title: Carbon Monoxide (CO) Released from Tricarbonyldichlororuthenium (II) Dimer (CORM-2) in Gastroprotection against Experimental Ethanol-Induced Gastric Damage.
abstract: The physiological gaseous molecule, carbon monoxide (CO) becomes a subject of extensive investigation due to its vasoactive activity throughout the body but its role in gastroprotection has been little investigated. We determined the mechanism of CO released from its donor tricarbonyldichlororuthenium (II) dimer (CORM-2) in protection of gastric mucosa against 75% ethanol-induced injury. Rats were pretreated with CORM-2 30 min prior to 75% ethanol with or without 1) non-selective (indomethacin) or selective cyclooxygenase (COX)-1 (SC-560) and COX-2 (celecoxib) inhibitors, 2) nitric oxide (NO) synthase inhibitor L-NNA, 3) ODQ, a soluble guanylyl cyclase (sGC) inhibitor, hemin, a heme oxygenase (HO)-1 inductor or zinc protoporphyrin IX (ZnPPIX), an inhibitor of HO-1 activity. The CO content in gastric mucosa and carboxyhemoglobin (COHb) level in blood was analyzed by gas chromatography. The gastric mucosal mRNA expression for HO-1, COX-1, COX-2, iNOS, IL-4, IL-1β was analyzed by real-time PCR while HO-1, HO-2 and Nrf2 protein expression was determined by Western Blot. Pretreatment with CORM-2 (0.5-10 mg/kg) dose-dependently attenuated ethanol-induced lesions and raised gastric blood flow (GBF) but large dose of 100 mg/kg was ineffective. CORM-2 (5 mg/kg and 50 mg/kg i.g.) significantly increased gastric mucosal CO content and whole blood COHb level. CORM-2-induced protection was reversed by indomethacin, SC-560 and significantly attenuated by celecoxib, ODQ and L-NNA. Hemin significantly reduced ethanol damage and raised GBF while ZnPPIX which exacerbated ethanol-induced injury inhibited CORM-2- and hemin-induced gastroprotection and the accompanying rise in GBF. CORM-2 significantly increased gastric mucosal HO-1 mRNA expression and decreased mRNA expression for iNOS, IL-1β, COX-1 and COX-2 but failed to affect HO-1 and Nrf2 protein expression decreased by ethanol. We conclude that CORM-2 released CO exerts gastroprotection against ethanol-induced gastric lesions involving an increase in gastric microcirculation mediated by sGC/cGMP, prostaglandins derived from COX-1, NO-NOS system and its anti-inflammatory properties.
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Magierowska
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Magierowski
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Hubalewska-Mazgaj
authors.affiliation: Department of Forensic Toxicology, Institute of Forensic Research, Cracow, Poland.
authors.forename: Juliusz
authors.initials: J
authors.lastname: Adamski
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Surmiak
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Sliwowski
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.
authors.forename: Slawomir
authors.initials: S
authors.lastname: Kwiecien
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Brzozowski
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism*; D002263:Carboxyhemoglobin / Q000378:metabolism; D002849:Chromatography, Gas; D051546:Cyclooxygenase 2 / Q000378:metabolism; D000431:Ethanol; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology*; D011524:Protoporphyrins / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D012039:Regional Blood Flow; D013270:Stomach / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*
chemical_list: D053583:Interleukin-1beta; D051267:NF-E2-Related Factor 2; D009942:Organometallic Compounds; D020011:Protective Agents; D011524:Protoporphyrins; D012333:RNA, Messenger; C447082:tricarbonyldichlororuthenium (II) dimer; C017803:zinc protoporphyrin; D000431:Ethanol; D002248:Carbon Monoxide; D002263:Carboxyhemoglobin; D052247:Nitric Oxide Synthase Type II; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D051546:Cyclooxygenase 2