Selective neutralization of the chemokine TCA3 reduces the increased injury of partial versus whole liver transplants induced by cold preservation
Selective neutralization of the chemokine TCA3 reduces the increased injury of partial versus whole liver transplants induced by cold preservation
复制标题
DOI：
10.1097/01.tp.0000243167.11566.eb
复制
发表时间：
2006-12-15
期刊：
影响因子：
6.2
通讯作者：
Olthoff, Kim M.
中科院分区：
文献类型：
--
作者：
Xie, Jin-Fu;Wang, Guodong;Olthoff, Kim M.
背景鉴于肝脏供体的短缺和部分肝移植技术的发展，我们在小鼠同基因肝移植模型中比较了部分和完整移植物的趋化因子表达和炎性细胞浸润。原位肝移植，使用整个或部分小鼠肝移植，进行后，在ViaSpan溶液中冷保存1至8小时。部分移植物表现出更严重的冷缺血/再灌注损伤和更大的炎性细胞浸润比整个移植物，并伴有多种趋化因子的肝内显著上调。定量分析显示，与相同时间冷缺血后收获的整个移植物中的表达相比，部分移植物中T细胞活化基因（TCA）-3（CCL 1）趋化因子信使RNA（mRNA）的表达增加了8倍诱导蛋白（IP）-10趋化因子（CCL 10）mRNA表达增加6倍（P < 0.01），以及趋化因子受体CCR 8（TCA 3受体）和CXCR 3（IP-10受体; P < 0.01）的表达增加。用中和性单克隆抗体阻断TCA 3可显著降低移植物内IP-10的表达（P < 0.05），但不影响部分移植物中肿瘤坏死因子-α和白细胞介素-6的表达，并显著降低冷缺血/再灌注损伤（P < 0.05）和相关的中性粒细胞和T细胞浸润（P < 0.01）。这些数据表明，趋化因子TCA 3/CCL 1是重要的实验性部分肝移植缺血性损伤的发病机制，其治疗靶向在这样的移植物可以克服长期的冷保存的有害影响，并恢复肝功能达到使用全肝移植的水平。
Background. Given the shortage of liver donors and the development of techniques for partial liver transplantation, we compared chemokine expression and inflammatory cell infiltration of partial versus whole grafts in a mouse syngeneic liver transplant model.Methods. Orthotopic liver transplantation, using whole or partial murine liver grafts, was performed following cold preservation in ViaSpan solution for periods of one to eight hours.Results. Partial grafts showed more severe cold ischemia/reperfusion injury and greater inflammatory cell infiltration than whole grafts, and was accompanied by the marked intrahepatic upregulation of multiple chemokines. Quantitative analysis showed that compared with expression in whole grafts harvested after the same period of cold ischemia, partial grafts had eightfold more T-cell activation gene (TCA)-3 (CCL1) chemokine messenger RNA (mRNA) expression (P < 0.01) and sixfold more inducible protein (IP)-10 chemokine (CCL10) mRNA expression (P < 0.01), as well as increased expression of the chemokine receptors CCR8 (receptor for TCA3) and CXCR3 (receptor for IP-10; P < 0.01). Blockade of TCA3 by neutralizing monoclonal antibody significantly decreased intragraft IP-10 expression (P < 0.05) but not tumor necrosis factor-alpha or interleukin-6 expression in partial grafts, and significantly decreased cold ischemia/reperfusion injury (P < 0.05) and associated neutrophil and T-cell infiltration (P < 0.01).Conclusions. These data demonstrate that the chemokine TCA3/CCL1 is important to the pathogenesis of ischemic injury of experimental partial liver grafts, and that its therapeutic targeting within such grafts can overcome the deleterious effects of prolonged cold preservation and restore liver function to the level achieved using whole liver grafts.