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.
Toxicol Appl Pharmacol. 2013 Nov 15;273(1):53-8. doi: 10.1016/j.taap.2013.08.019. Epub 2013 Aug 28.
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.
应激诱导蛋白血红素加氧酶-1（HO-1）在对抗氧化损伤和炎症应激方面具有重要作用，这涉及到酒精性肝病（ALD）的发病机制。然而，HO-1 代谢产物一氧化碳（CO）的潜在作用和信号通路仍不清楚。为了探索其确切机制，我们用乙醇处理成年雄性 Balb/c 小鼠（5.0g/kg.bw.）或乙醇孵育的原代大鼠肝细胞（100mmol/L），并用三羰基二氯钌（II）二聚体（CORM-2，小鼠 8mg/kg 或肝细胞 20μmol/L）以及其他药理学试剂进行预处理。我们的数据表明，槲皮素诱导 HO-1 产生的 CO 可防止乙醇引起的氧化损伤，而这种保护作用可被 CO 清除剂血红蛋白所消除。CORM-2 可模拟这种保护作用，同时减轻 GSH 耗竭、SOD 失活、MDA 过量产生以及血清和培养上清中 AST、ALT 或 LDH 的漏出，这是由乙醇诱导的。此外，CORM-2 的注射或孵育可刺激 p38 磷酸化，并抑制异常的 Tnfa 和 IL-6，同时减轻由乙醇引起的氧化还原失衡，并加重由炎症因子引起的失衡。CORM-2 的保护作用可被 SB203580（p38 抑制剂）消除，但不能被 PD98059（ERK 抑制剂）或 SP600125（JNK 抑制剂）消除。因此，HO-1 释放的 CO 通过激活 p38 MAPK 通路来防止乙醇引起的肝氧化损伤和炎症应激，这表明天然存在的植物化学物质诱导的 ALD 治疗中，气态信号分子具有潜在的治疗作用。
