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

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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.