Pauta Montse, Ribera Jordi, Melgar-Lesmes Pedro, Casals Gregori, Rodríguez-Vita Juan, Reichenbach Vedrana, Fernandez-Varo Guillermo, Morales-Romero Blai, Bataller Ramon, Michelena Javier, Altamirano Jose, Jiménez Wladimiro, Morales-Ruiz Manuel
Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS) and CIBERehd, Barcelona, Spain.
Liver Int. 2015 Apr;35(4):1383-92. doi: 10.1111/liv.12505. Epub 2014 Mar 11.
BACKGROUND & AIMS: Studies in experimental models of cirrhosis showed that anti-angiogenic treatments may be effective for the treatment of liver fibrosis. In this context, angiopoietins are potential therapeutic targets as they are involved in the maintenance and stabilization of newly formed blood vessels. In addition, angiopoietin-2 is expressed in fibrotic livers and its inhibition in tumours results in vessel stability. Therefore, our study was aimed to assess the therapeutic utility of inhibiting angiopoietin-2.
Circulating levels of angiopoietin-1 and angiopoietin-2 were quantified by ELISA in CCl4 -treated rats and in patients with cirrhosis. In vivo blockade of angiopoietin-2 in rats with liver fibrosis was performed with a chemically programmed antibody, CVX-060.
High levels of angiopoietin-2 were found in the systemic and suprahepatic circulation of cirrhotic patients and the ratio angiopoietin-1/angiopoietin-2 inversely correlated with prognostic models for alcoholic liver disease. Chronic treatment of CCl4 -treated rats with CVX-060 was associated with a significant decrease in inflammatory infiltrate, normalization of the hepatic microvasculature and reduction in VCAM-1 vascular expression. The anti-angiopoietin-2 treatment was also associated with less liver fibrosis and with lower levels of circulating transaminases. CVX-060 treatment was not associated with either vascular pruning in healthy tissue or compensatory overexpression of VEGF.
Inhibition of angiopoietin-2 is an effective and safe treatment for liver fibrosis in CCl4 -treated rats, acting mainly through the induction of vessel normalization and the attenuation of hepatic inflammatory infiltrate. Therefore, inhibition of angiopoietin-2 offers a therapeutic alternative for liver fibrosis.
在肝硬化实验模型中的研究表明，抗血管生成治疗可能对肝纤维化的治疗有效。在此背景下，血管生成素是潜在的治疗靶点，因为它们参与新生血管的维持和稳定。此外，血管生成素-2在纤维化肝脏中表达，其在肿瘤中的抑制导致血管稳定。因此，我们的研究旨在评估抑制血管生成素-2的治疗效用。
通过ELISA定量四氯化碳处理的大鼠和肝硬化患者中血管生成素-1和血管生成素-2的循环水平。用化学编程抗体CVX-060对肝纤维化大鼠进行血管生成素-2的体内阻断。
在肝硬化患者的全身和肝上循环中发现高水平的血管生成素-2，血管生成素-1/血管生成素-2的比值与酒精性肝病的预后模型呈负相关。用CVX-060对四氯化碳处理的大鼠进行长期治疗与炎症浸润的显著减少、肝微血管系统的正常化以及VCAM-1血管表达的降低有关。抗血管生成素-2治疗还与较少的肝纤维化和较低的循环转氨酶水平有关。CVX-060治疗与健康组织中的血管修剪或VEGF的代偿性过表达均无关。
抑制血管生成素-2对四氯化碳处理的大鼠肝纤维化是一种有效且安全的治疗方法，主要通过诱导血管正常化和减轻肝脏炎症浸润起作用。因此，抑制血管生成素-2为肝纤维化提供了一种治疗选择。
