title: Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs.
abstract: OBJECTIVE
  Hydrogen sulfide (H(2)S), an endogenous gaseous mediator that causes vasodilation, is generated in mammalian tissues by cystathionine beta-synthase (CBS) and cystathionine-gamma-lyase (CSE). Here, we have investigated the role of H(2)S in a rodent model of nonsteroidal anti-inflammatory drug (NSAID) gastropathy.
  
  
  METHODS
  Rats were given acetyl salycilic acid (ASA) or an NSAID alone or in combination with NaHS, an H(2)S donor, and killed 3 hours later. Gastric blood flow was measured by laser-Doppler flowmetry, whereas intravital microscopy was used to quantify adhesion of leukocytes to mesenteric postcapillary endothelium.
  
  
  RESULTS
  At a dose of 100 micromol/kg, NaHS attenuated by 60%-70% the gastric mucosal injury, and tumor necrosis factor (TNF)-alpha, intercellular adhesion molecule (ICAM)-1, and lymphocyte function-associated antigen (LFA)-1 mRNA up-regulation induced by NSAIDs (P < .05) NaHS administration prevented the associated reduction of gastric mucosal blood flow (P < .05) and reduced ASA-induced leukocyte adherence in mesenteric venules. NaHS did not affect suppression of prostaglandin E(2) (PGE(2)) synthesis by NSAIDs. Glibenclamide, a K(ATP) channel inhibitor, and DL-propargylglycine, a CSE inhibitor, exacerbated, whereas pinacidil, a K(ATP) opener, attenuated gastric injury caused by ASA. Exposure to NSAIDs reduced H(2)S formation and CSE expression (mRNA and protein) and activity by 60%-70%. By promoter deletion and mutation analysis, an Sp1 consensus site was identified in the CSE promoter. Exposure to NSAIDs inhibits Sp1 binding to its promoter and abrogates CSE expression in HEK-293 cells transfected with a vector containing the core CSE promoter. Exposure to NSAIDs inhibits Sp1 and ERK phosphorylation.
  
  
  CONCLUSIONS
  These data establish a physiologic role for H(2)S in regulating the gastric microcirculation and identify CSE as a novel target for ASA/NSAIDs.
authors.affiliation: Dipartimento di Medicina Clinica, Patologia, Clinica di Gastroenterologia ed Endoscopia Digestiva, University of Perugia, Italy. fiorucci@unipg.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Antonelli
authors.forename: Eleonora
authors.initials: E
authors.lastname: Distrutti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Rizzo
authors.forename: Andrea
authors.initials: A
authors.lastname: Mencarelli
authors.forename: Stefano
authors.initials: S
authors.lastname: Orlandi
authors.forename: Renata
authors.initials: R
authors.lastname: Zanardo
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.forename: Moses
authors.initials: M
authors.lastname: Di Sante
authors.forename: Antonio
authors.initials: A
authors.lastname: Morelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
authors.forename: John L
authors.initials: JL
authors.lastname: Wallace
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D001241:Aspirin / Q000633:toxicity; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003542:Cystathionine gamma-Lyase / Q000235:genetics; D004195:Disease Models, Animal; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D006862:Hydrogen Sulfide / Q000633:toxicity*; D008156:Luciferases / Q000235:genetics; D008297:Male; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D013272:Stomach Diseases / Q000139:chemically induced*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008156:Luciferases; D003542:Cystathionine gamma-Lyase; D001241:Aspirin; D006862:Hydrogen Sulfide