Carbon monoxide released from its pharmacological donor, tricarbonyldichlororuthenium (II) dimer, accelerates the healing of pre-existing gastric ulcers.

Abstract

Carbon monoxide (CO), a gaseous mediator produced by haem oxygenases (HOs), has been shown to prevent stress-, ethanol-, aspirin- and alendronate-induced gastric damage; however, its role in gastric ulcer healing has not been fully elucidated. We investigated whether CO released from tricarbonyldichlororuthenium (II) dimer (CORM-2) can affect gastric ulcer healing and determined the mechanisms involved in this healing action. Gastric ulcers were induced in Wistar rats by serosal application of acetic acid. Animals received 9days of treatment with RuCl3 [2.5mg·kg-1 intragastrically (i.g.)], haemin (5mg·kg-1 i.g.), CORM-2 (0.1-10mg·kg-1 i.g.) administered alone or with zinc protoporphyrin IX (ZnPP, 10mg·kg-1 i.g.), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 5mg·kg-1 i.g.), NG -nitro-l-arginine (l-NNA, 15mg·kg-1 i.g.), indomethacin (5mg·kg-1 i.g.) or glibenclamide (10mg·kg-1 i.g.). Gastric ulcer area and gastric blood flow (GBF) were assessed planimetrically, microscopically and by laser flowmeter respectively. Gastric mRNA/protein expressions of EGF, EGF receptors, VEGFA, HOs, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), COX-2, hypoxia-inducible factor (HIF)-1α and pro-inflammatory iNOS, IL-1β and TNF-α were determined by real-time PCR or Western blots. CORM-2 and haemin but not RuCl3 or ZnPP decreased ulcer size while increasing GBF. These effects were reduced by ODQ, indomethacin, l-NNA and glibenclamide. CORM-2 significantly decreased the expression of pro-inflammatory markers, Nrf2/HO1 and HIF-1α, and up-regulated EGF. CO released from CORM-2 or endogenously produced by the HO1/Nrf2 pathway accelerates gastric ulcer healing via an increase in GBF, an up-regulation in EGF expression and down-regulation of the inflammatory response.