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NADPH Oxidase-1 Plays a Crucial Role in Hyperoxia-induced Acute Lung Injury in Mice

¹ Department of Pediatrics and ² Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland; ³ Department of Anesthesia, University of California, San Francisco, San Francisco, California; and ⁴ Department of Genetic and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland

Correspondence and requests for reprints should be addressed to Stéphanie Carnesecchi, Ph.D., Department of Pediatrics and Department of Pathology and Immunology, Centre Médical Universitaire, 1, rue Michel Servet, 1211 Geneva 4, Switzerland. E-mail: Stephanie.Carnesecchi{at}unige.ch

Rationale: Hyperoxia-induced acute lung injury has been used for many years as a model of oxidative stress mimicking clinical acute lung injury and the acute respiratory distress syndrome. Excess quantities of reactive oxygen species (ROS) are responsible for oxidative stress–induced lung injury. ROS are produced by mitochondrial chain transport, but also by NADPH oxidase (NOX) family members. Although NOX1 and NOX2 are expressed in the lungs, their precise function has not been determined until now.

Objectives: To determine whether NOX1 and NOX2 contribute in vivo to hyperoxia-induced acute lung injury.

Methods: Wild-type and NOX1- and NOX2-deficient mice, as well as primary lung epithelial and endothelial cells, were exposed to room air or 100% O₂ for 72 hours.

Measurements and Main Results: Lung injury was significantly prevented in NOX1-deficient mice, but not in NOX2-deficient mice. Hyperoxia-dependent ROS production was strongly reduced in lung sections, in isolated epithelial type II cells, and lung endothelial cells from NOX1-deficient mice. Concomitantly, lung cell death in situ and in primary cells was markedly decreased in NOX1-deficient mice. In wild-type mice, hyperoxia led to phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal–regulated kinase (ERK), two mitogen-activated protein kinases involved in cell death signaling, and to caspase-3 activation. In NOX1-deficient mice, JNK phosphorylation was blunted, and ERK phosphorylation and caspase-3 activation were decreased.

Conclusions: NOX1 is an important contributor to ROS production and cell death of the alveolocapillary barrier during hyperoxia and is an upstream actor in oxidative stress–induced acute lung injury involving JNK and ERK pathways in mice.

Key Words: NADPH oxidase • reactive oxygen species • hyperoxia • apoptosis • mitogen-activated protein kinases

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Oxidative stress is a major feature of acute lung injury and the acute respiratory distress syndrome (ARDS) and may be responsible for pulmonary cell damage. What This Study Adds to the Field Targeting the NADPH oxidase NOX1 during hyperoxia-induced lung injury in mice inhibits oxidative-induced cell death pathway and lung damage, providing a new therapeutic approach in the treatment of acute lung injury.