title: Carbon monoxide alleviates ethanol-induced oxidative damage and inflammatory stress through activating p38 MAPK pathway.
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.
authors.affiliation: 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.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Li
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.forename: Yanru
authors.initials: Y
authors.lastname: Shi
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Tang
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.forename: Ting
authors.initials: T
authors.lastname: Xiong
authors.forename: Min
authors.initials: M
authors.lastname: Du
authors.forename: Mingyou
authors.initials: M
authors.lastname: Xing
authors.forename: Liegang
authors.initials: L
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Yao
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000097:blood; D002248:Carbon Monoxide / Q000494:pharmacology*; D000431:Ethanol / Q000009:adverse effects*; D005419:Flavonoids / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008108:Liver Diseases, Alcoholic / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009942:Organometallic Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D064209:Phytochemicals; D011725:Pyridines / Q000494:pharmacology; D011794:Quercetin / Q000494:pharmacology; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D000410:Alanine Transaminase; D000873:Anthracenes; D001219:Aspartate Aminotransferases; D002248:Carbon Monoxide; D000431:Ethanol; D005419:Flavonoids; D005978:Glutathione; D051547:Heme Oxygenase-1; D007093:Imidazoles; D015850:Interleukin-6; D007770:L-Lactate Dehydrogenase; D009942:Organometallic Compounds; D064209:Phytochemicals; D011725:Pyridines; D011794:Quercetin; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors; C447082:tricarbonyldichlororuthenium (II) dimer; C432165:pyrazolanthrone; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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