Contrasting effects of cyclooxygenase-1 (COX-1) and COX-2 deficiency on the host response to influenza A viral infection.
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.
Carey
Michelle A
MA
Laboratory of Respiratory Biology, Division of Intramural Research, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park, NC 27709, USA.
Bradbury
J Alyce
JA
Seubert
John M
JM
Langenbach
Robert
R
Zeldin
Darryl C
DC
Germolec
Dori R
DR
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D051545:Cyclooxygenase 1 / Q000172:deficiency* / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000172:deficiency* / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053122:Influenza A Virus, H3N2 Subtype / Q000302:isolation & purification; D007251:Influenza, Human / Q000201:enzymology* / Q000276:immunology* / Q000821:virology; D008168:Lung / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D016207:Cytokines; D018836:Inflammation Mediators; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone