title: Selective inhibition of COX-2 improves early survival in murine endotoxemia but not in bacterial peritonitis.
abstract: Prostaglandins of the E series are believed to act as important mediators of several pathophysiological events that occur in sepsis. Studies were performed to evaluate the effect of cyclooxygenase (COX)-2-specific inhibition on the outcome in murine endotoxemia and cecal ligation and puncture (CLP). We observed a significant time-dependent upregulation of PGE(2) production in both blood and lung homogenates of mice administered lipopolysaccharide intraperitoneally, which was nearly completely suppressed by the administration of the COX-2 inhibitor NS-398. Treatment with NS-398 significantly improved early but not late survival in lipopolysaccharide-challenged mice. On the contrary, elevated PGE(2) levels were found in bronchoalveolar lavage fluid but not in plasma of mice subjected to CLP (21 gauge). Pretreatment with NS-398 failed to significantly improve survival in CLP mice. No significant differences were noted in plasma or lung homogenate proinflammatory cytokine levels or lung neutrophil sequestration between the NS-398-treated and control groups. These results demonstrate that selective COX-2 inhibition confers early but not long-term benefits without affecting the expression of proinflammatory cytokines or the development of lung inflammation.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0360, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Reddy
authors.forename: G H
authors.initials: GH
authors.lastname: Chen
authors.forename: K
authors.initials: K
authors.lastname: Tateda
authors.forename: W C
authors.initials: WC
authors.lastname: Tsai
authors.forename: S M
authors.initials: SM
authors.lastname: Phare
authors.forename: P
authors.initials: P
authors.lastname: Mancuso
authors.forename: M
authors.initials: M
authors.lastname: Peters-Golden
authors.forename: T J
authors.initials: TJ
authors.lastname: Standiford
mesh_terms: D000818:Animals; D001424:Bacterial Infections; D001833:Body Temperature Regulation / Q000187:drug effects; D002432:Cecum; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019446:Endotoxemia / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008026:Ligation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D009504:Neutrophils / Q000473:pathology; D009578:Nitrobenzenes; D010538:Peritonitis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology* / Q000401:mortality; D011451:Prostaglandin-Endoperoxide Synthases; D011677:Punctures; D013449:Sulfonamides; D016019:Survival Analysis
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone