Amelioration of microcirculatory damage by an endothelin A receptor antagonist in a rat model of reversible acute liver failure
Amelioration of microcirculatory damage by an endothelin A receptor antagonist in a rat model of reversible acute liver failure
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DOI：
10.1016/j.jhep.2004.11.019
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发表时间：
2005-03-01
影响因子：
25.7
通讯作者：
Spiegel, HU
中科院分区：
文献类型：
--
作者：
Palmes, D;Skawran, S;Spiegel, HU
背景/目的：急性肝衰竭（ALF）中的肝细胞损伤因肝窦内壁细胞释放的促炎和细胞毒性介质而加剧。我们研究了选择性内皮素 A 受体 (ETAR) 拮抗剂在 ALF 情况下对微循环的潜在影响。方法：将 70 只 Wistar 大鼠分为五组：(I) 通过 70% 肝切除联合注射 400 μg/kg 内毒素诱导 ALF，(II) 用 ETAR 拮抗剂 LU 135252（1 mg/kg b.w. i.v.）治疗 ALF，(III)假手术，(IV)注射内毒素，(V)70%肝切除。通过活体显微镜测量肝脏微循环。通过组织学和免疫组织学研究实质损伤、生长分数、内皮素(ET)-1和ETAR。对存活率、肝功能和形态进行长达 14 天的随访。结果：诱导 ALF 后，观察到 100% 死亡率、肝功能受损、广泛的内皮病变、最高的 ET-1 和 ETAR 水平、灌注率降低、肝窦直径减小以及白细胞 - 内皮相互作用和肝窦血流量增加。 ETAR 拮抗剂治疗的大鼠表现出 ET-1 和 ETAR 水平降低，微循环功能、形态、肝功能得到改善，存活率达到 85%。结论：ALF 中微循环障碍与肝功能障碍相关。 ETAR 阻断代表了一种通过减少微循环病变及其后遗症来治疗 ALF 的新方法。 (c) 2004 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
Background/Aims: Hepatocellular damage in acute liver failure (ALF) is aggravated by proinflammatory and cytotoxic mediators released from sinusoidal-lining cells. We studied a selective endothelin A receptor (ETAR) antagonist for its potential influence on the microcirculation in the setting of ALF.Methods: Seventy Wistar rats were divided into five groups: (I) induction of ALF by a 70 % liver resection combined with injection of 400 mu g/kg endotoxin, (II) ALF treated with the ETAR antagonist LU 135252 (1 mg/kg b.w. i.v.), (III) sham operation, (IV) injection of endotoxin, (V) 70 % liver resection. Liver microcirculation was measured by intravital microscopy. Parenchymal injury, growth fractions, endothelin (ET)-1 and ETAR were studied by histology and immunohistology. Survival, liver function, and morphology were followed up to 14 days.Results: 100 % mortality, impaired liver function, widespread endothelial lesions, highest ET-1 and ETAR levels, a decreased perfusion rate, reduced sinusoidal diameter, as well as an increase in both leukocyte-endothelium interactions and sinusoidal blood flow were observed after induction of ALF. ETAR antagonist-treated rats showed decreased ET-1 and ETAR levels as well as improved microcirculatory function, morphology, liver function, and 85 % survival.Conclusions: Microcirculatory disturbances correlate with liver dysfunction in ALF. ETAR blockade represents a new therapeutic approach to ALF by reducing microcirculatory lesions and their sequelae. (c) 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.