Lipopolysacharide (LPS) induced iNOS expression and gastric injury: Role for prostaglandins (PGs)

Abstract

Introduction: LPS renders the stomach more susceptible to injury in part due to increased expression of inducible nitric oxide synthase (iNOS). Cyclo-oxygenase inhibition with salicylate enhances these effects of LPS. Because PGs influence iNOS expression in some tissues, we hypothesized that the detrimental effects of salicylate on LPS induced iNOS expression and gastric injury might be reversed by exogenous PGs. Methods: Adult rats were given salicylate (100mg/kg, IP) or saline one hour before LPS (20mg/kg, IP) with PGE2 (1mg/kg, sq) or saline. After 5 hours, rats were sacrificed, and gastric mucosa assessed for iNOS (Western immunoblot) In similar treatment groups, gastric injury was assessed (computerized planimetry) in an anesthetized model, using 3 ml of 5 mM acidified taurochlorate as the luminal irritant for 10 minutes. Results exresssed as mean +/− SEM. Results: PGE2 blunted LPS induced upregulation of iNOS, attenuated the effects of salicylate on iNOS, and increased the resistance of the gastric mucosa to injury in all groups (Table 1). Additionally, LPS decreased gastric mucosal PGE2 by 50% but not prostacyclin, whereas salicylate diminished gastric mucosal synthesis of both PGs by 98% (data not shown; radio immunoassay). ∗ Sal/ Sal Sal/ LPS NASA/ Sal NASA/ LPS NASA/ LPS + PGE2 Sal/ LPS + PGE2 Injury 1.38 ± .38 2.7 ± .97 ∗ p < 0.05 compared to saline. 4.78 ± 1.4 ∗ p < 0.05 compared to saline. 10.9 ± 1.6 ∗ p < 0.05 compared to saline. 1.82 ± .25 p < 0.05 compared to minus PGE2. 1.3 ± .42 p < 0.05 compared to minus PGE2. iNOS 0 .28 ± .03 ∗ p < 0.05 compared to saline. .08 ± .04 .40 ± .01 ∗ p < 0.05 compared to saline. .21 ± .03 p < 0.05 compared to minus PGE2. .17 ± .03 p < 0.05 compared to minus PGE2. N > 5, ANOVA. ∗ p < 0.05 compared to saline. ∗∗ p < 0.05 compared to minus PGE2. Open table in a new tab Conclusions: These data suggest that locally produced PGE2 may play a major role in maintaining gastric mucosal integrity during endotoxemia by limiting expression of the pro-inflammatory iNOS gene. Moreover, non-selective cyclo-oxygenase inhibitors should be used with caution in septic patients at risk for gastritis due to their ability to alter gastric iNOS. (Supported by NIGMS 38529)