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MECHANISMS AND PREVENTION OF GRAFT INJURY OF THE LIVER GRAFT IN NON-HEART-BEATING DONOR.

无心跳供体肝移植损伤的机制和预防。

基本信息

批准号：
11470253
负责人：
OHKOHCHI Nobuhiro
金额：
$ 10.43万
依托单位：
TOHOKU University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

[Background and Purpose] Microcirculatory disturbance is a main obstacle to liver transplantation (LTx) from non-heart beating donors (NHBD) and it is attributed to a deterioration of sinusoidal endothelial cells (SEC) and sinusoidal narrowing. We examined roles of Kupffer cells (KC) in the sinusoidal microcirculation of the graft of NHBD, focusing on NF-κB and cytokines and eicosanoids. We also investigated effects of KC elimination and cytokine suppression on LTx from agonal NHBD, [Materials/Methods] A) Livers of Wistar rat were isolated and perfused for 60 minutes with Krebs-Henseleit bicarbonate buffer. Animals were divided into four groups as follows (n=6) : control group, liver was perfused without preservation ; HB group, livers were perfused after 6 hr cold preservation ; NHB group, liver from NHBD was perfused after cold preservation ; KE group, rats were pretreated with liposome-encapsulated dichloromethlene diphoshonate to eliminate KC.Liver from NHBD was perfused after cold … More preservation. NF-κB, cytokines (TNFα, IL-1β, IL-6), eicosanoids (TXA2, 6-ket-PGF1α, LTB4), AST and LDH were measured. B) Pigs were allocated to five groups (n=6) : NHB group, liver graft from NHBD was transplanted ; NM group, graft from NHBD was rinsed with nafamostat mesilate (NM) rinse solution ; KC *inated group, KC eliminated graft from NHBD was transplanted ; KC eliminated+NM rinse group, KC eliminated graft from NHBD was transplanted with rinsing NM rinse solution ; cytokine suppression group, TNFθ and IL1β were suppressed and PGE1was administered before and after liver Tx from NHBD.[Results] A) NF-κB activity of the NHB group was significantly higher than those of the other groups. In KE group, NF-κB activity was suppressed as same level as in control group, In KE group, cytokine and eicosanoid levels were suppressed and sinusoidal structures were preserved well. B) Both in KC eliminated +NM rinse and cytokine suppression groups, four of five recipients survived. After reperfusion, it was histologically demonstrated that elimination of Kupffer cells prevented SEC deterioration and NM rinse prevented sinusoidal narrowing. The energy charge of liver tissue recovered in all groups except NHB group. [Conclusions] KC activities have an important roll in the disturbance of sinusoidal microcirculation in Tx from NHBD.Modulation of KC is a key for success in liver transplantation from NHBD and it is important to prevent microcirculatory disturbance of SEC deterioration and sinusoidal narrowing. Combination therapy consisting of suppression of KC activities and NM rinse will be able to prevent primary graft non-function in liver grafts from agonal NHBD. Less

[背景与目的]微循环障碍是非心脏跳动供体(NHBD)肝移植(LTX)的主要障碍，可归因于肝窦内皮细胞(SEC)的恶化和肝窦狭窄。我们研究了库普弗细胞(KC)在非酒精性肝病移植的肝窦微循环中的作用，重点研究了核因子-κB以及细胞因子和二十烷类化合物。[材料/方法]A)分离Wistar大鼠肝脏，用Krebs-Henseleit碳酸氢盐缓冲液灌流60min。动物分为4组(n=6)：对照组，肝脏不保存；HB组，冷保存6h后再灌流肝脏；NHB组，冷保存后肝脏再灌流；KE组，用脂质体包埋的二氯亚甲基二磷酸盐预处理，清除KC。冷…后，再灌流NHBD肝脏更多的保护。测定核因子κB、细胞因子(肿瘤坏死因子α、白介素1β、白介素6)、二十烷类化合物(血栓素A_2、6-酮-前列腺素F1α、白三烯B_4)、天门冬氨酸氨基转移酶和乳酸脱氢酶。B)将猪分为5组(n=6)：非酒精性肝病组(NHB组)，非酒精性肝病肝移植组(NM组)，非酒精性肝病肝移植组(NM组)，去KC组(KC组)，去KC组(NM组)，去KC组(KC组)，去KC组(KC组)，去KC组(NM组)，去KC组(NHBD组)，细胞因子抑制组，肿瘤坏死因子θ和白介素1β(IL1β)抑制组，PGE1给药组。KE组NF-κB活性受抑制程度与对照组相当，KE组细胞因子和二十烷类物质水平受到抑制，血窦结构保存完好。B)KC消除+NM冲洗组和细胞因子抑制组5例受体中4例存活。再灌流后，组织学证实消除枯否细胞可防止SEC恶化，NM冲洗可防止肝窦狭窄。除NHB组外，其余各组肝组织能荷均恢复正常。[结论]KC活性在NHBD引起的TX血窦微循环障碍中起重要作用。KC的调节是NHBD肝移植成功的关键，对防止SEC恶化和肝窦狭窄的微循环障碍具有重要意义。由抑制KC活性和NM冲洗组成的联合治疗将能够防止由无源性NHBD引起的移植物原发无功能。较少