Wang Qi, Dai Xuefei, Yang Wanzhi, Wang He, Zhao Han, Yang Feng, Yang Yan, Li Jun, Lv Xiongwen
School of Pharmacy, Anhui Medical University, Mei Shan Road, Hefei, Anhui Province, 230032, China; Institute for Liver Disease of Anhui Medical University, Mei Shan Road, Hefei, Anhui Province, 230032, China.
The Fourth Affiliated Hospital of Anhui Medical University, Tun Xi Road, Hefei, Anhui Province, 230000, China.
Int Immunopharmacol. 2015 Apr;25(2):340-52. doi: 10.1016/j.intimp.2015.02.012. Epub 2015 Feb 18.
Alcoholic liver fibrosis (ALF) is characterized by hyperplasia of extracellular matrix under long-term alcohol stimulation. Hepatic stellate cell (HSC) activation plays an important role in promoting hepatic fibrogenesis. Caffeine, as the main active component of coffee and tea, was widely consumed in daily life. It was always a thought that caffeine can reduce the probability of suffering from liver diseases. In this study, we attempt to validate the hypothesis that caffeine inhibits activation of HSCs which were isolated from rat ALF model. The rats were gavaged by ethanol to establish ALF model and then treated with different concentrations of caffeine or colchicine. Serum was collected to measure the contents of serum alanine aminotransferase (ALT), aspartate transaminase (AST), hyaluronic acid (HA), laminin (LN), N-terminal peptide of type III procollagen (PIIINP) and type IV collagen (CIV). Then liver tissues were obtained for hematoxylin-eosin staining and Sirius-red staining. Others were treated through liver perfusion to isolate primary rat HSCs. Interestingly, we found that caffeine significantly decreased ALT, AST, HA, LN, PIIINP and CIV levels and reversed liver fibrosis in rat ALF models. Results of immunohistochemistry, real-time PCR and western blot indicated that caffeine could reduce fibrosis and inhibit cAMP/PKA/CREB signal pathway in HSC. Caffeine has a preventive effect on ALF. The mechanism may be interpreted that caffeine inhibits the cAMP/PKA/CREB signal pathway through adenosine A2A receptors in HSC.
酒精性肝纤维化（ALF）的特征是在长期酒精刺激下细胞外基质增生。肝星状细胞（HSC）的激活在促进肝纤维化过程中起重要作用。咖啡因作为咖啡和茶的主要活性成分，在日常生活中被广泛饮用。一直以来人们认为咖啡因可以降低患肝病的几率。在本研究中，我们试图验证咖啡因抑制从大鼠ALF模型分离出的HSCs激活这一假设。通过给大鼠灌胃乙醇建立ALF模型，然后用不同浓度的咖啡因或秋水仙碱进行处理。收集血清以测量血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、透明质酸（HA）、层粘连蛋白（LN）、III型前胶原N端肽（PIIINP）和IV型胶原（CIV）的含量。然后获取肝组织进行苏木精-伊红染色和天狼星红染色。其他样本通过肝脏灌注处理以分离原代大鼠HSCs。有趣的是，我们发现咖啡因显著降低了大鼠ALF模型中ALT、AST、HA、LN、PIIINP和CIV的水平，并逆转了肝纤维化。免疫组织化学、实时PCR和蛋白质印迹结果表明，咖啡因可减少纤维化并抑制HSC中的cAMP/PKA/CREB信号通路。咖啡因对ALF有预防作用。其机制可能是咖啡因通过HSC中的腺苷A2A受体抑制cAMP/PKA/CREB信号通路。
