Research advances in signaling pathways involved in the development of hepatic fibrosis
-
摘要: 肝纤维化是肝脏对各种慢性肝损伤进行自我修复的一种病理过程,最终进展为肝硬化、肝衰竭,甚至肝癌。如何早期干预和治疗肝纤维化显得尤为重要。总结了TGFβ/Smad信号通路、Notch信号通路、Wnt信号通路、Hedgehog信号通路及整合素信号通路在肝纤维化发生机制中的最新研究进展,指出各信号通路在肝纤维化的发生发展中发挥极其重要的作用,有望为肝纤维化的治疗提供新的方向。Abstract: Liver fibrosis is a pathological process for the liver to repair various chronic liver injuries and may eventually progress to liver cirrhosis, liver failure, or even liver cancer.Therefore, early intervention and treatment of liver fibrosis is of particular importance.This article summarizes the latest research advances in the roles of TGF-β/Smad signaling pathway, Notch signaling pathway, Wnt signaling pathway, Hedgehog signaling pathway, and integrin signaling pathway in the pathogenesis of liver fibrosis and points out that these signaling pathways play an extremely important role in the development and progression of liver fibrosis and may provide new directions for the treatment of liver fibrosis
-
Key words:
- liver cirrhosis /
- signal transduction /
- hepatic stellate cells /
- review
-
[1]YANG Y, KIM B, PARK YK, et al.Astaxanthin prevents TGFβ1-induced pro-fibrogenic gene expression by inhibiting Smad3 activation in hepatic stellate cells[J].Biochim Biophys Acta, 2015, 1850 (1) :187-185. [2]CAO Y, XIA YZ, CHEN J, et al.Anti-fibrosis effects of deoxyschizandrin in human hepatic stellate cells[J].Chin J Clin Pharmacol Ther, 2016, 21 (8) :878-883. (in Chinese) 曹媛, 夏延哲, 陈杰, 等.五味子甲素在人肝星状细胞中的抗纤维化作用[J].中国临床药理学与治疗学, 2016, 21 (8) :878-883. [3]BATALLER R, BRENNER DA.Liver fibrosis[J].J Clin Invest, 2005, 115 (2) :209-218. [4] LUO SZ, LI ZH, XU MY, et al.Reversal of liver fibrosis through AG490 inhibition of the TGFβ1-STAT3 pathway[J].Chin J Hepatol, 2015, 23 (12) :939-943. (in Chinese) 罗声政, 李郑红, 徐铭益, 等.AG490抑制转化生长因子β1-STAT3信号通路逆转肝纤维化的机制研究[J].中华肝脏病杂志, 2015, 23 (12) :939-943. [5]ZHOU XL, YU SP.Role of Wnt signaling pathway in progression of liver cirrhosis[J].J Clin Hepatol, 2015, 31 (9) :1540-1542. (in Chinese) 周雪玲, 余水平.Wnt信号通路对肝硬化进展的影响[J].临床肝胆病杂志, 2015, 31 (9) :1540-1542. [6]REN CZ, HAO LS.Signal transduction involved in activation of hepatic stellate cells[J].J Clin Hepatol, 2015, 31 (3) :452-456. (in Chinese) 任昌镇, 郝礼森.肝星状细胞活化过程中的信号转导[J].临床肝胆病杂志, 2015, 31 (3) :452-456. [7]FABREGAT I, MORENO-CACERES J, SANCHEZ A, et al.TGF-βsignalling and liver disease[J].FEBS J, 2016, 283 (12) :2219-2232. [8] MASSAGUE J.TGFβsignalling in context[J].Nat Rev Mol Cell Biol, 2012, 13 (10) :616-630. [9]HANYU A, ISHIDOU Y, EBISAWA T, et al.The N domain of Smad7 is essential for specific inhibition of transforming growth factor-beta signaling[J].J Cell Biol, 2001, 155 (6) :1017-1027. [10]DOOLEY S, HAMZAVI J, BREIKOPF K, et al.Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats[J].Gastroenterology, 2003, 125 (1) :178-191. [11]SCHULTZE-MOSGAU S, BLAESE MA, GRABENBAUER G, et al.Smad-3 and Smad-7 expression following anti-transforming growth factor beta 1 (TGFbeta1) -treatment in irradiated rat tissue[J].Radiother Oncol, 2004, 70 (3) :249-259. [12]BALTA C, HERMAN H, BOLDURA OM, et al.Chrysin attenuates liver fibrosis and hepatic stellate cell activation through TGF-β/Smad signaling pathway[J].Chem Biol Interact, 2015, 240:94-101. [13]ARGENTOU N, GERMANIDIS G, HYTIROGLOU P, et al.TGF-βsignaling is activated in patients with chronic HBV infection and repressed by SMAD7 overexpression after successful antiviral treatment[J].Inflamm Res, 2016, 65 (5) :355-365. [14]GEISLER F, STRAZZABOSCO M.Emerging roles of Notch signaling in liver disease[J].Hepatology, 2015, 61 (1) :382-392. [15]CHEN Y, ZHENG S, Qi D, et al.Inhibition of Notch signaling by aγ-secretase inhibitor attenuates hepatic fibrosis in rats[J].PLo SOne, 2012, 7 (10) :e46512. [16]ZHANG X, DU G, XU Y, et al.Inhibition of notch signaling pathway prevents cholestatic liver fibrosis by decreasing the differentiation of hepatic progenitor cells into cholangiocytes[J].Lab Invest, 2016, 96 (3) :350-360. [17]TANRIVERDI G, KAYA-DAGISTANLI F, AYLA S, et al.Resveratrol can prevent CCl 4-induced liver injury by inhibiting Notch signaling pathway[J].Histol Histopathol, 2016, 31 (7) :769-784. [18]CHEN YX, WENG ZH, QI D, et al.Effect of Notch signaling on the activation of hepatic stellate cells[J].Chin J Hepatol, 2012, 20 (9) :677-682. (in Chinese) 陈毅雄, 翁志宏, 祁丹, 等.调控Notch信号对肝星状细胞活化的影响[J].中华肝脏病杂志, 2012, 20 (9) :677-682. [19]ZHANG QD, XU MY, CAI XB, et al.Myofibroblastic transformation of rat hepatic stellate cells:the role of Notch signaling and epithelial-mesenchymal transition regulation[J].Eur Rev Med Pharmacol Sci, 2015, 19 (21) :4130-4138. [20]BANSAL R, BAARLEN JV, STORM G, et al.The interplay of the Notch signaling in hepatic stellate cells and macrophages determines the fate of liver fibrogenesis[J].Sci Rep, 2015, 5:18272. [21]THOMPSON MD, MONGA SP.WNT/beta-catenin signaling in liver health and disease[J].Hepatology, 2007, 45 (5) :1298-1305. [22]CHENG JH, SHE H, HAN YP, et al.Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis[J].Am J Physiol Gastrointest Liver Physiol, 2008, 294 (1) :g39-g49. [23]LIN X, KONG LN, HUANG C, et al.Hesperetin derivative-7 inhibits PDGF-BB-induced hepatic stellate cell activation and proliferation by targeting Wnt/β-catenin pathway[J].Int Immunopharmacol, 2015, 25 (2) :311-320. [24]MONGA SP.Role of Wnt/β-catenin signaling in liver metabolism and cancer[J].Int J Biochem Cell Biol, 2011, 43 (7) :1021-1029. [25]ZHANG Y, ZHANG H, PENG R, et al.Mechanism research on Artesunate in the treatment of liver fibrosis by inhibiting miR-154/β-catenin in hepatic stellate cell[J].China Med Herald, 2016, 13 (1) :35-38. (in Chinese) 张英, 张洪, 彭锐, 等.青蒿琥酯抑制肝星状细胞microRNA-154/β-catenin治疗肝纤维化的机制研究[J].中国医药导报, 2016, 13 (1) :35-38. [26]MA ZG, LV XD, ZHAN LL, et al.Human urokinase-type plasminogen activator gene-modified bone marrow-derived mesenchymal stem cells attenuate liver fibrosis in rats by down-regulating the Wnt signaling pathway[J].World J Gastroenterol, 2016, 22 (6) :2092-2103. [27]MICHELOTTI GA, XIE G, SWIDERSKA M, et al.Smoothened is a master regulator of adult liver repair[J].J Clin Invest, 2013, 123 (6) :2380-2394. [28]VELCHETI V, GOVINDAN R.Hedgehog signaling pathway and lung cancer[J].J Thorac Oncol, 2007, 2 (1) :7-10. [29]PEREIRA TA, XIE G, CHOI SS, et al.Macrophage-derived Hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni[J].Liver Int, 2013, 33 (1) :149-161. [30]XIE G, KARACA G, SWIDERSKA-SYN M, et al.Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice[J].Hepatology, 2013, 58 (5) :1801-1813. [31]CHE L, YUAN YH, JIA J, et al.Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients[J].Chin J Cancer Res, 2012, 24 (4) :323-331. [32]HOOPER JE, SCOTT MP.Communicating with Hedgehogs[J].Na Rev Mol Cell Biol, 2005, 6 (4) :306-317. [33]LI T, LENG XS, ZHU JY, et al.Suppression of hedgehog signaling regulates hepatic stellate cell activation and collagen secretion[J].Int J Clin Exp Pathol, 2015, 8 (11) :14574-14579. [34]USCHNER FE, RANABHAT G, CHOI SS, et al.Statins activate the canonical hedgehog-signaling and aggravate non-cirrhotic portal hypertension, but inhibit the non-canonical hedgehog signaling and cirrhotic portal hypertension[J].Sci Rep, 2015, 5:14573. [35]YANG JJ, TAO H, LI J.Hedgehog signaling pathway as key player in liver fibrosis:new insights and perspectives[J].Expert Opin T-her Targets, 2014, 18 (9) :1011-1021. [36]YU F, LU Z, CHEN B, et al.Salvianolic acid B-induced microR-NA-152 inhibits liver fibrosis by attenuating DNMT1‐mediated Patched1 methylation[J].J Cell Mol Med, 2015, 19 (11) :2617-2632. [37]EIAGROUDY NN, EINAGA RN, EIRAZEQ RA, et al.Forskolin, a hedgehog signaling inhibitor, attenuates carbon tetrachloride-induced liver fibrosis in rats[J].Br J Pharmacol, 2016, 173 (22) :3248-3260. [38]ZHANG K, JIANG MN, ZHANG CH, et al.Effect of Gan-fukang compound on hepatic expression of integrinα5β1/FAK signal pathway in carbon tetrachloride-induced liver fibrosis in rats[J].J Clin Hepatol, 2012, 15 (2) :104-107. (in Chinese) 张坤, 姜妙娜, 张彩华, 等.肝复康对肝纤维化大鼠肝组织整合素α5β1/FAK信号通路的调节作用[J].实用肝脏病杂志, 2012, 15 (2) :104-107. [39]ELAHARKAWY AM, OAKLEY F, MANN DA.The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis[J].Apoptosis, 2005, 10 (5) :927-939. [40]BI H, MING L, CHENG R, et al.Liver extracellular matrix promotes BM-MSCs hepatic differentiation and reversal of liver fibrosis through activation of integrin pathway[J].J Tissue Eng Regen Med, 2016.[Epub ahead of print] [41]SUGIYAMA A, KANNO K, NISHIMICHI N, et al.Periostin promotes hepatic fibrosis in mice by modulating hepatic stellate cell activation viaαv integrin interaction[J].J Gastroenterol, 2016, 51 (12) :1161-1174.
本文二维码
计量
- 文章访问数: 2855
- HTML全文浏览量: 34
- PDF下载量: 550
- 被引次数: 0