Liver Transplant Section, Center for Organ Transplantation, Huashan Hospital, Fudan University, Shanghai, China.
Department of General Surgery, First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Am J Transplant. 2010 Apr;10(4):784-795. doi: 10.1111/j.1600-6143.2009.02993.x. Epub 2010 Jan 29.
Ischemia/reperfusion (I/R) and portal hypertension have been implicated in small-for-size liver graft dysfunction. Matrix metalloproteinases-2 and -9 (MMP-2/9) are critically proposed to involve in hepatic I/R injury and activated by hemodynamic force. We hypothesized that MMP-2/9 overexpression played a crucial role in acute graft injury following small-for-size liver transplantation (LT). Rats were randomly assigned into four groups: 75% partial hepatectomy (PH); 100% LT; 25% LT and 25% LT treated with CTT peptide (MMP-2/9 inhibitor). ELISA, real-time PCR, gelatin zymography and immunohistochemistry were used to determine the expression pattern of MMP-2/9 in liver tissue. MMP-9 expression was significantly increased 6 h after reperfusion and reached a peak 12 h in the 25% LT group, whereas MMP-2 was expressed in all groups invariably. Compared with the 25% LT group, rats from CTT-treated group exhibited markedly decreased alanine aminotransferase and total bilirubin values, downregulated proinflammatory cytokines, attenuated malondialdehyde (MDA) and myeloperoxidase (MPO) activities, and improved liver histology. Likewise, MMP-9 inhibition significantly reduced number of TUNEL-positive cells and caspase-3 activity, along with decreased protein levels of Fas and Fas-L. Specifically, rat survival was also improved in the CTT-treated group. These results support critical function of MMP-9 involved in acute small-for-size livergraft injury.
缺血再灌注（I/R）和门静脉高压与小体积肝移植物功能障碍有关。基质金属蛋白酶-2 和 -9（MMP-2/9）被认为在肝 I/R 损伤中起关键作用，并被血流动力激活。我们假设 MMP-2/9 过表达在小体积肝移植（LT）后急性移植物损伤中起关键作用。大鼠被随机分为四组：75%部分肝切除术（PH）；100%LT；25%LT 和 25%LT 用 CTT 肽（MMP-2/9 抑制剂）治疗。ELISA、实时 PCR、明胶酶谱和免疫组织化学用于确定 MMP-2/9 在肝组织中的表达模式。再灌注后 6 小时 MMP-9 表达显著增加，12 小时达到高峰在 25%LT 组，而 MMP-2 在所有组中均表达。与 25%LT 组相比，CTT 治疗组大鼠的丙氨酸氨基转移酶和总胆红素值明显降低，促炎细胞因子下调，丙二醛（MDA）和髓过氧化物酶（MPO）活性减弱，肝组织学改善。同样，MMP-9 抑制显著减少 TUNEL 阳性细胞和 caspase-3 活性，同时降低 Fas 和 Fas-L 的蛋白水平。具体来说，CTT 治疗组大鼠的存活率也有所提高。这些结果支持 MMP-9 在急性小体积肝移植物损伤中的关键作用。
