title: NS-398 treatment after trauma modifies NF-kappaB activation and improves survival.
abstract: Prostaglandin E(2) (PGE(2)) production after trauma contributes to immune alterations that increase susceptibility to infections. We hypothesize that blocking PGE(2) with NS-398, a selective COX-2 inhibitor, will modulate this response and improve outcome. This study evaluated the effect of NS-398 given over 7 days on proinflammatory cytokines, intracellular signaling, and survival after a septic challenge. Balb/C mice (n = 8/group) were given 10 mg/kg NS-398 intraperitoneally over 7 days, starting after anesthesia or trauma (femur fracture + 40% hemorrhage). Four groups, anesthesia + vehicle (C), anesthesia + NS-398 (CN), trauma + vehicle (T), or trauma + NS-398 (TN), were studied. On Day 7 after trauma, mice were sacrificed, serum was collected, and splenic macrophages were evaluated for PGE(2), LTB(4), IL-6, TNF-alpha, and NO production. Additionally, macrophage COX-2 mRNA, IkappaB-alpha, and NF-kappaB were evaluated. In a separate study, mice (n = 10-11/group) were traumatized and given NS-398 over 7 days, and then cecal ligation and puncture (CLP) were performed. Mice were then followed for survival over 10 days (via log-rank test). NS-398 treatment of injured mice decreased PGE(2) production compared to T (3.9 +/- 0.3 vs 3.1 +/- 0.4 pg/microg protein), and significantly decreased IL-6, NO, and TNF-alpha production. NS-398 treatment also attenuated COX-2 mRNA levels and NF-kappaB activation. These cellular events correlate with a significant survival advantage in TN versus T mice after CLP. These data suggest that a specific COX-2 inhibitor not only suppresses PGE(2), but normalizes proinflammatory cytokines after trauma through changes that may partly be mediated via transcriptional events. This correlates with significantly increased survival in TN mice given a septic challenge and suggests that COX-2 inhibitors contribute to modulating the inflammatory response and improving survival after trauma.
authors.affiliation: Department of Surgery, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, New York 10021, USA. vem9002@nyp.org
authors.forename: V E
authors.initials: VE
authors.lastname: Mack Strong
authors.forename: P J
authors.initials: PJ
authors.lastname: Mackrell
authors.forename: E M
authors.initials: EM
authors.lastname: Concannon
authors.forename: J R
authors.initials: JR
authors.lastname: Mestre
authors.forename: G P
authors.initials: GP
authors.lastname: Smyth
authors.forename: P A
authors.initials: PA
authors.lastname: Schaefer
authors.forename: P P
authors.initials: PP
authors.lastname: Stapleton
authors.forename: J M
authors.initials: JM
authors.lastname: Daly
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000150:complications / Q000503:physiopathology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000097:blood / Q000378:metabolism; D005260:Female; D005264:Femoral Fractures / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D015850:Interleukin-6 / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics; D007975:Leukotriene B4 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014947:Wounds and Injuries / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015850:Interleukin-6; D007527:Isoenzymes; D016328:NF-kappa B; D009578:Nitrobenzenes; D012333:RNA, Messenger; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D007975:Leukotriene B4; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone