Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA.
Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Netherlands.
JCI Insight. 2021 Jan 25;6(2):142189. doi: 10.1172/jci.insight.142189.
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.
慢性阻塞性肺疾病（COPD）是一种慢性呼吸道疾病，其特征是由于环境应激如吸烟（CS）导致小气道重塑和肺泡气肿。氧化应激通常与 COPD 病理学有关，但最近的研究结果表明，一种产生氧化剂的 NADPH 氧化酶同源物，双氧化酶 1（DUOX1），在 COPD 患者的气道中下调。我们评估了 COPD 患者的肺组织切片中小气道上皮 DUOX1 蛋白的表达，同时还评估了肺功能以及小气道和肺泡重塑的指标。我们还研究了 DUOX1 在 COPD 小鼠模型中的肺组织重塑中的作用。在晚期 COPD 中，小气道 DUOX1 水平降低，并与肺功能丧失以及肺气肿和重塑标志物相关。同样，在 COPD 的遗传模型，转 SPC-TNF-α 小鼠中，也观察到 DUOX1 下调与细胞外基质重塑相关。最后，由于暴露于 CS 成分丙烯醛而导致的亚上皮气道纤维化的发展，或弹性蛋白酶诱导的肺泡气肿，在 Duox1 缺陷型小鼠中均加剧。总之，我们的研究强调，DUOX1 的下调可能是 COPD 发病机制的一个特征，可能与 DUOX1 介导的上皮稳态相关的先天损伤反应受损有关。
