Understanding the mechanism of hepatic fibrosis and potential therapeutic approaches

Saudi Journal of Gastroenterology

Volumn 18, Issue 3, 2012, Pages 155-167

  Ahmad, Areeba ^a   Ahmad, Riaz ^a  

^a ALIGARH MUSLIM UNIVERSITY   (India)

Author keywords

Antifibrotic strategies; biochemical abnormalities; cell types; gene therapy; hepatic fibrosis

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ACETYLCYSTEINE; ANGIOTENSIN 2 RECEPTOR ANTAGONIST; BIOLOGICAL MARKER; COLLAGEN FIBER; COLLAGENASE 3; CURCUMIN; EMODIN; FAS ANTIGEN; FIBROBLAST GROWTH FACTOR; GINKGO BILOBA EXTRACT; GLIOTOXIN; GYPENOSIDE; IMATINIB; INTERLEUKIN 1; INTERLEUKIN 10; INTERLEUKIN 6; PROSTAGLANDIN J2; PROTEIN P75; REACTIVE OXYGEN METABOLITE; RETINOIC ACID; ROSIGLITAZONE; SALAZOSULFAPYRIDINE; SALVIA MILTIORRHIZA EXTRACT; SILYMARIN; TAURINE; TRANSFORMING GROWTH FACTOR BETA1; TUMOR NECROSIS FACTOR ALPHA; UNINDEXED DRUG; VASCULOTROPIN;

ARTICLE; CARDIOTOXICITY; CELL PROLIFERATION; CELL TYPE; DISEASE COURSE; DRUG MECHANISM; EARLY DIAGNOSIS; ENDOTHELIUM CELL; FATALITY; FIBROGENESIS; HUMAN; IMMUNOHISTOCHEMISTRY; INFLAMMATION; KUPFFER CELL; LIVER ENDOTHELIUM; LIVER FAILURE; LIVER FIBROSIS; LIVER HISTOLOGY; MEDIATOR RELEASE; NONHUMAN; PATHOGENESIS; RISK ASSESSMENT; RISK FACTOR; SCAR; STELLATE CELL; TREATMENT INDICATION; VIRAL GENE THERAPY;

BIOLOGICAL MARKERS; COLLAGEN; CYTOKINES; DISEASE PROGRESSION; GENE THERAPY; HUMANS; LIVER; LIVER CIRRHOSIS; PROTECTIVE AGENTS; RISK FACTORS;

EID: 84861668626     PISSN: 13193767     EISSN: 19984049     Source Type: Journal    
DOI: 10.4103/1319-3767.96445     Document Type: Article

References (159)

1. Friedman SL. Mechanism of hepatic fibrogenesis. Gastroenterology 2008;134:1655-69
2. Wells RG. The role of matrix stiffness in regulating cell behavior. Hepatology 2008;47:1394-400 (Pubitemid 351547925)
3. Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003;112:1776-84 (Pubitemid 38063698)
4. Wells RG, Kruglov E, Dranoff JA. Autocrine release of TGF-beta by portal fibroblasts regulates cell growth. FEBS Lett 2004;559:107-10 (Pubitemid 38186712)
5. Forbes SJ, Russo FP, Rey V, Burra P, Rugge M, Wright NA, et al. A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 2004;126:955-63 (Pubitemid 38451166)
6. Heidelbaugh JJ, Bruderly M. Cirrhosis and chronic liver failure: Part I. Diagnosis and evaluation. Am Fam Physician 2006;74:756-62
7. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006;45:529-38 (Pubitemid 44307383)
8. Lavanchy D. Worldwide epidemiology of HBV infection, disease burden, and vaccine prevention. J Clin Virol 2005;34(Suppl 1):S1-3 (Pubitemid 43197742)
9. Simmonds P, Bukh J, Combet C, Deleage G, Enomoto N, Feinstone S, et al. Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology 2005;42:962-73 (Pubitemid 41401136)
10. Seeff LB, Hoofnagle JH. Appendix: The national institutes of health consensus development conference management of hepatitis C 2002. Clin Liver Dis 2003;7:261-87 (Pubitemid 36350763)
11. Koike K. Antiviral treatment of hepatitis C: present status and future prospects. J Infect Chemother 2006;12:227-32 (Pubitemid 44760500)
12. van der Werf MJ, de Vlas SJ, Brooker S, Looman CW, Nagelkerke NJ, Habbema JD, et al. Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop 2003;86:125-39 (Pubitemid 36561364)
13. Geerts A. On the origin of stellate cells: mesodermal, endodermal or neuroectodermal? J Hepatol 2004;40:331-4 (Pubitemid 38115841)
14. Vogel S, Gamble MV, Blaner WS. Biosynthesis, absorption, metabolism and transport of retinoids. In: Nau H, Blaner WS, editors. Retinoids: The biochemical and molecular basis of vitamin A and retinoid action. Berlin: Springer; 1999. p. 31-95
15. Uyama N, Zhoa L, van Rossen E, Hirrako Y, Reynaert H, Adams DH, et al. Hepatic stellate cells express synemin, a protein bridging intermediate filaments to focal adhesions. Gut 2006;55:1276-89 (Pubitemid 44277359)
16. Kolterud A, Wandzioch E, Carlsson L. Lhx2 is expressed in the septum transversum mesenchyme that becomes an integral part of the liver and the formation of these cells is independent of function of Lhx2. Gene Expr Patterns 2004;4:521-8 (Pubitemid 38992393)
17. Yang L, Chan CC, Kwon OS, Liu S, McGhee J, Stimpson SA, et al. Regulation of peroxisome proliferator-activated receptor-g in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 2006;291:G902-11 (Pubitemid 44772017)
18. Matsumoto K, Nakamura T. Emerging multipotent aspects of hepatocyte growth factor. J Biochem 1996;119: 591-600. (Pubitemid 26131762)
19. Gressner AM, Weiskirchen R, Breitkopf K, Dooley S. Roles of TGF-b in hepatic fibrosis. Front Biosci 2002;7:d793-807
20. Saile B, DiRocco P, Dudas J, El-Armouche H, Sebb H, Eisenbach C, et al. IGF-1 induces DNA synthesis and apoptosis in rat liver hepatic stellate cells (HSC) proliferation in rat liver myofibroblasts (rMF). Lab Invest 2004;84:1037-49 (Pubitemid 39025038)
21. Haussinger D, Kubitz R, Reinehr R, Bode JG, Schliess F. Molecular aspects of medicine: from experimental to clinical Hepatology. Mol Aspects Med 2004;25:221-360 (Pubitemid 38684174)
22. Gassull X, Battaler R, Gines P, Sancho-Bru P, Nicolas JM, Gorbig MN, et al. Human myofibroblastic hepatic stellate cells express Ca2+-activated K+ channels that modulate the effects of endothelin-1 and nitric oxide. J Hepatol 2001;35:739-48 (Pubitemid 34717665)
23. Nakae J, Barr V, Accili D. Differential regulation of gene expression by insulin and IGF-1 receptors correlates with phosphorylation of a single amino acid residue in the forkhead transcription factor FKHR. EMBO J 2000;19:989-96 (Pubitemid 30119824)
24. van der Heide LP, Hoekman MF, Smidt MP. The ins and outs of FoxO shuttling: Mechanism of FoxO translocation and transcriptional regulation. Biochem J 2004;380:297-309 (Pubitemid 38788101)
25. Adachi M, Osawa Y, Uchinami H, Kitamura T, Accili D, Brenner DA. The forkhead transcription factor FoxO1 regulates proliferation and transdifferentiation of hepatic stellate cells. Gastroenterology 2007;132:1434-46 (Pubitemid 46627569)
26. Shafiei MS, Rockey DC. The role of integrin-linked kinase in liver wound healing. J Biol Chem 2006;281:24863-72 (Pubitemid 44274258)
27. Luster MI, Germolec DR, Yoshida T, Kayama F, Thompson M. Endotoxin-induced cytokine gene expression and excretion in the liver. Hepatology 1994;19:480-8 (Pubitemid 24046795)
28. Hironaka K, Sakaida I, Matsumura Y, Kaino S, Miyamoto K, Okita K. Enhanced interstitial collagenase (matrix metalloproteinase-13) production of Kupffer cell by gadolinium chloride prevents pig seruminduced rat liver fibrosis. Biochem Biophys Res Commun 2000;267:290-5 (Pubitemid 30072544)
29. Fischer R, Cariers A, Reinehr R, Haussinger D. Caspase 9-dependent killing of hepatic stellate cells by activated Kupffer cells. Gastroenterology 2002;123:845-61 (Pubitemid 34977091)
30. Taimr P, Higuchi H, Kocova E, Rippe RA, Friedman S, Gores GJ. Activated stellate cells express the TRAIL receptor-2/death receptor-5 and undergo TRAIL-mediated apoptosis. Hepatology 2003;37:87-95 (Pubitemid 36042149)
31. Knolle PA, Loser P, Protzer U, Duchmann R, Schimmit E, zum Büschenfelde KH, et al. Regulation of endotoxin-induced IL-6 production in liver sinusoidal endothelial cells and Kupffer cells by IL-10. Clin Exp Immunol 1997;107:555-61 (Pubitemid 27102146)
32. Annoni G, Weiner FR, Zern M. Increased transforming growth factor b-1 gene expression in human liver disease. J Hepatol 1992;14:259-64
33. Bataller R, Gines P, Nicolas JM, Gorbig MN, Garcia-Ramallo E, Gasull X, et al. Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology 2000;118:1149-56 (Pubitemid 30346992)
34. Kinnman N, Goria O, Wendum D, Gendron MC, Rey C, Poupon R, et al. Hepatic stellate cell proliferation is an early platelet-derived growth factor mediated cellular event in rat cholestatic liver injury. Lab Invest 2001;81:1709-16 (Pubitemid 33144433)
35. Pinzani M. PDGF and signal transduction in hepatic stellate cells. Front Biosci 2002;7:d1720-6
36. Borkham-Kamphorst E, van Roeyen CR, Ostendorf T, Floege J, Gressner AM, Weiskirchen R. Pro-fibrogenic potential of PDGF-D in liver fibrosis. J Hepatol 2007;46:1064-74 (Pubitemid 46669736)
37. Mathurin P, Xiong S, Kharbanda KK, Veal N, Miyahara T, Motomura K, et al. IL-10 receptor and co receptor expression in quiescent and activated hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 2002;282:981-90
38. Pinzani M, Marra F. Cytokine receptors and signaling in hepatic stellate cells. Semin Liver Dis 2001;21:397-416 (Pubitemid 32923768)
39. Lui C, Gaca MDA, Swenson ES, Velluci VF, Reiss M, Wells RG. Smads 2 and 3 are differentially activated by transforming growth factor b (TGF-b) in quiescent and activated hepatic stellate cells. Constitutive nuclear localization of Smads in activated cells is TGF-b-independent. J Biol Chem 2003;278:11721-8 (Pubitemid 36792736)
40. Reimann T, Hempel U, Krautwald S, Axmann A, Scheibe R, Seidel D, et al. Transforming growth factor-b1 induces activation of Ras, Raf-1, MEK and MAPK in rat hepatic stellate cells. FEBS Lett 1997;403:57-60 (Pubitemid 27079809)
41. De Bleser PJ, Niki T, Rogiers V, Geerts A. Transforming growth factorbeta gene expression in normal and fibrotic rat liver. J Hepatol 1997;26:886-93 (Pubitemid 27145714)
42. Rockey DC, Chung JJ. Endothelin antagonism in experimental hepatic fibrosis. Implications for endothelin in the pathogenesis of wound healing. J Clin Invest 1996;98:1381-8 (Pubitemid 26322063)
43. Pinzani M, Gesualdo L, Sabbah GM, Abboud HE. Effects of plateletderived growth factor and other polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat-storing cells. J Clin Invest 1989;84:1786-93 (Pubitemid 20016182)
44. Maher JJ, Lozier JS, Scott MK. Rat hepatic stellate cells produce cytokine-induced neutrophil chemoattractant in culture and in vivo. Am J Physiol 1998;275:G847-53
45. Lotersztajin S, Julien B, Teixeira-Clerc F, Grenard P, Mallat A. Hepatic fibrosis: molecular mechanisms and drug targets. Annu Rev Pharmacol Toxicol 2005;45:605-28 (Pubitemid 40261819)
46. Benyon RC, Arthur MJ. Extracellular matrix degradation and the role of hepatic stellate cells. Semin Liver Dis 2001;21:373-84 (Pubitemid 32923766)
47. Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley S, et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 1998;102:538-49 (Pubitemid 28376157)
48. Nie QH, Duan GR, Lou XD, Xie YM, Luo H, Zhou YX, et al. Expression of TIMP-1 and TIMP-2 in rats with hepatic fibrosis. World J Gastroenterol 2004;10:86-90 (Pubitemid 38071984)
49. Steinmann P, Keiser J, Bos R, Tanner M, Utzinger J. Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk. Lancet Infect Dis 2006;6:411-25 (Pubitemid 43949139)
50. Olds GR, Griffin A, Kresina TF. Dynamics of collagen accumulation and polymorphism in murine Schistosoma japonicum. Gastroenterology 1985;89:617-24 (Pubitemid 15239167)
51. Grimaud JA. Cell-matrix interactions in schistosomal portal fibrosis: a dynamic event. Mem Inst Oswaldo Cruz 1987;82 Suppl 4:55-65
52. Cheever AW, Williams ME, Wynn TA, Finkelman FD, Seder RA, Cox TM, et al. Anti-IL-4 treatment of Schistosoma mansoni-infected mice inhibits development of T cells and non-B, non-T cells expressing TH2 cytokines while decreasing egg-induced hepatic fibrosis. J Immunol 1994;153:753-9 (Pubitemid 24206304)
53. Wynn TA, Thompson RW, Cheever AW, Mentink-Kane MM. Immunopathogenesis of schistosomiasis. Immunol Rev 2004;201:156-67 (Pubitemid 39318450)
54. Fallon PG, Richardson EJ, McKenzie GJ, McKenzie AN. Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent. J Immunol 2000;164:2585-91 (Pubitemid 30115489)
55. Rojkind M, Mourelle M. Modification during regeneration and repair in collagen. In: Nimni ME, editor. The liver as bioecological system. Boca, Raton, Florida: CRC Press; 1988. p. 137-59
56. Matsui Y, Okuda Y, Nakagawa M, Kwon AH, Minoura T, Hiramatsu Y, et al. Effect of hepatocyte volume on energy status in the cirrhotic rat liver. J Gastroenterol Hepatol 1994;9:613-9 (Pubitemid 24364613)
57. Yamada S, Hirayama C. Clinical significance of serum hydroxyprolinecontaining peptides with special reference to hyproprotein. Eur J Clin Invest 1983;13:129-33 (Pubitemid 13163422)
58. George J, Chandrakasan G. Glycoprotein metabolism in dimethylnitrosamine induced hepatic fibrosis in rats. Int J Biochem Cell Biol 1996;28:353-61 (Pubitemid 26116667)
59. Ala-Kokko L, Pihlajaniemi T, Myers JC, Kivirikko KI, Savolainen ER. Gene expression of types, I, III, and IV collagens in hepatic fibrosis induced by dimethylnitrosamine in the rat. Biochem J 1987;244:75-9 (Pubitemid 17098811)
60. George J, Chandrakasan G. Molecular characteristics of dimethylnitrosamine induced fibrotic liver collagen. Biochim Biophys Acta 1996;1292:215-22 (Pubitemid 26068776)
61. Garcia-Trevijano ER, Iraburu MJ, Fontana L, Dominguez-Rosales JA, Auster A, Covarrubias-Pinedo A, et al. Transforming growth factor b1 induces the expression of alpha1(I) type(I) procollagen mRNA by a hydrogen peroxide-C/EBP beta-dependent mechanism in rat hepatic stellate cells. Hepatology 1999;29:960-70 (Pubitemid 29109616)
62. Panduro A, Shalaby F, Biempica L, Shafritz DA. Changes in albumin, a-fetoprotein and collagen gene transcription in CCl4-induced hepatic fibrosis. Hepatology 1990;8:259-66
63. George J. Mineral metabolism in dimethylnitrosamine-induced hepatic fibrosis. Clin Biochem 2006;39:984-91 (Pubitemid 44442159)
64. Kanzler S, Lohse AW, Keil A, Henninger J, Dienes HP, Schirmacher P, et al. TGF-b1 in liver fibrosis: an inducible transgenic mouse model to study liver fibrogenesis. Am J Physiol Liv Pathol 1999;276:G1059-68 (Pubitemid 29214121)
65. Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: A prospective study. Lancet 2001;357:1069-75 (Pubitemid 32322537)
66. Kawser CA, Iredale JP, Winwood PJ, Arthur MJ. Rat hepatic stellate cell expression of a 2-macroglobulin is a feature of cellular activation: implications for matrix remodeling in hepatic fibrosis. Clin Sci (Lond) 1998;95:179-86 (Pubitemid 28401268)
67. Poynard T, Bedossa P, Mathurin P, Ratziu V, Paradis V. Apolipoprotein A1 and hepatic fibrosis. J Hepatol 1995;22(2 Suppl):107-10
68. Hashimoto N, Ishikawa Y, Utsunomiya J. Effects of portacaval shunt, transposition and dimethylnitrosamine-induced chronic liver injury on pancreatic hormones and amino acid in dogs. J Surg Res 1989;46:35-40 (Pubitemid 19049668)
69. George J, Chandrakasan G. Lactate dehydrogenase isoenzymes in dimethylnitrosamine induced hepatic fibrosis in rats. J Clin Biochem Nutr 1997;22:51-62 (Pubitemid 28348817)
70. Ahmad R, Ahmad S, Khan NU, Hasnain A. Operculina turpethum attenuates NDMA-induced toxic liver injury and clastogenicity in rats. Chem Biol Interact 2009;181:145-53
71. George J, Suguna L, Jayalakshmi R, Chandrakasan G. Efficacy of silymarin and curcumin on dimethylnitrosamine induced liver fibrosis in rats. Biomedicine 2006;26:18-26 (Pubitemid 351578347)
72. Attallah AM, Toson el-SA, El-Waseef AM, Abo-Seif MA, Omran MM, Shiha GE. Discriminant function based on hyaluronic acid and its degrading enzymes and degradation products for differentiating cirrhotic from non-cirrhotic liver disease patients in chronic HCV infection. Clin Chim Acta 2006;369:66-72 (Pubitemid 43796312)
73. George J. Elevated serum b-glucuronidase reflects hepatic lysosomal fragility following toxic liver injury in rats. Biochem Cell Biol 2008;86:235-43 (Pubitemid 351810523)
74. Snodgrass PJ. Urea cycle enzyme activities are normal and inducible by a high-protein diet in CCl4 cirrhosis of rats. Hepatology 1989;9:373-9 (Pubitemid 19074968)
75. Vendemiale G, Grattagliano I, Caruso ML, Servidelio G, Valintini AM, Pirrellli M, et al. Increased oxidative stress in dimethylnitrosoamineinduced liver fibrosis in rats. Effect of N-acetylcysteine and interferonalpha. Toxicol Appl Pharmacol 2001;175:130-9 (Pubitemid 32848504)
76. George J, Chandrakasan G. Biochemical abnormalities during the progression of hepatic fibrosis induced by dimethylnitrosoamine. Clin Biochem 2000;33:563-70 (Pubitemid 32012440)
77. Kobayashi H, Horikoshi K, Yamataka A, Yamataka T, Okazaki T, Lane GJ, et al. Hyaluronic acid: A specific prognostic indicator of hepatic damage in biliary atresia. J Pediatr Surg 1999;34:1791-4 (Pubitemid 30002484)
78. Morrison WL, Bouchier IAD, Gibson JN, Rennie MJ. Skeletal muscle and whole body protein turnover in cirrhosis. Clin Sci (Lond) 1990;78:613-9 (Pubitemid 20187500)
79. Ahmad A, Fatima R, Maheshwari V, Ahmad R. Effect of N'- Nitrosodimethylamine on red blood cell rheology and proteomic profiles of brain in male albino rats. Interdiscip Toxicol 2011;4:125-31
80. George J. Ascorbic acid concentrations in dimethylnitrosamine-induced hepatic fibrosis in rats. Clin Chim Acta 2003;335:39-47 (Pubitemid 37338306)
81. Bengoa JM, Sitrin MD, Meredith S, Kelly SE, Shah N, Baker AL, et al. Intestinal calcium absorption and vitamin D status in chronic cholestatic liver disease. Hepatology 1984;4:261-5 (Pubitemid 14131434)
82. Masuda S, Okanao T, Osawa K, Shinjo M, Suematsu T, Kobayashi T. Concentrations of vitamin D-binding protein and vitamin D metabolites in plasma of patients with liver cirrhosis. J Nutr Sci Vitaminol (Tokyo) 1989;35:225-34 (Pubitemid 19268715)
83. Wong F, Blendis L. Pathophysiology of sodium retention and ascites formation in cirrhosis: Role of atrial natriuretic factor. Semin Liver Dis 1994;14:59-70 (Pubitemid 24116693)
84. Castello L, Pirisi M, Sainaghi PP, Bartoli E. Hyponatremia in liver cirrhosis: pathophysiological principles of management. Dig Liver Dis 2005;37:73-81 (Pubitemid 41070543)
85. Weiner ID, Wingo CS. Hypokalemia-consequences, causes and correction. J Am Soc Nephrol 1997;8:1179-88
86. Castro A, Ros J, Jimenez W, Claria J, Llibre J, Leivas A, et al. Intracellular calcium concentration in vascular smooth muscle cells of rats with cirrhosis. J Hepatol 1994;21:521-6 (Pubitemid 24324025)
87. Rocchi E, Borella P, Borghi A, Paolillo F, Pradelli M, Farina F, et al. Zinc and magnesium in liver cirrhosis. Eur J Clin Invest 1994;24:149-55 (Pubitemid 24197260)
88. Suzuki K, Oyama R, Hayashi E, Arakawa Y. Liver diseases and essential trace elements. Nippon Rinsho 1996;54:85-92
89. Cocchetto DM, Tschanz C, Bjornsson TD. Decreased rate of creatinine production in patients with hepatic disease: implications for estimation of creatinine clearance. Ther Drug Monit 1983;5:161-8 (Pubitemid 13065400)
90. Takabatake T, Ohta H, Ishida Y, Hara H, Ushiogi Y, Hattori N. Low serum creatinine levels in severe hepatic disease. Arch Intern Med 1988;148:1313-5
91. Ariosto F, Riggio O, Cantafora A, Colussi S, Gaudio E, Mechelli C, et al. Carbon tetrachloride induced experimental cirrhosis in the rat: A reappraisal of the model. Eur Surg Res 1989;21:280-6 (Pubitemid 20056302)
92. Kim KY, Rhim T, Choi I, Kim SS. N-Acetylcysteine induces cell cycle arrest in hepatic stellate cells through its reducing activity. J Biol Chem 2001;276:40591-8
93. Meurer SK, Lahme B, Tihaa L, Weiskirchen R, Gressner A.M. N-acetyll-cysteine suppresses TGF-b signaling at distinct molecular steps: the biochemical and biological efficacy of a multifunctional, antifibrotic drug. Biochem Pharmacol 2005;70:1026-34 (Pubitemid 41262078)
94. Zardi EM, Dobrina A, Amoroso A, Afeltra A. Prostacyclin in liver disease: a potential therapeutic option. Expert Opin Biol Ther 2007;7:785-90 (Pubitemid 46954425)
95. Yoshidome H, Kato A, Edwards MJ, Lentsch AB. Interleukin-10 suppresses hepatic ischemia/reperfusion injury in mice: implications of a central role for nuclear factor kappaB. Hepatology 1999;30:203-8 (Pubitemid 29300587)
96. Ulloa L, Doody J, Massague J. Inhibition of transforming growth factorbeta/ SMAD signaling by the interferon-gamma/STAT pathway. Nature 1999;397:710-13
97. Hui AY, Cheng AS, Chan HL, Go MY, Chan FK, Sakata R, et al. Effect of prostaglandin E2 and prostaglandin I2 on PDGF-induced proliferation of LI90, a human hepatic stellate cell line. Prostaglandins Leukot Essent Fatty Acids 2004;71:329-33 (Pubitemid 39233557)
98. Zhou Y, Zheng S, Lin J, Zhang QJ, Chen A. The interruption of PDGF and EGF signaling pathways by curcumin stimulates gene expression of PPAR-gamma in rat activated hepatic stellate cell in vitro. Lab Invest 2007;87:488-98 (Pubitemid 46633122)
99. Han J, Hajjar DP, Tauras JM, Feng J, Gotto AM Jr, Nicholson AC. Transforming growth factor-b1 (TGF-b1) and TGF-b2 decrease expression of CD36, the type B scavenger receptor, through mitogenactivated protein kinase phosphorylation of peroxisome proliferatoractivated receptor-g. J Biol Chem 2000;275:1241-6 (Pubitemid 30051177)
100. Galli A, Crabb DW, Ceni E, Salzano R, Mello T, Svegliati-Baroni G, et al. Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology 2002;122:1924-40 (Pubitemid 34651436)
101. . Sun K, Wang Q, Huang XH. PPAR-gamma inhibits growth of rat hepatic stellate cells and TGF beta-induced connective tissue growth factor expression. Acta Pharmacol Sin 2006;27:715-23 (Pubitemid 43943920)
102. . Ding X, Saxena NK, Lin S, Xu A, Srinivasan S, Anania FA. The role of leptin and adiponectin: a novel paradigm in adipocytokine regulation of liver fibrosis and stellate cell biology. Am J Pathol 2005;166:1655-69 (Pubitemid 40734389)
103. . Sanz S, Pucilowska JB, Liu S, Rodríguez-Ortigosa CM, Lund PK, Brenner DA, et al. Expression of insulin-like growth factor I by activated hepatic stellate cells reduces fibrogenesis and enhances regeneration after liver injury. Gut 2005;54:134-41 (Pubitemid 40007233)
104. . Elsharkawy AM, Wright MC, Hay RT, Arthur MJ, Hughes T, Bahr MJ, et al. Persistent activation of nuclear factor-kappa B in cultured rat hepatic stellate cells involves the induction of potentially novel Rel-like factors and prolonged changes in the expression of IkappaB family proteins. Hepatology 1999;30:761-9 (Pubitemid 29409421)
105. . Oakley F, Meso M, Iredale JP, Green K, Marek CJ, Zhou X, et al. Inhibition of inhibitor of kB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis. Gastroenterology 2005;128:108-20 (Pubitemid 40039963)
106. . Sonoyama T, Tamura N, Miyashita K, Park K, Oyamada M, Taura D, et al. Inhibition of hepatic damage and liver fibrosis by brain natiuretic peptide. FEBS Lett 2009;583:2067-70
107. . Wang L, Potter JJ, Rennie-Tankersley L, Novitskiy G, Sipes J, Mezey E. Effect of retinoic acid on the development of liver fibrosis produced by carbon tetrachloride in mice. Biochim Biophys Acta 2007;1772:66-71 (Pubitemid 44960723)
108. . Horie T, Sakaida I, Yokoya F, Nakajo M, Sonaka I, Okitab K. L-cysteine administration prevents liver fibrosis by suppressing hepatic stellate cell proliferation and activation. Biochem Biophys Res Commun 2003;305:94-100 (Pubitemid 36535413)
109. . Galli A, Crabb D, Price D, Ceni E, Salzano F, Surrenti C, et al. Peroxisome proliferator-activated receptor g transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate cells. Hepatology 2000;31:101-8 (Pubitemid 30033695)
110. . Okuno M, Akita K, Moriwaki H, Kawada N, Ikeda K, Kaneda K et al. Prevention of rat hepatic fibrosis by the protease inhibitor, camostat mesilate, via reduced generation of active TGF-beta. Gastroenterology 2001;120:1784-800 (Pubitemid 32523496)
111. . Williams EJ, Benyon RC, Trim N, Hadwin R, Grove BH, Arthur MJ, et al. Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo. Gut 2001;49:577-83 (Pubitemid 32896990)
112. . Bennett RG, Mahan KJ, Gentry-Nielsen MJ, Tuma DJ. Relaxin receptor expression in hepatic stellate cells and in cirrhotic rat liver tissue. Ann N Y Acad Sci 2005;1041:185-9 (Pubitemid 41132245)
113. . von Mehren M. Targeted therapy with imatinib: hits and misses?. J Clin Oncol 2005;23:8-10 (Pubitemid 41702617)
114. . Kerkela R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C, et al. Cardio toxicity of the cancer therapeutic agent imatinib mesilate. Nat Med 2006;12:908-16 (Pubitemid 44175142)
115. . Friedman SL. The answer: Angiotensin II. The question: what do inflammation, oxidant stress and fibrogenesis have in common? J Hepatol 2004;40:1050-2 (Pubitemid 38670150)
116. . Wei HS, Lu HM, Li DG, Zhan YT, Wang ZR, Huang X, et al. The regulatory role of AT1 receptor on activated HSCs in hepatic fibrogenesis: effects of RAS inhibitors on hepatic fibrosis induced by CCl4. World J Gastroenterol 2000;6:824-8 (Pubitemid 32015797)
117. . Kurikawa N, Suga M, Kuroda S, Yamada K, Ishikawa H. An angiotensin II type 1 receptor antagonist, olmesartan medoxomil, improves experimental liver fibrosis by suppression of proliferation and collagen synthesis in activated hepatic stellate cells. Br J Pharmacol 2003;139:1085-94 (Pubitemid 36920670)
118. . Zhang JP, Zhang M, Zhou JP, Liu FT, Zhou B, Xie WF et al. Antifibrotic effects of matrine on in vitro and in vivo models of liver fibrosis in rats. Acta Pharmacol Sin 2001;22:183-6 (Pubitemid 32158359)
119. . Miyazaki T, Karube M, Matsuzaki Y, Ikegami T, Doy M, Tanaka N, et al. Taurine inhibits oxidative damage and prevents fibrosis in carbon tetrachloride-induced hepatic fibrosis. J Hepatol 2005;43:117-25 (Pubitemid 40805282)
120. . Zhan Y, Li D, Wei H, Wang Z, Huang X, Xu Q, et al. Emodin on hepatic fibrosis in rats. Chin Med J (Engl) 2000;113:599-601
121. . Tan LX, Li XS, Liu ZQ, Liu LY. Effects of combination therapy of rehin and tetramethylpyrazine on experimental hepatic fibrosis induced by carbon tetrachloride. Zhonghua Gan Zang Bing Za Zhi 2004;12:692-3
122. . Liu SQ, Yu JP, Chen HL, Luo HS, Chen SM, Yu HG. Therapeutic effects and molecular mechanisms of Ginkgo biloba extract on liver fibrosis in rats. Am J Chin Med 2006;34:99-114
123. . Chen MH, Chen SH, Wang QF, Chen JC, Chang DC, Hsu SL et al. The molecular mechanism of gypenosides-induced G1 growth arrest of rat hepatic stellate cells. J Ethnopharmacol 2008;117:309-17
124. . Wasser S, Ho JMS, Ang HK, Tan CEL. Salvia miltiorrhiza reduces experimentally-induced hepatic fibrosis in rats. J Hepatol 1998;29:760-71
125. . Shalaby NM, Maghraby AS, El-Hagrassy A.M. Effect of Daucus carota var. boissieri extracts on immune response of Schistosoma mansoni infected mice. Folia Microbiol 1999;44:441-8 (Pubitemid 129558736)
126. . Massoud A. Myrrh; a schistosomicide for human Schistosomiasis mansoni. Ain Shams Med J 1999;50:1401-17
127. . Abdel Aziz SS, El-Badawy NM. Experimental trials of an artemisinin derivative in treatment of Schistosoma mansoni infected mice. J Egypt Soc Parasitol 2000;30:295-303
128. . McGaw LJ, Rabe T, Sparg SG, Jager AK, Eloff, JN, van Staden J. An investigation on the biological activity of Combretum species. J Ethnopharmacol 2001;75:45-50 (Pubitemid 32224872)
129. . El-Qadri AA, Emara MM. Effect of Nigella sativa crude oil on skin penetration and viability of Schistosoma mansoni cercariae. New Egypt J Med 1994;11:431-6
130. . Mostafa OM. Experimental use of black-seed oil against Schistosoma mansoni in albino mice: I. Some parasitological and biochemical parameters. Egypt J Med Lab Sci 2001;10:99-113
131. . Mahmoud MR, El-Abhar HS, Saleh S. The effect of Nigella sativa oil against the liver damage induced by Schistosoma mansoni infection in mice. J Ethnopharmacol 2002;70:1-11 (Pubitemid 34017233)
132. . Mohamed AM, Metwally NM, Mahmoud SS. Sativa seeds against Schistosoma mansoni different stages. Mem Inst Oswaldo Cruz 2005;100:205-11 (Pubitemid 40745442)
133. . Sanderson L, Bartlett A, Whitefield PJ. In vitro and in vivo studies on the bioactivity of ginger (Zingiber officinale) extract towards adult schistosomes and their egg production. J Helminthol 2002;76:241-7 (Pubitemid 35000989)
134. . Ahmed AH, Rifaat MM. Effects of Solanum nigrum leaves water extract on the penetration and infectivity of Schistosoma mansoni cercariae. J Egypt Soc Parasitol 2005;35:33-40
135. . Riad NHA, Fares NH, Mostafa OMS, Mahmoud YI. The effect of garlic on some parasitological and on hepatic tissue reactions in experimental Schistosomiasis mansoni. J Appl Sci Res 2007;3:949-60
136. . Riad NHA, Fares NH, Mostafa OMS, Mahmoud YI. The effect of garlic on murine schistosomiasis mansoni: A histological and ultrastructural study on the ileum. Res J Med Med Sci 2008;3:188-201
137. . Allam G. Immunomodulatory effects of curcumin treatment on murine schistosomiasis mansoni. Immunobiology 2009;214:712-27
138. . Dajem SMB, Shati AA, Adly MA, Ahmed OM, Ibrahim EH, Mostafa O.M.S. Green tea (Camellia sinensis) ameliorates female Schistosoma mansoni-induced changes in the liver of Balb/C mice. Saudi J Biol Sci 2011;18:361-8
139. . Chatterjee S, Mbaye A, Alfidja AT, Weyler J, Scott JT, Van Damme P, et al. Circulating levels of the neuropeptide hormone somatostatin may determine hepatic fibrosis in Schistosoma mansoni infections. Acta Trop 2004;90:191-203 (Pubitemid 38283769)
140. . Chu D, Luo Q, Li C, Gao Y, Yu L, Wei W, et al. Paeoniflorin inhibits TGFbeta1-mediated collagen production by Schistosoma japonicum soluble egg antigen in vitro. Parasitology 2007;134:1611-21 (Pubitemid 350194875)
141. . Weiner FR, Czaja MJ, Giambrone MA, Takahashi S, Biempica L, Zern M.A. Transcriptional and posttranscriptional effects of dexamethasone on albumin and procollagen messenger RNAs in murine schistosomiasis. Biochemistry 1987;26:1557-62 (Pubitemid 17047625)
142. . Chen H, He YW, Liu WQ, Zhang JH. Rosiglitazone prevents murine hepatic fibrosis induced by Schistosoma japonicum. World J Gastroenterol 2008;14:2905-11
143. . Beljaars L, Meijer DK, Poelstra K. Targeting hepatic stellate cells for cell specific treatment of liver fibrosis. Front Biosci 2002;7:e214-22
144. . Sato Y, Murase K, Kato J, Kobune M, Sato T, Kawano Y, et al. Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone. Nat Biotechnol 2008;26:431-42 (Pubitemid 351501817)
145. . Suzuki K, Aoki K, Ohnami S, Yoshida K, Kazui T, Kato N, et al. Adenovirus-mediated gene transfer of interferon alpha improves dimethylnitrosamine-induced liver cirrhosis in rat model. Gene Ther 2003;10:765-73 (Pubitemid 36621820)
146. . Iimuro Y, Nishio T, Morimoto T, Nitta T, Stefanovic B, Choi SK, et al. Delivery of matrix metalloproteinase-1 attenuates established liver fibrosis in the rat. Gastroenterology 2003;124:445-58 (Pubitemid 36169261)
147. . Arias M, Sauer-Lehnen S, Treptau J, Janoschek N, Theuerkauf I, Buettner R, et al. Adenoviral expression of a transforming growth factor-beta1 antisense mRNA is effective in preventing liver fibrosis in bile-duct ligated rats. BMC Gastroenterol 2003;3:29-40
148. . Hung KS, Lee TH, Chou WY, Wu CL, Cho CL, Lu CN et al. Interleukin-10 gene therapy reverses thioacetamide-induced liver fibrosis in mice. Biochem Biophys Res Commun 2005;336:324-31
149. . Wang CH, Lee TH, Lu CN, Chou WY, Hung KS, Concejero AM, et al. Electroporative alpha-MSH gene transfer attenuates thioacetamideinduced murine hepatic fibrosis by MMP and TIMP modulation. Gene Ther 2006;13:1000-9 (Pubitemid 43905853)
150. . Dooley S, Hamzavi J, Breitkopf K, Wiercinska E, Said HM, Lorenzen J, et
151. . Zhong Z, Froh M, Wheeler MD, Smutney O, Lehmann TG, Thurman RG. Viral gene delivery of superoxide dismutase attenuates experimental cholestasis-induced liver fibrosis in the rat. Gene Ther 2002;9:183-91 (Pubitemid 34189578)
152. . Tsui TY, Lau CK, Ma J, Wu X, Wang YQ, Farkas S, et al. rAAV-mediated stable expression of heme oxygenase-1 in stellate cells: a new approach to attenuate liver fibrosis in rats. Hepatology 2005;42:335-42 (Pubitemid 41061086)
153. . Siller-Lopez F, Sandoval A, Salgado S, Salazar A, Bueno M, Garcia J, et al. Treatment with human metalloproteinase-8 gene delivery ameliorates experimental rat liver cirrhosis. Gastroenterology 2004;126:1122-33 (Pubitemid 38451183)
154. . Borkham-Kamphorst E, Stoll D, Gressner AM, Weiskirchen R. Antisense strategy against PDGF B-chain proves effective in preventing experimental liver fibrogenesis. Biochem Biophys Res Commun 2004;321:413-23 (Pubitemid 39055762)
155. . Matsuno Y, Iwata H, Umeda Y, Takagi H, Mori Y, Kosugi A, et al. Hepatocyte growth factor gene transfer into the liver via the portal vein using electroporation attenuates rat liver cirrhosis. Gene Ther 2003;10:1559-66 (Pubitemid 37063261)
156. . Kakinuma S, Nakauchi H, Watanabe M. Hepatic stem/progenitor cells and stem-cell transplantation for the treatment of liver disease. J Gastroenterol 2009;44,167-72
157. . Zhou P, Wirthlin L, McGee J, Annett G, Nolta J. Contribution of human hematopoietic stem cells to liver repair. Semin Immunopathol 2009;31:411-19
158. . Matsumoto T, Terai S, Oishi T, Kuwashiro F, Fujisawa S, Yamamoto N, et al. Medaka as a model for human nonalcoholic Steatohepatitis. Dis Model Mech 2010;3,431-40
159. Said E, Said SA, Elkashef WF, Gameil NM, Ammar EM. Tranilast ameliorates impaired hepatic functions in Schistosoma mansoniinfected mice. Inflammopharmacology 2012;20:77-87.