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首页> 外文期刊>American Journal of Physiology >Xu, Q.a , Nakayama, M.a , Suzuki, Y.a , Sakai, K.a , Nakamura, T.a , Sakai, Y.b , Matsumoto, K.a Suppression of acute hepatic injury by a synthetic prostacyclin agonist through hepatocyte growth factor expression
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Xu, Q.a , Nakayama, M.a , Suzuki, Y.a , Sakai, K.a , Nakamura, T.a , Sakai, Y.b , Matsumoto, K.a Suppression of acute hepatic injury by a synthetic prostacyclin agonist through hepatocyte growth factor expression

机译：Xu，Q.a，Nakayama，M.a，Suzuki，Y.a，Sakai，K.a，Nakamura，T.a，Sakai，Y.b，Matsumoto，K.a通过肝细胞生长因子表达抑制合成前列环素激动剂对急性肝损伤的作用

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Previous studies have demonstrated that mice disrupted with the cyclooxygenase-2 gene showed much more severe liver damage compared with wild-type mice after liver injury, and prostaglandins (PGs) such as PGE 1/2 and PGI 2 have decreased hepatic injury, but the mechanisms by which prostaglandins exhibit protective action on the liver have yet to be addressed. In the present study, we investigated the mechanism of the protective action of PGI 2 using the synthetic IP receptor agonist ONO-1301. In primary cultures of hepatocytes and nonparenchymal liver cells, ONO-1301 did not show protective action directly on hepatocytes, whereas it stimulated expression of hepatocyte growth factor (HGF) in nonparenchymal liver cells. In mice, peroral administration of ONO-1301 increased hepatic gene expression and protein levels of HGF. Injections of CCl4 induced acute liver injury in mice, but the onset of acute liver injury was strongly suppressed by administration of ONO-1301. The increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) by CCl4 were suppressed by 10 mg/kg ONO-1301 to 39.4 and 33.6%, respectively. When neutralizing antibody against HGF was administered with ONO-1301 and CCl4, the decreases by ONO-1301 in serum ALT and AST, apoptotic liver cells, and expansion of necrotic areas in liver tissue were strongly reversed by neutralization of endogenous HGF. These results indicate that ONO-1301 increases expression of HGF and that hepatoprotective action of ONO-1301 in CCl4-induced liver injury may be attributable to its activity to induce expression of HGF, at least in part. The potential for involvement of HGF-Met-mediated signaling in the hepatotrophic action of endogenous prostaglandins generated by injury-dependent cyclooxygenase-2 induction is considerable.
机译：先前的研究表明，在肝损伤后，被环氧合酶2基因破坏的小鼠与野生型小鼠相比，肝脏损伤更为严重，而前列腺素（PGs）（例如PGE 1/2和PGI 2）减轻了肝损伤，但是前列腺素对肝脏表现出保护作用的机制尚待研究。在本研究中，我们使用合成的IP受体激动剂ONO-1301研究了PGI 2的保护作用机理。在肝细胞和非实质肝细胞的原代培养中，ONO-1301并未直接对肝细胞表现出保护作用，而刺激了非实质肝细胞中肝细胞生长因子（HGF）的表达。在小鼠中，口服ONO-1301可增加肝基因表达和HGF蛋白水平。注射CCl4会诱发小鼠急性肝损伤，但是通过施用ONO-1301可以强烈抑制急性肝损伤的发作。 CCl4引起的血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）的增加分别被10 mg / kg ONO-1301抑制至39.4和33.6％。当将抗HGF的中和抗体与ONO-1301和CCl4一起使用时，中和内源性HGF可以强烈逆转ONO-1301降低血清ALT和AST，凋亡肝细胞和肝脏组织坏死区域的能力。这些结果表明ONO-1301增加了HGF的表达，并且ONO-1301在CCl4诱导的肝损伤中的肝保护作用可能归因于其至少部分地诱导HGF表达的活性。 HGF-Met介导的信号传导参与由损伤依赖性环氧合酶2诱导产生的内源性前列腺素的肝营养作用的潜力很大。

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