PORTAL HYPERTENSION-ELUCIDATION OF THE MECHANISM IN THE LIGHT OF FUNCTIONAL ABNORMALITIES OF HEPATIC STELLATE CELLS AND DEVELOPMENT OF THERAPEUTIC STRATEGY

肝星状细胞(HSI)的收缩和移动被认为直接影响门脉血压。探讨新型脂质介质1-磷酸鞘氨醇(S1P)和溶血磷脂酸(LPA)对体外培养的大鼠肝星状细胞功能的影响及其在门静脉高压症中的作用。(1)S1P和LPA通过激活Rho和Rho激酶激活HSCs的收缩。(2)LPA还可通过激活Rho和Rho激酶来刺激HSCs的流动性。(3)在S1P受体中，肝星状细胞表达Edg1和Edg5。在HSCs中检测到Edg1和Edg7。在肝纤维化的过程中，Edg7mRNA的表达降低。(5)在大鼠肝脏门脉灌流系统液中加入S1P或LPA可引起门脉压力升高。在特异性抑制剂Y-27632或Rho激酶的存在下，这种作用被取消。我们的结果表明，S1P和LPA通过激活Rho和Rho激酶而使门脉血压升高。这些脂质介质可能参与了门静脉高压症的发病机制。

Contractility and mobility of hepatic stellate cells (HSIs) are considered to directly affect portal blood pressure. Effects of sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA), novel lipid mediators, on these cell functions of cultured rat HSCs and roles of these mediators in portal hypertension were investigated. (1) S1P and LPA stimulated contractility of HSCs by activation of Rho and Rho kinase. (2) LPA stimulated mobility of HSCs also by activation of Rho and Rho kinase. (3) Among S1P receptors, mRNA expressions of Edg1 and Edg5 were detected in HSCs. Edg1 and Edg7 were determined in HSCs. Edg7 mRNA expression was decreased in the process or hepatic fibrosis. (5) Addition of S1P or LPA in the solution of the portal perfusion system in the rat liver caused the enhancement of portal pressure. The effect was cancelled in the presence of Y-27632, a specific inhibitor or Rho kinase. Our results indicate that S1P and LPA enhance portal blood pressure by activation of Rho and Rho kinase. These lipid mediators may be involved in the pathogenesis of portal hypertension.