title: Exogenous and Endogenous Hydrogen Sulfide Protects Gastric Mucosa against the Formation and Time-Dependent Development of Ischemia/Reperfusion-Induced Acute Lesions Progressing into Deeper Ulcerations.
abstract: Hydrogen sulfide (H₂S) is an endogenous mediator, synthesized from l-cysteine by cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) or 3-mercaptopyruvate sulfurtransferase (3-MST). The mechanism(s) involved in H₂S-gastroprotection against ischemia/reperfusion (I/R) lesions and their time-dependent progression into deeper gastric ulcerations have been little studied. We determined the effect of l-cysteine, H₂S-releasing NaHS or slow H₂S releasing compound GYY4137 on gastric blood flow (GBF) and gastric lesions induced by 30 min of I followed by 3, 6, 24 and 48 h of R. Role of endogenous prostaglandins (PGs), afferent sensory nerves releasing calcitonin gene-related peptide (CGRP), the gastric expression of hypoxia inducible factor (HIF)-1α and anti-oxidative enzymes were examined. Rats with or without capsaicin deactivation of sensory nerves were pretreated i.g. with vehicle, NaHS (18-180 μmol/kg) GYY4137 (90 μmol/kg) or l-cysteine (0.8-80 μmol/kg) alone or in combination with (1) indomethacin (14 μmol/kg i.p.), SC-560 (14 μmol/kg), celecoxib (26 μmol/kg); (2) capsazepine (13 μmol/kg i.p.); and (3) CGRP (2.5 nmol/kg i.p.). The area of I/R-induced gastric lesions and GBF were measured by planimetry and H₂-gas clearance, respectively. Expression of mRNA for CSE, CBS, 3-MST, HIF-1α, glutathione peroxidase (GPx)-1, superoxide dismutase (SOD)-2 and sulfide production in gastric mucosa compromised by I/R were determined by real-time PCR and methylene blue method, respectively. NaHS and l-cysteine dose-dependently attenuated I/R-induced lesions while increasing the GBF, similarly to GYY4137 (90 μmol/kg). Capsaicin denervation and capsazepine but not COX-1 and COX-2 inhibitors reduced NaHS- and l-cysteine-induced protection and hyperemia. NaHS increased mRNA expression for SOD-2 and GPx-1 but not that for HIF-1α. NaHS which increased gastric mucosal sulfide release, prevented further progression of acute I/R injury into deeper gastric ulcers at 6, 24 and 48 h of R. We conclude that H₂S-induced gastroprotection against I/R-injury is due to increase in gastric microcirculation, anti-oxidative properties and afferent sensory nerves activity but independent on endogenous prostaglandins.
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland. m.magierowski@uj.edu.pl.
authors.forename: Marcin
authors.initials: M
authors.lastname: Magierowski
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland. k.jasnos@interia.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Magierowska
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland. magdalena.hubalewska@uj.edu.pl.|Department of Genetic Research and Nutrigenomics, Malopolska Centre of Biotechnology, Jagiellonian University, 30-387 Cracow, Poland. magdalena.hubalewska@uj.edu.pl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Hubalewska-Mazgaj
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland. agazs@poczta.fm.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Sliwowski
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland. mppajdo@cyf-kr.edu.pl.
authors.forename: Robert
authors.initials: R
authors.lastname: Pajdo
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland. grzegorz.ginter@uj.edu.pl.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Ginter
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland. skwiecien@cm-uj.krakow.pl.
authors.forename: Slawomir
authors.initials: S
authors.lastname: Kwiecien
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland. mpbrzozo@cyf-kr.edu.pl.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Brzozowski
mesh_terms: D000818:Animals; D015415:Biomarkers; D004195:Disease Models, Animal; D018450:Disease Progression; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology*; D015870:Gene Expression; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D008297:Male; D020011:Protective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000150:complications* / Q000473:pathology; D013276:Stomach Ulcer / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*
chemical_list: D015415:Biomarkers; D020011:Protective Agents; D012333:RNA, Messenger; D006862:Hydrogen Sulfide
keywords: afferent sensory neurons; gastric blood flow; hydrogen sulfide; ischemia/reperfusion; prostaglandins