Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model
Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model
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DOI：
10.1002/lt.21251
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发表时间：
2007-10-01
影响因子：
4.6
通讯作者：
Kupiec-Weglinski, Jerzy W.
中科院分区：
文献类型：
--
作者：
Shen, Xiu-Da;Ke, Bibo;Kupiec-Weglinski, Jerzy W.
本研究分析了供体器官中Toll样受体4(TLR4)信号对肝移植后缺血再灌注损伤(I R I)后遗症的影响。野生型(WT)和TLR4基因敲除(KO)小鼠供肝在4℃的威斯康星大学溶液中保存24小时后，行再动脉化的同种异体原位肝移植。与WT OLTS不同，移植到WT或TLR4 KO受者体内的TLR4缺陷的OLTS受到的肝细胞损害明显较小，从血清丙氨酸氨基转移酶水平和肝脏IRI的组织学Suzuki分级来证明。阻断TLR4信号可减少OLTS局部中性粒细胞的聚集、CD4(+)T细胞的浸润、干扰素诱导蛋白10(CXCL10)和细胞间黏附分子(ICAM-1)以及肿瘤坏死因子(TNF)-α、白介素1-β(IL-1β)、IL-2和干扰素-γ的表达，但增加IL-4和IL-10的表达。与TLR4信号完整的WT OLTS相比，功能良好的TLR4 KO供者的OLT表现出CAPase-3活性减弱，HO-1表达增强，内皮细胞/肝细胞凋亡水平降低。因此，供体器官中的功能性前哨TLR4复合体在肝移植后肝脏IRI的发生机制中起着关键作用。阻断TLR4通路可下调早期促炎反应，改善肝脏IRI。这些结果为局部修改供体器官中固有的TLR4信号以更有效地控制移植后适应性IRI依赖反应提供了理论基础。
This study analyzes how toll-like receptor 4 (TLR4) signaling in the donor organ affects the ischemia and reperfusion injury (I R I) sequel following liver transplantation. Isogenic orthotopic liver transplantations (OLTs) with rearterialization were performed in groups of wild-type (WT) and TLR4 knockout (KO) mice after donor liver preservation in University of Wisconsin solution at 4 degrees C for 24 hours. Unlike WT OLTs, TLR4-deficient OLTs transplanted to either WT or TLR4 KO recipients suffered significantly less hepatocellular damage, as evidenced by serum alanine aminotransferase levels, and histological Suzuki's grading of liver IRI. Disruption of TLR4 signaling in OLTs decreased local neutrophil sequestration, CD4(+) T cell infiltration, interferon (IFN)-gamma-inducible protein 10 (CXCL10) and an intercellular adhesion molecule (ICAM-1), as well as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-2, and IFN-gamma, yet increased IL-4 and IL-10 expression. The well-functioning OLTs from TLR4 KO donors revealed attenuated activity of capase-3, and enhanced heme oygenase-1 (HO-1) expression, along with decreased levels of apoptotic endothelial cells/hepatocytes, as compared with WT OLTs with intact TLR4 signaling. Thus, the functional sentinel TLR4 complex in the donor organ plays a key role in the mechanism of hepatic IRI after OLT. Disruption of TLR4 pathway downregulated the early proinflammatory responses and ameliorated hepatic IRI. These results provide the rationale to locally modify innate TLR4 signaling in the donor organ to more efficiently control the adaptive posttransplantation IRI-dependent responses.