lavage (BAL) cellularity, lung histology,more » levels of cytokines related to allergic inflammation in lung homogenates/BAL fluids (BALFs), and serum immunoglobulin levels were studied. Also, we evaluated the impact of MWCNT (0.1-1 {mu}g/ml) on the phenotype and function of bone marrow-derived dendritic cells (DC) in vitro. MWCNT aggravated allergen-induced airway inflammation characterized by the infiltration of eosinophils, neutrophils, and mononuclear cells in the lung, and an increase in the number of goblet cells in the bronchial epithelium. MWCNT with allergen amplified lung protein levels of Th cytokines and chemokines compared with allergen alone. MWCNT exhibited adjuvant activity for allergen-specific IgG{sub 1} and IgE. MWCNT significantly increased allergen (OVA)-specific syngeneic T-cell proliferation, particularly at a lower concentration in vitro. Taken together, MWCNT can exacerbate murine allergic airway inflammation, at least partly, via the promotion of a Th-dominant milieu. In addition, the exacerbation may be partly through the inappropriate activation of antigen-presenting cells including DC.« less

The root barks of Morus alba and the flavonoid constituents inhibit airway inflammation.

PubMed

Lim, Hun Jai; Jin, Hong-Guang; Woo, Eun-Rhan; Lee, Sang Kook; Kim, Hyun Pyo

2013-08-26

The root barks of Morus alba have been used in traditional medicine as an anti-inflammatory drug, especially for treating lung inflammatory disorders. To find new alternative agents against airway inflammation and to establish the scientific rationale of the herbal medicine in clinical use, the root barks of Morus alba and its flavonoid constituents were examined for the first time for their pharmacological activity against lung inflammation. For in vivo evaluation, an animal model of lipopolysaccharide-induced airway inflammation in mice was used. An inhibitory action against the production of proinflammatory molecules in lung epithelial cells and lung macrophages was examined. Against lipopolysaccharide-induced airway inflammation, the ethanol extract of the root barks of Morus alba clearly inhibited bronchitis-like symptoms, as determined by TNF-α production, inflammatory cells infiltration and histological observation at 200-400mg/kg/day by oral administration. In addition, Morus alba and their major flavonoid constituents including kuwanone E, kuwanone G and norartocarpanone significantly inhibited IL-6 production in lung epithelial cells (A549) and NO production in lung macrophages (MH-S). Taken together, it is concluded that Morus alba and the major prenylated flavonoid constituents have a potential for new agents to control lung inflammation including bronchitis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Airway epithelial homeostasis and planar cell polarity signaling depend on multiciliated cell differentiation.

PubMed

Vladar, Eszter K; Nayak, Jayakar V; Milla, Carlos E; Axelrod, Jeffrey D

2016-08-18

Motile airway cilia that propel contaminants out of the lung are oriented in a common direction by planar cell polarity (PCP) signaling, which localizes PCP protein complexes to opposite cell sides throughout the epithelium to orient cytoskeletal remodeling. In airway epithelia, PCP is determined in a 2-phase process. First, cell-cell communication via PCP complexes polarizes all cells with respect to the proximal-distal tissue axis. Second, during ciliogenesis, multiciliated cells (MCCs) undergo cytoskeletal remodeling to orient their cilia in the proximal direction. The second phase not only directs cilium polarization, but also consolidates polarization across the epithelium. Here, we demonstrate that in airway epithelia, PCP depends on MCC differentiation. PCP mutant epithelia have misaligned cilia, and also display defective barrier function and regeneration, indicating that PCP regulates multiple aspects of airway epithelial homeostasis. In humans, MCCs are often sparse in chronic inflammatory diseases, and these airways exhibit PCP dysfunction. The presence of insufficient MCCs impairs mucociliary clearance in part by disrupting PCP-driven polarization of the epithelium. Consistent with defective PCP, barrier function and regeneration are also disrupted. Pharmacological stimulation of MCC differentiation restores PCP and reverses these defects, suggesting its potential for broad therapeutic benefit in chronic inflammatory disease.

Loss of Cystic Fibrosis Transmembrane Conductance Regulator Function Enhances Activation of p38 and ERK MAPKs, Increasing Interleukin-6 Synthesis in Airway Epithelial Cells Exposed to Pseudomonas aeruginosa*

PubMed Central

Bérubé, Julie; Roussel, Lucie; Nattagh, Leila; Rousseau, Simon

2010-01-01

In cystic fibrosis (CF), the absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) translates into chronic bacterial infection, excessive inflammation, tissue damage, impaired lung function and eventual death. Understanding the mechanisms underlying this vicious circle of inflammation is important to design better therapies for CF. We found in CF lung biopsies increased immunoreactivity for p38 MAPK activity markers. Moreover, when compared with their non-CF counterpart, airway epithelial cells expressing the most common mutation in CF (CFTRΔF508) were more potent at inducing neutrophil chemotaxis through increased interleukin (IL)-6 synthesis when challenged with Pseudomonas aeruginosa diffusible material. We then discovered that in CFTRΔF508 cells, the p38 and ERK MAPKs are hyperactivated in response to P. aeruginosa diffusible material, leading to increased IL-6 mRNA expression and stability. Moreover, although TLR5 contributes to p38 MAPK activation upon P. aeruginosa challenge, it only played a weak role in IL-6 synthesis. Instead, we found that the production of reactive oxygen species is essential for IL-6 synthesis in response to P. aeruginosa diffusible material. Finally, we uncovered that in CFTRΔF508 cells, the extracellular glutathione levels are decreased, leading to a greater sensitivity to reactive oxygen species, providing an explanation for the hyperactivation of the p38 and ERK MAPKs and increased IL-6 synthesis. Taken together, our study has characterized a mechanism whereby the CFTRΔF508 mutation in airway epithelial cells contributes to increase inflammation of the airways. PMID:20460375

Incidence of non-pulmonary cancer and lung cancer by amount of emphysema and airway wall thickness: a community-based cohort.

PubMed

Aamli Gagnat, Ane; Gjerdevik, Miriam; Gallefoss, Frode; Coxson, Harvey O; Gulsvik, Amund; Bakke, Per

2017-05-01

There is limited knowledge about the prognostic value of quantitative computed tomography (CT) measures of emphysema and airway wall thickness in cancer.The aim of this study was to investigate if using CT to quantitatively assess the amount of emphysema and airway wall thickness independently predicts the subsequent incidence of non-pulmonary cancer and lung cancer.In the GenKOLS study of 2003-2005, 947 ever-smokers performed spirometry and underwent CT examination. The main predictors were the amount of emphysema measured by the percentage of low attenuation areas (%LAA) on CT and standardised measures of airway wall thickness (AWT-PI10). Cancer data from 2003-2013 were obtained from the Norwegian Cancer Register. The hazard ratio associated with emphysema and airway wall thickness was assessed using Cox proportional hazards regression for cancer diagnoses.During 10 years of follow-up, non-pulmonary cancer was diagnosed in 11% of the subjects with LAA <3%, in 19% of subjects with LAA 3-10%, and in 17% of subjects with LAA ≥10%. Corresponding numbers for lung cancer were 2%, 3% and 11%, respectively. After adjustment, the baseline amount of emphysema remained a significant predictor of the incidence of non-pulmonary cancer and lung cancer. Airway wall thickness did not predict cancer independently.This study offers a strong argument that emphysema is an independent risk factor for both non-pulmonary cancer and lung cancer. Copyright ©ERS 2017.

Composition and Predicted Metabolic Capacity of Upper and Lower Airway Microbiota of Healthy Dogs in Relation to the Fecal Microbiota.

PubMed

Ericsson, Aaron C; Personett, Alexa R; Grobman, Megan E; Rindt, Hansjorg; Reinero, Carol R

2016-01-01

The upper and lower airways of healthy humans are reported to harbor stable and consistent bacterial populations, and the composition of these communities is altered in individuals affected with several respiratory diseases. Data regarding the presence of airway microbiota in other animals are scant and a better understanding of the composition and metabolic function of such bacterial populations is essential for the development of novel therapeutic and diagnostic modalities for use in both veterinary and human medicine. Based on targeted next-generation sequencing of feces and samples collected at multiple levels of the airways from 16 healthy female dogs, we demonstrate that canine airways harbor a topographically continuous microbiota with increasing relative abundance of proteobacterial species from the upper to lower airways. The lung-associated microbiota, as assessed via bronchoalveolar lavage fluid (BALF), was the most consistent between dogs and was dominated by three distinct taxa, two of which were resolved to the species level and one to the level of family. The gene content of the nasal, oropharyngeal, and lung-associated microbiota, predicted using the Phylogenetic Investigations into Communities by Reconstruction of Unobserved States (PICRUSt) software, provided information regarding the glyoxylate and citrate cycle metabolic pathways utilized by these bacterial populations to colonize such nutrient-poor, low-throughput environments. These data generated in healthy subjects provide context for future analysis of diseased canine airways. Moreover, as dogs have similar respiratory anatomy, physiology, and immune systems as humans, are exposed to many of the same environmental stimuli, and spontaneously develop similar respiratory diseases, these data support the use of dogs as a model species for prospective studies of the airway microbiota, with findings translatable to the human condition.

Effect of Rho-kinase inhibition on complexity of breathing pattern in a guinea pig model of asthma

PubMed Central

Pazhoohan, Saeed; Javan, Mohammad; Hajizadeh, Sohrab

2017-01-01

Asthma represents an episodic and fluctuating behavior characterized with decreased complexity of respiratory dynamics. Several evidence indicate that asthma severity or control is associated with alteration in variability of lung function. The pathophysiological basis of alteration in complexity of breathing pattern in asthma has remained poorly understood. Regarding the point that Rho-kinase is involved in pathophysiology of asthma, in present study we investigated the effect of Rho-kinase inhibition on complexity of respiratory dynamics in a guinea pig model of asthma. Male Dunkin Hartley guinea pigs were exposed to 12 series of inhalations with ovalbumin or saline. Animals were treated by the Rho-kinase inhibitor Y-27632 (1mM aerosols) prior to each allergen challenge. We recorded respiration of conscious animals using whole-body plethysmography. Exposure to ovalbumin induced lung inflammation, airway hyperresponsiveness and remodeling including goblet cell hyperplasia, increase in the thickness of airways smooth muscles and subepithelial collagen deposition. Complexity analysis of respiratory dynamics revealed a dramatic decrease in irregularity of respiratory rhythm representing less complexity in asthmatic guinea pigs. Inhibition of Rho-kinase reduced the airway remodeling and hyperreponsiveness, but had no significant effect on lung inflammation and complexity of respiratory dynamics in asthmatic animals. It seems that airway hyperresponsiveness and remodeling do not significantly affect the complexity of respiratory dynamics. Our results suggest that inflammation might be the probable cause of shift in the respiratory dynamics away from the normal fluctuation in asthma. PMID:29088265

Expression of nitric oxide synthase-2 in the lungs decreases airway resistance and responsiveness.

PubMed

Hjoberg, Josephine; Shore, Stephanie; Kobzik, Lester; Okinaga, Shoji; Hallock, Arlene; Vallone, Joseph; Subramaniam, Venkat; De Sanctis, George T; Elias, Jack A; Drazen, Jeffrey M; Silverman, Eric S

2004-07-01

Individuals with asthma have increased levels of nitric oxide in their exhaled air. To explore its role, we have developed a regulatable transgenic mouse capable of overexpressing inducible nitric oxide synthase in a lung-specific fashion. The CC10-rtTA-NOS-2 mouse contains two transgenes, a reverse tetracycline transactivator under the control of the Clara cell protein promoter and the mouse nitric oxide synthase-2 (NOS-2) coding region under control of a tetracycline operator. Addition of doxycycline to the drinking water of CC10-rtTA-NOS-2 mice causes an increase in nitric oxide synthase-2 that is largely confined to the airway epithelium. The fraction of expired nitric oxide increases over the first 24 h from approximately 10 parts per billion to a plateau of approximately 20 parts per billion. There were no obvious differences between CC10-rtTA-NOS-2 mice, with or without doxycycline, and wild-type mice in lung histology, bronchoalveolar protein, total cell count, or count differentials. However, airway resistance was lower in CC10-rtTA-NOS-2 mice with doxycycline than in CC10-rtTA-NOS-2 mice without doxycycline or wild-type mice with doxycycline. Moreover, doxycycline-treated CC10-rtTA-NOS-2 mice were hyporesponsive to methacholine compared with other groups. These data suggest that increased nitric oxide in the airways has no proinflammatory effects per se and may have beneficial effects on pulmonary function.

Pressure oscillation delivery to the lung: Computer simulation of neonatal breathing parameters.

PubMed

Al-Jumaily, Ahmed M; Reddy, Prasika I; Bold, Geoff T; Pillow, J Jane

2011-10-13

Preterm newborn infants may develop respiratory distress syndrome (RDS) due to functional and structural immaturity. A lack of surfactant promotes collapse of alveolar regions and airways such that newborns with RDS are subject to increased inspiratory effort and non-homogeneous ventilation. Pressure oscillation has been incorporated into one form of RDS treatment; however, how far it reaches various parts of the lung is still questionable. Since in-vivo measurement is very difficult if not impossible, mathematical modeling may be used as one way of assessment. Whereas many models of the respiratory system have been developed for adults, the neonatal lung remains essentially ill-described in mathematical models. A mathematical model is developed, which represents the first few generations of the tracheo-bronchial tree and the 5 lobes that make up the premature ovine lung. The elements of the model are derived using the lumped parameter approach and formulated in Simulink™ within the Matlab™ environment. The respiratory parameters at the airway opening compare well with those measured from experiments. The model demonstrates the ability to predict pressures, flows and volumes in the alveolar regions of a premature ovine lung. Copyright © 2011 Elsevier Ltd. All rights reserved.

How irritating: the role of TRPA1 in sensing cigarette smoke and aerogenic oxidants in the airways

PubMed Central

Simon, Sidney A.; Liedtke, Wolfgang

2008-01-01

Airway irritants cause a variety of lung pathologies. Two separate studies, the first recently reported in the JCI by Bessac et al. and the second reported by Andrè et al. in the current issue of the JCI (see the related article beginning on page 2574), have identified irritants that activate transient receptor potential cation channel, subfamily A, member 1 (TRPA1) receptors in airway sensory neurons, resulting in neurogenic inflammation and respiratory hypersensitivity. The identification of TRPA1 activation by toxicants from cigarette smoke and polluted air, such as crotonaldehyde, acrolein, and oxidizing agents such as hydrogen peroxide, is an important finding. These two studies enhance our understanding of how pollution and cigarette smoke can damage airway function and will hopefully pave the way for the development of rational alternative therapeutics for such airway injury. PMID:18568080

Expression of Sproutys and SPREDs is decreased during lung branching morphogenesis in nitrofen-induced pulmonary hypoplasia.

PubMed

Friedmacher, Florian; Gosemann, Jan-Hendrik; Fujiwara, Naho; Takahashi, Hiromizu; Hofmann, Alejandro; Puri, Prem

2013-11-01

Pulmonary hypoplasia (PH) is a life-threatening condition associated with congenital diaphragmatic hernia (CDH), characterized by defective lung development. Sproutys and Sprouty-related proteins (SPREDs) play a key role in lung branching morphogenesis through modification of epithelial-mesenchymal interactions. During the pseudoglandular stage, Sproutys are highly expressed in distal airway epithelium, while SPREDs within the surrounding mesenchyme. Sprouty2/4 knockouts show severe defects in branching morphogenesis with reduced number of distal airways. SPRED-1 and SPRED-2 are strongly expressed in regions of new airway formation, highlighting their important function in branching pattern. We hypothesized that expression of Sprouty2, Sprouty4, SPRED-1 and SPRED-2 is decreased during lung branching morphogenesis in nitrofen-induced PH. Timed-pregnant rats received either nitrofen or vehicle on E9.5. On E15.5 (n = 16), fetal lungs were micro-dissected and divided into controls and PH, while on E18.5 (n = 24) groups were: control, PH without CDH [CDH(-)], and PH with CDH [CDH(+)]. Pulmonary gene expression levels of Sprouty2, Sprouty4, SPRED-1 and SPRED-2 were analyzed by qRT-PCR. Immunohistochemistry was performed to evaluate protein expression/distribution. On E18.5, relative mRNA expression levels of Sprouty2, Sprouty4, SPRED-1 and SPRED-2 were significantly decreased in CDH(-) and CDH(+) groups compared to controls (P < 0.05). Immunoreactivity of Sprouty2, Sprouty4, SPRED-1 and SPRED-2 was markedly diminished on E18.5 in nitrofen-induced PH. Decreased expression of Sproutys and SPREDs during the terminal pseudoglandular stage may disrupt lung branching morphogenesis by interfering with epithelial-mesenchymal interactions contributing to PH.

Aspergillosis and the role of mucins in cystic fibrosis.

PubMed

Cowley, Abigail C; Thornton, David J; Denning, David W; Horsley, Alexander

2017-04-01

The prevalence of aspergillosis in CF patients has until recently been underestimated, but increasing evidence suggests that it may play an important role in the progression of CF lung disease. In healthy airways, Aspergillus fumigatus can be efficiently removed from the lung by mechanisms such as mucociliary clearance and cough. However, these mechanisms are defective in CF, allowing pathogens such as A. fumigatus to germinate and establish chronic infections within the airways. The precise means by which A. fumigatus contributes to CF lung disease remain largely unclear. As the first point of contact within the lung, and an important component of the innate immune system, it is likely that the mucus barrier plays an important role in this process. Study of the functional interplay between this vital protective barrier, and in particular its principal structural components, the polymeric gel-forming mucins, and CF pathogens such as A. fumigatus, is at an early stage. A. fumigatus protease activity has been shown to upregulate mucus production by inducing mucin mRNA and protein expression, and A. fumigatus proteases and glycosidases are able to degrade mucins. This may allow A. fumigatus to alter mucus barrier properties to promote fungal colonization of the airways and/or utilize mucins as a nutrient source. Moreover, conidial surface lectin binding to mucin glycans is a key aspect of clearance of Aspergillus from the lung in health but may be an important aspect of colonization, where mucociliary clearance is compromised, as in the CF lung. Here we discuss the nature of the mucus barrier and its mucin components in CF, and how they may be implicated in A. fumigatus infection. Pediatr Pulmonol 2017;52:548-555. © 2016 The Authors. Pediatric Pulmonology. Published by Wiley Periodicals, Inc. © 2016 The Authors. Pediatric Pulmonology Published by Wiley Periodicals, Inc.

Aspergillosis and the role of mucins in cystic fibrosis

PubMed Central

Cowley, Abigail C.; Thornton, David J.; Denning, David W.

2016-01-01

Summary The prevalence of aspergillosis in CF patients has until recently been underestimated, but increasing evidence suggests that it may play an important role in the progression of CF lung disease. In healthy airways, Aspergillus fumigatus can be efficiently removed from the lung by mechanisms such as mucociliary clearance and cough. However, these mechanisms are defective in CF, allowing pathogens such as A. fumigatus to germinate and establish chronic infections within the airways. The precise means by which A. fumigatus contributes to CF lung disease remain largely unclear. As the first point of contact within the lung, and an important component of the innate immune system, it is likely that the mucus barrier plays an important role in this process. Study of the functional interplay between this vital protective barrier, and in particular its principal structural components, the polymeric gel‐forming mucins, and CF pathogens such as A. fumigatus, is at an early stage. A. fumigatus protease activity has been shown to upregulate mucus production by inducing mucin mRNA and protein expression, and A. fumigatus proteases and glycosidases are able to degrade mucins. This may allow A. fumigatus to alter mucus barrier properties to promote fungal colonization of the airways and/or utilize mucins as a nutrient source. Moreover, conidial surface lectin binding to mucin glycans is a key aspect of clearance of Aspergillus from the lung in health but may be an important aspect of colonization, where mucociliary clearance is compromised, as in the CF lung. Here we discuss the nature of the mucus barrier and its mucin components in CF, and how they may be implicated in A. fumigatus infection. Pediatr Pulmonol 2017;52:548–555. © 2016 The Authors. Pediatric Pulmonology. Published by Wiley Periodicals, Inc. PMID:27870227

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.

Phosphoinositide 3-kinase gamma regulates airway smooth muscle contraction by modulating calcium oscillations.

PubMed

Jiang, Haihong; Abel, Peter W; Toews, Myron L; Deng, Caishu; Casale, Thomas B; Xie, Yan; Tu, Yaping

2010-09-01

Phosphoinositide 3-kinase gamma (PI3Kgamma) has been implicated in the pathogenesis of asthma, but its mechanism has been considered indirect, through release of inflammatory cell mediators. Because airway smooth muscle (ASM) contractile hyper-responsiveness plays a critical role in asthma, the aim of the present study was to determine whether PI3Kgamma can directly regulate contractility of ASM. Immunohistochemistry staining indicated expression of PI3Kgamma protein in ASM cells of mouse trachea and lung, which was confirmed by Western blot analysis in isolated mouse tracheal ASM cells. PI3Kgamma inhibitor II inhibited acetylcholine (ACh)-stimulated airway contraction of cultured precision-cut mouse lung slices in a dose-dependent manner with 75% inhibition at 10 muM. In contrast, inhibitors of PI3Kalpha, PI3Kbeta, or PI3Kdelta, at concentrations 40-fold higher than their reported IC(50) values for their primary targets, had no effect. It is noteworthy that airways in lung slices pretreated with PI3Kgamma inhibitor II still exhibited an ACh-induced initial contraction, but the sustained contraction was significantly reduced. Furthermore, the PI3Kgamma-selective inhibitor had a small inhibitory effect on the ACh-stimulated initial Ca(2+) transient in ASM cells of mouse lung slices or isolated mouse ASM cells but significantly attenuated the sustained Ca(2+) oscillations that are critical for sustained airway contraction. This report is the first to show that PI3Kgamma directly controls contractility of airways through regulation of Ca(2+) oscillations in ASM cells. Thus, in addition to effects on airway inflammation, PI3Kgamma inhibitors may also exert direct effects on the airway contraction that contribute to pathologic airway hyper-responsiveness.

Phosphoinositide 3-Kinase γ Regulates Airway Smooth Muscle Contraction by Modulating Calcium Oscillations

PubMed Central

Jiang, Haihong; Abel, Peter W.; Toews, Myron L.; Deng, Caishu; Casale, Thomas B.; Xie, Yan

2010-01-01

Phosphoinositide 3-kinase γ (PI3Kγ) has been implicated in the pathogenesis of asthma, but its mechanism has been considered indirect, through release of inflammatory cell mediators. Because airway smooth muscle (ASM) contractile hyper-responsiveness plays a critical role in asthma, the aim of the present study was to determine whether PI3Kγ can directly regulate contractility of ASM. Immunohistochemistry staining indicated expression of PI3Kγ protein in ASM cells of mouse trachea and lung, which was confirmed by Western blot analysis in isolated mouse tracheal ASM cells. PI3Kγ inhibitor II inhibited acetylcholine (ACh)-stimulated airway contraction of cultured precision-cut mouse lung slices in a dose-dependent manner with 75% inhibition at 10 μM. In contrast, inhibitors of PI3Kα, PI3Kβ, or PI3Kδ, at concentrations 40-fold higher than their reported IC50 values for their primary targets, had no effect. It is noteworthy that airways in lung slices pretreated with PI3Kγ inhibitor II still exhibited an ACh-induced initial contraction, but the sustained contraction was significantly reduced. Furthermore, the PI3Kγ-selective inhibitor had a small inhibitory effect on the ACh-stimulated initial Ca2+ transient in ASM cells of mouse lung slices or isolated mouse ASM cells but significantly attenuated the sustained Ca2+ oscillations that are critical for sustained airway contraction. This report is the first to show that PI3Kγ directly controls contractility of airways through regulation of Ca2+ oscillations in ASM cells. Thus, in addition to effects on airway inflammation, PI3Kγ inhibitors may also exert direct effects on the airway contraction that contribute to pathologic airway hyper-responsiveness. PMID:20501633

Alveolar macrophages from allergic lungs are not committed to a pro-allergic response and can reduce airway hyperresponsiveness following ex vivo culture

PubMed Central

Pouliot, P.; Spahr, A.; Careau, É.; Turmel, V.; Bissonnette, E. Y.

2016-01-01

Summary Background We already demonstrated that adoptive transfer of alveolar macrophages (AMs) from non-allergic rats into AM-depleted allergic rats prevents airway hyperresponsiveness (AHR). We also showed that AMs from non-sensitized, but not from sensitized, allergy-prone rats can prevent AHR following allergen challenge in sensitized allergic animals, establishing the importance of rat immunological status on the modulation of AM functions and suggesting that an allergic lung environment alters AM functions. Objective We investigated how the activation of allergic AMs can be modulated to reinstitute them with their capacity to reduce AHR. Methods AMs from sensitized Brown Norway rats were cultured ex vivo for up to 18 h in culture media to deprogram them from the influence of the allergic lung before being reintroduced into the lung of AM-depleted sensitized recipient. AHR and cytokines in bronchoalveolar lavage (BAL) were measured following allergen challenge. AMs stimulated ex vivo with Bacillus Calmette-Guerin(BCG) were used as positive controls as BCG induces a T-helper type 1 activation in AMs. Results AMs ex vivo cultured for 4–18 h reduced AHR to normal level. Interestingly, pro-allergic functions of AMs were dampened by 18 h culture and they reduced AHR even after spending 48 h in an allergic lung microenvironment. Furthermore, transfer of cultured AMs caused an increase in the levels of IFN-γ and IL-12 in BAL when compared with their ovalbumin control. After 18 h of ex vivo culture, AMs expressed reduced levels of TNF, IL-1α, IL-6, and Arginase-2 mRNAs compared with freshly isolated AMs, suggesting that ex vivo culture exempted AMs from lung stimuli that affected their functions. Conclusions There is a significant crosstalk between lung microenvironment and AMs, affecting their functions. It is also the first report showing that sensitized AMs can be modulated ex vivo to reduce lung pro-allergic environment, opening the way to therapies targetting AMs. PMID:18201249

Association between lung function and mental health problems among adults in the United States: findings from the First National Health and Nutrition Examination Survey.

PubMed

Goodwin, Renee D; Chuang, Shirley; Simuro, Nicole; Davies, Mark; Pine, Daniel S

2007-02-15

The objective of this study was to determine the association between lung function and mental health problems among adults in the United States. Data were drawn from the First National Health and Nutrition Examination Survey (1971-1975), with available information on a representative sample of US adults aged 25-74 years. Lung function was assessed by spirometry, and provisional diagnoses of restrictive and obstructive airway disease were assigned based on percentage of expected forced expiratory volume. Mental health problems were assessed with the General Well-Being scales. Restrictive lung function and obstructive lung function, compared with normal lung function, were each associated with a significantly increased likelihood of mental health problems. After adjustment for differences in demographic characteristics, obstructive lung function was associated with significantly lower overall well-being (p = 0.025), and restrictive lung function was associated with significantly lower overall well-being (p < 0.001), general health (p < 0.0001), vitality (p < 0.0001), and self-control (p = 0.001) and with higher depression (p = 0.002) subscale scores compared with no lung function problems. Consistent with previous findings from clinical and community-based studies, these results extend available data by providing evidence of a link between objectively measured lung function and self-reported mental health problems in a representative sample of community adults. Future studies are needed to determine the mechanisms of these associations.

Comparison of low- and ultralow-dose computed tomography protocols for quantitative lung and airway assessment.

PubMed

Hammond, Emily; Sloan, Chelsea; Newell, John D; Sieren, Jered P; Saylor, Melissa; Vidal, Craig; Hogue, Shayna; De Stefano, Frank; Sieren, Alexa; Hoffman, Eric A; Sieren, Jessica C

2017-09-01

Quantitative computed tomography (CT) measures are increasingly being developed and used to characterize lung disease. With recent advances in CT technologies, we sought to evaluate the quantitative accuracy of lung imaging at low- and ultralow-radiation doses with the use of iterative reconstruction (IR), tube current modulation (TCM), and spectral shaping. We investigated the effect of five independent CT protocols reconstructed with IR on quantitative airway measures and global lung measures using an in vivo large animal model as a human subject surrogate. A control protocol was chosen (NIH-SPIROMICS + TCM) and five independent protocols investigating TCM, low- and ultralow-radiation dose, and spectral shaping. For all scans, quantitative global parenchymal measurements (mean, median and standard deviation of the parenchymal HU, along with measures of emphysema) and global airway measurements (number of segmented airways and pi10) were generated. In addition, selected individual airway measurements (minor and major inner diameter, wall thickness, inner and outer area, inner and outer perimeter, wall area fraction, and inner equivalent circle diameter) were evaluated. Comparisons were made between control and target protocols using difference and repeatability measures. Estimated CT volume dose index (CTDIvol) across all protocols ranged from 7.32 mGy to 0.32 mGy. Low- and ultralow-dose protocols required more manual editing and resolved fewer airway branches; yet, comparable pi10 whole lung measures were observed across all protocols. Similar trends in acquired parenchymal and airway measurements were observed across all protocols, with increased measurement differences using the ultralow-dose protocols. However, for small airways (1.9 ± 0.2 mm) and medium airways (5.7 ± 0.4 mm), the measurement differences across all protocols were comparable to the control protocol repeatability across breath holds. Diameters, wall thickness, wall area fraction, and equivalent diameter had smaller measurement differences than area and perimeter measurements. In conclusion, the use of IR with low- and ultralow-dose CT protocols with CT volume dose indices down to 0.32 mGy maintains selected quantitative parenchymal and airway measurements relevant to pulmonary disease characterization. © 2017 American Association of Physicists in Medicine.

A canine model for production of severe unilateral panacinar emphysema.

PubMed

Chino, Kimiaki; Choong, Cliff K; Toeniskoetter, P Diane; Cooper, Joel D; Lausberg, Henning F; Bae, Kyongtae T; Pierce, John A; Hogg, James C

2004-06-01

The authors created a canine model of severe emphysema using whole lung lavage to deliver repeated porcine pancreatic elastase solution to the terminal airways and alveoli of the right lung. This model produces extreme unilateral panacinar emphysema closely resembling that encountered in patients with alpha1-antitrypsin deficiency. Because the contralateral lung remains functional, the animals can be maintained indefinitely. The model will be of value in developing imaging techniques capable of safely evaluating the effect of treatment on panacinar emphysema in alpha1-antitrypsin-deficient patients.

Physiology of respiratory disturbances in muscular dystrophies

PubMed Central

Lo Mauro, Antonella

2016-01-01

Muscular dystrophy is a group of inherited myopathies characterised by progressive skeletal muscle wasting, including of the respiratory muscles. Respiratory failure, i.e. when the respiratory system fails in its gas exchange functions, is a common feature in muscular dystrophy, being the main cause of death, and it is a consequence of lung failure, pump failure or a combination of the two. The former is due to recurrent aspiration, the latter to progressive weakness of respiratory muscles and an increase in the load against which they must contract. In fact, both the resistive and elastic components of the work of breathing increase due to airway obstruction and chest wall and lung stiffening, respectively. The respiratory disturbances in muscular dystrophy are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered breathing. They can be present at different rates according to the type of muscular dystrophy and its progression, leading to different onset of each symptom, prognosis and degree of respiratory involvement. Key points A common feature of muscular dystrophy is respiratory failure, i.e. the inability of the respiratory system to provide proper oxygenation and carbon dioxide elimination. In the lung, respiratory failure is caused by recurrent aspiration, and leads to hypoxaemia and hypercarbia. Ventilatory failure in muscular dystrophy is caused by increased respiratory load and respiratory muscles weakness. Respiratory load increases in muscular dystrophy because scoliosis makes chest wall compliance decrease, atelectasis and fibrosis make lung compliance decrease, and airway obstruction makes airway resistance increase. The consequences of respiratory pump failure are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered breathing. Educational aims To understand the mechanisms leading to respiratory disturbances in patients with muscular dystrophy. To understand the impact of respiratory disturbances in patients with muscular dystrophy. To provide a brief description of the main forms of muscular dystrophy with their respiratory implications. PMID:28210319

Physiology of respiratory disturbances in muscular dystrophies.

PubMed

Lo Mauro, Antonella; Aliverti, Andrea

2016-12-01

Muscular dystrophy is a group of inherited myopathies characterised by progressive skeletal muscle wasting, including of the respiratory muscles. Respiratory failure, i.e . when the respiratory system fails in its gas exchange functions, is a common feature in muscular dystrophy, being the main cause of death, and it is a consequence of lung failure, pump failure or a combination of the two. The former is due to recurrent aspiration, the latter to progressive weakness of respiratory muscles and an increase in the load against which they must contract. In fact, both the resistive and elastic components of the work of breathing increase due to airway obstruction and chest wall and lung stiffening, respectively. The respiratory disturbances in muscular dystrophy are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered breathing. They can be present at different rates according to the type of muscular dystrophy and its progression, leading to different onset of each symptom, prognosis and degree of respiratory involvement. A common feature of muscular dystrophy is respiratory failure, i.e. the inability of the respiratory system to provide proper oxygenation and carbon dioxide elimination.In the lung, respiratory failure is caused by recurrent aspiration, and leads to hypoxaemia and hypercarbia.Ventilatory failure in muscular dystrophy is caused by increased respiratory load and respiratory muscles weakness.Respiratory load increases in muscular dystrophy because scoliosis makes chest wall compliance decrease, atelectasis and fibrosis make lung compliance decrease, and airway obstruction makes airway resistance increase.The consequences of respiratory pump failure are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered breathing. To understand the mechanisms leading to respiratory disturbances in patients with muscular dystrophy.To understand the impact of respiratory disturbances in patients with muscular dystrophy.To provide a brief description of the main forms of muscular dystrophy with their respiratory implications.

Overall and peripheral lung function assessment by spirometry and forced oscillation technique in relation to asthma diagnosis and control.

PubMed

Heijkenskjöld Rentzhog, C; Janson, C; Berglund, L; Borres, M P; Nordvall, L; Alving, K; Malinovschi, A

2017-12-01

Classic spirometry is effort dependent and of limited value in assessing small airways. Peripheral airway involvement, and relation to poor control, in asthma, has been highlighted recently. Forced oscillation technique (FOT) offers an effort-independent assessment of overall and peripheral lung mechanics. We studied the association between lung function variables, obtained either by spirometry or multifrequency (5, 11 and 19 Hz) FOT, and asthma diagnosis and control. Spirometry measures, resistance at 5 (R5) and 19 Hz (R19), reactance at 5 Hz (X5), resonant frequency (f res ), resistance difference between 5-19 Hz (R5-R19) and Asthma Control Test scores were determined in 234 asthmatic and 60 healthy subjects (aged 13-39 years). We used standardized lung function variables in logistic regression analyses, unadjusted and adjusted for age, height, gender and weight. Lower FEV 1 /FVC (OR [95% CI] 0.47 [0.32, 0.69]) and FEF 50 (0.62 [0.46, 0.85]) per standard deviation increase, and higher R5 (3.31 [1.95, 5.62]) and R19 (2.54 [1.65, 3.91]) were associated with asthma diagnosis. Independent predictive effects of FEV 1 /FVC and R5 or R19, respectively, were found for asthma diagnosis. Lower FEV 1 /FVC and altered peripheral FOT measures (X5, f res and R5-R19) were associated with uncontrolled asthma (P-values < .05). Resistance FOT measures were equally informative as spirometry, related to asthma diagnosis, and, furthermore, offered additive information to FEV 1 /FVC, supporting a complementary role for FOT. Asthma control was related to FOT measures of peripheral airways, suggesting a potential use in identifying such involvement. Further studies are needed to determine a clinical value and relevant reference values in children, for the multifrequency FOT measurements. © 2017 John Wiley & Sons Ltd.

Effect of Very-High-Flow Nasal Therapy on Airway Pressure and End-Expiratory Lung Impedance in Healthy Volunteers.

PubMed

Parke, Rachael L; Bloch, Andreas; McGuinness, Shay P

2015-10-01

Previous research has demonstrated a positive linear correlation between flow delivered and airway pressure generated by high-flow nasal therapy. Current practice is to use flows over a range of 30-60 L/min; however, it is technically possible to apply higher flows. In this study, airway pressure measurements and electrical impedance tomography were used to assess the relationship between flows of up to 100 L/min and changes in lung physiology. Fifteen healthy volunteers were enrolled into this study. A high-flow nasal system capable of delivering a flow of 100 L/min was purpose-built using 2 Optiflow systems. Airway pressure was measured via the nasopharynx, and cumulative changes in end-expiratory lung impedance were recorded using the PulmoVista 500 system at gas flows of 30-100 L/min in increments of 10 L/min. The mean age of study participants was 31 (range 22-44) y, the mean ± SD height was 171.8 ± 7.5 cm, the mean ± SD weight was 69.7 ± 10 kg, and 47% were males. Flows ranged from 30 to 100 L/min with resulting mean ± SD airway pressures of 2.7 ± 0.7 to 11.9 ± 2.7 cm H2O. A cumulative and linear increase in end-expiratory lung impedance was observed with increasing flows, as well as a decrease in breathing frequency. Measured airway pressure and lung impedance increased linearly with increased gas flow. Observed airway pressures were in the range used clinically with face-mask noninvasive ventilation. Developments in delivery systems may result in this therapy being an acceptable alternative to face-mask noninvasive ventilation. Copyright © 2015 by Daedalus Enterprises.

High-resolution three-dimensional 19F-magnetic resonance imaging of rat lung in situ: evaluation of airway strain in the perfluorocarbon-filled lung.

PubMed

Weigel, Julia K; Steinmann, Daniel; Emerich, Philipp; Stahl, Claudius A; v Elverfeldt, Dominik; Guttmann, Josef

2011-02-01

Perfluorocarbons (PFC) are biologically and chemically inert fluids with high oxygen and CO(2) carrying capacities. Their use as liquid intrapulmonary gas carriers during liquid ventilation has been investigated. We established a method of high resolution 3D-(19)F-MRI of the totally PFC-filled lung. The goal of this study was to investigate longitudinal and circumferential airway strain in the setting of increasing airway pressures on 3D-(19)F-MR images of the PFC-filled lung. Sixteen female Wistar rats were euthanized and the liquid perfluorocarbon FC-84 instilled into their lungs. 3D-(19)F-MRI was performed at various intrapulmonary pressures. Measurements of bronchial length and cross-sectional area were obtained from transversal 2D images for each pressure range. Changes in bronchial area were used to determine circumferential strain, while longitudinal strain was calculated from changes in bronchial length. Our method of 3D-(19)F-MRI allowed clear visualization of the great bronchi. Longitudinal strain increased significantly up to 31.1 cmH(2)O. The greatest strain could be found in the range of low airway pressures. Circumferential strain increased strongly with the initial pressure rise, but showed no significant changes above 10.4 cmH(2)O. Longitudinal strain was generally higher in distal airways, while circumferential strain showed no difference. Analysis of mechanical characteristics showed that longitudinal and circumferential airway expansion occurred in an anisotropic fashion. Whereas longitudinal strain still increased with higher pressures, circumferential strain quickly reached a 'strain limit'. Longitudinal strain was higher in distal bronchi, as dense PFCs gravitate to dependent, in this case to dorso-basal parts of the lung, acting as liquid positive end expiratory pressure.

Early treatment of chlorine-induced airway hyperresponsiveness and inflammation with corticosteroids.

PubMed

Jonasson, Sofia; Wigenstam, Elisabeth; Koch, Bo; Bucht, Anders

2013-09-01

Chlorine (Cl2) is an industrial gas that is highly toxic and irritating when inhaled causing tissue damage and an acute inflammatory response in the airways followed by a long-term airway dysfunction. The aim of this study was to evaluate whether early anti-inflammatory treatment can protect against the delayed symptoms in Cl2-exposed mice. BALB/c mice were exposed by nose-only inhalation using 200ppm Cl2 during 15min. Assessment of airway hyperresponsiveness (AHR), inflammatory cell counts in bronchoalveolar lavage, occurrence of lung edema and lung fibrosis were analyzed 24h or 14days post-exposure. A single dose of the corticosteroid dexamethasone (10 or 100mg/kg) was administered intraperitoneally 1, 3, 6, or 12h following Cl2 exposure. High-dose of dexamethasone reduced the acute inflammation if administered within 6h after exposure but treated animals still displayed a significant lung injury. The effect of dexamethasone administered within 1h was dose-dependent; high-dose significantly reduced acute airway inflammation (100mg/kg) but not treatment with the relatively low-dose (10mg/kg). Both doses reduced AHR 14days later, while lung fibrosis measured as collagen deposition was not significantly reduced. The results point out that the acute inflammation in the lungs due to Cl2 exposure only partly is associated with the long-term AHR. We hypothesize that additional pathogenic mechanisms apart from the inflammatory reactions contribute to the development of long-term airway dysfunction. By using this mouse model, we have validated early administration of corticosteroids in terms of efficacy to prevent acute lung injury and delayed symptoms induced by Cl2 exposure. Copyright © 2013 Elsevier Inc. All rights reserved.

Viral and Mycoplasma pneumoniae pneumonias in school-age children: three-year follow-up of respiratory function.

PubMed

Todisco, T; de Benedictis, F M; Dottorini, M

1989-01-01

We studied the evolution of respiratory function during and for 3 years after the acute onset of viral and Mycoplasma pneumoniae pneumonias in 13 school-age children. A mixed type transient ventilatory defect (restrictive and obstructive, but mainly restrictive) with large and small airway involvement was observed during the acute phase of the pneumonias. Residual small airway involvement was found over the next 12 months, but no pulmonary function abnormalities were present after 3 years. At that time, one of the 13 subjects displayed bronchial hyperreactivity to distilled water mist challenge. The authors concluded that viral and Mycoplasma pneumoniae pneumonia in previously healthy school-age children does not cause impaired lung function in later childhood.

Comparison of stochastic lung deposition fractions with experimental data.

PubMed

Majid, Hussain; Hofmann, Werner; Winkler-Heil, Renate

2012-04-01

Deposition fractions of inhaled particles predicted by different computational models vary with respect to physical and biological factors and mathematical modeling techniques. These models must be validated by comparison with available experimental data. Experimental data supplied by different deposition studies with surrogate airway models or lung casts were used in this study to evaluate the stochastic deposition model Inhalation, Deposition and Exhalation of Aerosols in the Lung at the airway generation level. Furthermore, different analytical equations derived for the three major deposition mechanisms, diffusion, impaction, and sedimentation, were applied to different cast or airway models to quantify their effect on calculated particle deposition fractions. The experimental results for ultrafine particles (0.00175 and 0.01) were found to be in close agreement with the stochastic model predictions; however, for coarse particles (3 and 8 μm), experimental deposition fractions became higher with increasing flow rate. An overall fair agreement among the calculated deposition fractions for the different cast geometries was found. However, alternative deposition equations resulted in up to 300% variation in predicted deposition fractions, although all equations predicted the same trends as functions of particle diameter and breathing conditions. From this comparative study, it can be concluded that structural differences in lung morphologies among different individuals are responsible for the apparent variability in particle deposition in each generation. The use of different deposition equations yields varying deposition results caused primarily by (i) different lung morphometries employed in their derivation and the choice of the central bifurcation zone geometry, (ii) the assumption of specific flow profiles, and (iii) different methods used in the derivation of these equations.

Continuous quantitative measurement of the proximal airway dimensions and lung density on four-dimensional dynamic-ventilation CT in smokers

PubMed Central

Yamashiro, Tsuneo; Moriya, Hiroshi; Tsubakimoto, Maho; Matsuoka, Shin; Murayama, Sadayuki

2016-01-01

Purpose Four-dimensional dynamic-ventilation computed tomography (CT) imaging demonstrates continuous movement of the airways and lungs, which cannot be depicted with conventional CT. We aimed to investigate continuous changes in lung density and airway dimensions and to assess the correlation with spirometric values in smokers. Materials and methods This retrospective study was approved by the Institutional Review Board, and informed consent was waived. Twenty-one smokers including six patients with COPD underwent four-dimensional dynamic-ventilation CT during free breathing (160 mm in length). The mean lung density (MLD) of the scanned lung and luminal areas (Ai) of fixed points in the trachea and the right proximal bronchi (main bronchus, upper bronchus, bronchus intermedius, and lower bronchus) were continuously measured. Concordance between the time curve of the MLD and that of the airway Ai values was expressed by cross-correlation coefficients. The associations between these quantitative measurements and the forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) values were assessed by Spearman’s rank correlation analysis. Results On the time curve for the MLD, the Δ-MLD1.05 values between the peak inspiratory frame to the later third frame (1.05 seconds later) were strongly correlated with the FEV1/FVC (ρ=0.76, P<0.0001). The cross-correlation coefficients between the airway Ai and MLD values were significantly correlated with the FEV1/FVC (ρ=−0.56 to −0.66, P<0.01), except for the right upper bronchus. This suggested that the synchrony between the airway and lung movement was lost in patients with severe airflow limitation. Conclusion Respiratory changes in the MLD and synchrony between the airway Ai and the MLD measured with dynamic-ventilation CT were correlated with patient’s spirometric values. PMID:27110108

Specificity of arrestin subtypes in regulating airway smooth muscle G protein-coupled receptor signaling and function.

PubMed

Pera, Tonio; Hegde, Akhil; Deshpande, Deepak A; Morgan, Sarah J; Tiegs, Brian C; Theriot, Barbara S; Choi, Yeon H; Walker, Julia K L; Penn, Raymond B

2015-10-01

Arrestins have been shown to regulate numerous G protein-coupled receptors (GPCRs) in studies employing receptor/arrestin overexpression in artificial cell systems. Which arrestin isoforms regulate which GPCRs in primary cell types is poorly understood. We sought to determine the effect of β-arrestin-1 or β-arrestin-2 inhibition or gene ablation on signaling and function of multiple GPCRs endogenously expressed in airway smooth muscle (ASM). In vitro [second messenger (calcium, cAMP generation)], ex vivo (ASM tension generation in suspended airway), and in vivo (invasive airway resistance) analyses were performed on human ASM cells and murine airways/whole animal subject to β-arrestin-1 or -2 knockdown or knockout (KO). In both human and murine model systems, knockdown or KO of β-arrestin-2 relative to control missense small interfering RNA or wild-type mice selectively increased (40-60%) β2-adrenoceptor signaling and function. β-arrestin-1 knockdown or KO had no effect on signaling and function of β2-adrenoceptor or numerous procontractile GPCRs, but selectively inhibited M3 muscarinic acetylcholine receptor signaling (∼50%) and function (∼25% ex vivo, >50% in vivo) without affecting EC50 values. Arrestin subtypes differentially regulate ASM GPCRs and β-arrestin-1 inhibition represents a novel approach to managing bronchospasm in obstructive lung diseases. © FASEB.

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

PubMed Central

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

2013-01-01

During lung development, proper epithelial cell arrangements are critical for the formation of an arborized network of tubes. Each tube requires a lumen, the diameter of which must be tightly regulated to enable optimal lung function. Lung branching and lumen morphogenesis require close epithelial cell–cell contacts that are maintained as a result of adherens junctions, tight junctions and by intact apical–basal (A/B) polarity. However, the molecular mechanisms that maintain epithelial cohesion and lumen diameter in the mammalian lung are unknown. Here we show that Scribble, a protein implicated in planar cell polarity (PCP) signalling, is necessary for normal lung morphogenesis. Lungs of the Scrib mouse mutant Circletail (Crc) are abnormally shaped with fewer airways, and these airways often lack a visible, ‘open’ lumen. Mechanistically we show that Scrib genetically interacts with the core PCP gene Vangl2 in the developing lung and that the distribution of PCP pathway proteins and Rho mediated cytoskeletal modification is perturbed in ScribCrc/Crc lungs. However A/B polarity, which is disrupted in Drosophila Scrib mutants, is largely unaffected. Notably, we find that Scrib mediates functions not attributed to other PCP proteins in the lung. Specifically, Scrib localises to both adherens and tight junctions of lung epithelia and knockdown of Scrib in lung explants and organotypic cultures leads to reduced cohesion of lung epithelial cells. Live imaging of Scrib knockdown lungs shows that Scrib does not affect bud bifurcation, as previously shown for the PCP protein Celsr1, but is required to maintain epithelial cohesion. To understand the mechanism leading to reduced cell–cell association, we show that Scrib associates with β-catenin in embryonic lung and the sub-cellular distribution of adherens and tight junction proteins is perturbed in mutant lung epithelia. Our data reveal that Scrib is required for normal lung epithelial organisation and lumen morphogenesis by maintaining cell–cell contacts. Thus we reveal novel and important roles for Scrib in lung development operating via the PCP pathway, and in regulating junctional complexes and cell cohesion. PMID:23195221

Systems for lung volume standardization during static and dynamic MDCT-based quantitative assessment of pulmonary structure and function.

PubMed

Fuld, Matthew K; Grout, Randall W; Guo, Junfeng; Morgan, John H; Hoffman, Eric A

2012-08-01

Multidetector-row computed tomography (MDCT) has emerged as a tool for quantitative assessment of parenchymal destruction, air trapping (density metrics), and airway remodeling (metrics relating airway wall and lumen geometry) in chronic obstructive pulmonary disease (COPD) and asthma. Critical to the accuracy and interpretability of these MDCT-derived metrics is the assurance that the lungs are scanned during a breathhold at a standardized volume. A computer monitored turbine-based flow meter system was developed to control patient breathholds and facilitate static imaging at fixed percentages of the vital capacity. Because of calibration challenges with gas density changes during multibreath xenon CT, an alternative system was required. The design incorporated dual rolling seal pistons. Both systems were tested in a laboratory environment and human subject trials. The turbine-based system successfully controlled lung volumes in 32/37 subjects, having a linear relationship for CT measured air volume between repeated scans: for all scans, the mean and confidence interval of the differences (scan1-scan2) was -9 mL (-169, 151); for total lung capacity alone 6 mL (-164, 177); for functional residual capacity alone, -23 mL (-172, 126). The dual-piston system successfully controlled lung volume in 31/41 subjects. Study failures related largely to subject noncompliance with verbal instruction and gas leaks around the mouthpiece. We demonstrate the successful use of a turbine-based system for static lung volume control and demonstrate its inadequacies for dynamic xenon CT studies. Implementation of a dual-rolling seal spirometer has been shown to adequately control lung volume for multibreath wash-in xenon CT studies. These systems coupled with proper patient coaching provide the tools for the use of CT to quantitate regional lung structure and function. The wash-in xenon CT method for assessing regional lung function, although not necessarily practical for routine clinical studies, provides for a dynamic protocol against which newly emerging single breath, dual-energy xenon CT measures can be validated. Copyright © 2012 AUR. Published by Elsevier Inc. All rights reserved.

Histologic and biochemical alterations predict pulmonary mechanical dysfunction in aging mice with chronic lung inflammation

PubMed Central

Laskin, Debra L.; Gow, Andrew J.

2017-01-01

Both aging and chronic inflammation produce complex structural and biochemical alterations to the lung known to impact work of breathing. Mice deficient in surfactant protein D (Sftpd) develop progressive age-related lung pathology characterized by tissue destruction/remodeling, accumulation of foamy macrophages and alteration in surfactant composition. This study proposes to relate changes in tissue structure seen in normal aging and in chronic inflammation to altered lung mechanics using a computational model. Alterations in lung function in aging and Sftpd -/- mice have been inferred from fitting simple mechanical models to respiratory impedance data (Zrs), however interpretation has been confounded by the simultaneous presence of multiple coexisting pathophysiologic processes. In contrast to the inverse modeling approach, this study uses simulation from experimental measurements to recapitulate how aging and inflammation alter Zrs. Histologic and mechanical measurements were made in C57BL6/J mice and congenic Sftpd-/- mice at 8, 27 and 80 weeks of age (n = 8/group). An anatomic computational model based on published airway morphometry was developed and Zrs was simulated between 0.5 and 20 Hz. End expiratory pressure dependent changes in airway caliber and recruitment were estimated from mechanical measurements. Tissue elements were simulated using the constant phase model of viscoelasticity. Baseline elastance distribution was estimated in 8-week-old wild type mice, and stochastically varied for each condition based on experimentally measured alteration in elastic fiber composition, alveolar geometry and surfactant composition. Weighing reduction in model error against increasing model complexity allowed for identification of essential features underlying mechanical pathology and their contribution to Zrs. Using a maximum likelihood approach, alteration in lung recruitment and diminished elastic fiber density were shown predictive of mechanical alteration at airway opening, to a greater extent than overt acinar wall destruction. Model-predicted deficits in PEEP-dependent lung recruitment correlate with altered lung lining fluid composition independent of age or genotype. PMID:28837561

Histologic and biochemical alterations predict pulmonary mechanical dysfunction in aging mice with chronic lung inflammation.

PubMed

Massa, Christopher B; Groves, Angela M; Jaggernauth, Smita U; Laskin, Debra L; Gow, Andrew J

2017-08-01

Both aging and chronic inflammation produce complex structural and biochemical alterations to the lung known to impact work of breathing. Mice deficient in surfactant protein D (Sftpd) develop progressive age-related lung pathology characterized by tissue destruction/remodeling, accumulation of foamy macrophages and alteration in surfactant composition. This study proposes to relate changes in tissue structure seen in normal aging and in chronic inflammation to altered lung mechanics using a computational model. Alterations in lung function in aging and Sftpd -/- mice have been inferred from fitting simple mechanical models to respiratory impedance data (Zrs), however interpretation has been confounded by the simultaneous presence of multiple coexisting pathophysiologic processes. In contrast to the inverse modeling approach, this study uses simulation from experimental measurements to recapitulate how aging and inflammation alter Zrs. Histologic and mechanical measurements were made in C57BL6/J mice and congenic Sftpd-/- mice at 8, 27 and 80 weeks of age (n = 8/group). An anatomic computational model based on published airway morphometry was developed and Zrs was simulated between 0.5 and 20 Hz. End expiratory pressure dependent changes in airway caliber and recruitment were estimated from mechanical measurements. Tissue elements were simulated using the constant phase model of viscoelasticity. Baseline elastance distribution was estimated in 8-week-old wild type mice, and stochastically varied for each condition based on experimentally measured alteration in elastic fiber composition, alveolar geometry and surfactant composition. Weighing reduction in model error against increasing model complexity allowed for identification of essential features underlying mechanical pathology and their contribution to Zrs. Using a maximum likelihood approach, alteration in lung recruitment and diminished elastic fiber density were shown predictive of mechanical alteration at airway opening, to a greater extent than overt acinar wall destruction. Model-predicted deficits in PEEP-dependent lung recruitment correlate with altered lung lining fluid composition independent of age or genotype.

A novel combination of the Arndt endobronchial blocker and the laryngeal mask airway ProSeal™ provides one-lung ventilation for thoracic surgery

PubMed Central

LI, QIONG; LI, PEIYING; XU, JIANGHUI; GU, HUAHUA; MA, QINYUN; PANG, LIEWEN; LIANG, WEIMIN

2014-01-01

In this study, the feasibility and performance of the combination of the Arndt endobronchial blocker and the laryngeal mask airway (LMA) ProSeal™ in airway establishment, ventilation, oxygenation and lung isolation was evaluated. Fifty-five patients undergoing general anesthesia for elective thoracic surgeries were randomly allocated to group Arndt (n=26) or group double-lumen tube (DLT; n=29). Data concerning post-operative airway morbidity, ease of insertion, hemodynamics, lung collapse, ventilators, oxygenation and ventilation were collected for analysis. Compared with group DLT, group Arndt showed a significantly attenuated hemodynamic response to intubation (blood pressure, 149±31 vs. 115±16 mmHg; heart rate, 86±15 vs. 68±15 bpm), less severe injuries to the bronchus (injury score, 1.4±0.2 vs. 0.4±0.1) and vocal cords (injury score, 1.3±0.2 vs. 0.6±0.1), and lower incidences of post-operative sore throat and hoarseness. Furthermore, the novel combination of the Arndt and the LMA ProSeal showed similar ease of airway establishment, comparable ventilation and oxygenation performance, and an analogous lung isolation effect to DLT. The novel combined use of the Arndt endobronchial blocker and the LMA ProSeal can serve as a promising alternative for thoracic procedures requiring one-lung ventilation. The less traumatic properties and equally ideal lung isolation are likely to promote its use in rapidly spreading minimally invasive thoracic surgeries. PMID:25289071

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

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.

The Role of Collateral Paths in Long-Range Diffusion of 3He in Lungs

PubMed Central

Conradi, Mark S.; Yablonskiy, Dmitriy A.; Woods, Jason C.; Gierada, David S.; Bartel, Seth-Emil T.; Haywood, Susan E.; Menard, Christopher

2008-01-01

Rationale and Objectives The hyperpolarized 3He long-range diffusion coefficient (LRDC) in lungs is sensitive to changes in lung structure due to emphysema, reflecting the increase in collateral paths resulting from tissue destruction. However, no clear understanding of LRDC in healthy lungs has emerged. Here we compare LRDC measured in healthy lungs with computer simulations of diffusion along the airway tree with no collateral connections. Materials and Methods Computer simulations of diffusion of spatially modulated spin magnetization were performed in computer generated, symmetric-branching models of lungs and compared with existing LRDC measurements in canine and human lungs. Results The simulations predict LRDC values of order 0.001 cm2/s, approximately 20 times smaller than the measured LRDC. We consider and rule out possible mechanisms for LRDC not included in the simulations: incomplete breath hold, cardiac motion, and passage of dissolved 3He through airway walls. However, a very low density of small (micron) holes in the airways is shown to account for the observed LRDC. Conclusion It is proposed that LRDC in healthy lungs is determined by small collateral pathways. PMID:18486004

DEPOSITION DISTRICUTION AMONG THE PARALLEL PATHWAYS IN THE HUMAN LUNG CONDUCTING AIRWAY STRUCTURE.

EPA Science Inventory

DEPOSITION DISTRIBUTION AMONG THE PARALLEL PATHWAYS IN THE HUMAN LUNG CONDUCTING AIRWAY STRUCTURE. Chong S. Kim*, USEPA National Health and Environmental Effects Research Lab. RTP, NC 27711; Z. Zhang and C. Kleinstreuer, Department of Mechanical and Aerospace Engineering, North C...

Particle Deposition in Human Lungs due to Varying Cross-Sectional Ellipticity of Left and Right Main Bronchi

NASA Astrophysics Data System (ADS)

Roth, Steven; Oakes, Jessica; Shadden, Shawn

2015-11-01

Particle deposition in the human lungs can occur with every breathe. Airbourne particles can range from toxic constituents (e.g. tobacco smoke and air pollution) to aerosolized particles designed for drug treatment (e.g. insulin to treat diabetes). The effect of various realistic airway geometries on complex flow structures, and thus particle deposition sites, has yet to be extensively investigated using computational fluid dynamics (CFD). In this work, we created an image-based geometric airway model of the human lung and performed CFD simulations by employing multi-domain methods. Following the flow simulations, Lagrangian particle tracking was used to study the effect of cross-sectional shape on deposition sites in the conducting airways. From a single human lung model, the cross-sectional ellipticity (the ratio of major and minor diameters) of the left and right main bronchi was varied systematically from 2:1 to 1:1. The influence of the airway ellipticity on the surrounding flow field and particle deposition was determined.

MTOR Suppresses Cigarette Smoke-Induced Epithelial Cell Death and Airway Inflammation in Chronic Obstructive Pulmonary Disease.

PubMed

Wang, Yong; Liu, Juan; Zhou, Jie-Sen; Huang, Hua-Qiong; Li, Zhou-Yang; Xu, Xu-Chen; Lai, Tian-Wen; Hu, Yue; Zhou, Hong-Bin; Chen, Hai-Pin; Ying, Song-Min; Li, Wen; Shen, Hua-Hao; Chen, Zhi-Hua

2018-04-15

Airway epithelial cell death and inflammation are pathological features of chronic obstructive pulmonary disease (COPD). Mechanistic target of rapamycin (MTOR) is involved in inflammation and multiple cellular processes, e.g., autophagy and apoptosis, but little is known about its function in COPD pathogenesis. In this article, we illustrate how MTOR regulates cigarette smoke (CS)-induced cell death, airway inflammation, and emphysema. Expression of MTOR was significantly decreased and its suppressive signaling protein, tuberous sclerosis 2 (TSC2), was increased in the airway epithelium of human COPD and in mouse lungs with chronic CS exposure. In human bronchial epithelial cells, CS extract (CSE) activated TSC2, inhibited MTOR, and induced autophagy. The TSC2-MTOR axis orchestrated CSE-induced autophagy, apoptosis, and necroptosis in human bronchial epithelial cells; all of which cooperatively regulated CSE-induced inflammatory cytokines IL-6 and IL-8 through the NF-κB pathway. Mice with a specific knockdown of Mtor in bronchial or alveolar epithelial cells exhibited significantly augmented airway inflammation and airspace enlargement in response to CS exposure, accompanied with enhanced levels of autophagy, apoptosis, and necroptosis in the lungs. Taken together, these data demonstrate that MTOR suppresses CS-induced inflammation and emphysema-likely through modulation of autophagy, apoptosis, and necroptosis-and thus suggest that activation of MTOR may represent a novel therapeutic strategy for COPD. Copyright © 2018 by The American Association of Immunologists, Inc.

Lung lavage with oxygenated perfluorochemical liquid in acute lung injury.

PubMed

Richman, P S; Wolfson, M R; Shaffer, T H

1993-05-01

To investigate the effects of lung lavage with oxygenated liquid perfluorochemical on gas exchange, lung mechanics, and cardiac function in animals with acute lung injury. Prospective, randomized, controlled trial. Animal laboratory. Eight adult cats (2 to 4 kg, random sex). Two insults were combined to cause lung injury: oleic acid infusion and saline whole-lung wash. Animals were assigned to either the control or treatment group which consisted of a perfluorochemical liquid (Rimar 101) lavage. Perfluorochemical liquid lavage was performed three times at hourly intervals after lung injury. Three other cats with identical injury but no perfluorochemical liquid lavage served as control animals. All cats were ventilated with an FIO2 of 0.95 and positive end-expiratory pressure of 2 cm H2O continuously. Arterial blood gas tensions and pH, dynamic pulmonary compliance were measured at 15-min intervals. Cardiac index was assessed hourly, and lung fluid was collected after each of the three perfluorochemical liquid lavages. Arterial oxygen tension and pulmonary compliance deteriorated abruptly after lung injury in all cats, and improved significantly (p < .001, two-way analysis of variance) 15 mins after perfluorochemical liquid lavage. These parameters gradually returned to their baseline over 60 mins. Arterial blood pressure and cardiac index decreased after injury in all cats, and were not significantly changed after perfluorochemical liquid lavage. Hemorrhagic fluid was recovered from distal airways by perfluorochemical liquid lavage, despite prior suctioning of the airway. Perfluorochemical liquid lavage removes pulmonary edema fluid and improves gas exchange and the mechanical properties of the lung, after acute severe lung injury.

Detection of airway ischaemic damage after lung transplantation by using autofluorescence imaging bronchoscopy.

PubMed

Iga, Norichika; Oto, Takahiro; Okada, Masanori; Harada, Masaaki; Nishikawa, Hitoshi; Miyoshi, Kentaroh; Otani, Shinji; Sugimoto, Seiichiro; Yamane, Masaomi; Toyooka, Shinichi; Miyoshi, Shinichiro

2014-03-01

Airway complications related to ischaemia are a major cause of morbidity after lung transplantation. Early detection of airway ischaemia and optimal management of the anastomotic site could reduce the risk of airway complications. Autofluorescence imaging (AFI) bronchoscopy has been increasingly recognized as an effective technique for detecting abnormal mucosal thickening. The aim of this study was to investigate whether AFI bronchoscopy can facilitate the detection of airway ischaemic damage in lung transplant patients. Twenty Landrace pigs were used to create a tracheal autotransplantation model. A four-ring length of trachea was excised and implanted orthotopically. The tracheal autograft was observed on postoperative days 0, 2, 4 and 7 with AFI bronchoscopy. The extent and origin of graft autofluorescence were examined using histology and measured according to fluorescence intensity. The lesions on the tracheal autografts appeared as bright green fluorescence on AFI bronchoscopy. On confocal fluorescence microscopy, high-intensity green fluorescence was observed in the elastin fibre layer of the submucosa. The fluorescence intensity of elastin was significantly higher in the graft showing fluorescence than the graft that did not show fluorescence and that at the control site. Bright green fluorescence was seen in an elastin fibre layer in the submucosa, which was likely a result of epithelial sloughing. There is a close relationship between the bright green fluorescence pattern observed using AFI bronchoscopy and airway ischaemic damage. We conclude that AFI bronchoscopy may detect airway ischaemic damage after lung transplantation.

Expression of protease activated receptor-2 (PAR-2) in central airways of smokers and non-smokers

PubMed Central

Miotto, D; Hollenberg, M; Bunnett, N; Papi, A; Braccioni, F; Boschetto, P; Rea, F; Zuin, A; Geppetti, P; Saetta, M; Maestrelli, P; Fabbri, L; Mapp, C

2002-01-01

Background: Protease activated receptor-2 (PAR-2) is a transmembrane G protein coupled receptor preferentially activated by trypsin and tryptase. The protease activated receptors play an important role in most components of injury responses including cell proliferation, migration, matrix remodelling, and inflammation. Cigarette smoking causes an inflammatory process in the central airways, peripheral airways, lung parenchyma, and adventitia of pulmonary arteries. Methods: To quantify the expression of PAR-2 in the central airways of smokers and non-smokers, surgical specimens obtained from 30 subjects undergoing lung resection for localised pulmonary lesions (24 with a history of cigarette smoking and six non-smoking control subjects) were examined. Central airways were immunostained with an antiserum specific for PAR-2 and PAR-2 expression was quantified using light microscopy and image analysis. Results: PAR-2 expression was found in bronchial smooth muscle, epithelium, glands, and in the endothelium and smooth muscle of bronchial vessels. PAR-2 expression was similar in the central airways of smokers and non-smokers. When smokers were divided according to the presence of symptoms of chronic bronchitis and chronic airflow limitation, PAR-2 expression was increased in smooth muscle (median 3.8 (interquartile range 2.9–5.8) and 1.4 (1.07–3.4) respectively); glands (33.3 (18.2–43.8) and 16.2 (11.5–22.2), respectively); and bronchial vessels (54.2 (48.7–56.8) and 40.0 (36–40.4), respectively) of smokers with symptoms of chronic bronchitis with normal lung function compared with smokers with chronic airflow limitation (COPD), but the increase was statistically significant (p<0.005) only for bronchial vessels. Conclusions: PAR-2 is present in bronchial smooth muscle, glands, and bronchial vessels of both smokers and non-smokers. An increased expression of PAR-2 was found in bronchial vessels of patients with bronchitis compared with those with COPD. PMID:11828045

Bifidobacterium breve and Lactobacillus rhamnosus treatment is as effective as budesonide at reducing inflammation in a murine model for chronic asthma.

PubMed

Sagar, Seil; Morgan, Mary E; Chen, Si; Vos, Arjan P; Garssen, Johan; van Bergenhenegouwen, Jeroen; Boon, Louis; Georgiou, Niki A; Kraneveld, Aletta D; Folkerts, Gert

2014-04-16

Asthma is estimated to affect as many as 300 million people worldwide and its incidence and prevalence are rapidly increasing throughout the world, especially in children and within developing countries. Recently, there has been a growing interest in the use of potentially beneficial bacteria for allergic diseases. This study is aimed at exploring the therapeutic effects of long-term treatment with two different beneficial bacterial strains (Bifidobacterium breve M-16 V and Lactobacillus rhamnosus NutRes1) and a glucocorticoid (budesonide), as a reference treatment, on inflammatory response in a murine model for chronic allergic asthma. To mimic the chronic disease in asthmatic patients, we used the murine ovalbumin-induced asthma model combined with prolonged allergen exposure. Airway function; pulmonary airway inflammation; airway remodelling, mRNA expression of pattern recognition receptors, Th-specific cytokines and transcription factors in lung tissue; mast cell degranulation; in vitro T cell activation; and expression of Foxp3 in blood Th cells were examined. Lactobacillus rhamnosus reduced lung resistance to a similar extent as budesonide treatment in chronically asthmatic mice. Pulmonary airway inflammation, mast cell degranulation, T cell activation and airway remodelling were suppressed by all treatments. Beneficial bacteria and budesonide differentially modulated the expression of toll-like receptors (TLRs), nod-like receptors (NLRs), cytokines and T cell transcription factors. Bifidobacterium breve induced regulatory T cell responses in the airways by increasing Il10 and Foxp3 transcription in lung tissue as well as systemic by augmenting the mean fluorescence intensity of Foxp3 in blood CD4+ T cells. These findings show that Bifidobacterium breve M-16 V and Lactobacillus rhamnosus NutRes1 have strong anti-inflammatory properties that are comparable to budesonide and therefore may be beneficial in the treatment of chronic asthma.

Bifidobacterium breve and Lactobacillus rhamnosus treatment is as effective as budesonide at reducing inflammation in a murine model for chronic asthma

PubMed Central

2014-01-01

Background Asthma is estimated to affect as many as 300 million people worldwide and its incidence and prevalence are rapidly increasing throughout the world, especially in children and within developing countries. Recently, there has been a growing interest in the use of potentially beneficial bacteria for allergic diseases. This study is aimed at exploring the therapeutic effects of long-term treatment with two different beneficial bacterial strains (Bifidobacterium breve M-16 V and Lactobacillus rhamnosus NutRes1) and a glucocorticoid (budesonide), as a reference treatment, on inflammatory response in a murine model for chronic allergic asthma. Methods To mimic the chronic disease in asthmatic patients, we used the murine ovalbumin-induced asthma model combined with prolonged allergen exposure. Airway function; pulmonary airway inflammation; airway remodelling, mRNA expression of pattern recognition receptors, Th-specific cytokines and transcription factors in lung tissue; mast cell degranulation; in vitro T cell activation; and expression of Foxp3 in blood Th cells were examined. Results Lactobacillus rhamnosus reduced lung resistance to a similar extent as budesonide treatment in chronically asthmatic mice. Pulmonary airway inflammation, mast cell degranulation, T cell activation and airway remodelling were suppressed by all treatments. Beneficial bacteria and budesonide differentially modulated the expression of toll-like receptors (TLRs), nod-like receptors (NLRs), cytokines and T cell transcription factors. Bifidobacterium breve induced regulatory T cell responses in the airways by increasing Il10 and Foxp3 transcription in lung tissue as well as systemic by augmenting the mean fluorescence intensity of Foxp3 in blood CD4+ T cells. Conclusion These findings show that Bifidobacterium breve M-16 V and Lactobacillus rhamnosus NutRes1 have strong anti-inflammatory properties that are comparable to budesonide and therefore may be beneficial in the treatment of chronic asthma. PMID:24735374

Variable tidal volumes improve lung protective ventilation strategies in experimental lung injury.

PubMed

Spieth, Peter M; Carvalho, Alysson R; Pelosi, Paolo; Hoehn, Catharina; Meissner, Christoph; Kasper, Michael; Hübler, Matthias; von Neindorff, Matthias; Dassow, Constanze; Barrenschee, Martina; Uhlig, Stefan; Koch, Thea; de Abreu, Marcelo Gama

2009-04-15

Noisy ventilation with variable Vt may improve respiratory function in acute lung injury. To determine the impact of noisy ventilation on respiratory function and its biological effects on lung parenchyma compared with conventional protective mechanical ventilation strategies. In a porcine surfactant depletion model of lung injury, we randomly combined noisy ventilation with the ARDS Network protocol or the open lung approach (n = 9 per group). Respiratory mechanics, gas exchange, and distribution of pulmonary blood flow were measured at intervals over a 6-hour period. Postmortem, lung tissue was analyzed to determine histological damage, mechanical stress, and inflammation. We found that, at comparable minute ventilation, noisy ventilation (1) improved arterial oxygenation and reduced mean inspiratory peak airway pressure and elastance of the respiratory system compared with the ARDS Network protocol and the open lung approach, (2) redistributed pulmonary blood flow to caudal zones compared with the ARDS Network protocol and to peripheral ones compared with the open lung approach, (3) reduced histological damage in comparison to both protective ventilation strategies, and (4) did not increase lung inflammation or mechanical stress. Noisy ventilation with variable Vt and fixed respiratory frequency improves respiratory function and reduces histological damage compared with standard protective ventilation strategies.

Exercise training attenuated chronic cigarette smoking-induced up-regulation of FIZZ1/RELMα in lung of rats.

PubMed

Ma, Wan-li; Cai, Peng-cheng; Xiong, Xian-zhi; Ye, Hong

2013-02-01

FIZZ/RELM is a new gene family named "found in inflammatory zone" (FIZZ) or "resistin-like molecule" (RELM). FIZZ1/RELMα is specifically expressed in lung tissue and associated with pulmonary inflammation. Chronic cigarette smoking up-regulates FIZZ1/RELMα expression in rat lung tissues, the mechanism of which is related to cigarette smoking-induced airway hyperresponsiveness. To investigate the effect of exercise training on chronic cigarette smoking-induced airway hyperresponsiveness and up-regulation of FIZZ1/RELMα, rat chronic cigarette smoking model was established. The rats were treated with regular exercise training and their airway responsiveness was measured. Hematoxylin and eosin (HE) staining, immunohistochemistry and in situ hybridization of lung tissues were performed to detect the expression of FIZZ1/RELMα. Results revealed that proper exercise training decreased airway hyperresponsiveness and pulmonary inflammation in rat chronic cigarette smoking model. Cigarette smoking increased the mRNA and protein levels of FIZZ1/RELMα, which were reversed by the proper exercise. It is concluded that proper exercise training prevents up-regulation of FIZZ1/RELMα induced by cigarette smoking, which may be involved in the mechanism of proper exercise training modulating airway hyperresponsiveness.

Endotoxin-induced nitric oxide production rescues airway growth and maturation in atrophic fetal rat lung explants

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

Rae, C.; Cherry, J.I.; Land, F.M.

Inflammation induces premature maturation of the fetal lung but the signals causing this effect remain unclear. We determined if nitric oxide (NO) synthesis, evoked by Escherichia coli lipopolysaccharide (LPS, 2 {mu}g ml{sup -1}), participated in this process. Fetal rat lung airway surface complexity rose 2.5-fold over 96 h in response to LPS and was associated with increased iNOS protein expression and activity. iNOS inhibition by N6-(1-iminoethyl)-L-lysine-2HCl (L-NIL) abolished this and induced airway atrophy similar to untreated explants. Surfactant protein-C (SP-C) expression was also induced by LPS and abolished by L-NIL. As TGF{beta} suppresses iNOS activity, we determined if feedback regulationmore » modulated NO-dependent maturation. LPS induced TGF{beta}1 release and SMAD4 nuclear translocation 96 h after treatment. Treatment of explants with a blocking antibody against TGF{beta}1 sustained NO production and airway morphogenesis whereas recombinant TGF{beta}1 antagonized these effects. Feedback regulation of NO synthesis by TGF{beta} may, thus, modulate airway branching and maturation of the fetal lung.« less

Simvastatin inhibits smoke-induced airway epithelial injury: implications for COPD therapy.

PubMed

Davis, Benjamin B; Zeki, Amir A; Bratt, Jennifer M; Wang, Lei; Filosto, Simone; Walby, William F; Kenyon, Nicholas J; Goldkorn, Tzipora; Schelegle, Edward S; Pinkerton, Kent E

2013-08-01

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death. The statin drugs may have therapeutic potential in respiratory diseases such as COPD, but whether they prevent bronchial epithelial injury is unknown. We hypothesised that simvastatin attenuates acute tobacco smoke-induced neutrophilic lung inflammation and airway epithelial injury. Spontaneously hypertensive rats were given simvastatin (20 mg·kg(-1) i.p.) daily for either 7 days prior to tobacco smoke exposure and during 3 days of smoke exposure, or only during tobacco smoke exposure. Pretreatment with simvastatin prior to and continued throughout smoke exposure reduced the total influx of leukocytes, neutrophils and macrophages into the lung and airways. Simvastatin attenuated tobacco smoke-induced cellular infiltration into lung parenchymal and airway subepithelial and interstitial spaces. 1 week of simvastatin pretreatment almost completely prevented smoke-induced denudation of the airway epithelial layer, while simvastatin given only concurrently with the smoke exposure had no effect. Simvastatin may be a novel adjunctive therapy for smoke-induced lung diseases, such as COPD. Given the need for statin pretreatment there may be a critical process of conditioning that is necessary for statins' anti-inflammatory effects. Future work is needed to elucidate the mechanisms of this statin protective effect.

CT-assessed large airway involvement and lung function decline in eosinophilic asthma: The association between induced sputum eosinophil differential counts and airway remodeling.

PubMed

Inoue, Hideki; Ito, Isao; Niimi, Akio; Matsumoto, Hisako; Matsuoka, Hirofumi; Jinnai, Makiko; Takeda, Tomoshi; Oguma, Tsuyoshi; Otsuka, Kojiro; Nakaji, Hitoshi; Tajiri, Tomoko; Iwata, Toshiyuki; Nagasaki, Tadao; Kanemitsu, Yoshihiro; Mishima, Michiaki

2016-11-01

Eosinophilic asthma (EA) is a distinct clinical phenotype characterized by eosinophilic airway inflammation and airway remodeling. Few studies have used computed tomography (CT) scanning to assess the association between sputum eosinophil differential counts and airway involvement. We aimed to investigate the clinical characteristics and airway involvement of EA, and to examine the correlation between induced sputum eosinophil differential counts and CT-assessed airway remodeling. We retrospectively divided 63 patients with stable asthma receiving inhaled corticosteroids into 2 groups: 26 patients with EA (sputum eosinophil >3%) and 37 patients with non-eosinophilic asthma (NEA). Clinical measurements such as spirometry, fractional exhaled nitric oxide levels (FeNO), and CT-assessed indices of airway involvement were compared between the groups. Multivariate analysis was performed to identify determinants of the percentage of wall area (WA%). The EA group had significantly longer asthma duration, lower pulmonary function, and higher FeNO than the NEA group. Also, the EA group had higher WA% and smaller airway luminal area than the NEA group. Sputum eosinophil differential counts and WA% were positively correlated. The multivariate linear regression analysis showed that the factors associated with WA% included sputum eosinophil differential counts, age, and body mass index. However, asthma duration was not associated with WA%. Our CT-assessed findings demonstrated large airway involvement in EA, and we observed a positive association between induced sputum eosinophil differential counts and WA%. The findings indicate that induced sputum eosinophil differential counts may be associated with airway remodeling in patients with stable asthma.

Pegylation of Antimicrobial Peptides Maintains the Active Peptide Conformation, Model Membrane Interactions, and Antimicrobial Activity while Improving Lung Tissue Biocompatibility following Airway Delivery

PubMed Central

Morris, Christopher J.; Beck, Konrad; Fox, Marc A.; Ulaeto, David; Clark, Graeme C.

2012-01-01

Antimicrobial peptides (AMPs) have therapeutic potential, particularly for localized infections such as those of the lung. Here we show that airway administration of a pegylated AMP minimizes lung tissue toxicity while nevertheless maintaining antimicrobial activity. CaLL, a potent synthetic AMP (KWKLFKKIFKRIVQRIKDFLR) comprising fragments of LL-37 and cecropin A peptides, was N-terminally pegylated (PEG-CaLL). PEG-CaLL derivatives retained significant antimicrobial activity (50% inhibitory concentrations [IC50s] 2- to 3-fold higher than those of CaLL) against bacterial lung pathogens even in the presence of lung lining fluid. Circular dichroism and fluorescence spectroscopy confirmed that conformational changes associated with the binding of CaLL to model microbial membranes were not disrupted by pegylation. Pegylation of CaLL reduced AMP-elicited cell toxicity as measured using in vitro lung epithelial primary cell cultures. Further, in a fully intact ex vivo isolated perfused rat lung (IPRL) model, airway-administered PEG-CaLL did not result in disruption of the pulmonary epithelial barrier, whereas CaLL caused an immediate loss of membrane integrity leading to pulmonary edema. All AMPs (CaLL, PEG-CaLL, LL-37, cecropin A) delivered to the lung by airway administration showed limited (<3%) pulmonary absorption in the IPRL with extensive AMP accumulation in lung tissue itself, a characteristic anticipated to be beneficial for the treatment of pulmonary infections. We conclude that pegylation may present a means of improving the lung biocompatibility of AMPs designed for the treatment of pulmonary infections. PMID:22430978

Smoking-Induced Upregulation of AKR1B10 Expression in the Airway Epithelium of Healthy Individuals

PubMed Central

Wang, Rui; Wang, Guoqing; Ricard, Megan J.; Ferris, Barbara; Strulovici-Barel, Yael; Salit, Jacqueline; Hackett, Neil R.; Gudas, Lorraine J.

2010-01-01

Background: The aldo-keto reductase (AKR) gene superfamily codes for monomeric, soluble reduced nicotinamide adenine dinucleotide phosphate-dependent oxidoreductases that mediate elimination reactions. AKR1B10, an AKR that eliminates retinals, has been observed as upregulated in squamous metaplasia and non-small cell lung cancer and has been suggested as a diagnostic marker specific to tobacco-related carcinogenesis. We hypothesized that upregulation of AKR1B10 expression may be initiated in healthy smokers prior to the development of evidence of lung cancer. Methods: Expression of AKR1B10 was assessed at the mRNA level using microarrays with TaqMan confirmation in the large airway epithelium (21 healthy nonsmokers, 31 healthy smokers) and small airway epithelium (51 healthy nonsmokers, 58 healthy smokers) obtained by fiberoptic bronchoscopy and brushing. Results: Compared with healthy nonsmokers, AKR1B10 mRNA levels were significantly upregulated in both large and small airway epithelia of healthy smokers. Consistent with the mRNA data, AKR1B10 protein was significantly upregulated in the airway epithelium of healthy smokers as assessed by Western blot analysis and immunohistochemistry, with AKR1B10 expressed in both differentiated and basal cells. Finally, cigarette smoke extract mediated upregulation of AKR1B10 in airway epithelial cells in vitro, and transfection of AKR1B10 into airway epithelial cells enhanced the conversion of retinal to retinol. Conclusions: Smoking per se mediates upregulation of AKR1B10 expression in the airway epithelia of healthy smokers with no evidence of lung cancer. In the context of these observations and the link of AKR1B10 to the metabolism of retinals and to lung cancer, the smoking-induced upregulation of AKR1B10 may be an early process in the multiple events leading to lung cancer. PMID:20705797

ASTHMA, CHRONIC BRONCHITIS AND EMPHYSEMA—The Use of Intermittent Positive Pressure Breathing with Inspiratory Flow Rate Control: A Review of the Literature

PubMed Central

Sheldon, Gerard P.

1963-01-01

In chronic obstructive lung disease (asthma, chronic bronchitis, obstructive emphysema) there is a segmental reduction in the caliber of the airways, which always results in obstruction to air-flow. Increased airway resistance is a physiological expression of airway obstruction. The addition of inspiratory flow rate control to an intermittent positive pressure breathing device permits slow filling of a lung with obstructed airways, and is presented as a simple means of reducing the high pulmonary flow resistance and increasing the tidal volume. ImagesFigure 1. PMID:13977070

Lung Metastases from Bile Duct Adenocarcinoma Mimicking Chronic Airway Infection and Causing Diagnostic Difficulty.

PubMed

Sato, Mitsuo; Okachi, Shotaro; Fukihara, Jun; Shimoyama, Yoshie; Wakahara, Keiko; Sakakibara, Toshihiro; Hase, Tetsunari; Onishi, Yasuharu; Ogura, Yasuhiro; Maeda, Osamu; Hasegawa, Yoshinori

2018-05-15

We herein report a case of lung metastases with unusual radiological appearances that mimicked those of chronic airway infection, causing diagnostic difficulty. A 60-year-old woman who underwent liver transplantation from a living donor was incidentally diagnosed with bile duct adenocarcinoma after a histopathological analysis of her explanted liver. Six months later, chest computed tomography (CT) revealed bilateral bronchogenic dissemination that had gradually worsened, suggesting chronic airway infection. A biopsy with bronchoscopy from a mass lesion beyond a segmental bronchus revealed adenocarcinoma identical to that of her bile duct adenocarcinoma, leading to the diagnosis of multiple lung metastases from bile duct adenocarcinoma.

Lung Metastases from Bile Duct Adenocarcinoma Mimicking Chronic Airway Infection and Causing Diagnostic Difficulty

PubMed Central

Sato, Mitsuo; Okachi, Shotaro; Fukihara, Jun; Shimoyama, Yoshie; Wakahara, Keiko; Sakakibara, Toshihiro; Hase, Tetsunari; Onishi, Yasuharu; Ogura, Yasuhiro; Maeda, Osamu; Hasegawa, Yoshinori

2017-01-01

We herein report a case of lung metastases with unusual radiological appearances that mimicked those of chronic airway infection, causing diagnostic difficulty. A 60-year-old woman who underwent liver transplantation from a living donor was incidentally diagnosed with bile duct adenocarcinoma after a histopathological analysis of her explanted liver. Six months later, chest computed tomography (CT) revealed bilateral bronchogenic dissemination that had gradually worsened, suggesting chronic airway infection. A biopsy with bronchoscopy from a mass lesion beyond a segmental bronchus revealed adenocarcinoma identical to that of her bile duct adenocarcinoma, leading to the diagnosis of multiple lung metastases from bile duct adenocarcinoma. PMID:29279503

Future directions in early cystic fibrosis lung disease research: an NHLBI workshop report.

PubMed

Ramsey, Bonnie W; Banks-Schlegel, Susan; Accurso, Frank J; Boucher, Richard C; Cutting, Garry R; Engelhardt, John F; Guggino, William B; Karp, Christopher L; Knowles, Michael R; Kolls, Jay K; LiPuma, John J; Lynch, Susan; McCray, Paul B; Rubenstein, Ronald C; Singh, Pradeep K; Sorscher, Eric; Welsh, Michael

2012-04-15

Since the 1989 discovery that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), there has been substantial progress toward understanding the molecular basis for CF lung disease, leading to the discovery and development of new therapeutic approaches. However, the earliest impact of the loss of CFTR function on airway physiology and structure and its relationship to initial infection and inflammation are poorly understood. Universal newborn screening for CF in the United States represents an unprecedented opportunity for investigating CF clinical manifestations very early in life. Recently developed animal models with pulmonary phenotypic manifestations also provide a window into the early consequences of this genetic disorder. For these reasons, the National Heart, Lung, and Blood Institute (NHLBI) convened a working group of extramural experts, entitled "Future Research Directions in Early CF Lung Disease" on September 21-22, 2010, to identify future research directions of great promise in CF. The priority areas identified included (1) exploring pathogenic mechanisms of early CF lung disease; (2) leveraging newborn screening to elucidate the natural history of early lung disease; (3) developing a spectrum of biomarkers of early lung disease that reflects CF pathophysiology, clinical outcome, and response to treatment; (4) exploring the role of genetics/genomics (e.g., modifier genes, gene-environmental interactions, and epigenetics) in early CF pathogenesis; (5) defining early microbiological events in CF lung disease; and (6) elucidating the initial airway inflammatory, remodeling, and repair mechanisms in CF lung disease.

Chronic electronic cigarette exposure in mice induces features of COPD in a nicotine-dependent manner.

PubMed

Garcia-Arcos, Itsaso; Geraghty, Patrick; Baumlin, Nathalie; Campos, Michael; Dabo, Abdoulaye Jules; Jundi, Bakr; Cummins, Neville; Eden, Edward; Grosche, Astrid; Salathe, Matthias; Foronjy, Robert

2016-12-01

The use of electronic (e)-cigarettes is increasing rapidly, but their lung health effects are not established. Clinical studies examining the potential long-term impact of e-cigarette use on lung health will take decades. To address this gap in knowledge, this study investigated the effects of exposure to aerosolised nicotine-free and nicotine-containing e-cigarette fluid on mouse lungs and normal human airway epithelial cells. Mice were exposed to aerosolised phosphate-buffered saline, nicotine-free or nicotine-containing e-cigarette solution, 1-hour daily for 4 months. Normal human bronchial epithelial (NHBE) cells cultured at an air-liquid interface were exposed to e-cigarette vapours or nicotine solutions using a Vitrocell smoke exposure robot. Inhalation of nicotine-containing e-cigarettes increased airway hyper-reactivity, distal airspace enlargement, mucin production, cytokine and protease expression. Exposure to nicotine-free e-cigarettes did not affect these lung parameters. NHBE cells exposed to nicotine-containing e-cigarette vapour showed impaired ciliary beat frequency, airway surface liquid volume, cystic fibrosis transmembrane regulator and ATP-stimulated K+ ion conductance and decreased expression of FOXJ1 and KCNMA1. Exposure of NHBE cells to nicotine for 5 days increased interleukin (IL)-6 and IL-8 secretion. Exposure to inhaled nicotine-containing e-cigarette fluids triggered effects normally associated with the development of COPD including cytokine expression, airway hyper-reactivity and lung tissue destruction. These effects were nicotine-dependent both in the mouse lung and in human airway cells, suggesting that inhaled nicotine contributes to airway and lung disease in addition to its addictive properties. Thus, these findings highlight the potential dangers of nicotine inhalation during e-cigarette use. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

The lung tissue microbiota of mild and moderate chronic obstructive pulmonary disease.

PubMed

Pragman, Alexa A; Lyu, Tianmeng; Baller, Joshua A; Gould, Trevor J; Kelly, Rosemary F; Reilly, Cavan S; Isaacson, Richard E; Wendt, Chris H

2018-01-09

Oral taxa are often found in the chronic obstructive pulmonary disease (COPD) lung microbiota, but it is not clear if this is due to a physiologic process such as aspiration or experimental contamination at the time of specimen collection. Microbiota samples were obtained from nine subjects with mild or moderate COPD by swabbing lung tissue and upper airway sites during lung lobectomy. Lung specimens were not contaminated with upper airway taxa since they were obtained surgically. The microbiota were analyzed with 16S rRNA gene qPCR and 16S rRNA gene hypervariable region 3 (V3) sequencing. Data analyses were performed using QIIME, SourceTracker, and R. Streptococcus was the most common genus in the oral, bronchial, and lung tissue samples, and multiple other taxa were present in both the upper and lower airways. Each subject's own bronchial and lung tissue microbiota were more similar to each other than were the bronchial and lung tissue microbiota of two different subjects (permutation test, p = 0.0139), indicating more within-subject similarity than between-subject similarity at these two lung sites. Principal coordinate analysis of all subject samples revealed clustering by anatomic sampling site (PERMANOVA, p = 0.001), but not by subject. SourceTracker analysis found that the sources of the lung tissue microbiota were 21.1% (mean) oral microbiota, 8.7% nasal microbiota, and 70.1% unknown. An analysis using the neutral theory of community ecology revealed that the lung tissue microbiota closely reflects the bronchial, oral, and nasal microbiota (immigration parameter estimates 0.69, 0.62, and 0.74, respectively), with some evidence of ecologic drift occurring in the lung tissue. This is the first study to evaluate the mild-moderate COPD lung tissue microbiota without potential for upper airway contamination of the lung samples. In our small study of subjects with COPD, we found oral and nasal bacteria in the lung tissue microbiota, confirming that aspiration is a source of the COPD lung microbiota.

Adam8 Limits the Development of Allergic Airway Inflammation in Mice

PubMed Central

Knolle, Martin D.; Nakajima, Takahiro; Hergrueter, Anja; Gupta, Kushagra; Polverino, Francesca; Craig, Vanessa J.; Fyfe, Susanne E.; Zahid, Muhammad; Permaul, Perdita; Cernadas, Manuela; Montano, Gilbert; Tesfaigzi, Yohannes; Sholl, Lynette; Kobzik, Lester; Israel, Elliot; Owen, Caroline A.

2013-01-01

To determine whether a disintegrin and a metalloproteinase-8 (Adam8) regulates allergic airway inflammation (AAI) and airway hyper-responsiveness (AHR), we compared AAI and AHR in wild type (WT) versus Adam8−/− mice in different genetic backgrounds sensitized and challenged with ovalbumin (OVA) or house dust mite protein extract (HDM). OVA- and HDM-treated Adam8−/− mice had higher lung leukocyte counts, more airway mucus metaplasia, greater lung levels of some TH2 cytokines, and higher methacholine-induced increases in central airway resistance than allergen-treated WT mice. Studies of OVA-treated Adam8 bone marrow chimeric mice confirmed that leukocyte-derived Adam8 predominantly mediated Adam8’s anti-inflammatory activities in murine airways. Airway eosinophils and macrophages both expressed Adam8 in WT mice with AAI. Adam8 limited AAI and AHR in mice by reducing leukocyte survival because: 1) Adam8−/− mice with AAI had fewer apoptotic eosinophils and macrophages in their airways than WT mice with AAI; and 2) Adam8−/− macrophages and eosinophils had reduced rates of apoptosis compared with WT leukocytes when the intrinsic (but not the extrinsic) apoptosis pathway was triggered in the cells in vitro. ADAM8 was robustly expressed by airway granulocytes in lung sections from human asthma patients but, surprisingly, airway macrophages had less ADAM8 staining than airway eosinophils. Thus, ADAM8 has anti-inflammatory activities during AAI in mice by activating the intrinsic apoptosis pathway in myeloid leukocytes. Strategies that increase ADAM8 levels in myeloid leukocytes may have therapeutic efficacy in asthma. PMID:23670189

Effects on symptoms and lung function in humans experimentally exposed to diesel exhaust.

PubMed Central

Rudell, B; Ledin, M C; Hammarström, U; Stjernberg, N; Lundbäck, B; Sandström, T

1996-01-01

OBJECTIVES: Diesel exhaust is a common air pollutant made up of several gases, hydrocarbons, and particles. An experimental study was carried out which was designed to evaluate if a particle trap on the tail pipe of an idling diesel engine would reduce effects on symptoms and lung function caused by the diesel exhaust, compared with exposure to unfiltered exhaust. METHODS: Twelve healthy non-smoking volunteers (aged 20-37) were investigated in an exposure chamber for one hour during light work on a bicycle ergometer at 75 W. Each subject underwent three separate double blind exposures in a randomised sequence: to air and to diesel exhaust with the particle trap at the tail pipe and to unfiltered diesel exhaust. Symptoms were recorded according to the Borg scale before, every 10 minutes during, and 30 minutes after the exposure. Lung function was measured with a computerised whole body plethysmograph. RESULTS: The ceramic wall flow particle trap reduced the number of particles by 46%, whereas other compounds were relatively constant. It was shown that the most prominent symptoms during exposure to diesel exhaust were irritation of the eyes and nose and an unpleasant smell increasing during exposure. Both airway resistance (R(aw)) and specific airway resistance (SR(aw)) increased significantly during the exposures to diesel exhaust. Despite the 46% reduction in particle numbers by the trap effects on symptoms and lung function were not significantly attenuated. CONCLUSION: Exposure to diesel exhaust caused symptoms and bronchoconstriction which were not significantly reduced by a particle trap. PMID:8943829

Exhaled breath condensate adenosine tracks lung function changes in cystic fibrosis

PubMed Central

Olsen, Bonnie M.; Lin, Feng-Chang; Fine, Jason; Boucher, Richard C.

2013-01-01

Measurement of exhaled breath condensate (EBC) biomarkers offers a noninvasive means to assess airway disease, but the ability of EBC biomarkers to track longitudinal changes in disease severity remains unproven. EBC was collected from pediatric patients with cystic fibrosis (CF) during regular clinic visits over 1 yr. EBC biomarkers urea, adenosine (Ado), and phenylalanine (Phe) were measured by mass spectrometry, and biomarker ratios were used to control for variable dilution of airway secretions. EBC biomarker ratios were assessed relative to lung function in longitudinal, multivariate models and compared with sputum inflammatory markers and quality of life assessment (CFQ-R). EBC was successfully analyzed from 51 subjects during 184 visits (3.6 ± 0.9 visits per subject). EBC Ado/urea ratio was reproducible in duplicate samples (r = 0.62, P < 0.01, n = 20) and correlated with sputum neutrophil elastase (β = 2.5, P < 0.05). EBC Ado/urea correlated with the percentage predicted of forced expiratory volume in 1 s in longitudinal, multivariate models (β = −2.9, P < 0.01); EBC Ado/Phe performed similarly (β = −2.1, P < 0.05). In contrast, IL-8 and elastase measured in spontaneously expectorated sputum (n = 57 samples from 25 subjects) and the CFQ-R respiratory scale (n = 90 tests from 47 subjects) were not significantly correlated with lung function. EBC was readily collected in a clinic setting from a wide range of subjects. EBC Ado tracked longitudinal changes in lung function in CF, with results similar to or better than established measures. PMID:23355385

The psychoactive substance of cannabis Δ9-tetrahydrocannabinol (THC) negatively regulates CFTR in airway cells.

PubMed

Chang, Sheng-Wei; Wellmerling, Jack; Zhang, Xiaoli; Rayner, Rachael E; Osman, Wissam; Mertz, Sara; Amer, Amal O; Peeples, Mark E; Boyaka, Prosper N; Cormet-Boyaka, Estelle

2018-06-18

Marijuana consumption is on the rise in the US but the health benefits of cannabis smoking are controversial and the impact of cannabis components on lung homeostasis is not well-understood. Lung function requires a fine regulation of the ion channel CFTR, which is responsible for fluid homeostasis and mucocilliary clearance. The goal of this study was to assess the effect that exposure to Δ9-tetrahydrocannabinol (THC), the psychoactive substance present in marijuana, has on CFTR expression and function. Cultures of human bronchial epithelial cell line 16HBE14o- and primary human airway epithelial cells were exposed to THC. The expression of CFTR protein was determined by immunoblotting and CFTR function was measured using Ussing chambers. We also used specific pharmacological inhibitors of EGFR and ERK to determine the role of this pathway in THC-induced regulation of CFTR. THC decreased CFTR protein expression in primary human bronchial epithelial cells. This decrease was associated with reduced CFTR-mediated short-circuit currents. THC also induced activation of the ERK MAPK pathway via activation of EGFR. Inhibition of EGFR or MEK/ERK prevented THC-induced down regulation of CFTR protein expression. THC negatively regulates CFTR and this is mediated through the EGFR/ERK axis. This study provides the first evidence that THC present in marijuana reduces the expression and function of CFTR in airway epithelial cells. Copyright © 2018. Published by Elsevier B.V.

Proteome Analysis for Downstream Targets of Oncogenic KRAS - the Potential Participation of CLIC4 in Carcinogenesis in the Lung

PubMed Central

Okudela, Koji; Katayama, Akira; Woo, Tetsukan; Mitsui, Hideaki; Suzuki, Takehisa; Tateishi, Yoko; Umeda, Shigeaki; Tajiri, Michihiko; Masuda, Munetaka; Nagahara, Noriyuki; Kitamura, Hitoshi; Ohashi, Kenichi

2014-01-01

This study investigated the proteome modulated by oncogenic KRAS in immortalized airway epithelial cells. Chloride intracellular channel protein 4 (CLIC4), S100 proteins (S100A2 and S100A11), tropomyosin 2, cathepsin L1, integrinsα3, eukaryotic elongation factor 1, vimentin, and others were discriminated. We here focused on CLIC4 to investigate its potential involvement in carcinogenesis in the lung because previous studies suggested that some chloride channels and chloride channel regulators could function as tumor suppressors. CILC4 protein levels were reduced in some lung cancer cell lines. The restoration of CLIC4 in lung cancer cell lines in which CLIC4 expression was reduced attenuated their growth activity. The immunohistochemical expression of the CLIC4 protein was weaker in primary lung cancer cells than in non-tumorous airway epithelial cells and was occasionally undetectable in some tumors. CLIC4 protein levels were significantly lower in a subtype of mucinous ADC than in others, and were also significantly lower in KRAS-mutated ADC than in EGFR-mutated ADC. These results suggest that the alteration in CLIC4 could be involved in restrictedly the development of a specific fraction of lung adenocarcinomas. The potential benefit of the proteome modulated by oncogenic KRAS to lung cancer research has been demonstrated. PMID:24503901

Protective mechanical ventilation does not exacerbate lung function impairment or lung inflammation following influenza A infection.

PubMed

Zosky, Graeme R; Cannizzaro, Vincenzo; Hantos, Zoltan; Sly, Peter D

2009-11-01

The degree to which mechanical ventilation induces ventilator-associated lung injury is dependent on the initial acute lung injury (ALI). Viral-induced ALI is poorly studied, and this study aimed to determine whether ALI induced by a clinically relevant infection is exacerbated by protective mechanical ventilation. Adult female BALB/c mice were inoculated with 10(4.5) plaque-forming units of influenza A/Mem/1/71 in 50 microl of medium or medium alone. This study used a protective ventilation strategy, whereby mice were anesthetized, tracheostomized, and mechanically ventilated for 2 h. Lung mechanics were measured periodically throughout the ventilation period using a modification of the forced oscillation technique to obtain measures of airway resistance and coefficients of tissue damping and tissue elastance. Thoracic gas volume was measured and used to obtain specific airway resistance, tissue damping, and tissue elastance. At the end of the ventilation period, a bronchoalveolar lavage sample was collected to measure inflammatory cells, macrophage inflammatory protein-2, IL-6, TNF-alpha, and protein leak. Influenza infection caused significant increases in inflammatory cells, protein leak, and deterioration in lung mechanics that were not exacerbated by mechanical ventilation, in contrast to previous studies using bacterial and mouse-specific viral infection. This study highlighted the importance of type and severity of lung injury in determining outcome following mechanical ventilation.

Nano-based theranostics for chronic obstructive lung diseases: challenges and therapeutic potential.

PubMed

Vij, Neeraj

2011-09-01

The major challenges in the delivery and therapeutic efficacy of nano-delivery systems in chronic obstructive airway conditions are airway defense, severe inflammation and mucous hypersecretion. Chronic airway inflammation and mucous hypersecretion are hallmarks of chronic obstructive airway diseases, including asthma, COPD (chronic obstructive pulmonary disease) and CF (cystic fibrosis). Distinct etiologies drive inflammation and mucous hypersecretion in these diseases, which are further induced by infection or components of cigarette smoke. Controlling chronic inflammation is at the root of treatments such as corticosteroids, antibiotics or other available drugs, which pose the challenge of sustained delivery of drugs to target cells or tissues. In spite of the wide application of nano-based drug delivery systems, very few are tested to date. Targeted nanoparticle-mediated sustained drug delivery is required to control inflammatory cell chemotaxis, fibrosis, protease-mediated chronic emphysema and/or chronic lung obstruction in COPD. Moreover, targeted epithelial delivery is indispensable for correcting the underlying defects in CF and targeted inflammatory cell delivery for controlling other chronic inflammatory lung diseases. We propose that the design and development of nano-based targeted theranostic vehicles with therapeutic, imaging and airway-defense penetrating capability, will be invaluable for treating chronic obstructive lung diseases. This paper discusses a novel nano-theranostic strategy that we are currently evaluating to treat the underlying cause of CF and COPD lung disease.

Respiratory fluid mechanics

NASA Astrophysics Data System (ADS)

Grotberg, James B.

2011-02-01

This article covers several aspects of respiratory fluid mechanics that have been actively investigated by our group over the years. For the most part, the topics involve two-phase flows in the respiratory system with applications to normal and diseased lungs, as well as therapeutic interventions. Specifically, the topics include liquid plug flow in airways and at airway bifurcations as it relates to surfactant, drug, gene, or stem cell delivery into the lung; liquid plug rupture and its damaging effects on underlying airway epithelial cells as well as a source of crackling sounds in the lung; airway closure from "capillary-elastic instabilities," as well as nonlinear stabilization from oscillatory core flow which we call the "oscillating butter knife;" liquid film, and surfactant dynamics in an oscillating alveolus and the steady streaming, and surfactant spreading on thin viscous films including our discovery of the Grotberg-Borgas-Gaver shock.

[Effect of airway humidification on lung injury induced by mechanical ventilation].

PubMed

Song, Junjie; Jiang, Min; Qi, Guiyan; Xie, Yuying; Wang, Huaiquan; Tian, Yonggang; Qu, Jingdong; Zhang, Xiaoming; Li, Haibo

2014-12-01

To explore the effect of airway humidification on lung injury as a result of mechanical ventilation with different tidal volume (VT). Twenty-four male Japanese white rabbits were randomly divided into four groups: low VT with airway humidification group, high VT with airway humidification group, low VT and high VT group without humidification, with 6 rabbits in each group. Mechanical ventilation was started after intubation and lasted for 6 hours. Low VT denoted 8 mL/kg, while high VT was 16 mL/kg, fraction of inspired oxygen (FiO₂) denoted 0.40, positive end-expiratory pressure (PEEP) was 0. Temperature at Y piece of circuit in airway humidification groups was monitored and controlled at 40 centigrade. Arterial blood gas analysis, including pH value, arterial partial pressure of oxygen (PaO₂), arterial partial pressure of carbon dioxide (PaCO₂), lung mechanics indexes, including peak airway pressure (P(peak)) and airway resistance (Raw), and lung compliance was measured at 0, 2, 4, 6 hours of mechanical ventilation. The levels of tumor necrosis factor-α (TNF-α) and interleukin-8 (IL-8) in plasma and bronchoalveolar lavage fluid (BALF) were determined by enzyme linked immunosorbent assay (ELISA). The animals were sacrificed at the end of mechanical ventilation. The wet to dry (W/D) ratio of lung tissues was calculated. Histopathologic changes in the lung tissueies were observed with microscope, and lung injury score was calculated. Scanning and transmission electron microscopies were used to examine the integrity of the airway cilia and the tracheal epithelium. Compared with low V(T) group, pH value in high V(T) group was significantly increased, PaCO₂was significantly lowered, and no difference in PaO₂was found. P(peak), Raw, and lung compliance were significantly increased during mechanical ventilation. There were no significant differences in blood gas analysis and lung mechanics indexes between low V(T) with airway humidification group and low V(T) group. Compared with high V(T) group, PaCO₂in high V(T) with airway humidification group was significantly decreased, Ppeak raised obviously, and no difference in pH value, PaO₂, Raw and pulmonary compliance was found. Compared with low V(T) with airway humidification group, no difference in blood gas analysis (PaCO2, mmHg, 1 mmHg=0.133 kPa) was found, but Ppeak (cmH₂O, 1 cmH₂O=0.098 kPa), Raw (cmH₂O), and lung compliance (mL/cmH₂O) were increased significantly in high V(T) with airway humidification group (PaCO₂at 2 hours: 27.96 ± 4.64 vs. 36.08 ± 2.11, 4 hours: 28.62 ± 2.93 vs. 34.55 ± 5.50, 6 hours: 29.33 ± 2.14 vs. 35.01 ± 5.53; Ppeak at 0 hour: 14.34 ± 1.97 vs. 8.84 ± 1.32, 2 hours: 17.33 ± 0.52 vs. 11.17 ± 2.14, 4 hours: 17.83 ± 0.98 vs. 12.67 ± 2.06, 6 hours: 18.67 ± 1.22 vs. 13.50 ± 2.16; Raw at 0 hour: 37.36 ± 5.14 vs. 27.0 5 ± 2.93, 2 hours: 43.94 ± 6.58 vs. 31.95 ± 3.56, 4 hours: 48.04 ± 6.07 vs. 35.24 ± 3.50, 6 hours: 50.33 ± 6.34 vs. 36.66 ± 3.64; pulmonary compliance at 6 hours: 2.28 ± 0.18 vs. 1.86 ± 0.37, all P<0.05). The lung W/D ratio in high VT group was significantly higher than that of the low V(T) group (6.17 ± 2.14 vs. 3.50 ± 1.52, P<0.05). W/D in high V(T) with airway humidification group was higher than that of low V(T) with airway humidification group but without statistically significant difference (5.17 ± 2.14 vs. 3.00 ± 1.10, P>0.05). Microscopic observation showed that cilia were partially detached, adhered and sparse in low V(T) group, while cilia in high V(T) group showed serious detachment and lodging. Remaining cilia were sparse, with lodging, and cellular structure was damaged. Lung tissue pathological injury score in the high V(T) group was significantly higher than that of low V(T) group (6.17 ± 2.14 vs. 3.50 ± 1.52, P<0.05). Cilia density and cellularity were normal in low V(T) with airway humidification group, and no difference in lung tissue pathological injury score was found compared with low V(T) group (3.00 ± 1.10 vs. 3.50 ± 1.52, P>0.05). Cilia were severely detached, adhered and lodging, and cellularity were not obvious in high V(T) with airway humidification group, and lung tissue pathological injury score was elevated significantly than that of the low V(T) with airway humidification group but without statistically significant difference (5.17 ± 2.14 vs. 3.00 ± 1.10, P>0.05). TNF-α and IL-8 concentrations showed no change in plasma and BALF in all groups during ventilation, and no significant difference was found among the groups. Airway humidification can alleviate pathological lung injury, damage of cilia and cellular structure in trachea caused by mechanical ventilation with low and high V(T). High V(T) with humidification can result in serious pulmonary edema.

Cell surface marker profiling of human tracheal basal cells reveals distinct subpopulations, identifies MST1/MSP as a mitogenic signal, and identifies new biomarkers for lung squamous cell carcinomas.

PubMed

Van de Laar, Emily; Clifford, Monica; Hasenoeder, Stefan; Kim, Bo Ram; Wang, Dennis; Lee, Sharon; Paterson, Josh; Vu, Nancy M; Waddell, Thomas K; Keshavjee, Shaf; Tsao, Ming-Sound; Ailles, Laurie; Moghal, Nadeem

2014-12-31

The large airways of the lungs (trachea and bronchi) are lined with a pseudostratified mucociliary epithelium, which is maintained by stem cells/progenitors within the basal cell compartment. Alterations in basal cell behavior can contribute to large airway diseases including squamous cell carcinomas (SQCCs). Basal cells have traditionally been thought of as a uniform population defined by basolateral position, cuboidal cell shape, and expression of pan-basal cell lineage markers like KRT5 and TP63. While some evidence suggests that basal cells are not all functionally equivalent, few heterogeneously expressed markers have been identified to purify and study subpopulations. In addition, few signaling pathways have been identified that regulate their cell behavior. The goals of this work were to investigate tracheal basal cell diversity and to identify new signaling pathways that regulate basal cell behavior. We used flow cytometry (FACS) to profile cell surface marker expression at a single cell level in primary human tracheal basal cell cultures that maintain stem cell/progenitor activity. FACS results were validated with tissue staining, in silico comparisons with normal basal cell and lung cancer datasets, and an in vitro proliferation assay. We identified 105 surface markers, with 47 markers identifying potential subpopulations. These subpopulations generally fell into more (~ > 13%) or less abundant (~ < 6%) groups. Microarray gene expression profiling supported the heterogeneous expression of these markers in the total population, and immunostaining of large airway tissue suggested that some of these markers are relevant in vivo. 24 markers were enriched in lung SQCCs relative to adenocarcinomas, with four markers having prognostic significance in SQCCs. We also identified 33 signaling receptors, including the MST1R/RON growth factor receptor, whose ligand MST1/MSP was mitogenic for basal cells. This work provides the largest description to date of molecular diversity among human large airway basal cells. Furthermore, these markers can be used to further study basal cell function in repair and disease, and may aid in the classification and study of SQCCs.

DIESEL PARTICLE INSTILLATION ENHANCES INFLAMMATORY AND NEUROTROPHIN RESPONSES IN THE LUNGS OF ALLERGIC BALB/C MICE

EPA Science Inventory

Neurotrophins, including nerve growth factor (NGF) partially mediate many features of allergic airways disease including airways resistance and inflammation. Antibody blockade of NGF attenuates airways resistance associated with the allergen-specific airways responses in mice. ...

SRC-mediated EGF Receptor Activation Regulates Ozone-induced Interleukin 8 Expression in Human Bronchial Epithelial Cells

EPA Science Inventory

BACKGROUND: Human exposure to ozone (03) results in pulmonary function decrements and airway inflammation. The mechanisms underlying these adverse effects remain unclear. Epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of lung inflammation. ...

Impact of Scedosporium apiospermum complex seroprevalence in patients with cystic fibrosis.

PubMed

Parize, Perrine; Billaud, Sandrine; Bienvenu, Anne L; Bourdy, Stéphanie; le Pogam, Marie A; Reix, Philippe; Picot, Stéphane; Robert, Raymond; Lortholary, Olivier; Bouchara, Jean-Philippe; Durieu, Isabelle

2014-12-01

Species of the Scedosporium apiospermum complex (S. a complex) are emerging fungi responsible for chronic airway colonization in cystic fibrosis (CF) patients. Recent studies performed on Aspergillus fumigatus suggest that the colonization of the airways by filamentous fungi may contribute to the progressive deterioration of lung function. We studied S. a complex seroprevalence, as a marker of close contact between patient and the fungi, in a large monocentric cohort of CF patients attended in a reference centre in Lyon, France. Serum samples from 373 CF patients were analysed. Antibodies against S. a complex were detected in 35 patients (9.4%). In multivariate analysis, S. a complex seropositivity was only associated with seropositivity to A. fumigatus. This study does not suggest an association between sensitization against S. a complex and poorer lung function in CF. Prospective studies are needed to evaluate the impact of both seropositivity and S. a complex colonization on the course of CF. Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Integrin Beta 1 Suppresses Multilayering of a Simple Epithelium

PubMed Central

Chen, Jichao; Krasnow, Mark A.

2012-01-01

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

Long-term clearance from small airways in patients with cystic fibrosis.

PubMed

Lindström, M; Camner, P; Falk, R; Hjelte, L; Philipson, K; Svartengren, M

2005-02-01

Impaired mucociliary clearance is a hallmark of cystic fibrosis (CF). Early morphological changes first appear in the small airways. Lung clearance was investigated in 11 young CF adults with mild-to-moderate lung disease using a method depositing particles mainly in the small airways. Radiolabelled Teflon particles (6 microm) were inhaled with an extremely slow inhalation flow, 0.05 L x s(-1). Lung retention was measured immediately following inhalations and, on four occasions up to 21 days. The results were compared with data from healthy subjects. The lung retention at 24 h in % of deposition was 67% (95% confidence interval 58-76) in the CF patients, compared to 48% (42-53) in the healthy subjects. Clearance on days 1-7 was larger in the CF patients, 22% (15-29) compared to the healthy subjects, 14% (12-16). No difference was observed between the CF patients and the healthy subjects in the slow clearance phase at day 7 to day 21, representing small airway clearance. Impaired mucociliary clearance in CF patients results in increased 24-h retention and a prolonged rapid clearance phase. The results of the study do not support the current authors' hypothesis that clearance from small airways is slower in cystic fibrosis patients compared to healthy subjects. Furthermore, the data suggest that mucociliary transport is not the dominant clearance mechanism in small airways.

Role of Rho kinase isoforms in murine allergic airway responses.

PubMed

Zhu, M; Liu, P-Y; Kasahara, D I; Williams, A S; Verbout, N G; Halayko, A J; Fedulov, A; Shoji, T; Williams, E S; Noma, K; Shore, S A; Liao, J K

2011-10-01

Inhibition of Rho-associated coiled-coil forming kinases (ROCKs) reduces allergic airway responses in mice. The purpose of this study was to determine the roles of the two ROCK isoforms, ROCK1 and ROCK2, in these responses. Wildtype (WT) mice and heterozygous ROCK1 and ROCK2 knockout mice (ROCK1(+/-) and ROCK2(+/-), respectively) were sensitised and challenged with ovalbumin. ROCK expression and activation were assessed by western blotting. Airway responsiveness was measured by forced oscillation. Bronchoalveolar lavage was performed and the lungs were fixed for histological assessment. Compared with WT mice, ROCK1 and ROCK2 expression were 50% lower in lungs of ROCK1(+/-) and ROCK2(+/-) mice, respectively, without changes in the other isoform. In WT lungs, ROCK activation increased after ovalbumin challenge and was sustained for several hours. This activation was reduced in ROCK1(+/-) and ROCK2(+/-) lungs. Airway responsiveness was comparable in WT, ROCK1(+/-), and ROCK2(+/-) mice challenged with PBS. Ovalbumin challenge caused airway hyperresponsiveness in WT, but not ROCK1(+/-) or ROCK2(+/-) mice. Lavage eosinophils and goblet cell hyperplasia were significantly reduced in ovalbumin-challenged ROCK1(+/-) and ROCK2(+/-) versus WT mice. Ovalbumin-induced changes in lavage interleukin-13, interleukin-5 and lymphocytes were also reduced in ROCK1(+/-) mice. In conclusion, both ROCK1 and ROCK2 are important in regulating allergic airway responses.

Influence of Pulmonary Rehabilitation on Lung Function Changes After the Lung Resection for Primary Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease.

PubMed

Mujovic, Natasa; Mujovic, Nebojsa; Subotic, Dragan; Ercegovac, Maja; Milovanovic, Andjela; Nikcevic, Ljubica; Zugic, Vladimir; Nikolic, Dejan

2015-11-01

Influence of physiotherapy on the outcome of the lung resection is still controversial. Study aim was to assess the influence of physiotherapy program on postoperative lung function and effort tolerance in lung cancer patients with chronic obstructive pulmonary disease (COPD) that are undergoing lobectomy or pneumonectomy. The prospective study included 56 COPD patients who underwent lung resection for primary non small-cell lung cancer after previous physiotherapy (Group A) and 47 COPD patients (Group B) without physiotherapy before lung cancer surgery. In Group A, lung function and effort tolerance on admission were compared with the same parameters after preoperative physiotherapy. Both groups were compared in relation to lung function, effort tolerance and symptoms change after resection. In patients with tumors requiring a lobectomy, after preoperative physiotherapy, a highly significant increase in FEV1, VC, FEF50 and FEF25 of 20%, 17%, 18% and 16% respectively was registered with respect to baseline values. After physiotherapy, a significant improvement in 6-minute walking distance was achieved. After lung resection, the significant loss of FEV1 and VC occurred, together with significant worsening of the small airways function, effort tolerance and symptomatic status. After the surgery, a clear tendency existed towards smaller FEV1 loss in patients with moderate to severe, when compared to patients with mild baseline lung function impairment. A better FEV1 improvement was associated with more significant loss in FEV1. Physiotherapy represents an important part of preoperative and postoperative treatment in COPD patients undergoing a lung resection for primary lung cancer.

Bacteriology and treatment of infections in the upper and lower airways in patients with primary ciliary dyskinesia: adressing the paranasal sinuses.

PubMed

Alanin, Mikkel Christian

2017-05-01

The respiratory tract is lined with motile cilia that transport respiratory mucus. Primary ciliary dyskinesia (PCD) is a chronic genetic disease caused by mutations in genes responsible for ciliary structure and function. Non-functional airway cilia impair the mucociliary clearance (MCC), causing mucostasis, lung infections and destruction, chronic rhinosinusitis (CRS) and hearing impairment. It is of paramount importance to postpone chronic lung infection mainly with Gram-negative bacteria (GNB) in patients with an impaired MCC. When successful, lung function can be stabilized and quality of life (QoL) improved. In this thesis, we evaluated whether PCD patients can benefit from the experience we have gained from our operative approach towards the paranasal sinuses in cystic fibrosis (CF) patients. In CF, it has been established that bacterial sinusitis can be a focus for initial lung colonization and chronic lung infection. Combined endoscopic sinus surgery (ESS) and adjuvant therapy can eradicate sinus bacteria, reduce pulmonary infections and improve quality of life (QoL).      Currently, approximately 120 patients are diagnosed with PCD in Denmark and all are affiliated with the Danish PCD Centre. Patients included in this thesis were recruited from this cohort. In papers (I, IV), we found that the most frequent sinus pathogen was P. aeruginosa, which was isolated in 12 out of 31 (39%) patients who underwent ESS. In searching for a non-pulmonary infectious focus, we observed simultaneous sinus and lung infec-tions with identical pathogens in two out of three patients. This supports our hypothesis of a bacterial reservoir in the sinuses. Next (II), we examined the bacterial flora associated with acute and chronic pulmonary infections in PCD. A high prevalence of chronic infections encouraged a search for new treatment regimens, including ESS with adjuvant therapy, to impact the course of infection. We revealed that P. aeruginosa frequently colonizes the airways in PCD and during the 11-year study period a total of 42 out of 107 (39%) patients fulfilled the definition of chronic lung infection at some point. Importantly, 10 out of 12 patients (83%) with chronic lung infection had the same clone type of P. aeruginosa for years, as determined by pulsed field gel-electrophoresis (PFGE), thus substantiating factual chronic airway infection. Further, we found an increase in the prevalence of P. aeruginosa with age and observed a negative association between early PCD diagnosis and prevalence of P. aeruginosa. This indicates a positive effect of early diagnosis and initiation of therapy. In paper (III), we performed whole genome sequencing (WGS) of P. aeruginosa isolated from the same 12 patients who were included in the PFGE analysis in paper II. By sequencing and phenotypically characterizing multiple isolates from the same patients we were able to study the with-in host bacterial evolution for the first time in PCD. The analyses provided detailed insight into how P. aeruginosa evolves in PCD when they are stressed by the host immune system and antibiotics. We verified the persistence of clonal lineages and confirmed that different clone types of P. aeruginosa can establish persistent infections in PCD patients. Further, we showed that P. aeruginosa acclimatizes grad-ually to the PCD airway by accumulating pathoadaptive mutations and phenotypic characteristics similar to those of CF. Such information may provide valuable clinical information, and as an example we identified mutations in genes responsible for the development of antibiotic resistance. Based on our research we conclude that P. aeruginosa is a major pathogen in PCD and that future research should focus on pre-venting or eradicating these bacteria. Implementing ESS with adjuvant therapy to PCD patients (I, IV) significantly ameliorated CRS symptoms. Further, postoperatively patients tended to have fewer positive lower airway cultures and better lung function; approximately one out of four operated patients, in search of an infectious focus, remained free of lung colonization with P. aeruginosa during follow-up for at least six months. Based on these results, it is tempting to speculate that ESS with adjuvant therapy can eradicate sinus bacteria and thereby reduce lung re-colonization from the sinuses. However, further evidence is needed to support this hypothesis, preferably from a multicentre randomized controlled trial. Articles published in the Danish Medical Journal are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

Lung volumes: measurement, clinical use, and coding.

PubMed

Flesch, Judd D; Dine, C Jessica

2012-08-01

Measurement of lung volumes is an integral part of complete pulmonary function testing. Some lung volumes can be measured during spirometry; however, measurement of the residual volume (RV), functional residual capacity (FRC), and total lung capacity (TLC) requires special techniques. FRC is typically measured by one of three methods. Body plethysmography uses Boyle's Law to determine lung volumes, whereas inert gas dilution and nitrogen washout use dilution properties of gases. After determination of FRC, expiratory reserve volume and inspiratory vital capacity are measured, which allows the calculation of the RV and TLC. Lung volumes are commonly used for the diagnosis of restriction. In obstructive lung disease, they are used to assess for hyperinflation. Changes in lung volumes can also be seen in a number of other clinical conditions. Reimbursement for measurement of lung volumes requires knowledge of current procedural terminology (CPT) codes, relevant indications, and an appropriate level of physician supervision. Because of recent efforts to eliminate payment inefficiencies, the 10 previous CPT codes for lung volumes, airway resistance, and diffusing capacity have been bundled into four new CPT codes.

The contribution of airway smooth muscle to airway narrowing and airway hyperresponsiveness in disease.

PubMed

Martin, J G; Duguet, A; Eidelman, D H

2000-08-01

Airway hyperresponsiveness (AHR), the exaggerated response to constrictor agonists in asthmatic subjects, is incompletely understood. Changes in either the quantity or properties of airway smooth muscle (ASM) are possible explanations for AHR. Morphometric analyses demonstrate structural changes in asthmatic airways, including subepithelial fibrosis, gland hyperplasia/hypertrophy, neovascularization and an increase in ASM mass. Mathematical modelling of airway narrowing suggests that, of all the changes in structure, the increase in ASM mass is the most probable cause of AHR. An increase in ASM mass in the large airways is more closely associated with a greater likelihood of dying from asthma than increases in ASM mass in other locations within the airway tree. ASM contraction is opposed by the elastic recoil of the lungs and airways, which appears to limit the degree of bronchoconstriction in vivo. The cyclical nature of tidal breathing applies stresses to the airway wall that enhance the bronchodilating influence of the lung tissues on the contracting ASM, in all probability by disrupting cross-bridges. However, the increase in ASM mass in asthma may overcome the limitation resulting from the impedances to ASM shortening imposed by the lung parenchyma and airway wall tissues. Additionally, ASM with the capacity to shorten rapidly may achieve shorter lengths and cause a greater degree of bronchoconstriction when stimulated to contract than slower ASM. Changes in ASM properties are induced by the process of sensitization and allergen-exposure such as enhancement of phospholipase C activity and inositol phosphate turnover, and increases in myosin light chain kinase activity. Whether changes in ASM mass or biochemical/biomechanical properties form the basis for asthma remains to be determined.

CD8+IL-17+ T Cells Mediate Neutrophilic Airway Obliteration in T-bet–Deficient Mouse Lung Allograft Recipients

PubMed Central

Dodd-o, Jeffrey M.; Coon, Tiffany A.; Miller, Hannah L.; Ganguly, Sudipto; Popescu, Iulia; O'Donnell, Christopher P.; Cardenes, Nayra; Levine, Melanie; Rojas, Mauricio; Weathington, Nathaniel M.; Zhao, Jing; Zhao, Yutong; McDyer, John F.

2015-01-01

Acute cellular rejection is a known risk factor for the development of obliterative bronchiolitis, which limits the long-term survival of lung transplant recipients. However, the T cell effector mechanisms in both of these processes remain incompletely understood. Using the mouse orthotopic lung transplant model, we investigated whether C57BL/6 T-bet−/− recipients of major histocompatibility complex (MHC)-mismatched BALB/c lung grafts develop rejection pathology and allospecific cytokine responses that differ from wild-type mice. T-bet−/− recipients demonstrated vigorous allograft rejection at 10 days, characterized by neutrophilic inflammation and predominantly CD8+ T cells producing allospecific IL-17 and/or IFN-γ, in contrast to IFN-γ–dominant responses in WT mice. CD4+ T cells produced IL-17 but not IFN-γ responses in T-bet−/− recipients, in contrast to WT controls. Costimulation blockade using anti-CD154 Ab significantly reduced allospecific CD8+IFN-γ+ responses in both T-bet−/− and WT mice but had no attenuating effect on lung rejection pathology in T-bet−/− recipients or on the development of obliterative airway inflammation that occurred only in T-bet−/− recipients. However, neutralization of IL-17A significantly attenuated costimulation blockade–resistant rejection pathology and airway inflammation in T-bet−/− recipients. In addition, CXCL1 (neutrophil chemokine) was increased in T-bet−/− allografts, and IL-17 induced CXCL1 from mouse lung epithelial cells in vitro. Taken together, our data show that T-bet–deficient recipients of complete MHC-mismatched lung allografts develop costimulation blockade–resistant rejection characterized by neutrophilia and obliterative airway inflammation that is predominantly mediated by CD8+IL-17+ T cells. Our data support T-bet–deficient mouse recipients of lung allografts as a viable animal model to study the immunopathogenesis of small airway injury in lung transplantation. PMID:25286244

Inhibition of Protease-Epithelial Sodium Channel Signaling Improves Mucociliary Function in Cystic Fibrosis Airways.

PubMed

Reihill, James A; Walker, Brian; Hamilton, Robert A; Ferguson, Timothy E G; Elborn, J Stuart; Stutts, M Jackson; Harvey, Brian J; Saint-Criq, Vinciane; Hendrick, Siobhan M; Martin, S Lorraine

2016-09-15

In cystic fibrosis (CF) a reduction in airway surface liquid (ASL) height compromises mucociliary clearance, favoring mucus plugging and chronic bacterial infection. Inhibitors of the epithelial sodium channel (ENaC) have therapeutic potential in CF airways to reduce hyperstimulated sodium and fluid absorption to levels that can restore airway hydration. To determine whether a novel compound (QUB-TL1) designed to inhibit protease/ENaC signaling in CF airways restores ASL volume and mucociliary function. Protease activity was measured using fluorogenic activity assays. Differentiated primary airway epithelial cell cultures (F508del homozygotes) were used to determined ENaC activity (Ussing chamber recordings), ASL height (confocal microscopy), and mucociliary function (by tracking the surface flow of apically applied microbeads). Cell toxicity was measured using a lactate dehydrogenase assay. QUB-TL1 inhibits extracellularly located channel activating proteases (CAPs), including prostasin, matriptase, and furin, the activities of which are observed at excessive levels at the apical surface of CF airway epithelial cells. QUB-TL1-mediated CAP inhibition results in diminished ENaC-mediated Na(+) absorption in CF airway epithelial cells caused by internalization of a prominent pool of cleaved (active) ENaCγ from the cell surface. Importantly, diminished ENaC activity correlates with improved airway hydration status and mucociliary clearance. We further demonstrate QUB-TL1-mediated furin inhibition, which is in contrast to other serine protease inhibitors (camostat mesylate and aprotinin), affords protection against neutrophil elastase-mediated ENaC activation and Pseudomonas aeruginosa exotoxin A-induced cell death. QUB-TL1 corrects aberrant CAP activities, providing a mechanism to delay or prevent the development of CF lung disease in a manner independent of CF transmembrane conductance regulator mutation.

Characteristic patterns in the fibrotic lung. Comparing idiopathic pulmonary fibrosis with chronic lung allograft dysfunction.

PubMed

Fernandez, Isis E; Heinzelmann, Katharina; Verleden, Stijn; Eickelberg, Oliver

2015-03-01

Tissue fibrosis, a major cause of death worldwide, leads to significant organ dysfunction in any organ of the human body. In the lung, fibrosis critically impairs gas exchange, tissue oxygenation, and immune function. Idiopathic pulmonary fibrosis (IPF) is the most detrimental and lethal fibrotic disease of the lung, with an estimated median survival of 50% after 3-5 years. Lung transplantation currently remains the only therapeutic alternative for IPF and other end-stage pulmonary disorders. Posttransplant lung function, however, is compromised by short- and long-term complications, most importantly chronic lung allograft dysfunction (CLAD). CLAD affects up to 50% of all transplanted lungs after 5 years, and is characterized by small airway obstruction with pronounced epithelial injury, aberrant wound healing, and subepithelial and interstitial fibrosis. Intriguingly, the mechanisms leading to the fibrotic processes in the engrafted lung exhibit striking similarities to those in IPF; therefore, antifibrotic therapies may contribute to increased graft function and survival in CLAD. In this review, we focus on these common fibrosis-related mechanisms in IPF and CLAD, comparing and contrasting clinical phenotypes, the mechanisms of fibrogenesis, and biomarkers to monitor, predict, or prognosticate disease status.

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

PubMed Central

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

2007-01-01

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

EFFECTS OF TITANIUM DIOXIDE NANOPARTICLE EXPOSURE ON NEUROIMMUNE RESPONSES IN RAT AIRWAYS

PubMed Central

Scuri, Mario; Chen, Bean T.; Castranova, Vincent; Reynolds, Jeffrey S.; Johnson, Victor J.; Samsell, Lennie; Walton, Cheryl; Piedimonte, Giovanni

2013-01-01

Exposure to ambient nanoparticles (defined as particulate matter [PM] having one dimension < 100 nm) is associated with increased risk of childhood and adult asthma. Nanomaterials feature a smaller aerodynamic diameter and a higher surface area per unit mass ratio compared to fine or coarse-sized particles, resulting in greater lung deposition efficiency and an increased potential for biological interaction. The neurotrophins nerve growth factor and brain-derived neurotrophic factor are key regulatory elements of neuronal development and responsiveness of airway sensory neurons. Changes in their expression are associated with bronchoconstriction, airway hyperresponsiveness, and airway inflammation. The neurogenic-mediated control of airway responses is a key pathophysiological mechanism of childhood asthma. However, the effects of nanoparticle exposure on neurotrophin-driven airway responses and their potential role as a predisposing factor for developing asthma have not been clearly elucidated. In this study, in vivo inhalation exposure to titanium dioxide nanoparticles (12 mg/m13; 5.6 h/d for 3 d) produced upregulation of lung neurotrophins in weanling (2-wk-old) and newborn (2-d-old) rats but not in adult (12-wk-old) animals compared to controls. This effect was associated with increased airway responsiveness and upregulation of growth-related oncogene/keratine-derived chemokine (GRO/KC; CXCL1, rat equivalent of human interleukin [IL]-8) in bronchoalveolar lavage fluid. These data show for the first time that exposure to nanoparticulate upregulates the expression of lung neurotrophins in an age-dependent fashion and that this effect is associated with airway hyperresponsiveness and inflammation. These results suggest the presence of a critical window of vulnerability in earlier stages of lung development, which may lead to a higher risk of developing asthma. PMID:20818535

Direct sampling of cystic fibrosis lungs indicates that DNA-based analyses of upper-airway specimens can misrepresent lung microbiota.

PubMed

Goddard, Amanda F; Staudinger, Benjamin J; Dowd, Scot E; Joshi-Datar, Amruta; Wolcott, Randall D; Aitken, Moira L; Fligner, Corinne L; Singh, Pradeep K

2012-08-21

Recent work using culture-independent methods suggests that the lungs of cystic fibrosis (CF) patients harbor a vast array of bacteria not conventionally implicated in CF lung disease. However, sampling lung secretions in living subjects requires that expectorated specimens or collection devices pass through the oropharynx. Thus, contamination could confound results. Here, we compared culture-independent analyses of throat and sputum specimens to samples directly obtained from the lungs at the time of transplantation. We found that CF lungs with advanced disease contained relatively homogenous populations of typical CF pathogens. In contrast, upper-airway specimens from the same subjects contained higher levels of microbial diversity and organisms not typically considered CF pathogens. Furthermore, sputum exhibited day-to-day variation in the abundance of nontypical organisms, even in the absence of clinical changes. These findings suggest that oropharyngeal contamination could limit the accuracy of DNA-based measurements on upper-airway specimens. This work highlights the importance of sampling procedures for microbiome studies and suggests that methods that account for contamination are needed when DNA-based methods are used on clinical specimens.

Design of the exhale airway stents for emphysema (EASE) trial: an endoscopic procedure for reducing hyperinflation

PubMed Central

2011-01-01

Background Airway Bypass is a catheter-based, bronchoscopic procedure in which new passageways are created that bypass the collapsed airways, enabling trapped air to exit the lungs. The Exhale Airway Stents for Emphysema (EASE) Trial was designed to investigate whether Exhale® Drug-Eluting Stents, placed in new passageways in the lungs, can improve pulmonary function and reduce breathlessness in severely hyperinflated, homogeneous emphysema patients (NCT00391612). Methods/Design The multi-center, randomized, double-blind, sham-controlled trial design was posted on http://www.clinicaltrials.gov in October 2006. Because Bayesian statistics are used for the analysis, the proposed enrollment ranged from 225 up to 450 subjects at up to 45 institutions. Inclusion criteria are: high resolution CT scan with evidence of homogeneous emphysema, post-bronchodilator pulmonary function tests showing: a ratio of FEV1/FVC < 70%, FEV1≤50% of predicted or FEV1 < 1 liter, RV/TLC≥0.65 at screening, marked dyspnea score ≥2 on the modified Medical Research Council scale of 0-4, a smoking history of at least 20 pack years and stopped smoking for at least 8 weeks prior to enrollment. Following 16 to 20 supervised pulmonary rehabilitation sessions, subjects were randomized 2:1 to receive either a treatment (Exhale® Drug-Eluting Stent) or a sham bronchoscopy. A responder analysis will evaluate the co-primary endpoints of an FVC improvement ≥12% of the patient baseline value and modified Medical Research Council dyspnea scale improvement (reduction) ≥1 point at the 6-month follow-up visit. Discussion If through the EASE Trial, Airway Bypass is shown to improve pulmonary function and reduce dyspnea while demonstrating an acceptable safety profile, then homogeneous patients will have a minimally invasive treatment option with meaningful clinical benefit. Trial Registration ClinicalTrials.gov: NCT00391612 PMID:21214899

Toll-like receptor-2 agonist-allergen coupling efficiently redirects Th2 cell responses and inhibits allergic airway eosinophilia.

PubMed

Krishnaswamy, Jayendra Kumar; Jirmo, Adan Chari; Baru, Abdul Mannan; Ebensen, Thomas; Guzmán, Carlos A; Sparwasser, Tim; Behrens, Georg M N

2012-12-01

Toll-like receptor (TLR) agonists beneficially modulate allergic airway inflammation. However, the efficiency of TLR agonists varies considerably, and their exact cellular mechanisms (especially of TLR 2/6 agonists) are incompletely understood. We investigated at a cellular level whether the administration of the pharmacologically improved TLR2/6 agonist S-[2,3-bispalmitoyiloxy-(2R)-propyl]-R-cysteinyl-amido-monomethoxy polyethylene glycol (BPP) conjugated to antigenic peptide (BPP-OVA) could divert an existing Th2 response and influence airway eosinophilia. The effects of BPP-OVA on airway inflammation were assessed in a classic murine sensitization/challenge model and an adoptive transfer model, which involved the adoptive transfer of in vitro differentiated ovalbumin (OVA)-specific Th2 cells. Functional T-cell stimulation by lung dendritic cells (DCs) was determined both in vitro and in vivo, combined with a cytokine secretion analysis. A single mucosal application of BPP-OVA efficiently delivered antigen, led to TLR2-mediated DC activation, and resulted in OVA-specific T-cell proliferation via lung DCs in vivo. In alternative models of allergic airway disease, a single administration of BPP-OVA before OVA challenge (but not BPP alone) significantly reduced airway eosinophilia, most likely through altered antigen-specific T-cell stimulation via DCs. Analyses of adoptively transferred Th2-biased cells after BPP-OVA administration in vivo suggested that BPP-OVA guides antigen-specific Th2 cells to produce significantly higher amounts of IFN-γ upon allergen challenge. In conclusion, our data show for the first time that a single mucosal administration of a TLR 2/6 agonist-allergen conjugate can provoke IFN-γ responses in Th2-biased cells and alleviate allergic airway inflammation.

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

PubMed

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

2007-11-27

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

Airway bypass treatment of severe homogeneous emphysema: taking advantage of collateral ventilation.

PubMed

Choong, Cliff K; Cardoso, Paulo F G; Sybrecht, Gerhard W; Cooper, Joel D

2009-05-01

Airway bypass is being investigated as a new form of minimally invasive therapy for the treatment of homogeneous emphysema. It is a bronchoscopic catheter-based procedure that creates transbronchial extra-anatomic passages at the bronchial segmental level. The passages are expanded, supported with the expectation that the patency is maintained by paclitaxel drug-eluting airway bypass stents. The concept of airway bypass has been demonstrated in two separate experimental studies. These studies have shown that airway bypass takes advantage of collateral ventilation present in homogeneous emphysema to allow trapped gas to escape and reduce hyperinflation. It improves lung mechanics, expiratory flow, and volume. Airway bypass stent placements have been shown to be feasible and safe in both animal and human studies. Paclitaxel-eluting airway bypass stents were found to prolong stent patency and were adopted for clinical studies. A study evaluating the early results of the clinical application of airway bypass with paclitaxel-eluting stents found that airway bypass procedures reduced hyperinflation and improved pulmonary function and dyspnea in selected subjects who have severe emphysema. The duration of benefit appeared to correlate with the degree of pretreatment hyperinflation. These preliminary clinical results supported further evaluation of the procedure and led to the EASE Trial. The EASE Trial is a prospective, multicenter, randomized, double-blind, sham-controlled study. The trial aims to evaluate the safety and effectiveness of the airway bypass to improve pulmonary function and reduce dyspnea in homogeneous emphysema subjects who have severe hyperinflation. The trial is presently ongoing worldwide, though enrollment was completed.

Structural and functional localization of airway effects from episodic exposure of infant monkeys to allergen and/or ozone

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

Joad, Jesse P.; Kott, Kayleen S.; Bric, John M.

2006-08-01

Both allergen and ozone exposure increase asthma symptoms and airway responsiveness in children. Little is known about how these inhalants may differentially modify airway responsiveness in large proximal as compared to small distal airways. We evaluated whether bronchi and respiratory bronchioles from infant monkeys exposed episodically to allergen and/or ozone differentially develop intrinsic hyperresponsiveness to methacholine and whether eosinophils and/or pulmonary neuroendocrine cells play a role. Infant monkeys were exposed episodically for 5 months to: (1) filtered air, (2) aerosolized house dust mite allergen, (3) ozone 0.5 ppm, or (4) house dust mite allergen + ozone. Studying the function/structure relationshipmore » of the same lung slices, we evaluated methacholine airway responsiveness and histology of bronchi and respiratory bronchioles. In bronchi, intrinsic responsiveness was increased by allergen exposure, an effect reduced by bombesin antagonist. In respiratory bronchioles, intrinsic airway responsiveness was increased by allergen + ozone exposure. Eosinophils were increased by allergen and allergen + ozone exposure in bronchi and by allergen exposure in respiratory bronchioles. In both airways, exposure to allergen + ozone resulted in fewer tissue eosinophils than did allergen exposure alone. In bronchi, but not in respiratory bronchioles, the number of eosinophils and neuroendocrine cells correlated with airway responsiveness. We conclude that episodically exposing infant monkeys to house dust mite allergen with or without ozone increased intrinsic airway responsiveness to methacholine in bronchi differently than in respiratory bronchioles. In bronchi, eosinophils and neuroendocrine cells may play a role in the development of airway hyperresponsiveness.« less

Right ventricular function during one-lung ventilation: effects of pressure-controlled and volume-controlled ventilation.

PubMed

Al Shehri, Abdullah M; El-Tahan, Mohamed R; Al Metwally, Roshdi; Qutub, Hatem; El Ghoneimy, Yasser F; Regal, Mohamed A; Zien, Haytham

2014-08-01

To test the effects of pressure-controlled (PCV) and volume-controlled (VCV) ventilation during one-lung ventilation (OLV) for thoracic surgery on right ventricular (RV) function. A prospective, randomized, double-blind, controlled, crossover study. A single university hospital. Fourteen pairs of consecutive patients scheduled for elective thoracotomy. Patients were assigned randomly to ventilate the dependent lung with PCV or VCV mode, each in a randomized crossover order using tidal volume of 6 mL/kg, I: E ratio 1: 2.5, positive end-expiratory pressure (PEEP) of 5 cm H2O and respiratory rate adjusted to maintain normocapnia. Intraoperative changes in RV function (systolic and early diastolic tricuspid annular velocity (TAV), end-systolic volume (ESV), end-diastolic volume (EDV) and fractional area changes (FAC)), airway pressures, compliance and oxygenation index were recorded. The use of PCV during OLV resulted in faster systolic (10.1±2.39 vs. 5.8±1.67 cm/s, respectively), diastolic TAV (9.2±1.99 vs. 4.6±1.42 cm/s, respectively) (p<0.001) and compliance and lower ESV, EDV and airway pressures (p<0.05) than during the use of VCV. Oxygenation indices were similar during the use of VCV and PCV. The use of PCV offers more improved RV function than the use of VCV during OLV for open thoracotomy. These results apply specifically to younger patients with good ventricular and pulmonary functions. © 2014 Elsevier Inc. All rights reserved.

Oxidative stress–induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease

PubMed Central

Wiegman, Coen H.; Michaeloudes, Charalambos; Haji, Gulammehdi; Narang, Priyanka; Clarke, Colin J.; Russell, Kirsty E.; Bao, Wuping; Pavlidis, Stelios; Barnes, Peter J.; Kanerva, Justin; Bittner, Anton; Rao, Navin; Murphy, Michael P.; Kirkham, Paul A.; Chung, Kian Fan; Adcock, Ian M.; Brightling, Christopher E.; Davies, Donna E.; Finch, Donna K.; Fisher, Andrew J.; Gaw, Alasdair; Knox, Alan J.; Mayer, Ruth J.; Polkey, Michael; Salmon, Michael; Singh, David

2015-01-01

Background Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress–induced pathology. Objective We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells. Methods Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ. Results Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-β–induced ASM cell proliferation and CXCL8 release. Conclusions Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation. Targeting mitochondrial ROS represents a promising therapeutic approach in patients with COPD. PMID:25828268

8-oxoguanine DNA Glycosylase 1-Deficiency Modifies Allergic Airway Inflammation by Regulating STAT6 and IL-4 in Cells and in Mice

PubMed Central

Li, Guoping; Yuan, Kefei; Yan, Chunguang; Fox, John; Gaid, Madeleine; Breitwieser, Wayne; Bansal, Arvind K.; Zeng, Huawei; Gao, Hongwei; Wu, Min

2013-01-01

8-oxoguanine-DNA glycosylase (OGG-1) is a base excision DNA repair enzyme; however, its function in modulating allergic diseases remains undefined. Using OGG-1 knockout (KO) mice, we show that this protein impacts allergic airway inflammation following sensitization and challenge by ovalbumin (OVA). OGG-1 KO mice exhibited less inflammatory cell infiltration and reduced oxidative stress in the lungs after OVA challenge compared to WT mice. The KO phenotype included decreased IL-4, IL-6, IL-10, and IL-17 in lung tissues. In addition, OGG-1 KO mice showed decreased expression and phosphorylation of STAT6 as well as NF-κB. Down-regulation of OGG-1 by siRNA lowered ROS and IL-4 levels but increased INF-γ production in cultured epithelial cells following exposure to house dust mite (HDM) extracts. OGG-1 may affect the levels of oxidative stress and proinflammatory cytokines during asthmatic conditions. OGG-1-deficiency negatively regulates allergen-induced airway inflammatory response. PMID:22100973

A brief review of chronic obstructive pulmonary disease.

PubMed

Hogg, James C

2012-01-01

A recent study, based on a combination of multidetector computed tomography scanning of an intact specimen with microcomputed tomography and histological analysis of lung tissue samples, reported that the number of terminal bronchioles were reduced from approximately 44,500/lung pair in control (donor) lungs to approximately 4800/lung pair in lungs donated by individuals with very severe (Global initiative for chronic Obstructive Lung Disease stage 4) chronic obstructive pulmonary disease (COPD) treated by lung transplantation. The present short review discusses the hypothesis that a rapid rate of terminal bronchiolar destruction causes the rapid decline in lung function leading to advanced COPD. With respect to why the terminal bronchioles are targeted for destruction, the postulated mechanisms of this destruction and the possibility that new treatments are able to either prevent or reverse the underlying cause of airway obstruction in COPD are addressed.

Development and application of pulmonary structure-function registration methods: towards pulmonary image-guidance tools for improved airway targeted therapies and outcomes

NASA Astrophysics Data System (ADS)

Guo, Fumin; Pike, Damien; Svenningsen, Sarah; Coxson, Harvey O.; Drozd, John J.; Yuan, Jing; Fenster, Aaron; Parraga, Grace

2014-03-01

Objectives: We aimed to develop a way to rapidly generate multi-modality (MRI-CT) pulmonary imaging structurefunction maps using novel non-rigid image registration methods. This objective is part of our overarching goal to provide an image processing pipeline to generate pulmonary structure-function maps and guide airway-targeted therapies. Methods: Anatomical 1H and functional 3He MRI were acquired in 5 healthy asymptomatic ex-smokers and 7 ex-smokers with chronic obstructive pulmonary disease (COPD) at inspiration breath-hold. Thoracic CT was performed within ten minutes of MRI using the same breath-hold volume. Landmark-based affine registration methods previously validated for imaging of COPD, was based on corresponding fiducial markers located in both CT and 1H MRI coronal slices and compared with shape-based CT-MRI non-rigid registration. Shape-based CT-MRI registration was developed by first identifying the shapes of the lung cavities manually, and then registering the two shapes using affine and thin-plate spline algorithms. We compared registration accuracy using the fiducial localization error (FLE) and target registration error (TRE). Results: For landmark-based registration, the TRE was 8.4±5.3 mm for whole lung and 7.8±4.6 mm for the R and L lungs registered independently (p=0.4). For shape-based registration, the TRE was 8.0±4.6 mm for whole lung as compared to 6.9±4.4 mm for the R and L lung registered independently and this difference was significant (p=0.01). The difference for shape-based (6.9±4.4 mm) and landmark-based R and L lung registration (7.8±4.6 mm) was also significant (p=.04) Conclusion: Shape-based registration TRE was significantly improved compared to landmark-based registration when considering L and R lungs independently.

Enhanced gene delivery to the lung using biodegradable polyunsaturated cationic phosphatidylcholine-detergent conjugates.

PubMed

Pierrat, Philippe; Kereselidze, Dimitri; Lux, Marie; Lebeau, Luc; Pons, Françoise

2016-09-10

Lung diseases are among the more representative causes of mortality and morbidity worldwide and gene therapy is considered as a promising therapeutic approach for their treatment. However the design of efficient nucleic acid carriers for airway administration still is a challenge and there is a pressing need for new developments in this field. Herein, new synthetic DNA carriers based on the conjugation of a phospholipid and C12E4, a nonionic detergent, are developed. DNA complexes with phosphatidylcholine-detergent conjugates are administered in mouse airways, and transgene expression and inflammatory activity as an index of toxicity are investigated as a function of time, DNA dose, and presence of helper and stealth lipids. Introduction of a biodegradable linker between the phosphatidylcholine and detergent moieties significantly attenuates the severity of inflammatory response that characterizes cationic lipid-mediated gene transfer. Concurrent introduction of polyunsaturated fatty acid chains in the carrier scaffold improves transgene expression and further reduces airway inflammation. Finally, the biodegradable phosphatidylcholine-detergent conjugates favorably compare to GL67A, the gold standard for DNA delivery to the airway that is currently under clinical evaluation. Our findings indicate that the lipid formulations described herein may have great potential as nucleic acid carriers for gene therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

The role of adjustment of expiratory effort in the control of vocal intensity: clinical assessment of phonatory function.

PubMed

Makiyama, Kiyoshi; Yoshihashi, Hidetaka; Mogitate, Manabu; Kida, Akinori

2005-04-01

To determine the role of the adjustment of expiratory effort in the control of vocal intensity. An intensity-loading test was performed by using the airway interruption method. Three groups of subjects were used: a control group thought to resemble normal vocal fold closure, a group of patients with Reinke's edema thought to represent increased mass at the level of the vocal folds, and a group with vocal fold paralysis that was thought to represent a group with lack of adequate vocal fold closure. In the control group, expiratory lung pressure and airway resistance slightly increased. In the patients with Reinke's edema, expiratory lung pressure, and airway resistance significantly increased. In this group, the voice intensity was controlled by laryngeal adjustment, but a greater expiratory effort was needed because of a greater increase in glottal resistance. In the patients with vocal cord paralysis, airway resistance did not increase even with a high-intensity voice. Vocal intensity was controlled by expiratory effort. If there is sufficient ability for laryngeal adjustment, vocal intensity is controlled primarily by laryngeal adjustment and by expiratory adjustment in response to increased glottal resistance. However, vocal intensity is controlled by expiratory effort when laryngeal adjustment ability is poor.

WE-AB-202-02: Incorporating Regional Ventilation Function in Predicting Radiation Fibrosis After Concurrent Chemoradiotherapy for Lung Cancer

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

Lan, F; Jeudy, J; Tseng, H

Purpose: To investigate the incorporation of pre-therapy regional ventilation function in predicting radiation fibrosis (RF) in stage III non-small-cell lung cancer (NSCLC) patients treated with concurrent thoracic chemoradiotherapy. Methods: 37 stage III NSCLC patients were retrospectively studied. Patients received one cycle of cisplatin-gemcitabine, followed by two to three cycles of cisplatin-etoposide concurrently with involved-field thoracic radiotherapy between 46 and 66 Gy (2 Gy per fraction). Pre-therapy regional ventilation images of the lung were derived from 4DCT via a density-change-based image registration algorithm with mass correction. RF was evaluated at 6-months post-treatment using radiographic scoring based on airway dilation and volumemore » loss. Three types of ipsilateral lung metrics were studied: (1) conventional dose-volume metrics (V20, V30, V40, and mean-lung-dose (MLD)), (2) dose-function metrics (fV20, fV30, fV40, and functional mean-lung-dose (fMLD) generated by combining regional ventilation and dose), and (3) dose-subvolume metrics (sV20, sV30, sV40, and subvolume mean-lung-dose (sMLD) defined as the dose-volume metrics computed on the sub-volume of the lung with at least 60% of the quantified maximum ventilation status). Receiver operating characteristic (ROC) curve analysis and logistic regression analysis were used to evaluate the predictability of these metrics for RF. Results: In predicting airway dilation, the area under the ROC curve (AUC) values for (V20, MLD), (fV20, fMLD), and (sV20, and sMLD) were (0.76, 0.70), (0.80, 0.74) and (0.82, 0.80), respectively. The logistic regression p-values were (0.09, 0.18), (0.02, 0.05) and (0.004, 0.006), respectively. With regard to volume loss, the corresponding AUC values for these metrics were (0.66, 0.57), (0.67, 0.61) and (0.71, 0.69), and p-values were (0.95, 0.90), (0.43, 0.64) and (0.08, 0.12), respectively. Conclusion: The inclusion of regional ventilation function improved predictability of radiation fibrosis. Dose-subvolume metrics provided a promising method for incorporating functional information into the conventional dose-volume parameters for outcome assessment.« less

Relationship between the baseline alveolar volume-to-total lung capacity ratio and airway responsiveness.

PubMed

Kaminsky, David A; Daud, Anees; Chapman, David G

2014-10-01

Ventilation heterogeneity (VH) has been linked to airway responsiveness (AR) based on various measures of VH involving inert gas washout, forced oscillation and lung imaging. We explore whether VH at baseline, as measured by the simple ratio of single breath alveolar volume to plethysmographically determined total lung capacity (VA/TLC), would correlate with AR as measured by methacholine challenge testing. We analysed data from spirometry, lung volumes, diffusing capacity and methacholine challenge to derive the VA/TLC and the dose-response slope (DRS) of forced expiratory volume in 1 s (DRS-FEV1) during methacholine challenge from 136 patients. We separated out airway closure versus narrowing by examining the DRS for forced vital capacity (DRS-FVC) and the DRS for FEV1/FVC (DRS-FEV1/FVC), respectively. Similarly, we calculated the DRS for sGaw (DRS-sGaw) as another measure of airway narrowing. We performed statistical analysis using Spearman rank correlation and multifactor linear regression using a backward stepwise modelling procedure. We found that the DRS-FEV1 correlated with baseline VA/TLC (rho = -0.26, P < 0.01), and VA/TLC and FEV1 were independently associated with DRS-FEV1 (R(2)  = 0.14, P = 0.01). In addition, VA/TLC was associated with both airway narrowing and closure in response to methacholine. These results confirm that baseline VA/TLC is associated with AR, and reflects both airway closure and airway narrowing following methacholine challenge. © 2014 Asian Pacific Society of Respirology.

Molecular Profiles for Lung Cancer Pathogenesis and Detection in U.S. Veterans

DTIC Science & Technology

2014-12-18

that the adjacent field cancerization extends to relatively less invasive large airways and harbors markers that can detect lung cancer in smokers ; 5...profiles have been described in the normal-appearing bronchial epithelium of healthy smokers (9) including those that were diagnostic of lung cancer...10). In addition, modulation of global gene expression in the normal epithelium in health smokers is similar in the large and small airways and the

Airway epithelial homeostasis and planar cell polarity signaling depend on multiciliated cell differentiation

PubMed Central

Vladar, Eszter K.; Nayak, Jayakar V.; Milla, Carlos E.; Axelrod, Jeffrey D.

2016-01-01

Motile airway cilia that propel contaminants out of the lung are oriented in a common direction by planar cell polarity (PCP) signaling, which localizes PCP protein complexes to opposite cell sides throughout the epithelium to orient cytoskeletal remodeling. In airway epithelia, PCP is determined in a 2-phase process. First, cell-cell communication via PCP complexes polarizes all cells with respect to the proximal-distal tissue axis. Second, during ciliogenesis, multiciliated cells (MCCs) undergo cytoskeletal remodeling to orient their cilia in the proximal direction. The second phase not only directs cilium polarization, but also consolidates polarization across the epithelium. Here, we demonstrate that in airway epithelia, PCP depends on MCC differentiation. PCP mutant epithelia have misaligned cilia, and also display defective barrier function and regeneration, indicating that PCP regulates multiple aspects of airway epithelial homeostasis. In humans, MCCs are often sparse in chronic inflammatory diseases, and these airways exhibit PCP dysfunction. The presence of insufficient MCCs impairs mucociliary clearance in part by disrupting PCP-driven polarization of the epithelium. Consistent with defective PCP, barrier function and regeneration are also disrupted. Pharmacological stimulation of MCC differentiation restores PCP and reverses these defects, suggesting its potential for broad therapeutic benefit in chronic inflammatory disease. PMID:27570836

HEALTH EFFECTS OF REAL-WORLD EXPOSURE TO DIESEL EXHAUST IN PERSONS WITH ASTHMA

EPA Science Inventory

Investigators anticipate that this proposed research will indicate that lung function is slightly decreased and some markers of airway inflammation are increased in people with asthma who are exposed to ambient urban air in a roadside environment dominated by diesel vehicle...

SMALL AIRWAYS FUNCTION RESPONSE IN SMOKERS AND PATIENTS WITH CHRONIC OBSTRUCTIVE LUNG DISEASE FOLLOWING EXPOSURE TO CONCENTRATED AMBIENT AIR PARTICLES

EPA Science Inventory

Numerous field and epidemiological studies have shown significant associations between particulate matter (PM) exposure and various morbidity outcomes including hospital admissions for bronchitis and asthma. These population based studies indicate that persons with chronic obstru...

Degradation of airway neuropeptides by human lung tryptase.

PubMed

Tam, E K; Caughey, G H

1990-07-01

Several lines of evidence suggest a possible role for mast cell proteases in modulating the biologic effects of neuropeptides. To explore the potential of such interactions in human airway, we examined the activity of human tryptase, the major secretory protease of human lung mast cells, against several neuropeptides with proposed regulatory functions in human airway. Using highly purified tryptase obtained from extracts of human lung, we determined the sites and rats of hydrolysis of vasoactive intestinal peptide (VIP), peptide histidine-methionine (PHM), calcitonin gene-related peptide (CGRP), and the tachykinins substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). Tryptase hydrolyzes VIP rapidly at several sites (Arg12, Arg14, Lys20, and Lys21) with an overall kcat/Km of 1.5 x 10(5) M-1 s-1 and hydrolyzes PHM primarily at a single site (Lys20) with a kcat/Km of 1.9 x 10(4) M-1 s-1. Tryptase also rapidly hydrolyzes CGRP at two sites (Arg18 and Lys24) with a kcat/Km of 2.7 x 10(5) M-1 s-1. The tachykinins are not hydrolyzed by tryptase. These observations raise the possibility that tryptase-mediated degradation of the bronchodilators VIP and PHM combined with exaggerated mast cell release of tryptase may contribute to the increase in bronchial responsiveness and the decrease in immunoreactive VIP in airway nerves associated with asthma. The favorable rates of hydrolysis of CGRP suggest that tryptase may also terminate the effects of CGRP on bronchial and vascular smooth muscle tone and permeability.

Absorbed doses of lungs from radon retained in airway lumens of mice and rats.

PubMed

Sakoda, Akihiro; Ishimori, Yuu; Yamaoka, Kiyonori; Kataoka, Takahiro; Mitsunobu, Fumihiro

2013-08-01

This paper provides absorbed doses arising from radon gas in air retained in lung airway lumens. Because radon gas exposure experiments often use small animals, the calculation was performed for mice and rats. For reference, the corresponding computations were also done for humans. Assuming that radon concentration in airway lumens is the same as that in the environment, its progeny's production in and clearance from airways were simulated. Absorbed dose rates were obtained for three lung regions and the whole lung, considering that secretory and basal cells are sensitive to radiation. The results showed that absorbed dose rates for all lung regions and whole lung generally increase from mice to rats to humans. For example, the dose rates for the whole lung were 25.4 in mice, 41.7 in rats, and 59.9 pGy (Bq m⁻³)⁻¹ h⁻¹ in humans. Furthermore, these values were also compared with lung dose rates from two other types of exposures, that is, due to inhalation of radon or its progeny, which were already reported. It was confirmed that the direct inhalation of radon progeny in the natural environment, which is known as a cause of lung cancer, results in the highest dose rates for all species. Based on the present calculations, absorbed dose rates of the whole lung from radon gas were lower by a factor of about 550 (mice), 200 (rats), or 70 (humans) than those from radon progeny inhalation. The calculated dose rate values are comparatively small. Nevertheless, the present study is considered to contribute to our understanding of doses from inhalation of radon and its progeny.

Normal expiratory flow rate and lung volumes in patients with combined emphysema and interstitial lung disease: a case series and literature review.

PubMed

Heathcote, Karen L; Cockcroft, Donald W; Fladeland, Derek A; Fenton, Mark E

2011-01-01

Pulmonary function tests in patients with idiopathic pulmonary fibrosis characteristically show a restrictive pattern including small lung volumes and increased expiratory flow rates resulting from a reduction in pulmonary compliance due to diffuse fibrosis. Conversely, an obstructive pattern with hyperinflation results in emphysema by loss of elastic recoil, expiratory collapse of the peripheral airways and air trapping. When the diseases coexist, pulmonary volumes are compensated, and a smaller than expected reduction or even normal lung volumes can be found. The present report describes 10 patients with progressive breathlessness, three of whom experienced severe limitation in their quality of life. All patients showed lung interstitial involvement and emphysema on computed tomography scan of the chest. The 10 patients showed normal spirometry and lung volumes with severe compromise of gas exchange. Normal lung volumes do not exclude diagnosis of idiopathic pulmonary fibrosis in patients with concomitant emphysema. The relatively preserved lung volumes may underestimate the severity of idiopathic pulmonary fibrosis and attenuate its effects on lung function parameters.

Parasympathetic Control of Airway Submucosal Glands: Central Reflexes and the Airway Intrinsic Nervous System

PubMed Central

Wine, Jeffrey J.

2007-01-01

Airway submucosal glands produce the mucus that lines the upper airways to protect them against insults. This review summarizes evidence for two forms of gland secretion, and hypothesizes that each is mediated by different but partially overlapping neural pathways. Airway innate defense comprises low level gland secretion, mucociliary clearance and surveillance by airway-resident phagocytes to keep the airways sterile in spite of nearly continuous inhalation of low levels of pathogens. Gland secretion serving innate defense is hypothesized to be under the control of intrinsic (peripheral) airway neurons and local reflexes, and these may depend disproportionately on non-cholinergic mechanisms, with most secretion being produced by VIP and tachykinins. In the genetic disease cystic fibrosis, airway glands no longer secrete in response to VIP alone and fail to show the synergy between VIP, tachykinins and ACh that is observed in normal glands. The consequent crippling of the submucosal gland contribution to innate defense may be one reason that cystic fibrosis airways are infected by mucus-resident bacteria and fungi that are routinely cleared from normal airways. By contrast, the acute (emergency) airway defense reflex is centrally mediated by vagal pathways, is primarily cholinergic, and stimulates copious volumes of gland mucus in response to acute, intense challenges to the airways, such as those produced by very vigorous exercise or aspiration of foreign material. In cystic fibrosis, the acute airway defense reflex can still stimulate the glands to secrete large amounts of mucus, although its properties are altered. Importantly, treatments that recruit components of the acute reflex, such as inhalation of hypertonic saline, are beneficial in treating cystic fibrosis airway disease. The situation for recipients of lung transplants is the reverse; transplanted airways retain the airway intrinsic nervous system but lose centrally mediated reflexes. The consequences of this for gland secretion and airway defense are poorly understood, but it is possible that interventions to modify submucosal gland secretion in transplanted lungs might have therapeutic consequences. Introduction and overviewProtecting the Airways: mucus and submucosal glands.The airway intrinsic nervous system: a special role in innate defense?Innate defense: prophylactic secretion and local responses.Acute ‘Emergency’ airway defense reflexesAirway receptors: Improved methods reveal greater diversityHijacking emergency defense for innate defense: receptor plasticity and airways sensitization.Conclusion: Implications for cystic fibrosis and lung transplantation. PMID:17350348

[Ca2+]i oscillations in ASM: relationship with persistent airflow obstruction in asthma.

PubMed

Sweeney, David; Hollins, Fay; Gomez, Edith; Saunders, Ruth; Challiss, R A John; Brightling, Christopher E

2014-07-01

The cause of airway smooth muscle (ASM) hypercontractility in asthma is not fully understood. The relationship of spontaneous intracellular calcium oscillation frequency in ASM to asthma severity was investigated. Oscillations were increased in subjects with impaired lung function abolished by extracellular calcium removal, attenuated by caffeine and unaffected by verapamil or nitrendipine. Whether modulation of increased spontaneous intracellular calcium oscillations in ASM from patients with impaired lung function represents a therapeutic target warrants further investigation. © 2014 The Authors. Respirology published by Wiley Publishing Asia Pty Ltd on behalf of Asian Pacific Society of Respirology.

Postoperative respiratory muscle dysfunction: pathophysiology and preventive strategies.

PubMed

Sasaki, Nobuo; Meyer, Matthew J; Eikermann, Matthias

2013-04-01

Postoperative pulmonary complications are responsible for significant increases in hospital cost as well as patient morbidity and mortality; respiratory muscle dysfunction represents a contributing factor. Upper airway dilator muscles functionally resist the upper airway collapsing forces created by the respiratory pump muscles. Standard perioperative medications (anesthetics, sedatives, opioids, and neuromuscular blocking agents), interventions (patient positioning, mechanical ventilation, and surgical trauma), and diseases (lung hyperinflation, obesity, and obstructive sleep apnea) have differential effects on the respiratory muscle subgroups. These effects on the upper airway dilators and respiratory pump muscles impair their coordination and function and can result in respiratory failure. Perioperative management strategies can help decrease the incidence of postoperative respiratory muscle dysfunction. Such strategies include minimally invasive procedures rather than open surgery, early and optimal mobilizing of respiratory muscles while on mechanical ventilation, judicious use of respiratory depressant anesthetics and neuromuscular blocking agents, and noninvasive ventilation when possible.

Epithelial and endothelial cell plasticity in chronic obstructive pulmonary disease (COPD).

PubMed

Sohal, Sukhwinder Singh

2017-03-01

Chronic Obstructive Pulmonary Disease (COPD) is mainly caused by smoking and presents with shortness of breath that is progressive and irreversible. It is a worldwide health problem and the fourth most common cause of chronic disability and mortality (even in developed countries). It is a complex disease involving both the airway and lung parenchyma. Small-airway fibrosis is the main contributor to physiological airway dysfunction in COPD. One potential mechanism contributing to small-airway fibrosis is epithelial mesenchymal transition (EMT). When associated with angiogenesis (EMT-type-3), EMT may well also be linked to the development of airway epithelial cancer, which is closely associated with COPD and predominantly observed in large airways. Vascular remodeling has also been widely reported in smokers and patients with COPD but the mechanisms behind it are poorly understood. It is quite possible that the process of endothelial to mesenchymal transition (EndMT) is also active in COPD lungs, in addition to EMT. Understanding these pathological mechanisms will greatly enhance our knowledge of the immunopathology of smoking-related lung disease. Only by understanding these processes can new therapies be developed. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

CXCR3 Signaling Is Required for Restricted Homing of Parenteral Tuberculosis Vaccine-Induced T Cells to Both the Lung Parenchyma and Airway.

PubMed

Jeyanathan, Mangalakumari; Afkhami, Sam; Khera, Amandeep; Mandur, Talveer; Damjanovic, Daniela; Yao, Yushi; Lai, Rocky; Haddadi, Siamak; Dvorkin-Gheva, Anna; Jordana, Manel; Kunkel, Steven L; Xing, Zhou

2017-10-01

Although most novel tuberculosis (TB) vaccines are designed for delivery via the muscle or skin for enhanced protection in the lung, it has remained poorly understood whether systemic vaccine-induced memory T cells can readily home to the lung mucosa prior to and shortly after pathogen exposure. We have investigated this issue by using a model of parenteral TB immunization and intravascular immunostaining. We find that systemically induced memory T cells are restricted to the blood vessels in the lung, unable to populate either the lung parenchymal tissue or the airway under homeostatic conditions. We further find that after pulmonary TB infection, it still takes many days before such T cells can enter the lung parenchymal tissue and airway. We have identified the acquisition of CXCR3 expression by circulating T cells to be critical for their entry to these lung mucosal compartments. Our findings offer new insights into mucosal T cell biology and have important implications in vaccine strategies against pulmonary TB and other intracellular infections in the lung. Copyright © 2017 by The American Association of Immunologists, Inc.

Local small airway epithelial injury induces global smooth muscle contraction and airway constriction

PubMed Central

Zhou, Jian; Alvarez-Elizondo, Martha B.; Botvinick, Elliot

2012-01-01

Small airway epithelial cells form a continuous sheet lining the conducting airways, which serves many functions including a physical barrier to protect the underlying tissue. In asthma, injury to epithelial cells can occur during bronchoconstriction, which may exacerbate airway hyperreactivity. To investigate the role of epithelial cell rupture in airway constriction, laser ablation was used to precisely rupture individual airway epithelial cells of small airways (<300-μm diameter) in rat lung slices (∼250-μm thick). Laser ablation of single epithelial cells using a femtosecond laser reproducibly induced airway contraction to ∼70% of the original cross-sectional area within several seconds, and the contraction lasted for up to 40 s. The airway constriction could be mimicked by mechanical rupture of a single epithelial cell using a sharp glass micropipette but not with a blunt glass pipette. These results suggest that soluble mediators released from the wounded epithelial cell induce global airway contraction. To confirm this hypothesis, the lysate of primary human small airway epithelial cells stimulated a similar airway contraction. Laser ablation of single epithelial cells triggered a single instantaneous Ca2+ wave in the epithelium, and multiple Ca2+ waves in smooth muscle cells, which were delayed by several seconds. Removal of extracellular Ca2+ or decreasing intracellular Ca2+ both blocked laser-induced airway contraction. We conclude that local epithelial cell rupture induces rapid and global airway constriction through release of soluble mediators and subsequent Ca2+-dependent smooth muscle shortening. PMID:22114176