Respiratory syncytial virus (RSV) infection induces cyclooxygenase 2: a potential target for RSV therapy.
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.
Richardson
Joann Y
JY
Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Ottolini
Martin G
MG
Pletneva
Lioubov
L
Boukhvalova
Marina
M
Zhang
Shuling
S
Vogel
Stefanie N
SN
Prince
Gregory A
GA
Blanco
Jorge C G
JC
D000818:Animals; D051546:Cyclooxygenase 2; D016503:Drug Delivery Systems; D004847:Epithelial Cells / Q000201:enzymology / Q000821:virology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008168:Lung / Q000473:pathology / Q000821:virology; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D018357:Respiratory Syncytial Virus Infections / Q000201:enzymology* / Q000473:pathology / Q000628:therapy
D008565:Membrane Proteins; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin