EFFECTS OF ANTI-INFLAMMATORY CYTOKINE AGENT (FR167653) AND SERINE PROTEASE INHIBITOR ON WARM ISCHEMIA-REPERFUSION INJURY OF THE LIVER GRAFT
EFFECTS OF ANTI-INFLAMMATORY CYTOKINE AGENT (FR167653) AND SERINE PROTEASE INHIBITOR ON WARM ISCHEMIA-REPERFUSION INJURY OF THE LIVER GRAFT
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DOI：
10.1097/01.tp.0000122418.87680.c1
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发表时间：
2004-05
期刊：
影响因子：
6.2
通讯作者：
S. Miyagi;N. Ohkohchi;Kohsei Oikawa;Masahide Satoh;S. Tsukamoto;S. Satomi
中科院分区：
文献类型：
--
作者：
S. Miyagi;N. Ohkohchi;Kohsei Oikawa;Masahide Satoh;S. Tsukamoto;S. Satomi
背景捐助者短缺已成为一个严重问题。一些研究机构曾尝试使用无心跳供体（NH-BD）的移植物，但结果并不令人满意。本研究阐明了甲磺酸萘莫司他（NM）（一种强丝氨酸蛋白酶抑制剂）和FR 167653（一种肿瘤坏死因子-α和白细胞介素-1 β释放抑制剂）对热缺血-再灌注损伤的影响，并建立了使用不受控制的NHBD进行成功肝移植的移植物采购。方法.雄性Wistar大鼠分为5组（n=5）：（1）心脏跳动（HB）组，从心脏跳动供体中取出肝脏;（2）无心脏跳动（NHB）组，从NHBDs中取出肝脏;（3）NM组，从NM预处理的NHBDs中取出肝脏（0.2 mg/kg/hr，持续30 min）;（4）FR组，其中从用FR 167653（2 mg/kg）预处理的NHBD中取出肝脏;和（5）FR+NM组，其中从用FR 167653和NM预处理的NHBD中取出肝脏。肝脏冷保存6小时后，用Krebs-Henseleit碳酸氢盐缓冲液灌注60分钟。NHB组白细胞介素1β、肿瘤坏死因子α、血栓素B2、白三烯B4水平及核因子κB、活化蛋白1、环氧合酶2的表达均显著高于HB组。在FR+NM组中，这些值较低，窦状隙结构得到保留，窦腔得以维持（与HB组中观察到的相同）。结论. FR 167653和NM抑制炎性细胞因子和花生四烯酸级联介质的诱导。这种联合疗法对NHBDs移植肝窦微循环的保护是有效的。
Background. The shortage of donors has become a serious problem. Some institutes have tried to use grafts retrieved from non–heart-beating donors (NH-BDs), 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-α and interleukin-1β release, on warm ischemia-reperfusion injury and establishes the procurement of the grafts for a successful liver transplant using uncontrolled NHBDs. Methods. 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. Results. In the NHB group, the values of interleukin-1β, tumor necrosis factor-α, thromboxane B2, and leukotriene B4, and the expressions of nuclear factor-κB, 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). Conclusions. 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.