内皮素转换酶抑制剂（FR901533）在肝缺血/再灌注损伤中的保护作用。

Uhlmann D, Witzigmann H, Senninger N, Hauss J, Spiegel H U

Second Department of Surgery, University of Leipzig, Leipzig, 04103, Germany.

Microvasc Res. 2001 Jul;62(1):43-54. doi: 10.1006/mvre.2001.2309.

INTRODUCTION

There is evidence that endothelin (ET) contributes to disturbances of the hepatic microcirculation after warm ischemia/reperfusion (I/R) by causing vasoconstriction and by enhancing leukocyte endothelium interactions. The aim of this study was to investigate a possible protective role of the endothelin converting enzyme (ECE) inhibitor FR901533 in this setting.

METHODS

In an in vivo model (42 Wistar rats), hepatic ischemia was induced for 30 min by Pringle's maneuver. Sham operated (I), untreated ischemic (II), and treatment (III) groups with FR901533 (1 mg/kg bw iv) were investigated. The effect of FR901533 in I/R was assessed by in vivo microscopy (30-90 min after reperfusion), measurement of local tissue pO2 (30 and 60 min after reperfusion), and determination of AST/ALT levels (2 h, 6 h, and 2, 6, and 14 days after reperfusion).

RESULTS

In the untreated ischemic group (II) sinusoidal constriction to 76.3 +/- 4.2% of basic diameters was observed, leading to significant decreases in perfusion rate (82.3 +/- 3.6% of sham group) and in liver tissue pO(2) (43.5 +/- 3.2% of sham group) (P < 0.05). In addition, we found an increased percentage of stagnant leukocytes in sinusoids (138.3 +/- 9.8) and sticking leukocytes in postsinusoidal venules (155.2 +/- 3.3% of sham group) (P < 0.05). Hepatocellular damage (AST/ALT increase to 430.6 +/- 47.7 U/L/200.2 +/- 23.8 U/L, pre: 27.4 +/- 2.7 U/L/28.1 +/- 2.7 U/L) was detected 6 h after reperfusion (P < 0.05). Administration of the ECE inhibitor before ischemia significantly reduced I/R injury. Sinusoidal diameters were maintained (102.2 +/- 1.7%), while perfusion rate (93.1 +/- 1.8%) and tissue pO2 (105.3 +/- 2.7%) increased significantly (P < 0.05). Hepatocellular damage was decreased (AST/ALT levels after 6 h of reperfusion: 166.6 +/- 26.3 U/L/132.4 +/- 22.5 U/L, P < 0.05) and leukocyte sticking and rolling were significantly reduced (P < 0.05).

CONCLUSION

Our results provide evidence that the new therapeutic approach with an ECE inhibitor is effective in reducing hepatic I/R injury.

引言

有证据表明，内皮素（ET）通过引起血管收缩和增强白细胞与内皮细胞的相互作用，导致热缺血/再灌注（I/R）后肝微循环紊乱。本研究的目的是探讨内皮素转化酶（ECE）抑制剂FR901533在此情况下可能的保护作用。

方法

在一个体内模型（42只Wistar大鼠）中，通过Pringle手法诱导肝脏缺血30分钟。研究假手术组（I）、未治疗的缺血组（II）和用FR901533（1mg/kg体重静脉注射）治疗的组（III）。通过体内显微镜检查（再灌注后30 - 90分钟）、局部组织pO2测量（再灌注后30分钟和60分钟）以及AST/ALT水平测定（再灌注后2小时、6小时以及2、6和14天）评估FR901533在I/R中的作用。

结果

在未治疗的缺血组（II）中，观察到肝血窦直径收缩至基础直径的76.3±4.2%，导致灌注率显著降低（假手术组的82.3±3.6%）和肝组织pO2显著降低（假手术组的43.5±3.2%）（P < 0.05）。此外，我们发现肝血窦中停滞白细胞的百分比增加（138.3±9.8），肝血窦后小静脉中黏附白细胞增加（假手术组的155.2±3.3%）（P < 0.05）。再灌注6小时后检测到肝细胞损伤（AST/ALT升高至430.6±47.7 U/L/200.2±23.8 U/L，术前：27.4±2.7 U/L/28.1±2.7 U/L）（P < 0.05）。缺血前给予ECE抑制剂可显著减轻I/R损伤。肝血窦直径得以维持（102.2±1.7%），而灌注率（93.1±1.8%）和组织pO2（105.3±2.7%）显著增加（P < 0.05）。肝细胞损伤减轻（再灌注6小时后AST/ALT水平：166.6±26.3 U/L/132.4±22.5 U/L，P < 0.05），白细胞黏附和滚动显著减少（P < 0.05）。