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Published ahead of print on March 4, 2005, doi:10.1164/rccm.200411-1564OC

Am. J. Respir. Crit. Care Med., Volume 171, Number 12, June 2005, 1414-1420

A more recent version of this article appeared on June 15, 2005
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Submitted on November 22, 2004
Accepted on February 24, 2005

Inducible Nitric Oxide Synthase in Long-Term Intermittent Hypoxia: Hypersomnolence and Brain Injury

Guanxia Zhan1, Polina Fenik1, Domenico Pratico2, 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 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: Long-term intermittent hypoxia exposure in adult mice, modeling oxygenation patterns of moderate-severe obstructive sleep apnea, results in lasting hypersomnolence and is associated with nitration and oxidation injuries in many brain regions, including wake-active regions. Objectives: We sought to determine if long-term intermittent hypoxia activates inducible nitric oxide synthase in sleep/wake regions, and if this source of nitric oxide contributes to the long-term intermittent hypoxia-induced proinflammatory gene response, oxidative injury and wake impairments. Methods: Mice with genetic absence of inducible nitric oxide synthase activity and wild type controls were exposed to 6 weeks of long-term hypoxia/reoxygenation prior to behavioral state recordings, molecular and biochemical assays and a pharmacological intervention. Measurements and main results: Two weeks after recovery from hypoxia/reoxygenation exposures, wild type mice showed increased inducible nitric oxide synthase activity in representative wake-active regions, increased sleep times and shortened sleep latencies. Mutant mice, with higher baseline sleep times, showed no effect of long-term hypoxia/reoxygenation on sleep times latencies and were resistant to hypoxia/reoxygenation increases in lipid peroxidation and proinflammatory gene responses (tumor necrosis factor-{alpha} and cyclooxygenase-2). Inhibition of inducible nitric oxide synthase following long-term hypoxia/reoxygenation in wild type mice was effective in reversing the proinflammatory gene response. Conclusions: These data support a critical role for inducible nitric oxide activity in the development of long-term intermittent hypoxia wake impairments, lipid peroxidation and proinflammatory responses in wake-active brain regions and suggest a potential role for inducible nitric oxide inhibition in protection from proinflammatory responses, oxidative injury and residual hypersomnolence in obstructive sleep apnea.
Key words: chronic intermittent hypoxia, locus coeruleus, basal forebrain, carbonylation, oxidative




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