Antifibrogenic role of the cannabinoid receptor CB2 in the liver
Antifibrogenic role of the cannabinoid receptor CB2 in the liver
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DOI：
10.1053/j.gastro.2004.12.050
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发表时间：
2005-03-01
期刊：
影响因子：
29.4
通讯作者：
Lotersztajn, S
中科院分区：
文献类型：
--
作者：
Julien, B;Grenard, P;Lotersztajn, S
背景和目标：肝肌成纤维细胞是慢性肝病相关的肝纤维化发展的核心，阻断它们的积累可以防止纤维化。大麻素是大麻的活性成分，通过2种G蛋白偶联受体CB 1和CB 2起作用。在这里，我们研究了肝纤维化细胞是否是大麻素的靶点。研究方法：CB 2受体的特点是在活检标本的正常人肝和活动性肝硬化的免疫组化，并在培养的肝星状细胞和肝肌成纤维细胞的逆转录聚合酶链反应（RT-PCR），免疫细胞化学，和GTP γ S测定。在培养的肝肌成纤维细胞和活化的肝星状细胞中进行功能研究。在CB 2受体失效的小鼠中研究了四氯化碳诱导的肝纤维化。结果如下：在各种病因的活动性肝硬化患者的肝活检标本中，CB 2受体表达于平滑肌α-肌动蛋白阳性细胞中位于纤维间隔内和纤维间隔边缘的非实质细胞中。相反，在正常人肝脏中未检测到CB 2受体。在培养的肝肌成纤维细胞和活化的肝星状细胞中也检测到CB 2受体。它们的激活触发了有效的抗纤维化作用，即生长抑制和细胞凋亡。生长抑制涉及环氧合酶-2，细胞凋亡导致氧化应激。最后，与野生型小鼠相比，CB 2受体无效的小鼠在慢性四氯化碳治疗后发生了增强的肝纤维化。结论：这些数据构成了第一个证明，CB 2受体是高度上调，主要是在肝纤维化细胞中的肝硬化的肝脏。此外，这项研究还强调了CB 2受体在慢性肝损伤中的抗纤维化作用。
Background & Aims: Hepatic myofibroblasts are central for the development of liver fibrosis associated with chronic liver diseases, and blocking their accumulation may prevent fibrogenesis. Cannabinoids are the active components of marijuana and act via 2 G-protein-coupled receptors, CB1 and CB2. Here, we investigated whether liver fibrogenic cells are a target of cannabinoids. Methods: CB2 receptors were characterized in biopsy specimens of normal human liver and active cirrhosis by immunohistochemistry, and in cultures of hepatic stellate cells and hepatic myofibroblasts by reverse-transcription polymerase chain reaction (RT-PCR), immunocytochemistry, and GTPgammaS assays. Functional studies were performed in cultured hepatic myofibroblasts and activated hepatic stellate cells. Carbon tetrachloride-induced liver fibrosis was studied in mice invalidated for CB2 receptors. Results: In liver biopsy specimens from patients with active cirrhosis of various etiologies, CB2 receptors were expressed in nonparenchymal cells located within and at the edge of fibrous septa in smooth muscle alpha-actin-positive cells. In contrast, CB2 receptors were not detected in normal human liver. CB2 receptors were also detected in cultured hepatic myofibroblasts and in activated hepatic stellate cells. Their activation triggered potent antifibrogenic effects, namely, growth inhibition and apoptosis. Growth inhibition involved cyclooxygenase-2, and apoptosis resulted from oxidative stress. Finally, mice invalidated for CB2 receptors developed enhanced liver fibrosis following chronic carbon tetrachloride treatment as compared with wild-type mice. Conclusions: These data constitute the first demonstration that CB2 receptors are highly up-regulated in the cirrhotic liver, predominantly in hepatic fibrogenic cells. Moreover, this study also highlights the antifibrogenic role of CB2 receptors during chronic liver injury.