Alteration in heme oxygenase-1 and nitric oxide synthase-2 gene expression during endotoxemia in cyclooxygenase-2-deficient mice.
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 article reviews our recent studies involving the role of cyclooxygenase (COX)-2 in host responses to bacterial endotoxemia and its role in the regulation of nitric oxide synthase (NOS)2 and heme oxygenase (HO)-1. COX-2-deficient (-/-) mice display a blunted and delayed induction of the cytokine-inducible genes NOS2 and HO-1 after administration of Escherichia coli lipopolysaccharide (LPS or endotoxin). Translocation and activation of transcription factors important for signaling events during an inflammatory response, such as nuclear factor-kappaB and activating protein-1, are also reduced. In addition, COX-2(-/-) mice have reduced leukocyte infiltration into critical organs (kidneys and lungs) after LPS administration. Interestingly, the absence of COX-2 does not alter the LPS induction of several proinflammatory cytokines in tissue macrophages, but induction of the antiinflammatory cytokine interleukin-10 is exaggerated. After LPS administration, 50% of wild-type (+/+) mice die; however, COX-2(-/-) mice display a dramatic improvement in survival during endotoxemia. Taken together, our findings suggest that COX-2(-/-) mice are resistant to many of the detrimental consequences of endotoxemia.
Ejima
Kuniaki
K
Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Perrella
Mark A
MA
D000818:Animals; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000378:metabolism; D019446:Endotoxemia / Q000276:immunology / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D007668:Kidney / Q000201:enzymology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate
D016207:Cytokines; D008070:Lipopolysaccharides; D008565:Membrane Proteins; 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