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Toxicol Appl Pharmacol. 2013 Nov 15;273(1):53-8. doi: 10.1016/j.taap.2013.08.019. Epub 2013 Aug 28.

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

Author information

1
Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, 13 Hangkong Road, Wuhan 430030, PR China; Ministry of Education Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, 13 Hangkong Road, Wuhan 430030, PR China; Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, 13 Hangkong Road, Wuhan 430030, PR China.

Abstract

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 (5.0g/kg.bw.) or ethanol-incubated primary rat hepatocytes (100mmol/L) were pretreated by tricarbonyldichlororuthenium (II) dimmer (CORM-2, 8mg/kg for mice or 20μmol/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.

KEYWORDS:

ALT; AST; Alcohol; CO; CORM-2; Carbon monoxide; GSH; HO-1; Inflammation; LDH; MDA; Oxidative damage; SOD; alanine aminotransferases; aspartate aminotransferases; carbon monoxide; heme oxygenase-1; lactate dehydrogenase; malondialdehyde; p38 MAPK; reduced glutathione; superoxide dismutase; tricarbonyldichlororuthenium (II) dimmer

PMID:
23994557
DOI:
10.1016/j.taap.2013.08.019
[Indexed for MEDLINE]
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