NADPH oxidase subunit NOXO1 is a target for emphysema treatment in COPD

• DOI: 10.1038/s42255-020-0215-8
• Publication Date: 2020-06-08T16:05:41Z
• Authors: Michael Seimetz; Natascha Sommer; Mariola Bednorz; Oleg Pak; Christine Veith; Stefan Hadzic; Marija Gredic; Nirmal Parajuli; Baktybek Kojonazarov; Simone Kraut; Jochen Wilhelm; Fenja Knoepp; Ingrid Henneke; Alexandra Pichl; Zeki I. Kanbagli; Susan Scheibe; Athanasios Fysiko...; Cheng-Yu Wu; Walter Klepetko; Peter Jaksch; Christina Eichstaedt; Ekkehard Grünig; Katrin Hinderhofer; Miklós Geiszt; Niklas Müller; Flavia Rezende; Giulia Buchmann; Ilka Wittig; Matthias Hecker; Andreas Hecker; Winfried Padberg; Peter Dorfmüller; Stefan Gattenlöhner; Claus F. Vogelmeier; Andreas Günther; Srikanth Karnati; Eveline Baumgart-...; Ralph T. Schermuly; Hossein A. Ghofrani; Werner Seeger; Katrin Schröder; Friedrich Grimminger; Ralf P. Brandes; Norbert Weissmann
• Keywords: Emphysema; Mice, Knockout; 0301 basic medicine; Hypertension, Pulmonary; Apoptosis; Nitric Oxide; 3. Good health; Mice, Inbred C57BL; Mice; Pulmonary Disease, Chronic Obstructive; 03 medical and health sciences; Superoxides; Peroxynitrous Acid; Animals; Humans; Tyrosine; Tobacco Smoke Pollution; Adaptor Proteins, Signal Transducing; Signal Transduction

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.