Research advances in main signaling pathways for inducing apoptosis of activated hepatic stellate cells
-
摘要: 肝纤维化是各种病因引起的肝脏慢性进行性的病理过程,肝纤维化时细胞外基质(ECM)合成大于降解导致ECM在肝内大量沉积。肝星状细胞(HSC)的激活、转化并产生分泌大量ECM是肝纤维化形成的关键环节。而通过诱导活化的HSC发生凋亡是逆转肝纤维化的重要手段之一。就主要的凋亡信号通路:死亡受体通路、线粒体通路、内质网通路、神经生长因子通路进行一一阐述。指出了对活化HSC的凋亡途径进行选择性的药物干预有望发挥抗肝纤维化的作用。Abstract: Hepatic fibrosis is a chronic progressive pathological process of the liver induced by various cases. When hepatic fibrosis develops, a large amount of extracellular matrix ( ECM) is deposited in the liver due to the fact that the synthesis of ECM is greater than its degradation. The key step in the development of hepatic fibrosis is the activation and transformation of hepatic stellate cells ( HSC) and secretion of a large amount of ECM. One of the important means for reversing hepatic fibrosis is to induce the apoptosis of activated HSC. The main apoptotic signaling pathways, death receptor pathway, mitochondrial pathway, endoplasmic reticulum pathway, and nerve growth factor pathway, are reviewed. Selective drug intervention for the apoptotic signaling pathways of activated HSCs is expected to reverse hepatic fibrosis.
-
Key words:
- liver cirrhosis /
- astrocytes /
- apoptosis /
- review
-
[1]ZHANG XM, LE XH, XU LM, et al.HBV influences the expression of intrahepatic transforming growth factor beta 1 and the activity of human hepatic stellate cell line LX-2[J].Chin J Exp Clin Infect Dis:Electronic Edition, 2012, 6 (6) :566-569. (in Chinese) 张香梅, 乐晓华, 徐六妹, 等.HBV对肝内TGF-β1蛋白表达和人肝星状细胞系LX-2活性的影响[J].中华实验和临床感染病杂志:电子版, 2012, 6 (6) :566-569. [2]ATZORI L, POLI G, PERRA A.Hepatic stellate cell:A star cell in the liver[J].Int J Biochem Cell Biol, 2009, 41 (8-9) :1639-1642. [3]XU GX, ZHENG Y.Endogenous hydrogen sulfide and liver cirrhosis[J].J Clin Exp Med, 2012, 11 (15) :1245-1246. (in Chinese) 许广鑫, 郑勇.内源性硫化氢与肝硬化[J].临床和实验医学杂志, 2012, 11 (15) :1245-1246. [4]KONG D, ZHANG F, ZHANG Z, et al.Clearance of activated stellate cells for hepatic fibrosis regression:Molecular basis and translational potential[J].Biomed Pharmacother, 2013, 67 (3) :246-250. [5]ELSHARKAWY 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. [6]ZHU YH, CHEN Z, QIAN ZY, et al.Effects of crocetin on acetaldehyde-induced hepatic stellate cell proliferation and collagen synthesis[J].Chin J Clin Pharmacol Ther, 2013, 18 (8) :841-847. (in Chinese) 朱艳虹, 陈真, 钱之玉, 等.西红花酸对乙醛诱导的肝星状细胞增殖和胶原合成的影响[J].中国临床药理学与治疗学, 2013, 18 (8) :841-847. [7]LI JT, LIAO ZX, PING J, et al.Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies[J].J Gastroenterol, 2008, 43 (6) :419-428. [8]XU GW, SHI XY.Apoptosis signaling pathways and lymphocyte homeostasis[J].Cell Res, 2007, 17:759-771. [9]PORTT L, NORMAN G, CLAPP C, et al.Anti-apoptosis and cell survival:A review[J].Biochim Biophys Acta, 2011, 1813 (1) :238-259. [10]DUPREZ L, WIRAWAN E, BERGHE TV, et al.Major cell death pathways at a glance[J].Microbes Infect, 2009, 11 (13) :1050-1062. [11]BRAZ MM, RAMOLHO FS, CARDOSO RL, et al.Slight activation of nuclear kappa-B is associated with increased hepatic stellate cell apoptosis in human schistosomal fibrosis[J].Acta Trop, 2010, 113 (1) :66-71. [12]CUI D, ZHANG S, MA J, et al.Short interfering RNA targeting NF-kappa B induces apoptosis of hepatic stellate cells and attenuates extracelluar matrix production[J].Dig Liver Dis, 2010, 42 (11) :813-817. [13]SCHWERTASSEK U, BUCKLEY DA, XU CF, et al.Myristoylation of the dual-specificity phosphatase c-JUN N-terminal kinase (JNK) stimulatory phosphatase 1 is necessary for its activation of JNK signaling and apoptosis[J].FEBS J, 2010, 277 (11) :2463-2473. [14]LI CC, YANG CZ, LI XM, et al.Hydroxysafflor yellow A induces apoptosis in activated hepatic stellate cells through ERK1/2 pathway in vitro[J].Eur J Pharm Sci, 2012, 46 (5) :397-404. [15]PARDO M, MELENDEZ JA, TIROSH O, et al.Manganese superoxide dismutase inactivation during Fas (CD95) -mediated apoptosis in Jurkat T cells[J].Free Radic Biol Med, 2006, 41 (12) :1795-1806. [16]KUMAR R, HERBERT PE, WARRENS AN.An introduction to death receptors in apoptosis[J].Int J Surg, 2005, 3 (4) :268-277. [17]LEE SH, ZHAO YZ, PARK EJ, et al.2’, 4’, 6’-Tris (methoxymethoxy) chalcone induces apoptosis by enhancing Fas-ligand in activated hepatic stellate cells[J].Eur J Pharmacol, 2011, 658 (1) :9-15. [18] MALHI H, GORES GJ, LEMASTERS JJ.Apoptosis and necrosis in the liver:a tale of two deaths[J].Hepatology, 2006, 43 (2 Suppl1) :s31-s44. [19]PARK SJ, SOHN HY, YOON J, et al.Down-regulation of FoxO-depengdent c-FILP expression mediates TRAIL-induced apoptosis in activated hepatic stellate cells[J].Cell Signal, 2009, 21 (10) :1495-1503. [20]TAIMR P, HIGUCHI H, KOCOVA E, et al.Activated stellate cells express the TRAIL receptor-2/death receptor-5 and undergo TRAIL-mediated apoptosis[J].Hepatology, 2003, 37 (1) :87-95. [21] MAZUMDAR B, MEYER K, RAY R.N-Termianl region of gelsolin induces apoptosis of activated hepatic stellate cells by a caspase-dependent mechanism[J].PLoS One, 2012, 7 (8) :1-8. [22]GAO J, XU CH, LIANG M, et al.Effect of fibronectin on protection of rat hepatic stellate cells HSC-T6 from TRAIL-induced apoptosis[J].J Clin Hepatol, 2011, 27 (11) :1199-1202. (in Chinese) 高杰, 许春海, 梁明, 等.纤连蛋白对肿瘤坏死因子相关凋亡诱导配体诱导肝星状细胞凋亡的影响[J].临床肝胆病杂志, 2011, 27 (11) :1199-1202. [23]RODRIQUEZ-BERRIQUETE G, GALVIS L, FRAILE B, et al.Immunoreactivity to caspase-3, caspase-7, caspase-8, and caspase-9 forms is frequently lost in human prostate tumors[J].Hum Pathol, 2012, 43 (2) :229-237. [24]WENG SG, XU CG, SUN Y, et al.Study on the apoptosis of rat hepatic stellate cells induced by kapamycin[J].J Clin Hepatol, 2012, 28 (3) :219-222. (in Chinese) 翁山耕, 徐常国, 孙颖, 等.雷帕霉素诱导大鼠肝星状细胞凋亡的研究[J].临床肝胆病杂志, 2012, 28 (3) :219-222. [25]THIRUNAVUKKARASU C, WATKINS S, HARVEY SA, et al.Superoxide-induced apoptosis of activated rat hepatic stellate cells[J].J Hepatol, 2004, 41 (4) :567-575. [26]LAVINE B, SINHA S, KROEMER G.Bcl-2 family members:Dual regulators of apoptosis and autophagy[J].Autophagy, 2008, 4 (5) :600-606. [27]AUTRET A, MARTIN SJ.Emerging role for members of the Bcl-2 family in mitochondrial morphogenesis[J].Mol Cell, 2009, 36 (3) :355-363. [28]KIM IH, KIM SW, KIM SH, et al.Parthenolide-induced apoptosis of hepatic stellate cells and anti-fibrotic effects in an in vivo rat model[J].Exp Mol Med, 2012, 44 (7) :448-456. [29]de MINICIS S, CANDELARESI C, AQOSTINELLI L, et al.Endoplasmic reticulum stress induces hepatic stellate cell apoptosis and contributes to fibrosis resolution[J].Liver Int, 2012, 32 (10) :1574-1584. [30]LIM MP, DEVI LA, ROZENFELD R.Cannabidiol causes activated hepatic stellate cell death through a mechanism of endoplasmic reticulum stress-induced apoptosis[J].Cell Death Dis, 2011, 2:e170. [31]HE YJ, ZHU HY, SHU JC, et al.Effects of nerve growth factor on proliferation of hepatic stellate cells[J].Chin J Hepatol, 2012, 20 (12) :912-914. (in Chinese) 何雅军, 朱海燕, 舒建昌, 等.神经生长因子抑制肝星状细胞增殖的观察[J].中华肝脏病杂志, 2012, 20 (12) :912-914. [32]JIN H, TERAI S, SAKAIDA I.The iron chelator deferoxamine causes activated hepatic stellate cells to become quiescent and to undergo apoptosis[J].J Gastroenterol, 2007, 42 (6) :475-484. [33]TANG X, YANG JT, LI J, et al.Accelerative effect of leflunomide on recovery from hepatic fibrosis involves TRAIL-mediated hepatic stellate cell apoptosis[J].Life Sci, 2009, 84 (15-16) :552-557. [34]CHE XH, PARK EJ, ZHAO YZ, et al.Tanshinone II A induces apoptosis and S phase cell cycle arrest in activated rat hepatic stellate cell[J].Basic Clin Pharmacol Toxicol, 2009, 106 (1) :30-37. [35]LI J, LIU P, ZHANG R, et al.Icaritin induces cell death in activated hepatic stellate cells through mitochondrial activated apoptosis and ameliorates the development of liver fibrosis in rats[J].J Ethnopharmacol, 2011, 137 (1) :714-723. [36]WU XX, WU LM, FAN JJ, et al.Cortex Dictamni extract induces apoptosis of activated hepatic stellate cells via STAT1 and attenuates liver fibrosis in mice[J].J Ethnopharmacol, 2011, 135 (1) :173-178. [37]WANG R, YU XY, GUO ZY, et al.Inhibitory effects of salvianolic acid B on CCl4-induced hepatic fibrosis through regulating NF-κB/IκBαsignaling[J].J Ethnopharmacol, 2012, 144 (3) :592-598.
本文二维码
计量
- 文章访问数: 3159
- HTML全文浏览量: 17
- PDF下载量: 657
- 被引次数: 0