Increased myofibroblasts in the small airways and relation to remodelling and functional changes in smokers and COPD patients: potential role of epithelial-mesenchymal transition (EMT)

IntroductionPrevious reports showed epithelial mesenchymal transition (EMT) as an active process that contributes to small airway (SA) fibrotic pathology. Myofibroblasts are highly active pro-fibrotic cells that secrete excessive and altered extracellular matrix (ECM). Here we relate SA myofibroblast presence with airway remodelling, physiology and EMT activity in smokers and COPD patients.MethodsLung resections from non-smoker controls (NC), normal lung function smokers (NLFS), COPD current (CS) and ex-smokers (ES) were stained with anti-human αSMA, collagen 1, and fibronectin. αSMA+ive cells were computed in reticular basement membrane (Rbm), lamina propria (LP), and adventitia and presented per mm of Rbm and mm2 of LP. Collagen-1 and fibronectin are presented as a percentage change from normal. All analysis including airway thickness were measured using Image-pro-plus 7.0.ResultsWe found an increase in sub-epithelial LP (especially) and adventitia thickness in all pathological groups compared to NC. Increases in αSMA+ive myofibroblasts were observed in sub-epithelial Rbm, LP, and adventitia in both the smoker and COPD groups compared to NCs. Further, the increase in the myofibroblast population in the LP was strongly associated with decrease in lung function, LP thickening, increase in ECM protein deposition, and finally EMT activity in epithelial cells.ConclusionsThis is the first systematic characterisation of small airway myofibroblasts in COPD based on their localisation, with statistically significant correlations between them and other pan-airway structural, lung function, and ECM protein changes. Finally, we suggest that EMT may be involved in such changes.

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Expiratory reactance abnormalities in patients with expiratory dynamic airway collapse: a new application of impulse oscillometry

ERJ Open Research ◽

10.1183/23120541.00080-2018 ◽

2018 ◽

Vol 4 (4) ◽

pp. 00080-2018 ◽

Cited By ~ 3

Author(s):

David I. Fielding ◽

Justin Travers ◽

Phan Nguyen ◽

Michael G. Brown ◽

Gunter Hartel ◽

...

Keyword(s):

Lung Function ◽

Regression Tree ◽

Classification And Regression Tree ◽

Normal Lung ◽

Chronic Obstructive ◽

Stepwise Logistic Regression ◽

Impulse Oscillometry ◽

Obstructive Pulmonary Disease ◽

Copd Patients ◽

Normal Lung Function

Expiratory dynamic airways collapse (EDAC) is a condition that affects the central airways; it is not well characterised physiologically, with relatively few studies. We sought to characterise impulse oscillometry (IOS) features of EDAC in patients with normal spirometry. Expiratory data were hypothesised to be the most revealing. In addition, we compared IOS findings in chronic obstructive pulmonary disease (COPD) patients with and without EDAC.EDAC was identified at bronchoscopy as 75–100% expiratory closure at the carina or bilateral main bronchi. Four patient groups were compared: controls with no EDAC and normal lung function; lone EDAC with normal lung function; COPD-only patients; and COPD patients with EDAC.38 patients were studied. Mean IOS data z-scores for EDAC compared to controls showed significantly higher reactance (X) values including X at 5 Hz, resonance frequency and area under the reactance curve (AX). EDAC showed significantly greater expiratory/inspiratory differences in all IOS data compared to controls. Stepwise logistic regression showed that resonant frequency best discriminated between EDAC and normal control, whereas classification and regression tree analysis found AX ≥3.523 to be highly predictive for EDAC in cases with normal lung function (14 out of 15 cases, and none out of eight controls).These data show a new utility of IOS: detecting EDAC in patients with normal lung function.

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Current smoking alters phospholipid- and surfactant protein A levels in small airway lining fluid: An explorative study on exhaled breath

PLoS ONE ◽

10.1371/journal.pone.0253825 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0253825

Author(s):

Emilia Viklund ◽

Björn Bake ◽

Laith Hussain-Alkhateeb ◽

Hatice Koca Akdeva ◽

Per Larsson ◽

...

Keyword(s):

Lung Function ◽

Inflammatory Responses ◽

Protein A ◽

Surfactant Protein ◽

Small Airway ◽

Surfactant Protein A ◽

Normal Lung ◽

Small Airways ◽

Current Smoking ◽

Never Smokers

Small airways are difficult to access. Exhaled droplets, also referred to as particles, provide a sample of small airway lining fluid and may reflect inflammatory responses. We aimed to explore the effect of smoking on the composition and number of exhaled particles in a smoker-enriched study population. We collected and chemically analyzed exhaled particles from 102 subjects (29 never smokers, 36 former smokers and 37 current smokers) aged 39 to 83 years (median 63). A breathing maneuver maximized the number exhaled particles, which were quantified with a particle counter. The contents of surfactant protein A and albumin in exhaled particles was quantified with immunoassays and the contents of the phospholipids dipalmitoyl- and palmitoyl-oleoyl- phosphatidylcholine with mass spectrometry. Subjects also performed spirometry and nitrogen single breath washout. Associations between smoking status and the distribution of contents in exhaled particles and particle number concentration were tested with quantile regression, after adjusting for potential confounders. Current smokers, compared to never smokers, had higher number exhaled particles and more surfactant protein A in the particles. The magnitude of the effects of current smoking varied along the distribution of each PEx-variable. Among subjects with normal lung function, phospholipid levels were elevated in current smokers, in comparison to no effect of smoking on these lipids at abnormal lung function. Smoking increased exhaled number of particles and the contents of lipids and surfactant protein A in the particles. These findings might reflect early inflammatory responses to smoking in small airway lining fluid, also when lung function is within normal limits.

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Small airway morphology and lung function in the transition from normality to chronic airway obstruction

Journal of Applied Physiology ◽

10.1152/japplphysiol.01018.2002 ◽

2003 ◽

Vol 95 (1) ◽

pp. 441-447 ◽

Cited By ~ 31

Author(s):

Angelo Corsico ◽

Manlio Milanese ◽

Simonetta Baraldo ◽

Gian Luca Casoni ◽

Alberto Papi ◽

...

Keyword(s):

Lung Function ◽

Airway Obstruction ◽

Pulmonary Function Tests ◽

Lung Resection ◽

Muscle Thickness ◽

Forced Expiratory Volume ◽

Normal Lung ◽

Small Airways ◽

Airway Wall ◽

Normal Lung Function

This study investigated the relationships between pathological changes in small airways (<6 mm perimeter) and lung function in 22 nonasthmatic subjects (20 smokers) undergoing lung resection for peripheral lesions. Preoperative pulmonary function tests revealed airway obstruction [ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) < 70%] in 12 subjects and normal lung function in 10. When all subjects were considered together, total airway wall thickness was significantly correlated with FEV1/FVC ( r2 = 0.25), reactivity to methacholine ( r2 = 0.26), and slope of linear regression of FVC against FEV1 values recorded during the methacholine challenge ( r2 = 0.56). Loss of peribronchiolar alveolar attachments was significantly associated ( r2 = 0.25) with a bronchoconstrictor effect of deep inhalation, as assessed from a maximal-to-partial expiratory flow ratio <1, but not with airway responses to methacholine. No significant correlation was found between airway smooth muscle thickness and lung function measurements. In conclusion, this study suggests that thickening of the airway wall is a major mechanism for airway closure, whereas loss of airway-to-lung interdependence may contribute to the bronchoconstrictor effect of deep inhalation in the transition from normal lung function to airway obstruction in nonasthmatic smokers.

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Dysregulation of endocytic machinery and ACE2 in small airways of smokers and COPD patients can augment their susceptibility to SARS-CoV-2 (COVID-19) infections

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00437.2020 ◽

2020 ◽

Author(s):

Mathew Suji Eapen ◽

Wenying Lu ◽

Tillie-Louise Hackett ◽

Gurpreet K Singhera ◽

Isobel E. Thompson ◽

...

Keyword(s):

Lung Function ◽

Cathepsin L ◽

Smoking History ◽

Receptor Protein ◽

Normal Lung ◽

Small Airways ◽

Cross Sectional ◽

Viral Attachment ◽

Copd Patients ◽

Patient Groups

Lungs of smokers and COPD are severely compromised and are susceptible to SARS-CoV-2 attack. The lethal combination of enhanced SARS-CoV-2 attachment receptor protein ACE2 along with an increase in endocytic vacuoles will enable viral attachment, entry, and replication. The objective of the study was to identify the presence of SARS-CoV-2 host attachment receptor angiotensin-converting enzyme-2 (ACE2) along with endocytic vacuoles, early endosome antigen-1 (EEA1), late endosome marker RAB7, cathepsin-L and lysosome-associated membrane protein-1 (LAMP-1) as lysosome markers, in the airways of smokers and COPD patients. The study design was cross-sectional and involved lung resections from 39 patients in total, which included 19 patients with GOLD stage I or stage II COPD, of which 9 were current smokers with COPD (COPD-CS), and 10 ex-smokers with COPD (COPD-ES), 10 normal lung function smokers (NLFS) and 10 were never smoking normal controls (NC). Immunostaining for ACE2, EEA1, RAB7, and cathepsin-L was done. A comparative description for ACE2, EEA1, RAB7, and cathepsin-L expression pattern is provided for the patient groups. Further, staining intensity for LAMP-1 lysosomes was measured as the ratio of the LAMP-1 stained areas per total area of epithelium or sub-epithelium, using Image ProPlus software. LAMP-1 expression showed a positive correlation to patient smoking history while in COPD LAMP-1 negatively correlated to lung function. The active presence of ACE2 protein along with endocytic vacuoles such as early/late endosomes and lysosomes in the small airways of smokers and COPD patients provides evidence that these patient groups could be more susceptible to COVID-19.

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Epithelial mesenchymal transition (EMT) in small airways of COPD patients

Thorax ◽

10.1136/thoraxjnl-2013-203373 ◽

2013 ◽

Vol 68 (8) ◽

pp. 783-784 ◽

Cited By ~ 17

Author(s):

Sukhwinder Singh Sohal ◽

Eugene Haydn Walters

Keyword(s):

Epithelial Mesenchymal Transition ◽

Small Airways ◽

Mesenchymal Transition ◽

Copd Patients

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Poor Cognitive Function Is Associated with Obstructive Lung Diseases in Taiwanese Adults

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18052344 ◽

2021 ◽

Vol 18 (5) ◽

pp. 2344

Author(s):

Sun-Wung Hsieh ◽

Da-Wei Wu ◽

Chih-Wen Wang ◽

Szu-Chia Chen ◽

Chih-Hsing Hung ◽

...

Keyword(s):

Cognitive Function ◽

Lung Function ◽

Lung Diseases ◽

Mmse Score ◽

Multivariable Analysis ◽

Forced Expiratory Volume ◽

Normal Lung ◽

Obstructive Lung Diseases ◽

Normal Lung Function ◽

Function Group

Previous studies have reported an association between the impairment of cognitive performance and lung diseases. However, whether obstructive or restrictive lung diseases have an impact on cognitive function is still inconclusive. We aimed to investigate the association between cognitive function and obstructive or restrictive lung diseases in Taiwanese adults using the Mini-Mental State Examination (MMSE). In this study, we used data from the Taiwan Biobank. Cognitive function was evaluated using the MMSE. Spirometry measurements of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were obtained to assess lung function. Participants were classified into three groups according to lung function, namely, normal, restrictive, and obstructive lung function. In total, 683 patients enrolled, of whom 357 participants had normal lung function (52.3%), 95 had restrictive lung function (13.9%), and 231 had obstructive lung function (33.8%). Compared to the normal lung function group, the obstructive lung function group was associated with a higher percentage of cognitive impairment (MMSE < 24). In multivariable analysis, a low MMSE score was significantly associated with low FVC, low FEV1, and low FEV1/FVC. Furthermore, a low MMSE score was significantly associated with low FEV1 in the participants with FEV1/FVC < 70%, whereas MMSE was not significantly associated with FVC in the participants with FEV1/FVC ≥ 70%. Our results showed that a low MMSE score was associated with low FEV1, low FVC and low FEV1/FVC. Furthermore, a low MMSE score was associated with obstructive lung diseases but not with restrictive lung diseases.

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Correlation between Level of Autophagy and Amount of CD8+T Cells in Chronic Obstructive Pulmonary Disease

10.21203/rs.3.rs-36595/v1 ◽

2020 ◽

Author(s):

Songming Zhuo ◽

Hong Zhuang ◽

Na Li ◽

Sida Chen ◽

Wugen Zhan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Lung Function ◽

Normal Lung ◽

Stable Phase ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Normal Lung Function ◽

Healthy Control ◽

Function Group

Abstract Background: This study aimed to shed light on the correlation between the amounts of CD8+ T cells and autophagy level in COPD. Results: The objects (n = 90) were divided into three groups: COPD group (patients in the stable phase; n = 30), SN group (healthy control of smoking with normal lung function group; n = 30), and NSN groups (healthy control of non-smoking with normal lung function group; n = 30). The amounts of CD8+ (32.33 ± 4.23%), CD8+ effector (25.63 ± 8.57%) and CD8+memory (11.94 ± 5.77%) T cell in the COPD group were significantly higher those in the other two groups, while the apoptotic rate was lower in the COPD group (P < 0.05). Significant linear correlations were found of P62/GAPDH (‰) with CD8+, CD8+effector, and CD8+ memory- T cell amounts (P<0.001). Conclusions: Autophagy level is positively and linearly associated with the amounts of CD8+ T cells, suggesting that cell autophagy might be involved in COPD pathogenesis.

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Asthma‐chronic obstructive pulmonary disease overlap: A clinical entity?

Journal of Precision Respiratory Medicine ◽

10.2500/jprm.2020.3.200003 ◽

2020 ◽

Vol 3 (1) ◽

pp. 2-8

Author(s):

Robert A. Wise

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Lung Function ◽

Middle Age ◽

Clinical Manifestations ◽

Normal Lung ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Neutrophilic Inflammation ◽

Normal Lung Function

Asthma and COPD are easily recognizable clinical entities in their characteristic presentations. Asthma is an early-onset disorder characterized by Type 2, eosinophil-predominant, inflammation of the airways and is associated with atopy. COPD presents in middle age and is characterized by neutrophilic inflammation of the airways and is associated with cigarette smoking or biomass fuel exposure. Between exacerbations, asthma typically has normal lung function whereas COPD has incompletely reversible lung function. Approximately one in five patients with either of these disorders will show some features of both COPD and Asthma. This overlap is far more common than can be accounted for by chance concurrence of two common diseases. There are likely genetic and environmental susceptibilities to both disorders, but there is no single pathobiological mechanism that identifies all such overlap patients. Most likely there are numerous predispositions that lead to Asthma-COPD overlap that may be grounded in early childhood or even pre-natal events. Thus, Asthma-COPD overlap is best considered a family of diseases with overlapping clinical manifestations. The future elucidation of these different pathways to Asthma-COPD overlap, in conjunction with highly targeted therapies will aid clinicians in treating these patients.

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Predicted Values for Spirometry may Underestimate Long-Standing Asthma Severity

The Open Respiratory Medicine Journal ◽

10.2174/1874306401610010070 ◽

2016 ◽

Vol 10 (1) ◽

pp. 70-78 ◽

Cited By ~ 1

Author(s):

Bruno Sposato

Keyword(s):

Lung Function ◽

Reference Point ◽

Asthma Severity ◽

Normal Lung ◽

Bronchial Obstruction ◽

Z Score ◽

Lung Function Decline ◽

Normal Lung Function ◽

Z Scores ◽

Predicted Values

Background: Asthma may show an accelerated lung function decline. Asthmatics, although having FEV1 and FEV1/VC (and z-scores) higher than the lower limit of normality, may show a significant FEV1 decline when compared to previous measurements. We assessed how many asymptomatic long-standing asthmatics (LSA) with normal lung function showed a significant FEV1 decline when an older FEV1 was taken as reference point. Methods: 46 well-controlled LSA (age: 48.8±12.1; 23 females) with normal FEV1 and FEV1/VC according to GLI2012 references (FEV1: 94.8±10.1%, z-score:-0.38±0.79; FEV1/VC: 79.3±5.2, z-score:-0.15±0.77) were selected. We considered FEV1 decline, calculated by comparing the latest value to one at least five years older or to the highest predicted value measured at 21 years for females and 23 for males. A FEV1 decline >15% or 30 ml/years was regarded as pathological. Results: When comparing the latest FEV1 to an at least 5-year-older one (mean 8.1±1.4 years between 2 measurements), 14 subjects (30.4%) showed a FEV1 decline <5% (mean: -2.2±2.6%), 19 (41.3%) had a FEV1 5-15% change (mean: -9.2±2.5%) and 13 (28.3%) a FEV1 decrease>15% (mean: -18.3±2.4). Subjects with a FEV1 decline>30 ml/year were 28 (60.8%). When using the highest predicted FEV1 as reference point and declines were corrected by subtracting the physiological decrease, 6 (13%) patients showed a FEV1 decline higher than 15%, whereas asthmatics with a FEV1 loss>30 ml/year were 17 (37%). Conclusion: FEV1 decline calculation may show how severe asthma actually is, avoiding a bronchial obstruction underestimation and a possible under-treatment in lots of apparent “well-controlled” LSA with GLI2012-normal-range lung function values.

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