Rho-kinase inhibitor prevents hepatocyte damage in acute liver injury induced by carbon tetrachloride in rats
Rho-kinase inhibitor prevents hepatocyte damage in acute liver injury induced by carbon tetrachloride in rats
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DOI：
10.1152/ajpgi.00210.2007
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发表时间：
2007-10-01
影响因子：
4.5
通讯作者：
Yatomi, Yutaka
中科院分区：
文献类型：
--
作者：
Ikeda, Hitoshi;Kume, Yukio;Yatomi, Yutaka
rho激酶抑制剂对四氯化碳急性肝损伤大鼠肝细胞损伤的保护作用。[J] .中国生物医学工程学报，2009,31(2):389 - 391。首次发表于2007年8月30日；doi: 10.1152 / ajpgi.00210.2007。rho激酶抑制剂对各种器官损伤的保护作用正在引起人们的关注。在肝损伤方面，rho激酶抑制剂有报道可预防四氯化碳（CCl4）或二甲基亚硝胺引起的大鼠肝纤维化和肝缺血再灌注损伤。由于rho激酶抑制剂不仅可以改善肝纤维化，还可以降低ccl4诱导的肝纤维化的血清丙氨酸转氨酶（ALT）水平，我们想知道rho激酶抑制剂是否可能发挥直接的肝细胞保护作用。我们在大鼠急性CCl4中毒中检验了这种可能性。rho激酶抑制剂HA-1077可降低CCl4急性肝损伤大鼠血清丙氨酸ALT水平，改善肝组织损伤，减少凋亡细胞数量。在无血清条件下培养的大鼠肝细胞中，HA-1077通过定量测定细胞质组蛋白相关DNA寡核体片段，通过降低caspase-3活性和增强Bcl-2表达来减少细胞凋亡。HA-1077刺激Akt磷酸化，而磷脂酰肌醇3-激酶（pi3 -激酶）/Akt通路抑制剂wortmannin在体外消除了HA-1077对肝细胞凋亡的抑制作用。此外，wortmannin消除了HA-1077对CCl4急性肝损伤大鼠血清ALT水平的降低，提示体内rho激酶抑制剂对肝细胞的保护作用可能与pi3 -激酶/Akt通路的激活有关。综上所述，rho激酶抑制剂在体外对肝细胞有直接的抗凋亡作用，可预防CCl4诱导的大鼠急性肝损伤中肝细胞的损伤，值得考虑作为肝细胞保护剂。
Rho-kinase inhibitor prevents hepatocyte damage in acute liver injury induced by carbon tetrachloride in rats. Am J Physiol Gastrointest Liver Physiol 293: G911-G917, 2007. First published August 30, 2007; doi:10.1152/ajpgi.00210.2007. - A protective effect of Rho-kinase inhibitor on various organ injuries is gaining attention. Regarding liver injury, Rho-kinase inhibitor is reported to prevent carbon tetrachloride ( CCl4)- or dimethylnitrosamine-induced liver fibrosis and hepatic ischemia-reperfusion injury in rats. Because Rho-kinase inhibitor not only improved liver fibrosis but also reduced serum alanine aminotransferase ( ALT) level in CCl4-induced liver fibrosis, we wondered whether Rho-kinase inhibitor might exert a direct hepatocyte-protective effect. We examined this possibility in acute CCl4 intoxication in rats. Rho-kinase inhibitor, HA-1077, reduced serum alanine ALT level in rats with acute liver injury induced by CCl4 with the improvement of histological damage and the reduction of the number of apoptotic cells. In cultured rat hepatocytes in serum-free condition, HA-1077 reduced apoptosis evaluated by quantitative determination of cytoplasmic histone-associated DNA oligonucleosome fragments with the reduction of caspase-3 activity and the enhancement of Bcl-2 expression. HA-1077 stimulated phosphorylation of Akt, and wortmannin, an inhibitor of phosphatidylinositol 3-kinase ( PI3-kinase)/Akt pathway, abrogated the reduction of hepatocyte apoptosis by HA-1077 in vitro. Furthermore, wortmannin abrogated the reduction of serum ALT level by HA-1077 in rats with acute liver injury induced by CCl4, suggesting that the activation of PI3-kinase/Akt pathway may be involved in the hepatocyte-protective effect by Rho-kinase inhibitor in vivo. In conclusion, Rho-kinase inhibitor prevented hepatocyte damage in acute liver injury induced by CCl4 in rats and merits consideration as a hepatocyte-protective agent in liver injury, considering its direct antiapoptotic effect on hepatocytes in vitro.