Downregulation of epithelial DUOX1 in chronic obstructive pulmonary disease

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.

Downregulation of DUOX1 function contributes to aging-related impairment of innate airway injury responses and accelerated senile emphysema

“…It is important to note that such associations in humans may also be impacted by exposure history (such as smoking), and lung epithelial DUOX1 was indeed found to be suppressed in smokers compared with nonsmokers (89). Moreover, we recently reported that airway DUOX1 protein levels are downregulated in small airways of patients with advanced (stage IV) COPD relative to age-matched non-COPD control subjects, which may be linked with altered smoking status and/or history (33). In these studies, we also observed that DUOX1 downregulation correlated significantly with loss of lung function and that DUOX1-deficiency worsened experimentally induced emphysema in mice (33).…”

“…Moreover, we recently reported that airway DUOX1 protein levels are downregulated in small airways of patients with advanced (stage IV) COPD relative to age-matched non-COPD control subjects, which may be linked with altered smoking status and/or history (33). In these studies, we also observed that DUOX1 downregulation correlated significantly with loss of lung function and that DUOX1-deficiency worsened experimentally induced emphysema in mice (33). Hence, we believe that loss of DUOX1 with age (perhaps related to chronic exposure history to, e.g., tobacco smoke) may enhance the risk of COPD and may also contribute to lung function decline during "healthy" aging.…”

Redox Dysregulation in Aging and COPD: Role of NOX Enzymes and Implications for Antioxidant Strategies

“…Analysis of tracheal and bronchial epithelium collected by airway brushing or laser capture micro-dissection, revealed that DUOX1 was significantly suppressed in the airways of healthy smokers and patients with COPD, when compared to age-matched control subjects, implying that chronic smoking leads to decreased airway epithelial expression of DUOX1 as a potential contributing factor in COPD development [ 216 , 217 ]. Our group expanded on these findings, by showing a gradual downregulation of DUOX1 protein in the small airways of GOLD II-IV COPD patients, which was found to be strongly correlated with various measures of lung function decline, and several markers of small airway remodeling and destruction [ 218 ]. On one hand, these results may imply that variable DUOX1 downregulation as a result of normal aging (see above) or smoking history may predispose for COPD development and progression.…”

“…Alternatively, it is also possible that DUOX1 downregulation may be a consequence of COPD, for example secondary to production of inflammatory mediators or growth factors such as TGF-β. Indeed, we observed that chronic exposure of bronchial epithelial cells to TGF-β also downregulates DUOX1 [ 218 ]. Downregulation of DUOX1 may be related to smoking history, although some studies suggest that exposure to CS extract can actually enhance DUOX1 expression [ 219 ].…”

“…Downregulation of DUOX1 may be related to smoking history, although some studies suggest that exposure to CS extract can actually enhance DUOX1 expression [ 219 ]. In contrast, chronic exposure of mice to the CS-component acrolein was found to result in DUOX1 downregulation, a response that could be mimicked by chronic in vitro exposure of epithelial cells to acrolein [ 218 ]. Nevertheless, the relationship between airway or alveolar DUOX1 and smoking status/history is complex, and observed correlations of airway DUOX1 with lung function parameters in our recent studies were largely independent of smoking status [ 218 ], suggesting the contribution of other factors to DUOX1 downregulation in COPD.…”