Abstract
Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease characterized by small airway remodeling and alveolar emphysema due to environmental stresses such as cigarette smoking (CS). Oxidative stress is commonly implicated in COPD pathology, but recent findings suggest that one oxidant-producing NADPH oxidase homolog, dual oxidase 1 (DUOX1), is downregulated in the airways of patients with COPD. We evaluated lung tissue sections from patients with COPD for small airway epithelial DUOX1 protein expression, in association with measures of lung function and small airway and alveolar remodeling. We also addressed the impact of DUOX1 for lung tissue remodeling in mouse models of COPD. Small airway DUOX1 levels were decreased in advanced COPD and correlated with loss of lung function and markers of emphysema and remodeling. Similarly, DUOX1 downregulation in correlation with extracellular matrix remodeling was observed in a genetic model of COPD, transgenic SPC-TNF-α mice. Finally, development of subepithelial airway fibrosis in mice due to exposure to the CS-component acrolein, or alveolar emphysema induced by administration of elastase, were in both cases exacerbated in Duox1-deficient mice. Collectively, our studies highlight that downregulation of DUOX1 may be a contributing feature of COPD pathogenesis, likely related to impaired DUOX1-mediated innate injury responses involved in epithelial homeostasis.
Highlights
Chronic obstructive pulmonary disease (COPD) is a chronic irreversible disease of the lungs characterized by airflow limitation due to destruction of the lung parenchyma and/or remodeling of the small airways [1, 2]
The GOLD IV patients included in this study underwent lung volume reduction surgery (LVRS) because of severe emphysema [29], suggesting that dual oxidase 1 (DUOX1) downregulation may be associated with emphysema
Our present findings extend intriguing previous observations that the primary epithelial NADPH oxidases (NOX) isoform DUOX1 is downregulated within the airways of subjects with COPD [22, 23], and demonstrate a gradual loss of small airway DUOX1 protein expression in patients with COPD in correlation with lung function decline and extracellular matrix remodeling and emphysema
Summary
Chronic obstructive pulmonary disease (COPD) is a chronic irreversible disease of the lungs characterized by airflow limitation due to destruction of the lung parenchyma (emphysema) and/or remodeling of the small airways [1, 2]. Environmental insults such as cigarette smoke (CS) are at the foundation of COPD pathogenesis, which is characterized by persistent inflammation and a protease/ antiprotease imbalance, collectively contributing to alveolar destruction and airway remodeling [4]. Small airway disease and emphysema development may mechanistically be linked, since CS-induced small airway inflammation may propagate to the alveolar septa, in turn destroying bronchiolar-alveolar attachments, and eventually proceed into lung parenchymal destruction [5]. Classically thought to be independent pathological manifestations of COPD, more recent evidence indicates that more emphysematous lungs tend to have fewer small airways [6]. The disappearance of small airways, which begins in the early stages of COPD, is a dominant characteristic in all patients with COPD and appears to precede emphysema development [7]
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