Lipopolysaccharide of Helicobacter pylori protects gastric mucosa via generation of nitric oxide.

Lipopolysaccharide (LPS) has been proposed to act as the major virulence factor in Helicobacter pylori (Hp)-infected stomach but its action on mucosal integrity has been little studied. We determined the effects of LPS of Hp, expressing cytotoxic antigens CagA and VacA on acute gastric lesions induced by 100% ethanol, mucosal blood flow (GBF) and expression of constitutive nitric oxide (NO) synthase (cNOS) mRNA and inducible NO synthase (iNOS) mRNA in gastric mucosa using RT-PCR. Two major series (A and B) of rats were employed; A--with suppressed NOS activity by nonspecific NOS inhibitor, such as NG-nitro-L-arginine methyl ester, (L-NAME) (5 mg/kg i.v.), or by specific iNOS inhibitor, NG-(1-Immunoethyl) lysine (L-NIL) (30 mg/kg i.g.), or with inhibited induction of NOS activity by dexamethasone (2 mg/kg i.p.) and series B--vehicle (saline)-treated controls. LPS (0.01-1.0 mg/kg) given i.p. attenuated dose-dependently ethanol-induced mucosal lesions and this protective effect was accompanied by a rise in the GBF and excessive mucosal production and luminal release of NO. LPS (1 mg/kg i.p.) administered at lower dose (1 mg/kg i.p.) to rats without ethanol instillation significantly elevated GBF and luminal release of NO, while higher doses of LPS (20 and 40 mg/kg i.p.) or SNAP (6 mg/kg), which produced systemic hypotension, were not protective. Suppression of NOS activity by pretreatment with standard dose of L-NAME or L-NIL and inhibition of NOS induction by treatment with dexamethasone reversed the protective and hyperemic effects of LPS and this reversal was significantly antagonized by the addition of the substrate for cNOS, L-arginine, but not D-arginine. Administration of L-NAME, L-NIL or dexamethasone, completely abolished the enhanced mucosal NO production and the hyperemia induced by LPS in rats without or with topical application of ethanol. Expression of cNOS was detected by RT-PCR in the intact mucosa but intense signals for expression of both cNOS and iNOS were detected by RT-PCR in the gastric mucosa of LPS-treated rats. We conclude that parenteral LPS protects gastric mucosa from acute ethanol-induced damage via an increase in mucosal microcirculation mediated by NO due to the overexpression of iNOS and activation of arginine-NO-system.