Cyclooxygenase-2-deficient mice are resistant to endotoxin-induced inflammation and death.
Sepsis is a systemic inflammatory response to a blood-borne infection that is associated with an extremely high rate of morbidity and mortality. The present study investigates the role of cyclooxygenase (COX)-2 in host responses to bacterial endotoxemia. After administration of Escherichia coli lipopolysaccharide, 50% of wild-type mice die within 96 h. COX-2 deficient mice displayed a dramatic improvement in survival with reduced leukocyte infiltration into critical organs (kidneys and lungs) and a blunted and delayed induction of the cytokine inducible genes nitric oxide synthase 2 and heme oxygenase-1. Translocation and activation of transcription factors important for signaling events during an inflammatory response, such as nuclear factor (NF)-kappaB, were also markedly reduced. While the absence of COX-2 did not alter the induction of several pro-inflammatory cytokines in tissue macrophages, induction of the anti-inflammatory cytokine IL-10 was exaggerated. Administration of IL-10 to wild-type mice reduced NF-kappaB activation. Taken together, our data suggest that COX-2 deficient mice are resistant to many of the detrimental consequences of endotoxemia. These beneficial effects occur, in part, by a compensatory increase in IL-10 that counterbalances the pro-inflammatory host response to endotoxemia.
Brigham and Women's Hospital, Pulmonary and Critical Care Medicine, 75 Francis St., Boston, MA 02115, USA.
Kuniaki
K
Ejima
Matthew D
MD
Layne
Irvith M
IM
Carvajal
Patricia A
PA
Kritek
Rebecca M
RM
Baron
Yen-Hsu
YH
Chen
Jeffrey
J
Vom Saal
Bruce D
BD
Levy
Shaw-Fang
SF
Yet
Mark A
MA
Perrella
D021581:Active Transport, Cell Nucleus; D000818:Animals; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004247:DNA / Q000378:metabolism; D019446:Endotoxemia / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D004927:Escherichia coli Infections / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000235:genetics; D051547:Heme Oxygenase-1; D007249:Inflammation / Q000382:microbiology; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000502:physiology*; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism
D016207:Cytokines; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D014157:Transcription Factors; D004247:DNA; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases