Department of Clinical Medicine, Alma Mater Studiorum University of Bologna, Bologna, Italy.
Lab Invest. 2012 Mar;92(3):384-95. doi: 10.1038/labinvest.2011.191. Epub 2011 Dec 19.
The endocannabinoid system is involved in the pathogenesis of liver fibrosis. Although many substances have been proved to reduce fibrosis in experimental models of chronic liver injury, most of them appear to be effective only if given as a prophylactic or early treatment. This study aimed to explore the effect of pharmacological antagonism of the endocannabinoid cannabinoid type 1 (CB1) receptor started after the stage of full-blown cirrhosis had been reached. Wistar-Han rats with carbon tetrachloride (CCl(4))-induced cirrhosis were randomized to receive the CB1 receptor antagonist Rimonabant (10 mg/kg/day) or the vehicle for 2 weeks. Age-matched healthy rats served as controls. Liver fibrosis was assessed using Sirius red staining, hydroxyproline concentration and α-smooth muscle actin expression. Hepatic gene expression of mediators of fibrogenesis and inflammation were evaluated by real-time PCR. We also assessed the hepatic expression of CB1 and CB2 receptors and that of the enzymes implicated in the endocannabinoid metabolism. Fibrosis was significantly reduced in rats treated with Rimonabant compared with rats receiving the vehicle. CB1 receptor antagonism limited the gene upregulation of fibrogenic and inflammatory mediators occurring in untreated cirrhotic rats. CB1 and CB2 receptor expression was increased in cirrhotic animals. Interestingly, pharmacological CB1 receptor antagonism was associated with a further induction of the CB2 receptor expression. Regression of fibrosis can be achieved by pharmacological blockade of the CB1 receptor even when started in an advanced stage of the disease. This effect is associated with the suppression of pro-fibrogenic and inflammatory mediators and may have been indirectly favoured by the induction of CB2 receptor expression.
内源性大麻素系统参与肝纤维化的发病机制。虽然许多物质已被证明可减少慢性肝损伤实验模型中的纤维化，但大多数物质似乎仅在预防性或早期治疗时才有效。本研究旨在探讨在肝硬化阶段达到完全期后开始拮抗内源性大麻素大麻素 1 型（CB1）受体的药理学作用。用四氯化碳（CCl4）诱导肝硬化的 Wistar-Han 大鼠被随机分为接受 CB1 受体拮抗剂利莫那班（10mg/kg/天）或载体 2 周。年龄匹配的健康大鼠作为对照。通过天狼星红染色、羟脯氨酸浓度和α-平滑肌肌动蛋白表达评估肝纤维化。通过实时 PCR 评估纤维化形成和炎症的介质的肝基因表达。我们还评估了肝内 CB1 和 CB2 受体的表达以及内源性大麻素代谢中涉及的酶的表达。与接受载体的大鼠相比，接受利莫那班治疗的大鼠的纤维化明显减少。CB1 受体拮抗作用限制了未治疗的肝硬化大鼠中纤维生成和炎症介质的基因上调。CB1 和 CB2 受体在肝硬化动物中表达增加。有趣的是，即使在疾病的晚期开始，药理学 CB1 受体拮抗作用也与 CB2 受体表达的进一步诱导相关。即使在疾病的晚期开始，通过药理学阻断 CB1 受体也可以实现纤维化的消退。这种作用与抑制促纤维化和炎症介质有关，可能间接受到 CB2 受体表达的诱导。
