Dibba Pratima, Li Andrew A, Cholankeril George, Iqbal Umair, Gadiparthi Chiranjeevi, Khan Muhammad Ali, Kim Donghee, Ahmed Aijaz
Division of Gastroenterology, Women and Infants Hospital/Warren Alpert School of Medicine, Brown University, Providence, RI 02905, USA.
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94304, USA.
Medicines (Basel). 2018 Jun 9;5(2):52. doi: 10.3390/medicines5020052.
Although the mortality rates of cirrhosis are underestimated, its socioeconomic burden has demonstrated a significant global impact. Cirrhosis is defined by the disruption of normal liver architecture after years of chronic insult by different etiologies. Treatment modalities are recommended primarily in decompensated cirrhosis and specifically tailored to the different manifestations of hepatic decompensation. Antifibrogenic therapies are within an active area of investigation. The endocannabinoid system has been shown to play a role in liver disease, and cirrhosis specifically, with intriguing possible therapeutic benefits. The endocannabinoid system comprises cannabinoid receptors 1 (CB1) and cannabinoid receptor 2 (CB2) and their ligands, endocannabinoids and exocannabinoids. CB1 activation enhances fibrogenesis, whereas CB2 activation counteracts progression to fibrosis. Conversely, deletion of CB1 is associated with an improvement of hepatic fibrosis and steatosis, and deletion of CB2 results in increased collagen deposition, steatosis, and enhanced inflammation. CB1 antagonism has also demonstrated vascular effects in patients with cirrhosis, causing an increase in arterial pressure and vascular resistance as well as a decrease in mesenteric blood flow and portal pressure, thereby preventing ascites. In mice with hepatic encephalopathy, CB1 blockade and activation of CB2 demonstrated improved neurologic score and cognitive function. Endocannabinoids, themselves also have mechanistic roles in cirrhosis. Arachidonoyl ethanolamide (AEA) exhibits antifibrogenic properties by inhibition of HSC proliferation and induction of necrotic death. AEA induces mesenteric vasodilation and hypotension via CB1 induction. 2-arachidonoyl glycerol (2-AG) is a fibrogenic mediator independent of CB receptors, but in higher doses induces apoptosis of HSCs, which may actually show antifibrotic properties. 2-AG has also demonstrated growth-inhibitory and cytotoxic effects. The exocannabinoid, THC, suppresses proliferation of hepatic myofibroblasts and stellate cells and induces apoptosis, which may reveal antifibrotic and hepatoprotective mechanisms. Thus, several components of the endocannabinoid system have therapeutic potential in cirrhosis.
尽管肝硬化的死亡率被低估，但其社会经济负担已在全球产生重大影响。肝硬化是由不同病因多年慢性损伤后正常肝脏结构破坏所定义的。治疗方法主要推荐用于失代偿期肝硬化，并针对肝失代偿的不同表现进行专门调整。抗纤维化疗法是一个活跃的研究领域。内源性大麻素系统已被证明在肝脏疾病中发挥作用，尤其是在肝硬化中，可能具有引人关注的治疗益处。内源性大麻素系统由大麻素受体1（CB1）和大麻素受体2（CB2）及其配体、内源性大麻素和外源性大麻素组成。CB1激活会增强纤维化形成，而CB2激活则会抵消纤维化进展。相反，CB1缺失与肝纤维化和脂肪变性的改善相关，而CB2缺失则导致胶原沉积增加、脂肪变性和炎症增强。CB1拮抗作用在肝硬化患者中也显示出血管效应，导致动脉压和血管阻力增加，肠系膜血流和门静脉压力降低，从而预防腹水。在患有肝性脑病的小鼠中，CB1阻断和CB2激活显示神经评分和认知功能得到改善。内源性大麻素自身在肝硬化中也具有机制性作用。花生四烯酸乙醇酰胺（AEA）通过抑制肝星状细胞增殖和诱导坏死性死亡表现出抗纤维化特性。AEA通过诱导CB1引起肠系膜血管舒张和低血压。2-花生四烯酸甘油（2-AG）是一种独立于CB受体的纤维化介质，但在高剂量时会诱导肝星状细胞凋亡，这实际上可能显示出抗纤维化特性。2-AG还显示出生长抑制和细胞毒性作用。外源性大麻素四氢大麻酚（THC）抑制肝肌成纤维细胞和星状细胞的增殖并诱导凋亡，这可能揭示抗纤维化和肝保护机制。因此，内源性大麻素系统的几个组成部分在肝硬化中具有治疗潜力。
