Gao Bin
Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Park Building Room 120, 12420 Parklawn Drive, MSC 8115, Bethesda, MD 20892, USA.
Alcohol. 2004 Aug;34(1):59-65. doi: 10.1016/j.alcohol.2004.07.006.
Donor organ shortage significantly hinders orthotopic liver transplantation therapy, the only effective treatment for chronic end-stage liver disease and acute liver failure. Further complicating this matter is the prevalence of steatosis in 13% to 50% of donor livers obtained from obese and alcoholic individuals. When transplanted, these livers are associated with primary nonfunction and an elevated risk of dysfunction. New therapeutic approaches to render marginal fatty livers worthy for clinical transplantation are actively being sought. Study findings obtained from my group show that in vitro treatment with interleukin-6 (IL-6) dramatically reduces mortality, liver injury, and necrapoptosis in steatotic Zucker rat liver isografts. Findings of additional studies indicate that IL-6 induces hepatoprotection of steatotic liver isografts by preventing sinusoidal endothelial cell damage and, consequently, the amelioration of hepatic microcirculation, and by protecting against hepatocyte death, which is likely mediated through activation of signal transducer and activator of transcription 3/Bcl-x(L). Finally, in vitro IL-6 treatment also prevents mortality associated with alcoholic fatty liver transplants. Relative to the protective effect of IL-6 on steatotic Zucker rat liver, IL-6 is less effective in alcoholic fatty livers, which may be due to the inhibitory effects of ethanol on IL-6 activation of signal transducer and activator of transcription 3 in hepatocytes and sinusoidal endothelial cells. Collectively, these results support the assertion that in vitro IL-6 treatment of steatotic livers may render allografts usable for clinical transplantation, thereby decreasing the gap between the short supply of cadaver liver allografts and high demands for replacement livers. Higher concentrations of IL-6 may be required to protect against alcoholic fatty liver isograft injury because alcohol inhibits IL-6 signaling in the liver.
供体器官短缺严重阻碍了原位肝移植治疗，而原位肝移植是治疗慢性终末期肝病和急性肝衰竭的唯一有效方法。更复杂的是，从肥胖和酗酒个体获取的供体肝脏中，13%至50%存在脂肪变性。这些肝脏移植后会出现原发性无功能以及功能障碍风险升高的情况。目前正在积极寻找新的治疗方法，以使边缘性脂肪肝适合临床移植。我们团队的研究结果表明，用白细胞介素-6（IL-6）进行体外处理可显著降低脂肪变性的Zucker大鼠肝脏同种异体移植的死亡率、肝损伤和坏死性凋亡。其他研究结果表明，IL-6通过防止肝窦内皮细胞损伤从而改善肝微循环，并通过保护肝细胞免于死亡来诱导脂肪变性肝脏同种异体移植的肝保护作用，这可能是通过激活信号转导和转录激活因子3/Bcl-x(L)介导的。最后，体外IL-6处理还可预防与酒精性脂肪肝移植相关的死亡。相对于IL-6对脂肪变性的Zucker大鼠肝脏的保护作用，IL-6在酒精性脂肪肝中的效果较差，这可能是由于乙醇对肝细胞和肝窦内皮细胞中IL-6激活信号转导和转录激活因子3的抑制作用。总体而言，这些结果支持这样的观点，即体外IL-6处理脂肪变性肝脏可能使同种异体移植物可用于临床移植，从而缩小尸体肝脏同种异体移植物供应短缺与对替代肝脏的高需求之间的差距。可能需要更高浓度的IL-6来预防酒精性脂肪肝同种异体移植损伤，因为酒精会抑制肝脏中的IL-6信号传导。
