title: Central and peripheral neural aspects of gastroprotective and ulcer healing effects of lipopolysaccharides.
abstract: Lipopolysaccharides (LPS) are major components of the outer membrane of gram-negative bacteria playing a central role as potent endotoxins in the pathogenesis of endotoxic shock. Although large amounts of endotoxin may produce hemorrhagic lesions in the stomach, the possible gastroprotective effect of central or peripheral LPS against the acute gastric lesions has not been extensively studied. The aim of the present study was to compare the effect of intracerebroventricular (i.c.v.) and parenteral (i.p.) injection of LPS against gastric lesions induced by 100% ethanol. Male Wistar rats were treated either with a) vehicle (control); b) E-coli-LPS in various concentrations (1-10 microg/kg i.c.v or 0.1-40 mg/kg i.p.) followed 30 min later by 100% ethanol. The effects of pretreatment with nonselective inhibitor of nitric oxide synthase (L-NAME, 20 mg/kg i.g.) or selective inhibitor of inducible nitric oxide synthase, L-NIL (30 mg/kg i.g.) on the gastroprotection induced by LPS was investigated. One hour after ethanol application, the gastric blood flow (GBF) and the area of gastric lesions were determined. In addition, the mucosal expression of iNOS, cNOS and leptin was assessed using RT-PCR. LPS applied i.c.v. or i.p. dose dependently reduced gastric lesions induced by ethanol and this effect was similar to that observed after the administration of NO donor (SNAP). LPS-induced protection was significantly abolished by L-NAME and significantly attenuated by the selective inhibitor of iNOS (L-NIL). The expression of cNOS was detected in vehicle treated gastric mucosa and did not change after LPS administration. iNOS was not detectable in intact mucosa but its expression dose-dependently increased after the LPS administration. The i.c.v. administration of LPS did not upregulate further the iNOS expression, and dose-dependently inhibited the leptin mRNA expression in gastric mucosa. We conclude that LPS applied centrally or peripherally protects gastric mucosa against ethanol-induced damage through an increase in gastric microcirculation mediated by NO due to overexpression of iNOS. Transcriptional downregulation of leptin in gastric mucosa is probably due to the increased leptin release induced by the intracerebroventricular application lipopolysaccharide.
authors.affiliation: First Department of Medicine, University Erlangen-Nuremberg, Germany. pkonturek@med1.imed.uni-erlangen.de
authors.forename: P C
authors.initials: PC
authors.lastname: Konturek
authors.forename: T
authors.initials: T
authors.lastname: Brzozowski
authors.forename: H
authors.initials: H
authors.lastname: Meixner
authors.forename: A
authors.initials: A
authors.lastname: Ptak
authors.forename: E G
authors.initials: EG
authors.lastname: Hahn
authors.forename: S J
authors.initials: SJ
authors.lastname: Konturek
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D019610:Cytoprotection; D000431:Ethanol / Q000633:toxicity; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D007276:Injections, Intraventricular; D020738:Leptin / Q000235:genetics; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D013276:Stomach Ulcer / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D020738:Leptin; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C110881:S-nitro-N-acetylpenicillamine; D009569:Nitric Oxide; D000431:Ethanol; D010396:Penicillamine; D019331:NG-Nitroarginine Methyl Ester