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Published ahead of print on June 30, 2005, doi:10.1164/rccm.200504-581OC

Am. J. Respir. Crit. Care Med., Volume 172, Number 7, October 2005, 921-929

A more recent version of this article appeared on October 1, 2005
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Submitted on April 14, 2005
Accepted on June 17, 2005

NADPH Oxidase Mediates Hypersomnolence and Brain Oxidative Injury in a Murine Model of Sleep Apnea

Guanxia Zhan1, Faridis Serrano2, Polina Fenik1, Ray Hsu1, Linghao Kong1, Domenico Pratico3, Eric Klann2, and Sigrid C Veasey1*

1 Center for Sleep and Respiratory Neurobiology and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA, 2 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA, 3 Center for Experimental Therapeutics, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

* To whom correspondence should be addressed. E-mail: veasey{at}mail.med.upenn.edu.

Rationale: Persons with obstructive sleep apnea may have significant residual hypersomnolence, despite therapy. Long-term hypoxia/reoxygenation events in adult mice, simulating oxygenation patterns of moderate-severe sleep apnea, result in lasting hypersomnolence, oxidative injury and proinflammatory responses in wake-active brain regions. We hypothesized that long-term intermittent hypoxia activates brain NADPH oxidase and that this enzyme serves as a critical source of superoxide in the oxidation injury and hypersomnolence. Objectives: We sought to determine whether long-term hypoxia/reoxygenation events in mice result in NADPH oxidase activation and whether NADPH oxidase is essential for the proinflammatory response and hypersomnolence. Methods: NADPH oxidase gene and protein responses were measured in wake-active brain regions in wild-type mice exposed to long-term hypoxia/reoxygenation. Sleep, oxidative and proinflammatory responses were measured in adult mice either devoid of NADPH oxidase activity (gp91phox null mice) or in which NADPH oxidase activity was systemically inhibited with apocynin osmotic pumps throughout hypoxia/reoxygenation. Main Results: Long-term intermittent hypoxia increased NADPH oxidase gene and protein responses in wake-active brain regions. Both transgenic absence and pharmacological inhibition of NADPH oxidase activity throughout long-term hypoxia/reoxygenation confered resistance to, not only long-term hypoxia/reoxygenation hypersomnolence, but also to carbonylation, lipid peroxidation injury and the proinflammatory response, including inducible nitric oxide synthase activity in wake-active brain regions. Conclusions: Collectively, these findings strongly support a critical role for NADPH oxidase in the lasting hypersomnolence, oxidative and proinflammatory responses following hypoxia/reoxygenation patterns simulating severe obstructive sleep apnea oxygenation, highlighting the potential of inhibiting NADPH oxidase to prevent oxidation-mediated morbidities in obstructive sleep apnea.
Key words: intermittent hypoxia, NREM sleep, peroxynitrite, oxidation




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