Ke Bibo, Shen Xiu-Da, Lassman Charles R, Gao Feng, Busuttil Ronald W, Kupiec-Weglinski Jerzy W
The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Am J Transplant. 2003 Sep;3(9):1076-82. doi: 10.1034/j.1600-6143.2003.00147.x.
Liver injury caused by ischemia/reperfusion (I/R) insult represents the major problem following orthotopic liver transplantation (OLT). I/R damage has been linked to Th1-like cytokine producers. This study evaluates putative cytoprotective effects/mechanisms of Th2-type IL-13 gene transfer. IL-13 overexpression prevented hepatic insult in a rat model of 24 h cold ischemia followed by OLT, as assessed: (i) profoundly decreased hepatocellular damage (sGOT levels), and ameliorated histological signs of I/R injury (Suzuki criteria), consistent with long-term OLT survival; (ii) prevented hepatic apoptosis (TUNEL stains) and up-regulated expression of antiapoptotic (A20, Bcl-2/Bcl-xl)/antioxidant (HO-1) genes. However, inhibition of HO-1 with tin protoporphyrin reversed cytoprotective/antiapoptotic effects of IL-13. In conclusion, cytoprotection rendered by virally induced IL-13 against hepatic I/R injury in this clinically relevant rat hepatic cold I/R injury model was accomplished via decreased apoptosis and induction of antiapoptotic/antioxidant molecules. HO-1 neutralization studies suggest that HO-1 represents one of putative IL-13 downstream effectors. This study provides the rationale for novel approaches to maximize organ donor pool through the safer use of OLTs despite prolonged periods of cold ischemia.
缺血/再灌注（I/R）损伤所致的肝损伤是原位肝移植（OLT）后的主要问题。I/R损伤与Th1样细胞因子产生有关。本研究评估了Th2型白细胞介素13（IL-13）基因转移的假定细胞保护作用/机制。在24小时冷缺血后行OLT的大鼠模型中，评估发现IL-13过表达可预防肝损伤：（i）显著降低肝细胞损伤（血清谷草转氨酶水平），改善I/R损伤的组织学征象（铃木标准），这与OLT长期存活一致；（ii）预防肝细胞凋亡（TUNEL染色），上调抗凋亡（A20、Bcl-2/Bcl-xl）/抗氧化（HO-1）基因的表达。然而，用锡原卟啉抑制HO-1可逆转IL-13的细胞保护/抗凋亡作用。总之，在这个具有临床相关性的大鼠肝脏冷I/R损伤模型中，病毒诱导的IL-13对肝脏I/R损伤的细胞保护作用是通过减少凋亡和诱导抗凋亡/抗氧化分子来实现的。HO-1中和研究表明，HO-1是IL-13假定的下游效应分子之一。本研究为通过更安全地使用OLT来扩大器官供体库提供了理论依据，尽管存在长时间的冷缺血。
