ABSTRACT
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.
Subject(s)
Adaptor Proteins, Signal Transducing/drug effects , Emphysema/drug therapy , Emphysema/genetics , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/genetics , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Apoptosis/drug effects , Emphysema/etiology , Humans , Hypertension, Pulmonary/genetics , Hypertension, Pulmonary/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Nitric Oxide/metabolism , Peroxynitrous Acid/metabolism , Pulmonary Disease, Chronic Obstructive/complications , Signal Transduction/genetics , Superoxides/metabolism , Tobacco Smoke Pollution/adverse effects , Tyrosine/analogs & derivatives , Tyrosine/metabolismABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
