scholarly journals Small airway determinants of airflow limitation in chronic obstructive pulmonary disease

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2020-216037
Author(s):  
Vasiliy V Polosukhin ◽  
Sergey S Gutor ◽  
Rui-Hong Du ◽  
Bradley W Richmond ◽  
Pierre P Massion ◽  
...  
Keyword(s):  
Inflammatory Cells ◽  
Small Airway ◽  
Airflow Limitation ◽  
Ct Scans ◽  
Chronic Obstructive ◽  
Small Airways ◽  
Pathological Feature ◽  
Obstructive Pulmonary Disease ◽  
Subepithelial Tissue ◽  
Airway Walls

BackgroundAlthough a variety of pathological changes have been described in small airways of patients with COPD, the critical anatomic features determining airflow limitation remain incompletely characterised.MethodsWe examined lung tissue specimens from 18 non-smokers without chronic lung disease and 55 former smokers with COPD for pathological features of small airways that could contribute to airflow limitation. Morphometric evaluation was performed for epithelial and subepithelial tissue thickness, collagen and elastin content, luminal mucus and radial alveolar attachments. Immune/inflammatory cells were enumerated in airway walls. Quantitative emphysema scoring was performed on chest CT scans.ResultsSmall airways from patients with COPD showed thickening of epithelial and subepithelial tissue, mucus plugging and reduced collagen density in the airway wall (in severe COPD). In patients with COPD, we also observed a striking loss of alveolar attachments, which are connective tissue septa that insert radially into the small airway adventitia. While each of these parameters correlated with reduced airflow (FEV1), multivariable regression analysis indicated that loss of alveolar attachments was the major determinant of airflow limitation related to small airways. Neutrophilic infiltration of airway walls and collagen degradation in airway adventitia correlated with loss of alveolar attachments. In addition, quantitative analysis of CT scans identified an association between the extent of emphysema and loss of alveolar attachments.ConclusionIn COPD, loss of radial alveolar attachments in small airways is the pathological feature most closely related to airflow limitation. Destruction of alveolar attachments may be mediated by neutrophilic inflammation.

scholarly journals The Expression of NOX4 in Smooth Muscles of Small Airway Correlates with the Disease Severity of COPD

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Xianyan Liu ◽  
Binwei Hao ◽  
Ailing Ma ◽  
Jinxi He ◽  
Xiaoming Liu ◽  
...  
Keyword(s):  
Disease Severity ◽  
Transforming Growth Factor ◽  
Smooth Muscles ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Small Airway ◽  
Chronic Obstructive ◽  
Small Airways ◽  
Obstructive Pulmonary Disease ◽  
Pulmonary Functions ◽  
Copd Patients

Airway smooth muscle (ASM) remodeling is a hallmark in chronic obstructive pulmonary disease (COPD), and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases (NOXs) produced reactive oxygen species (ROS) play a crucial role in COPD pathogenesis. In the present study, the expression of NOX4 and its correlation with the ASM hypertrophy/hyperplasia, clinical pulmonary functions, and the expression of transforming growth factorβ(TGF-β) in the ASM of COPD small airways were investigated by semiquantitative morphological and/or immunohistochemistry staining methods. The results showed that an elevated expression of NOX4 and TGF-β, along with an increased volume of ASM mass, was found in the ASM of small airways in COPD patients. The abundance of NOX4 protein in the ASM was increased with disease severity and inversely correlated with the pulmonary functions in COPD patients. In addition, the expression of NOX4 and ASM markerα-SMA was colocalized, and the increased NOX4 expression was found to accompany an upregulated expression of TGF-βin the ASM of small airways of COPD lung. These results indicate that NOX4 may be a key regulator in ASM remodeling of small airway, in part through a mechanism interacting with TGF-βsignaling in the pathogenesis of COPD, which warrants further investigation.

scholarly journals The role of airway remodeling in the pathogenesis and treatment of chronic obstructive pulmonary disease

2021 ◽  
Vol 8 (3) ◽  
pp. 96-102
Author(s):  
Nightingale Syabbalo
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Epithelial Cells ◽  
Pulmonary Disease ◽  
Airway Remodeling ◽  
Inflammatory Cells ◽  
Lymphoid Cells ◽  
Standards Of Care ◽  
Chronic Obstructive ◽  
Small Airways ◽  
Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is currently considered the third leading cause of death in the world. COPD represents an important public health challenge and a socio-economical problem that is preventable and treatable. The main cause of COPD is chronic inhalation of cigarette smoke, and other harmful constituents of air pollution, which cause epithelial injury, chronic inflammation and airway remodeling. Airway remodeling is most prominent in small airways. It is due to infiltration of the airways by inflammatory cells, such as neutrophils, eosinophils, macrophages, and immune cells, including CD8+ T-cells, Th1, Th17 lymphocytes, and innate lymphoid cells group 3. Fibroblasts, myofibroblasts, and airway smooth muscle (ASM) cells also contribute to airway remodeling by depositing extracellular matrix (ECM) proteins, which increase the thickness of the airway wall. Activated inflammatory cells, and structural cells secrete cytokines, chemokines, growth factors, and enzymes which propagate airway remodeling. Airway remodeling is an active process which leads to thickness of the reticular basement membrane, subepithelial fibrosis, peribronchiolar fibrosis, and ASM cells hyperplasia and hypertrophy. It is also accompanied by submucosal glands and goblet cells hypertrophy and mucus hypersecretion, and angiogenesis. Epithelial mesenchymal transmission (EMT) plays a key role in airway remodeling. In patients with COPD and smokers, cellular reprograming in epithelial cells leads to EMT, whereby epithelial cells assume a mesencymal phenotype. Additionally, COPD is associated with increased parasympathetic cholinergic activity, which leads to ASM cells hypercontractility, increased mucus secretion, and vasodilatation. Treatment of COPD is intricate because of the heterogeneous nature of the disease, which requires specific treatment of the pathophysiological pathways, such as airway inflammation, ASM cell hypercontractility, and parasympathetic cholinergic hyperreactivity. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 strategy report recommends personalized approach for the treatment of COPD. However, some patients with COPD are unresponsive to the standards of care. They may require a triple combination of LABA/LAMA/ICS. Single-inhaler triple therapy (SITT), such as fluticasone fuorate/vilanterol/umeclidinium has been shown to significantly improve symptoms and asthma control, reduce moderate and severe exacerbations, and to improve lung function.

scholarly journals Role of IL-17A in murine models of COPD airway disease

2017 ◽  
Vol 312 (1) ◽  
pp. L122-L130 ◽  
Author(s):  
Haruhiko Yanagisawa ◽  
Mitsuo Hashimoto ◽  
Shunsuke Minagawa ◽  
Naoki Takasaka ◽  
Royce Ma ◽  
...  
Keyword(s):  
T Cells ◽  
Airway Inflammation ◽  
Γδ T Cells ◽  
Small Airway ◽  
Lymphoid Cells ◽  
Chronic Obstructive ◽  
Polymorphonuclear Cells ◽  
Small Airways ◽  
Pathological Feature ◽  
Airway Fibrosis

Small airway fibrosis is a major pathological feature of chronic obstructive pulmonary disease (COPD) and is refractory to current treatments. Chronic inflammatory cells accumulate around small airways in COPD and are thought to play a major role in small airway fibrosis. Mice deficient in α/β T cells have recently been shown to be protected from both experimental airway inflammation and fibrosis. In these models, CD4+Th17 cells and secretion of IL-17A are increased. However, a pathogenic role for IL-17 in specifically mediating fibrosis around airways has not been demonstrated. Here a role for IL-17A in airway fibrosis was demonstrated using mice deficient in the IL-17 receptor A ( il17ra). Il17ra-deficient mice were protected from both airway inflammation and fibrosis in two different models of airway fibrosis that employ COPD-relevant stimuli. In these models, CD4+ Th17 are a major source of IL-17A with other expressing cell types including γδ T cells, type 3 innate lymphoid cells, polymorphonuclear cells, and CD8+ T cells. Antibody neutralization of IL-17RA or IL-17A confirmed that IL-17A was the relevant pathogenic IL-17 isoform and IL-17RA was the relevant receptor in airway inflammation and fibrosis. These results demonstrate that the IL-17A/IL-17 RA axis is crucial to murine airway fibrosis. These findings suggest that IL-17 might be targeted to prevent the progression of airway fibrosis in COPD.

scholarly journals Different Patterns of Lung Sirtuin Expression in Smokers With and Without Chronic Obstructive Pulmonary Disease

Medicina ◽  
2012 ◽  
Vol 48 (10) ◽  
pp. 80 ◽  
Author(s):  
Sergejs Isajevs ◽  
Gunta Strazda ◽  
Uldis Kopeika ◽  
Immanuels Taivans
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Inflammatory Responses ◽  
Airflow Limitation ◽  
Chronic Obstructive ◽  
Small Airways ◽  
Obstructive Pulmonary Disease ◽  
Nonhistone Proteins ◽  
Proinflammatory Mediators ◽  
Large Airways

Background and Objective. Chronic obstructive pulmonary disease is characterized by persistent and modified inflammatory responses in lung. Human sirtuin, an antiaging and antiinflammatory protein, is a metabolic NAD(+)-dependent protein/histone deacetylase that regulates proinflammatory mediators by deacetylating histone and nonhistone proteins. The aim of our study was to compare the expression of sirtuin in large and small airways in nonsmokers, asymptomatic smokers, and smokers with chronic obstructive pulmonary disease. Material and Methods. A total of 12 nonsmokers, 14 asymptomatic smokers, and 12 smokers with moderate chronic obstructive pulmonary disease were enrolled into the study. Immunohistochemical and Western blot methods were used to analyze sirtuin expression in the airways. Results. The obtained results showed the nonuniform sirtuin expression throughout the bronchial tree. Smokers both with and without chronic obstructive pulmonary disease had decreased sirtuin expression in large airways. However, in small airways, sirtuin expression was decreased only in patients with chronic obstructive pulmonary disease. In addition, a correlation between airflow limitation, smoked pack-years and the number of sirtuin-positive cells in airways was found. Conclusions. Smoking is characterized by suppressed sirtuin expression in large airways, whereas chronic obstructive pulmonary disease is characterized by more severe suppression of sirtuin expression both in large and small airways.

scholarly journals Recent advances in pre-clinical mouse models of COPD

2013 ◽  
Vol 126 (4) ◽  
pp. 253-265 ◽  
Author(s):  
Ross Vlahos ◽  
Steven Bozinovski
Keyword(s):  
Chronic Inflammation ◽  
Cigarette Smoke ◽  
Mouse Models ◽  
Airflow Limitation ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Small Airways ◽  
Obstructive Pulmonary Disease ◽  
New Therapies ◽  
Progression Of Disease

COPD (chronic obstructive pulmonary disease) is a major incurable global health burden and will become the third largest cause of death in the world by 2020. It is currently believed that an exaggerated inflammatory response to inhaled irritants, in particular cigarette smoke, causes progressive airflow limitation. This inflammation, where macrophages, neutrophils and T-cells are prominent, leads to oxidative stress, emphysema, small airways fibrosis and mucus hypersecretion. The mechanisms and mediators that drive the induction and progression of chronic inflammation, emphysema and altered lung function are poorly understood. Current treatments have limited efficacy in inhibiting chronic inflammation, do not reverse the pathology of disease and fail to modify the factors that initiate and drive the long-term progression of disease. Therefore there is a clear need for new therapies that can prevent the induction and progression of COPD. Animal modelling systems that accurately reflect disease pathophysiology continue to be essential to the development of new therapies. The present review highlights some of the mouse models used to define the cellular, molecular and pathological consequences of cigarette smoke exposure and whether they can be used to predict the efficacy of new therapeutics for COPD.

Mechanisms of cigarette smoke-induced COPD: insights from animal models

2008 ◽  
Vol 294 (4) ◽  
pp. L612-L631 ◽  
Author(s):  
Andrew Churg ◽  
Manuel Cosio ◽  
Joanne L. Wright
Keyword(s):  
Pulmonary Hypertension ◽  
Animal Models ◽  
Cigarette Smoke ◽  
Airway Remodeling ◽  
Small Airway ◽  
Laboratory Animals ◽  
Chronic Obstructive ◽  
Small Airways ◽  
Mucus Production ◽  
Obstructive Pulmonary Disease

Cigarette smoke-induced animal models of chronic obstructive pulmonary disease support the protease-antiprotease hypothesis of emphysema, although which cells and proteases are the crucial actors remains controversial. Inhibition of either serine or metalloproteases produces significant protection against emphysema, but inhibition is invariably accompanied by decreases in the inflammatory response to cigarette smoke, suggesting that these inhibitors do more than just prevent matrix degradation. Direct anti-inflammatory interventions are also effective against the development of emphysema, as are antioxidant strategies; the latter again decrease smoke-induced inflammation. There is increasing evidence for autoimmunity, perhaps directed against matrix components, as a driving force in emphysema. There is intriguing but controversial animal model evidence that failure to repair/failure of lung maintenance also plays a role in the pathogenesis of emphysema. Cigarette smoke produces small airway remodeling in laboratory animals, possibly by direct induction of fibrogenic growth factors in the airway wall, and also produces pulmonary hypertension, at least in part through direct upregulation of vasoactive mediators in the intrapulmonary arteries. Smoke exposure causes goblet cell metaplasia and excess mucus production in the small airways and proximal trachea, but these changes are not good models of either chronic bronchitis or acute exacerbations. Emphysema, small airway remodeling, pulmonary hypertension, and mucus production appear to be at least partially independent processes that may require different therapeutic approaches.

scholarly journals Loss of IL-33 enhances elastase-induced and cigarette smoke extract-induced emphysema in mice

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Daisuke Morichika ◽  
Akihiko Taniguchi ◽  
Naohiro Oda ◽  
Utako Fujii ◽  
Satoru Senoo ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Intratracheal Instillation ◽  
Inflammatory Cells ◽  
Cigarette Smoke Extract ◽  
Lymphoid Cells ◽  
Chronic Obstructive ◽  
Porcine Pancreas ◽  
Obstructive Pulmonary Disease ◽  
Quantitative Morphometry ◽  
Cytokines And Chemokines

Abstract Background IL-33, which is known to induce type 2 immune responses via group 2 innate lymphoid cells, has been reported to contribute to neutrophilic airway inflammation in chronic obstructive pulmonary disease. However, its role in the pathogenesis of emphysema remains unclear. Methods We determined the role of interleukin (IL)-33 in the development of emphysema using porcine pancreas elastase (PPE) and cigarette smoke extract (CSE) in mice. First, IL-33−/− mice and wild-type (WT) mice were given PPE intratracheally. The numbers of inflammatory cells, and the levels of cytokines and chemokines in the bronchoalveolar lavage (BAL) fluid and lung homogenates, were analyzed; quantitative morphometry of lung sections was also performed. Second, mice received CSE by intratracheal instillation. Quantitative morphometry of lung sections was then performed again. Results Intratracheal instillation of PPE induced emphysematous changes and increased IL-33 levels in the lungs. Compared to WT mice, IL-33−/− mice showed significantly greater PPE-induced emphysematous changes. No differences were observed between IL-33−/− and WT mice in the numbers of macrophages or neutrophils in BAL fluid. The levels of hepatocyte growth factor were lower in the BAL fluid of PPE-treated IL-33−/− mice than WT mice. IL-33−/− mice also showed significantly greater emphysematous changes in the lungs, compared to WT mice, following intratracheal instillation of CSE. Conclusion These observations suggest that loss of IL-33 promotes the development of emphysema and may be potentially harmful to patients with COPD.

scholarly journals COPD Guidelines in the Asia-Pacific Regions: Similarities and Differences

Diagnostics ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1153
Author(s):  
Shih-Lung Cheng ◽  
Ching-Hsiung Lin
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Global Strategy ◽  
Airflow Limitation ◽  
Asia Pacific ◽  
Pharmacologic Therapy ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Country Level ◽  
Similarities And Differences

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease that is associated with significant morbidity and mortality, giving rise to an enormous social and economic burden. The Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (GOLD) report is one of the most frequently used documents for managing COPD patients worldwide. A survey was conducted across country-level members of Asia-Pacific Society of Respiratory (APSR) for collecting an updated version of local COPD guidelines, which were implemented in each country. This is the first report to summarize the similarities and differences among the COPD guidelines across the Asia-Pacific region. The degree of airflow limitation, assessment of COPD severity, management, and pharmacologic therapy of stable COPD will be reviewed in this report.

scholarly journals Alternative methods for assessing bronchodilator reversibility in chronic obstructive pulmonary disease

Thorax ◽  
2001 ◽  
Vol 56 (9) ◽  
pp. 713-720
Author(s):  
J Hadcroft ◽  
P M A Calverley
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Lung Volume ◽  
Tidal Flow ◽  
Airflow Limitation ◽  
Alternative Methods ◽  
Chronic Obstructive ◽  
Flow Limitation ◽  
Inspiratory Capacity ◽  
Obstructive Pulmonary Disease

BACKGROUNDBronchodilator reversibility testing is recommended in all patients with chronic obstructive pulmonary disease (COPD) but does not predict improvements in breathlessness or exercise performance. Two alternative ways of assessing lung mechanics—measurement of end expiratory lung volume (EELV) using the inspiratory capacity manoeuvre and application of negative expiratory pressure (NEP) during tidal breathing to detect tidal airflow limitation—do relate to the degree of breathlessness in COPD. Their usefulness as end points in bronchodilator reversibility testing has not been examined.METHODSWe studied 20 patients with clinically stable COPD (mean age 69.9 (1.5) years, 15 men, forced expiratory volume in one second (FEV1) 29.5 (1.6)% predicted) with tidal flow limitation as assessed by their maximum flow-volume loop. Spirometric parameters, slow vital capacity (SVC), inspiratory capacity (IC), and NEP were measured seated, before and after nebulised saline, and at intervals after 5 mg nebulised salbutamol and 500 μg nebulised ipratropium bromide. The patients attended twice and the treatment order was randomised.RESULTSMean FEV1, FVC, SVC, and IC were unchanged after saline but the degree of tidal flow limitation varied. FEV1 improved significantly after salbutamol and ipratropium (0.11 (0.02) l and 0.09 (0.02) l, respectively) as did the other lung volumes with further significant increases after the combination. Tidal volume and mean expiratory flow increased significantly after all bronchodilators but breathlessness fell significantly only after the combination treatment. The initial NEP score was unrelated to subsequent changes in lung volume.CONCLUSIONSNEP is not an appropriate measurement of acute bronchodilator responsiveness. Changes in IC were significantly larger than those in FEV1and may be more easily detected. However, our data showed no evidence for separation of “reversible” and “irreversible” groups whatever outcome measure was adopted.

Ventilation-perfusion imbalance and chronic obstructive pulmonary disease staging severity

2009 ◽  
Vol 106 (6) ◽  
pp. 1902-1908 ◽  
Author(s):  
Roberto Rodríguez-Roisin ◽  
Mitra Drakulovic ◽  
Diego A. Rodríguez ◽  
Josep Roca ◽  
Joan Albert Barberà ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Gas Exchange ◽  
Pulmonary Disease ◽  
Forced Expiratory Volume ◽  
Pulmonary Gas Exchange ◽  
Airflow Limitation ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Gold Stage ◽  
Stage 1

Chronic obstructive pulmonary disease (COPD) is characterized by a decline in forced expiratory volume in 1 s (FEV1) and, in many advanced patients, by arterial hypoxemia with or without hypercapnia. Spirometric and gas exchange abnormalities have not been found to relate closely, but this may reflect a narrow range of severity in patients studied. Therefore, we assessed the relationship between pulmonary gas exchange and airflow limitation in patients with COPD across the severity spectrum. Ventilation-perfusion (V̇A/Q̇) mismatch was measured using the multiple inert gas elimination technique in 150 patients from previous studies. The distribution of patients according to the GOLD stage of COPD was: 15 with stage 1; 40 with stage 2; 32 with stage 3; and 63 with stage 4. In GOLD stage 1, AaPo2 and V̇A/Q̇ mismatch were clearly abnormal; thereafter, hypoxemia, AaPo2, and V̇A/Q̇ imbalance increased, but the changes from GOLD stages 1–4 were modest. Postbronchodilator FEV1 was related to PaO2 ( r = 0.62) and PaCO2 ( r = −0.59) and to overall V̇A/Q̇ heterogeneity ( r = −0.48) ( P < 0.001 each). Pulmonary gas exchange abnormalities in COPD are related to FEV1 across the spectrum of severity. V̇A/Q̇ imbalance, predominantly perfusion heterogeneity, is disproportionately greater than airflow limitation in GOLD stage 1, suggesting that COPD initially involves the smallest airways, parenchyma, and pulmonary vessels with minimal spirometric disturbances. That progression of V̇A/Q̇ inequality with spirometric severity is modest may reflect pathogenic processes that reduce both local ventilation and blood flow in the same regions through airway and alveolar disease and capillary involvement.

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