Man Kwan, Lee Terence K, Liang Ting Bo, Lo Chung Mau, Fung Peter Chin-Wan, Tsui Steven H, Li Xian Liang, Ng Kevin T, Fan Sheung Tat
Department of Surgery, Centre for the Study of Liver Disease, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong, China.
Ann Surg. 2004 Jul;240(1):159-68. doi: 10.1097/01.sla.0000129673.13552.c0.
To investigate whether low-dose nitric oxide donor FK 409 could attenuate small-for-size graft injury in liver transplantation using small-for-size grafts.
The major concern of live donor liver transplantation is small-for-size graft injury at the early phase after transplantation. Novel therapeutic strategies should be investigated.
We employed a rat orthotopic liver transplantation model using small-for-size (40%) graft. FK 409 was given at 30 minutes before graft harvesting (2 mg/kg) to the donor and immediately after reperfusion (1 mg/kg) to the recipient (FK group). Graft survival, intragraft genes expression, portal hemodynamics, and hepatic ultrastructural changes were compared between the 2 groups.
Seven-day graft survival rates in the FK group were significantly improved compared with those of rats not receiving FK 409 (control group; 80% versus 28.6%, P = 0.018). In the FK group, portal pressure was significantly decreased within the first 60 minutes after reperfusion whereas in the control group, transient portal hypertension was observed. Intragraft expression (both mRNA and protein) of early growth response-1, endothelin-1, endothelin-1 receptor A, tumor necrosis factor-alpha, macrophage-inflammatory protein-2, and inducible nitric oxide synthase was significantly down-regulated accompanied with up-regulation of heme oxygenase-1, A20, interferon-gamma-inducible protein-10, and interleukin-10 during the first 24 hours after reperfusion. Hepatic ultrastructure, especially the integrity of sinusoids was well protected in the FK group.
Low-dose FK 409 rescues small-for-size grafts in liver transplantation by attenuation of portal hypertension and amelioration of acute phase inflammatory response by down-regulation of Egr-1, together with prior induction of heat shock proteins.
研究低剂量一氧化氮供体FK 409是否能减轻小体积移植肝在肝移植中的损伤。
活体供肝肝移植的主要问题是移植后早期的小体积移植肝损伤。应研究新的治疗策略。
我们采用大鼠原位肝移植模型，使用小体积（40%）的移植肝。在供体获取移植物前30分钟给予FK 409（2毫克/千克），并在受体再灌注后立即给予（1毫克/千克）（FK组）。比较两组的移植物存活率、移植物内基因表达、门静脉血流动力学和肝脏超微结构变化。
与未接受FK 409的大鼠（对照组）相比，FK组的7天移植物存活率显著提高（80%对28.6%，P = 0.018）。在FK组，再灌注后最初60分钟内门静脉压力显著降低，而在对照组中观察到短暂的门静脉高压。再灌注后最初24小时内，早期生长反应-1、内皮素-1、内皮素-1受体A、肿瘤坏死因子-α、巨噬细胞炎性蛋白-2和诱导型一氧化氮合酶的移植物内表达（mRNA和蛋白质）均显著下调，同时血红素加氧酶-1、A20、干扰素-γ诱导蛋白-10和白细胞介素-10上调。FK组的肝脏超微结构，尤其是肝血窦的完整性得到了很好的保护。
低剂量FK 409通过减轻门静脉高压和下调Egr-1改善急性期炎症反应，同时预先诱导热休克蛋白，从而挽救肝移植中的小体积移植物。
