Miyagi Shigehito, Ohkohchi Nobuhiro, Oikawa Kohsei, Satoh Masahide, Tsukamoto Shigeki, Satomi Susumu
Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Transplantation. 2004 May 27;77(10):1487-93. doi: 10.1097/01.tp.0000122418.87680.c1.
The shortage of donors has become a serious problem. Some institutes have tried to use grafts retrieved from non-heart-beating donors (NHBDs), but the results have not been satisfactory. This study clarifies the effects of nafamostat mesilate (NM), a strong serine protease inhibitor, and FR167653, a suppressant of both tumor necrosis factor-alpha and interleukin-1beta release, on warm ischemia-reperfusion injury and establishes the procurement of the grafts for a successful liver transplant using uncontrolled NHBDs.
Male Wistar rats were divided into five groups as follows (n = 5): (1) heart-beating (HB) group, in which livers were retrieved from heart-beating donors; (2) non-heart-beating (NHB) group, in which livers were retrieved from NHBDs; (3) NM group, in which livers were retrieved from NHBDs pretreated with NM (0.2 mg/kg/hr, for 30 min); (4) FR group, in which livers were retrieved from NHBDs pretreated with FR167653 (2 mg/kg); and (5) FR+NM group, in which livers were retrieved from NHBDs pretreated with FR167653 and NM. The livers were perfused for 60 min with Krebs-Henseleit bicarbonate buffer after cold preservation 6 hr.
In the NHB group, the values of interleukin-1beta, tumor necrosis factor-alpha, thromboxane B2, and leukotriene B4, and the expressions of nuclear factor-kappaB, activating protein 1, and cyclooxygenase-2 were significantly higher than those in the HB group. In the FR+NM group, those values were low, the structure of the sinusoids was preserved, and the sinusoidal lumen was maintained (the same as observed in the HB group).
FR167653 and NM inhibited the induction of inflammatory cytokines and arachidonic acid cascade mediators. This combined therapy was effective in preserving sinusoidal microcirculation in the liver grafts from NHBDs.
供体短缺已成为一个严重问题。一些机构已尝试使用从非心脏跳动供体（NHBD）获取的移植物，但结果并不令人满意。本研究阐明了强效丝氨酸蛋白酶抑制剂甲磺酸萘莫司他（NM）和肿瘤坏死因子-α及白细胞介素-1β释放抑制剂FR167653对热缺血再灌注损伤的影响，并确立了使用非控制性NHBD成功进行肝移植时移植物的获取方法。
将雄性Wistar大鼠分为以下五组（n = 5）：（1）心脏跳动（HB）组，从心脏跳动供体获取肝脏；（2）非心脏跳动（NHB）组，从NHBD获取肝脏；（3）NM组，从用NM（0.2 mg/kg/小时，共30分钟）预处理的NHBD获取肝脏；（4）FR组，从用FR167653（2 mg/kg）预处理的NHBD获取肝脏；（5）FR + NM组，从用FR167653和NM预处理的NHBD获取肝脏。肝脏在冷保存6小时后用Krebs-Henseleit碳酸氢盐缓冲液灌注60分钟。
在NHB组中，白细胞介素-1β、肿瘤坏死因子-α、血栓素B2和白三烯B4的值以及核因子-κB、活化蛋白1和环氧化酶-2的表达均显著高于HB组。在FR + NM组中，这些值较低，肝血窦结构得以保留，肝血窦腔保持通畅（与HB组观察到的相同）。
FR167653和NM抑制了炎性细胞因子和花生四烯酸级联介质的诱导。这种联合治疗有效地保留了来自NHBD的肝移植物中的肝血窦微循环。
