Inhibition of cyclooxygenase-2 by NS-398 following hemorrhage and subsequent sepsis: no beneficial effects in either gender.
BACKGROUND
Inhibition of cyclooxygenase-2 with a reduction of prostaglandin E(2)production by the specific antagonist NS-398 has been shown to have beneficial effects on immune function and survival in a trauma model. Immune function after experimental hemorrhagic shock and subsequent sepsis may be gender-related, with enhanced immunity and better survival in females. However, it remains unclear if the observed effect of NS-398 treatment is gender-related following hemorrhagic shock and subsequent sepsis.


METHODS
Male and female CBA/J mice (age: 2-3 months) were subjected to hemorrhagic shock (35 +/- 5 mm Hg for 90 min and fluid resuscitation) or sham operation. At resuscitation and after 20 and 40 h each received either NS-398 10 mg/kg or placebo i.p. At 48 h after resuscitation, either splenocytes and peritoneal macrophages (pM phi) were harvested (n = 8 per group), or polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Following CLP, either 10-day survival (n = 15 per group) was determined or pM phi and splenocytes were harvested 4 h after CLP (n = 8 per group). Cytokine release of pM phi, and splenocyte proliferation and responsiveness in vitro were assessed.


RESULTS
Treatment with NS-398 led to lower PGE(2) levels as compared to placebo-treated animals, reaching significance (p < 0.05) in males. Placebo-treated males had significantly depressed proinflammatory immune response (IL-1, IL-6, IL-2, IFN-gamma) after hemorrhagic shock and experienced further suppression by CLP (all, p < 0.05). In contrast, young females displayed unchanged cytokine release after hemorrhagic shock, but a comparable suppression following CLP. Treatment with NS-398 did not influence cytokine release nor survival.


CONCLUSIONS
Despite a significant reduction of PGE(2) concentration, NS-398 treatment has no beneficial effects on cytokine release and survival in this model of hemorrhage and subsequent sepsis.
Kahlke
Volker
V
Department of General Surgery, University of Schleswig-Holstein, Kiel, Germany. Vkahlke@surgery.uni0kiel.de
Seidel
Mirja
M
Stapela
Sietje
S
Brötzmann
Kerstin
K
Schafmayer
Clemens
C
Schröder
Jörg
J
D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D015232:Dinoprostone / Q000032:analysis / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D007274:Injections, Intraperitoneal; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D009578:Nitrobenzenes / Q000494:pharmacology*; D011336:Probability; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012016:Reference Values; D012680:Sensitivity and Specificity; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality; D012737:Sex Factors; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000401:mortality; D013449:Sulfonamides / Q000494:pharmacology*; D016019:Survival Analysis
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D007527:Isoenzymes; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone