Yoshiji Hitoshi, Kuriyama Shigeki, Fukui Hiroshi
Third Department of Internal Medicine, Nara Medical University, Nara, Japan.
J Gastroenterol Hepatol. 2007 Jun;22 Suppl 1:S93-5. doi: 10.1111/j.1440-1746.2006.04663.x.
Recent studies have shown that the renin-angiotensin system (RAS) plays a pivotal role in liver fibrosis. An intrahepatic RAS is expressed in chronically damaged livers, and angiotensin-II (AT-II) reportedly stimulates contraction and proliferation of the activated hepatic stellate cells (Ac-HSC), and increases the transforming growth factor-beta (TGF-beta) expression through angiotensin type-I receptors (AT1-R). Some studies have demonstrated that the clinically used angiotensin-converting enzyme (ACE) inhibitor (ACE-I), and AT1-R blockers (ARB) significantly attenuated experimental liver fibrosis along with suppression of the Ac-HSC and hepatic TGF-beta expression. Angiotensin-II also stimulates the tissue inhibitor of metalloproteinases-1 (TIMP-1) in a dose- and time-dependent manner via protein kinase-C as an intracellular signaling cascade in the Ac-HSC, and these effects are completely suppressed by ARB. Combination treatment with low-dose interferon (IFN) and ACE-I exerts a stronger inhibitory effect than either single agent on its own. In humans it has been reported that ARB markedly improved the liver fibrosis score and TGF-beta expression in patients with chronic hepatitis C and non-alcoholic steatohepatitis. Serum fibrosis markers also significantly improved by treatment with low-dose IFN and ACE-I in patients with chronic hepatitis C, refractory to IFN monotherapy. Collectively, these data suggest that the interaction between AT-II and AT1-R plays a pivotal role in liver fibrosis development. Because both ACE-I and ARB are widely used in clinical practice without serious side-effects, these drugs in combination with IFN may provide a new strategy for antifibrosis therapy.
最近的研究表明，肾素-血管紧张素系统（RAS）在肝纤维化中起关键作用。肝内RAS在慢性损伤的肝脏中表达，据报道血管紧张素-II（AT-II）可刺激活化的肝星状细胞（Ac-HSC）收缩和增殖，并通过血管紧张素I型受体（AT1-R）增加转化生长因子-β（TGF-β）的表达。一些研究表明，临床使用的血管紧张素转换酶（ACE）抑制剂（ACE-I）和AT1-R阻滞剂（ARB）可显著减轻实验性肝纤维化，同时抑制Ac-HSC和肝脏TGF-β的表达。血管紧张素-II还通过蛋白激酶-C作为Ac-HSC中的细胞内信号级联反应，以剂量和时间依赖性方式刺激金属蛋白酶组织抑制剂-1（TIMP-1），而这些作用被ARB完全抑制。低剂量干扰素（IFN）和ACE-I联合治疗比单独使用任何一种药物都具有更强的抑制作用。在人类中，据报道ARB可显著改善慢性丙型肝炎和非酒精性脂肪性肝炎患者的肝纤维化评分和TGF-β表达。在对IFN单一疗法难治的慢性丙型肝炎患者中，低剂量IFN和ACE-I治疗也可显著改善血清纤维化标志物。总体而言，这些数据表明AT-II与AT1-R之间的相互作用在肝纤维化发展中起关键作用。由于ACE-I和ARB在临床实践中广泛使用且无严重副作用，这些药物与IFN联合使用可能为抗纤维化治疗提供新策略。
