Carbon Monoxide (CO) Released from Tricarbonyldichlororuthenium (II) Dimer (CORM-2) in Gastroprotection against Experimental Ethanol-Induced Gastric Damage.

Katarzyna Magierowska,Juliusz Adamski,Tomasz Brzozowski,Slawomir Kwiecien,Magdalena Hubalewska-Mazgaj,Zbigniew Sliwowski,Marcin Magierowski,Marcin Surmiak,Prasun K Datta

doi:10.1371/journal.pone.0140493

Katarzyna Magierowska, Juliusz Adamski + Show 7 more

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https://doi.org/10.1371/journal.pone.0140493

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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.

Highlights

Carbon monoxide (CO) is a gaseous molecule generated intracellularly during the degradation of heme, a product of iron protoporphyrin IX, in reaction catalyzed by heme oxygenase (HO) in the presence of molecular oxygen and reducing equivalents (NADPH) [1]
CO-releasing molecules (CORMs)-2 applied in a dose of 0.5 mg/kg i.g. failed to significantly affect the area of gastric lesions and the GBF, but the significant decrease in the mean lesion area and increase in the GBF (p
It is anticipated that the HO/CO pathway plays emerging role in the mucosal defense system of GI tract but the mechanism underlying the gastroprotective effect of HO/CO system in the stomach exposed to irritating action of necrotizing agent such as ethanol has been little studied

Summary

Introduction

Carbon monoxide (CO) is a gaseous molecule generated intracellularly during the degradation of heme, a product of iron protoporphyrin IX, in reaction catalyzed by heme oxygenase (HO) in the presence of molecular oxygen and reducing equivalents (NADPH) [1]. Previous studies revealed that CO can modulate a variety of physiological processes, including vasodilatation, neurotransmission, platelet activation and aggregation [6]. As a result of high affinity to hemoproteins such as cytochromes and NADPH oxidase, CO can downregulate production of reactive oxygen species (ROS) [12]. Based on these findings a novel class of compounds, termed CO-releasing molecules (CORMs), has been designed to liberate this gaseous molecule in variety of biological systems and to determine its effects in different organs [13]. CORMs were reported to serve as pharmacological tool to assess the involvement of CO in protection against various diseases due to anti-inflammatory action of CO-released from these compounds [13]

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