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The Journal of Immunology, 2005, 174: 4356-4364.
Copyright © 2005 by The American Association of Immunologists

Respiratory Syncytial Virus (RSV) Infection Induces Cyclooxygenase 2: A Potential Target for RSV Therapy1

Joann Y. Richardson*, Martin G. Ottolini*, Lioubov Pletneva§, Marina Boukhvalova§, Shuling Zhang{dagger}, Stefanie N. Vogel{ddagger}, Gregory A. Prince§ and Jorge C. G. Blanco2,§

Departments of * Pediatrics and {dagger} Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; {ddagger} Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201; and § Virion Systems, Rockville, MD 20850

Cyclooxygenases (COXs) are rate-limiting enzymes that initiate the conversion of arachidonic acid to prostanoids. COX-2 is the inducible isoform that is up-regulated by proinflammatory agents, initiating many prostanoid-mediated pathological aspects of inflammation. The roles of cyclooxygenases and their products, PGs, have not been evaluated during respiratory syncytial virus (RSV) infection. In this study we demonstrate that COX-2 is induced by RSV infection of human lung alveolar epithelial cells with the concomitant production of PGs. COX-2 induction was dependent on the dose of virus and the time postinfection. PG production was inhibited preferentially by NS-398, a COX-2-specific inhibitor, and indomethacin, a pan-COX inhibitor, but not by SC-560, a COX-1-specific inhibitor. In vivo, COX-2 mRNA expression and protein production were strongly induced in the lungs and cells derived from bronchioalveolar lavage of cotton rats infected with RSV. The pattern of COX-2 expression in vivo in lungs is cyclical, with a final peak on day 5 that correlates with maximal histopathology. Treatment of cotton rats with indomethacin significantly mitigated lung histopathology produced by RSV. The studies described in this study provide the first evidence that COX-2 is a potential therapeutic target in RSV-induced disease.




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