Involvement of nitric oxide and prostaglandins in gastroprotection induced by bacterial lipopolysaccharide

Lipopolysaccharide (LPS) has been proposed to act as one of the pathogens in endotoxemia-induced gastric lesions, but its action on mucosal integrity has not been fully clarified.

We compared the effects of LPS originating from Escherichia coli and the chemical donor of nitric oxide (NO), S-nitroso-acetylpenicillamine (SNAP), on acute gastric lesions induced by 100% ethanol, mucosal blood flow (GBF), and mucosal generation of prostaglandin E2 (PGE2) and examined the expression of constitutive NO synthase (cNOS) and inducible NO synthase (iNOS) mRNA in the gastric mucosa of rats treated with LPS, by using reverse transcription polymerase chain reaction (RT-PCR).

LPS (0.01-1.0 mg/kg) or SNAP (0.37-3.0 mg/kg) given intraperitoneally, dose-dependently prevented ethanol-induced mucosal lesions, and these protective effects were accompanied by a significant increase in the GBF and excessive mucosal release of NO. Suppression of NOS activity by NG-nitro-L-arginine methyl ester (L-NAME) (20mg/kg intravenously) or L-NG-(1-iminoethyl)-lysine (L-NIL) (30mg/kg intraperitoneally) and NOS induction by treatment with dexamethasone (2 mg/kg intraperitoneally) reversed the protective and hyperemic effects of LPS, and this reversal by L-NAME was significantly antagonized by addition of the substrate for NOS, L-arginine, but not D-arginine. Both LPS and SNAP increased PGE2 generation significantly, and this effect was reduced by pretreatment with L-NAME, L-NIL, or dexamethasone. Expression of cNOS was detected by RT-PCR in the intact mucosa, but intense signals for expression of both cNOS and iNOS were detected in the mucosa of LPS-treated rats.

Parenteral LPS, similarly to the chemical NO donor, SNAP, protects the gastric mucosa against ethanol-induced damage via an increase in GBF mediated by NO due to the activation of arginine-NO system and possibly also enhanced generation of PGE2.