Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and death worldwide. Peroxynitrite, formed from nitric oxide, which is derived from inducible nitric oxide synthase, and superoxide, has been implicated in the development of emphysema, but the source of the superoxide was hitherto not characterized. Here, we identify the non-phagocytic NADPH oxidase organizer 1 (NOXO1) as the superoxide source and an essential driver of smoke-induced emphysema and pulmonary hypertension development in mice. NOXO1 is consistently upregulated in two models of lung emphysema, Cybb (also known as NADPH oxidase 2, Nox2)-knockout mice and wild-type mice with tobacco-smoke-induced emphysema, and in human COPD. Noxo1-knockout mice are protected against tobacco-smoke-induced pulmonary hypertension and emphysema. Quantification of superoxide, nitrotyrosine and multiple NOXO1-dependent signalling pathways confirm that peroxynitrite formation from nitric oxide and superoxide is a driver of lung emphysema. Our results suggest that NOXO1 may have potential as a therapeutic target in emphysema.

慢性阻塞性肺疾病 (COPD) 是全球发病率和死亡的主要原因。由诱导型一氧化氮合酶衍生的一氧化氮和超氧化物形成的过氧亚硝酸盐与肺气肿的发展有关，但迄今为止尚未确定超氧化物的来源。在这里，我们将非吞噬性 NADPH 氧化酶组织者 1 (NOXO1) 确定为超氧化物来源，并且是小鼠烟雾诱发肺气肿和肺动脉高压发展的重要驱动因素。NOXO1 在两种肺气肿模型、Cybb（也称为 NADPH 氧化酶 2、Nox2）基因敲除小鼠和患有烟草烟雾诱导的肺气肿的野生型小鼠以及人类 COPD 中持续上调。Noxo1- 基因敲除小鼠免受烟草烟雾诱发的肺动脉高压和肺气肿。超氧化物、硝基酪氨酸和多种 NOXO1 依赖性信号通路的量化证实，一氧化氮和超氧化物形成的过氧亚硝酸盐是肺气肿的驱动因素。我们的结果表明 NOXO1 可能有潜力作为肺气肿的治疗靶点。