Carbon monoxide alleviates ethanol-induced oxidative damage and inflammatory stress through activating p38 MAPK pathway

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• 作者：Yanyan Li ; Chao Gao ; Yanru Shi ; Yuhan Tang ; Liang Liu ; Ting Xiong ; Min Du ; Mingyou Xing ; Liegang Liu ; Ping Yao
• 关键词：HO-1 ; heme oxygenase-1 ; CO ; carbon monoxide ; CORM-2 ; tricarbonyldichlororuthenium (II) dimmer ; GSH ; reduced glutathione ; MDA ; malondialdehyde ; SOD ; superoxide dismutase ; AST ; aspartate aminotransferases ; ALT ; alanine aminotransferases ; LDH ; lactate dehydrogenase
• 刊名：Toxicology and Applied Pharmacology
• 出版年：15 November, 2013
• 年：2013
• 卷：273
• 期：1
• 页码：53-58
• 全文大小：378 K

文摘

Stress-inducible protein heme oxygenase-1(HO-1) is well-appreciative to counteract oxidative damage and inflammatory stress involving the pathogenesis of alcoholic liver diseases (ALD). The potential role and signaling pathways of HO-1 metabolite carbon monoxide (CO), however, still remained unclear. To explore the precise mechanisms, ethanol-dosed adult male Balb/c mice (5.0 g/kg.bw.) or ethanol-incubated primary rat hepatocytes (100 mmol/L) were pretreated by tricarbonyldichlororuthenium (II) dimmer (CORM-2, 8 mg/kg for mice or 20 渭mol/L for hepatocytes), as well as other pharmacological reagents. Our data showed that CO released from HO-1 induction by quercetin prevented ethanol-derived oxidative injury, which was abolished by CO scavenger hemoglobin. The protection was mimicked by CORM-2 with the attenuation of GSH depletion, SOD inactivation, MDA overproduction, and the leakage of AST, ALT or LDH in serum and culture medium induced by ethanol. Moreover, CORM-2 injection or incubation stimulated p38 phosphorylation and suppressed abnormal Tnfa and IL-6, accompanying the alleviation of redox imbalance induced by ethanol and aggravated by inflammatory factors. The protective role of CORM-2 was abolished by SB203580 (p38 inhibitor) but not by PD98059 (ERK inhibitor) or SP600125 (JNK inhibitor). Thus, HO-1 released CO prevented ethanol-elicited hepatic oxidative damage and inflammatory stress through activating p38 MAPK pathway, suggesting a potential therapeutic role of gaseous signal molecule on ALD induced by naturally occurring phytochemicals.