Teixeira-Clerc Fatima, Julien Boris, Grenard Pascale, Tran Van Nhieu Jeanne, Deveaux Vanessa, Li Liying, Serriere-Lanneau Valérie, Ledent Catherine, Mallat Ariane, Lotersztajn Sophie
INSERM, Unité 581, Hôpital Henri Mondor Créteil, F-9400 France.
Nat Med. 2006 Jun;12(6):671-6. doi: 10.1038/nm1421. Epub 2006 May 21.
Hepatic fibrosis, the common response associated with chronic liver diseases, ultimately leads to cirrhosis, a major public health problem worldwide. We recently showed that activation of hepatic cannabinoid CB2 receptors limits progression of experimental liver fibrosis. We also found that during the course of chronic hepatitis C, daily cannabis use is an independent predictor of fibrosis progression. Overall, these results suggest that endocannabinoids may drive both CB2-mediated antifibrogenic effects and CB2-independent profibrogenic effects. Here we investigated whether activation of cannabinoid CB1 receptors (encoded by Cnr1) promotes progression of fibrosis. CB1 receptors were highly induced in human cirrhotic samples and in liver fibrogenic cells. Treatment with the CB1 receptor antagonist SR141716A decreased the wound-healing response to acute liver injury and inhibited progression of fibrosis in three models of chronic liver injury. We saw similar changes in Cnr1-/- mice as compared to wild-type mice. Genetic or pharmacological inactivation of CB1 receptors decreased fibrogenesis by lowering hepatic transforming growth factor (TGF)-beta1 and reducing accumulation of fibrogenic cells in the liver after apoptosis and growth inhibition of hepatic myofibroblasts. In conclusion, our study shows that CB1 receptor antagonists hold promise for the treatment of liver fibrosis.
肝纤维化是与慢性肝病相关的常见反应，最终会导致肝硬化，这是一个全球性的重大公共卫生问题。我们最近发现，肝大麻素CB2受体的激活可限制实验性肝纤维化的进展。我们还发现，在慢性丙型肝炎病程中，每日使用大麻是纤维化进展的独立预测因素。总体而言，这些结果表明内源性大麻素可能既驱动CB2介导的抗纤维化作用，也驱动不依赖CB2的促纤维化作用。在此，我们研究了大麻素CB1受体（由Cnr1编码）的激活是否会促进纤维化进展。CB1受体在人类肝硬化样本和肝纤维化细胞中高度诱导表达。用CB1受体拮抗剂SR141716A治疗可降低对急性肝损伤的伤口愈合反应，并在三种慢性肝损伤模型中抑制纤维化进展。与野生型小鼠相比，我们在Cnr1-/-小鼠中也观察到了类似的变化。CB1受体的基因或药理学失活通过降低肝转化生长因子（TGF）-β1以及在肝肌成纤维细胞凋亡和生长抑制后减少肝脏中纤维化细胞的积累，从而减少纤维化形成。总之，我们的研究表明CB1受体拮抗剂有望用于治疗肝纤维化。
