| Literature DB >> 32694733 |
Michael Seimetz1, Natascha Sommer1, Mariola Bednorz1, Oleg Pak1, Christine Veith1, Stefan Hadzic1, Marija Gredic1, Nirmal Parajuli1,2, Baktybek Kojonazarov1,3, Simone Kraut1, Jochen Wilhelm1,3, Fenja Knoepp1, Ingrid Henneke1,3, Alexandra Pichl1, Zeki I Kanbagli1, Susan Scheibe1, Athanasios Fysikopoulos1, Cheng-Yu Wu1, Walter Klepetko4, Peter Jaksch4, Christina Eichstaedt5,6,7, Ekkehard Grünig5,7, Katrin Hinderhofer6, Miklós Geiszt8, Niklas Müller9, Flavia Rezende9, Giulia Buchmann9, Ilka Wittig10, Matthias Hecker1, Andreas Hecker11, Winfried Padberg11, Peter Dorfmüller12, Stefan Gattenlöhner12, Claus F Vogelmeier13, Andreas Günther1, Srikanth Karnati14,15, Eveline Baumgart-Vogt14, Ralph T Schermuly1, Hossein A Ghofrani1,16, Werner Seeger1,17, Katrin Schröder9, Friedrich Grimminger1, Ralf P Brandes9, Norbert Weissmann18.
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.Entities:
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Year: 2020 PMID： 32694733 DOI： 10.1038/s42255-020-0215-8
Source DB: PubMed Journal: Nat Metab ISSN： 2522-5812