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

门静脉高压——肝星状细胞功能异常的机制阐明及治疗策略的制定

• 批准号: 12670461
• 负责人: IKEDA Hitoshi
• 金额: $ 2.18万
• 依托单位: THE UNIVERSITY OF TOKYO
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670461/
• 关键词: PORTAL HYPERTENSION; HEPATIC STELLATE CELLS; SPHINGOSINE 1-PHOSPHATE; LYSOPHOSPHATIDIC ACID; スフィンゴシンコリン酸

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.

肝星状细胞（HSI）的收缩性和运动性被认为直接影响门静脉血压。研究新型脂质介质1-磷酸鞘氨醇（S1 P）和溶血磷脂酸（LPA）对培养的大鼠肝星状细胞上述功能的影响及其在门脉高压中的作用。(1)S1 P和LPA通过激活Rho和Rho激酶促进HSC的收缩。(2)LPA还通过激活Rho和Rho激酶促进HSC的迁移。(3)S1 P受体中Edg 1和Edg 5的mRNA在HSC中表达。在HSC中测定Edg 1和Edg 7。Edg 7 mRNA表达在肝纤维化过程中呈下降趋势。(5)在大鼠肝脏门脉灌注系统溶液中加入S1 P或LPA可引起门脉压力的增加。在Y-27632（一种特异性抑制剂或Rho激酶）的存在下，该作用被取消。我们的研究结果表明，S1 P和LPA通过激活Rho和Rho激酶提高门静脉血压。这些脂质介质可能参与了门静脉高压症的发病过程。

项目成果

Yanase M: "Lysophosphatidic acid enhances collagen gel contraction by hepatic stellate cells : Association with Rho-kinase"Biochem. Biophys Res Commun. 277. 72-78 (2000)

Yanase M：“溶血磷脂酸增强肝星状细胞的胶原蛋白凝胶收缩：与 Rho 激酶的关联”Biochem。

Yanase M: "Involvement of Ryo-kinase in lysophosphatic acid-induced migration of hepatic stellate cells"Cells of the Hepatic Sinusoid. 8. 266-268 (2001)

Yanase M：“Ryo 激酶参与溶血磷酸诱导的肝星状细胞迁移”肝窦细胞。

Ikeda H: "Biological activities of a novel lipid mediator sphingosine 1-phosphate, in rat hepatic stellate cells"Am. J. Physiol. 279. G304-G310 (2000)

Ikeda H：“新型脂质介质 1-磷酸鞘氨醇在大鼠肝星状细胞中的生物活性”Am。

Yanase M.: "Involvement of Rho-kinase in lysophosphatic acid-induced migration of hepatic stellate cells"Cells of the Hepatic Sinusoid. 8. 266-268 (2001)

Yanase M.：“Rho 激酶参与溶血磷酸诱导的肝星状细胞迁移”肝窦细胞。

Ikeda H.: "Biological activities of novel lipid mediator, sphingosine 1-phosphate, in rat hepatic stellate cells"Am. J. Physiol.. 279. G304-G310 (2000)

Ikeda H.：“新型脂质介质 1-磷酸鞘氨醇在大鼠肝星状细胞中的生物活性”Am。