Beneficial Effects of Sorafenib on Splanchnic, Intrahepatic, and Portocollateral Circulations in Portal Hypertensive and Cirrhotic Rats
Beneficial Effects of Sorafenib on Splanchnic, Intrahepatic, and Portocollateral Circulations in Portal Hypertensive and Cirrhotic Rats
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DOI：
10.1002/hep.22758
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发表时间：
2009-04-01
期刊：
影响因子：
13.5
通讯作者：
Fernandez, Mercedes
中科院分区：
文献类型：
--
作者：
Mejias, Marc;Garcia-Pras, Ester;Fernandez, Mercedes
门静脉高压症是肝硬变患者最重要的并发症，是一种严重的危及生命的疾病，治疗方案很少。由于血管生成是门静脉高压症的病理标志，本研究的目的是确定索拉非尼对两种不同门静脉高压症实验模型的内脏、肝内、全身和门体侧支循环的影响。索拉非尼是血管生成前血管内皮生长因子受体2(VEGFR-2)、血小板衍生生长因子受体β(PDGFR-β)和Raf激酶的有效抑制剂。这种全面的方法对于任何旨在确定新治疗剂的有效性和潜在临床应用的转化性研究都是必要的。在实验性门脉高压和肝硬变模型中，索拉非尼每天口服一次，连续两周，有效地抑制了血管内皮生长因子、PDGF和Raf信号通路，并通过诱导内脏新生血管减少约80%、高动力内脏和体循环显著减弱以及门体侧支循环显著减少18%而产生多种保护作用。在肝硬变大鼠中，索拉非尼治疗还导致门脉压力降低25%，并显著改善肝损伤和肝内纤维化、炎症和血管生成。值得注意的是，索拉非尼对组织损伤和炎症的有益作用也在内脏器官中观察到。结论：考虑到将动物研究结果转化为人类的局限性，我们相信我们的发现将促使人们考虑将索拉非尼作为一种有效的治疗晚期门静脉高压症患者的药物。(《肝病》2009；49：1245-1256。)
Portal hypertension, the most important complication in patients with cirrhosis of the liver, is a serious and life-threatening disease for which there are few therapeutic options. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of this study was to determine the effects of sorafenib-a potent inhibitor of proangiogenic vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFR-beta), and Raf kinases-on splanchnic, intrahepatic, systemic, and portosystemic collateral circulations in two different experimental models of portal hypertension: rats with prehepatic portal hypertension induced by partial portal vein ligation and rats with intrahepatic portal hypertension and secondary biliary cirrhosis induced by bile duct ligation. Such a comprehensive approach is necessary for any translational research directed toward defining the efficacy and potential clinical application of new therapeutic agents. Sorafenib administered orally once a day for 2 weeks in experimental models of portal hypertension and cirrhosis effectively inhibited VEGF, PDGF, and Raf signaling pathways, and produced several protective effects by inducing an approximately 80% decrease in splanchnic neovascularization and a marked attenuation of hyperdynamic splanchnic and systemic circulations, as well as a significant 18% decrease in the extent of portosystemic collaterals. In cirrhotic rats, sorafenib treatment also resulted in a 25% reduction in portal pressure, as well as a remarkable improvement in liver damage and intrahepatic fibrosis, inflammation, and angiogenesis. Notably, beneficial effects of sorafenib against tissue damage and inflammation were also observed in splanchnic organs. Conclusion: Taking into account the limitations of translating animal study results into humans, we believe that our findings will stimulate consideration of sorafenib as an effective therapeutic agent in patients suffering from advanced portal hypertension. (HEPATOLOGY 2009;49:1245-1256.)