Pinzani M, Milani S, De Franco R, Grappone C, Caligiuri A, Gentilini A, Tosti-Guerra C, Maggi M, Failli P, Ruocco C, Gentilini P
Istituto di Medicina Interna-Centro Interuniversitario di Fisiopatologia Epatica, Florence, Italy.
Gastroenterology. 1996 Feb;110(2):534-48. doi: 10.1053/gast.1996.v110.pm8566602.
BACKGROUND & AIMS: Endothelin (ET) 1 could be involved in the regulation of hepatic microcirculation and in the development of portal hypertension. The expression and distribution of ET-1 in normal and cirrhotic liver tissue and its effects on hepatic stellate cells (HSCs), liver-specific pericytes, were investigated.
ET-1 expression in liver tissue was analyzed using in situ hybridization and immunohistochemistry. Secretion of ET-1 by HSC was evaluated by radioimmunoassay. Changes in intracellular Ca2+ concentration and cell contraction were studied using digital video imaging. Specific binding of ET-1 was evaluated using self- and cross-displacement curves.
ET-1 expression was markedly enhanced in cirrhotic liver tissue, where activated HSCs were shown to be major sites of ET-1 synthesis, as confirmed by studies performed on cultured human HSC. ET-1 exerted several biological actions on HSC, including mitogenicity, activation of mitogen-activated protein kinase, and a rapid increase in intracellular Ca2+ coupled with reversible cell contraction. All these effects appeared to be mediated by ETA receptors. Finally, the relative prevalence of ETA and ETB binding sites changed with the progressive phenotypical modulation of HSC.
ET-1 may act as a paracrine and autocrine factor for activated HSC and contribute to the increased resistance to portal flow in cirrhotic liver.
内皮素（ET）-1可能参与肝微循环的调节及门静脉高压的发生发展。本研究调查了ET-1在正常及肝硬化肝组织中的表达与分布及其对肝星状细胞（HSCs）即肝脏特异性周细胞的影响。
采用原位杂交和免疫组化分析肝组织中ET-1的表达。通过放射免疫分析法评估肝星状细胞分泌ET-1的情况。利用数字视频成像研究细胞内Ca2+浓度变化和细胞收缩情况。通过自身及交叉置换曲线评估ET-1的特异性结合。
肝硬化肝组织中ET-1表达显著增强，对培养的人肝星状细胞进行的研究证实，活化的肝星状细胞是ET-1合成的主要部位。ET-1对肝星状细胞发挥多种生物学作用，包括促有丝分裂、激活丝裂原活化蛋白激酶以及细胞内Ca2+迅速增加并伴有可逆性细胞收缩。所有这些作用似乎均由ETA受体介导。最后，ETA和ETB结合位点的相对比例随肝星状细胞表型的逐渐调节而变化。
ET-1可能作为活化肝星状细胞的旁分泌和自分泌因子，并有助于肝硬化肝脏门静脉血流阻力增加。
