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Contrasting Effects of Cyclooxygenase-1 (COX-1) and COX-2 Deficiency on the Host Response to Influenza A Viral Infection¹

Michelle A. Carey^*, J. Alyce Bradbury^*, John M. Seubert^*, Robert Langenbach, Darryl C. Zeldin^* and Dori R. Germolec^2,

^* Laboratory of Respiratory Biology, Laboratory of Molecular Toxicology, Laboratory of Molecular Carcinogenesis, Division of Intramural Research, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park, NC 27709

Influenza is a significant cause of morbidity and mortality worldwide despite extensive research and vaccine availability. The cyclooxygenase (COX) pathway is important in modulating immune responses and is also a major target of nonsteroidal anti-inflammatory drugs (NSAIDs) and the newer COX-2 inhibitors. The purpose of the present study was to examine the effect of deficiency of COX-1 or COX-2 on the host response to influenza. We used an influenza A viral infection model in wild type (WT), COX-1^–/–, and COX-2^–/– mice. Infection induced less severe illness in COX-2^–/– mice in comparison to WT and COX-1^–/– mice as evidenced by body weight and body temperature changes. Mortality was significantly reduced in COX-2^–/– mice. COX-1^–/– mice had enhanced inflammation and earlier appearance of proinflammatory cytokines in the BAL fluid, whereas the inflammatory and cytokine responses were blunted in COX-2^–/– mice. However, lung viral titers were markedly elevated in COX-2^–/– mice relative to WT and COX-1^–/– mice on day 4 of infection. Levels of PGE₂ were reduced in COX-1^–/– airways whereas cysteinyl leukotrienes were elevated in COX-2^–/– airways following infection. Thus, deficiency of COX-1 and COX-2 leads to contrasting effects in the host response to influenza infection, and these differences are associated with altered production of prostaglandins and leukotrienes following infection. COX-1 deficiency is detrimental whereas COX-2 deficiency is beneficial to the host during influenza viral infection.

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