Skip to main content
SpringerLink
Log in

Oxidative Stress and Liver Fibrogenesis

  • Chapter
Studies on Hepatic Disorders

  • 995 Accesses

Abstract

Liver fibrogenesis is a dynamic and highly integrated molecular and cellular process, involving the whole tissue and potentially reversible, which drives the progression of chronic liver diseases (CLD) first towards liver fibrosis (i.e., the “result” of fibrogenesis) and eventually towards liver cirrhosis and hepatic failure. Hepatic myofibroblasts (MFs), whatever their origin, are major pro-fibrogenic cells that also represent a critical cellular crossroads able to represent both a source and a target for mediators involved in CLD progression. Oxidative stress, reactive oxygen species (ROS), and redox signalling are believed to play a critical role in the process of activation of MFs as well as in mediating or modulating the phenotypic responses of activated MFs. In particular, hepatic MFs respond to a sustained increase in intracellular levels of ROS or other oxidative stress-related mediators of extracellular origin (i.e., released by damaged hepatocytes or activated inflammatory cells) as well as to a raise in ROS levels that follows exposure to either hypoxic conditions or to several critical polypeptides leading, through ligand–receptor interaction, to activation of NADPH oxidase (NOX) activity.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Friedman SL (2008) Mechanisms of hepatic fibrogenesis. Gastroenterology 134:1655–1669

    PubMed Central  CAS  PubMed  Google Scholar 

  2. Parola M, Marra F, Pinzani M (2008) Myofibroblast—like cells and liver fibrogenesis: emerging concepts in a rapidly moving scenario. Mol Aspects Med 29:58–66

    CAS  PubMed  Google Scholar 

  3. Dranoff JA, Wells RG (2010) Portal fibroblasts: underappreciated mediators of biliary fibrosis. Hepatology 51:1438–1444

    PubMed Central  PubMed  Google Scholar 

  4. Forbes SJ, Parola M (2011) Liver fibrogenic cells. Best Pract Res Clin Gastroenterol 25:207–218

    CAS  PubMed  Google Scholar 

  5. Lee UE, Friedman SL (2011) Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol 25:195–206

    PubMed Central  CAS  PubMed  Google Scholar 

  6. Novo E, Cannito S, Paternostro C, Bocca C, Miglietta A, Parola M (2014) Cellular and molecular mechanisms in liver fibrogenesis. Arch Biochem Biophys 548:20–37

    CAS  PubMed  Google Scholar 

  7. Rosselli M, MacNaughtan J, Jalan M, Pinzani M (2013) Liver cirrhosis. Gut 62:1234–1241

    PubMed  Google Scholar 

  8. El-Serag HB (2011) Hepatocellular carcinoma. N Engl J Med 365:1118–1127

    CAS  PubMed  Google Scholar 

  9. El-Serag HB (2012) Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142:1264–1273

    PubMed Central  PubMed  Google Scholar 

  10. Rehm J, Samokhvalov AV, Shield KD (2013) Global burden of alcoholic liver diseases. J Hepatol 59:160–168

    PubMed  Google Scholar 

  11. Iredale JP, Thompson A, Henderson NC (2013) Extracellular matrix degradation in liver fibrosis: biochemistry and regulation. Biochim Biophys Acta 1832:876–883

    CAS  PubMed  Google Scholar 

  12. Povero D, Busletta C, Novo E, Valfrè di Bonzo L, Cannito S, Paternostro C, Parola M (2010) Liver fibrosis: a dynamic and potentially reversible process. Histol Histopathol 25:1075–1091

    PubMed  Google Scholar 

  13. Cassiman D, Libbrecht L, Desmet V, Denef C, Roskams T (2002) Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers. J Hepatol 36:200–209

    PubMed  Google Scholar 

  14. Novo E, Valfrè di Bonzo L, Cannito S, Colombatto S, Parola M (2008) Hepatic myofibroblasts: a heterogeneous population of multifunctional cells in liver fibrogenesis. Int J Biochem Cell Biol 41:2089–2093

    Google Scholar 

  15. Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, Pradere JP, Schwabe RF (2013) Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun 4:2823. doi:10.1038/ncomms3823

    PubMed Central  PubMed  Google Scholar 

  16. Siani A, Tirelli N (2014) Myofibroblast differentiation: main features, biomedical relevance, and the role of reactive oxygen species. Antioxid Redox Signal 21(5):768–785. doi:10.1089/ars.2013.5724

    CAS  PubMed  Google Scholar 

  17. Pinzani M (2011) Epithelial-mesenchymal transition in chronic liver disease: fibrogenesis or escape from death? J Hepatol 55:459–465

    CAS  PubMed  Google Scholar 

  18. Xie G, Diehl AM (2013) Evidence for and against epithelial-to-mesenchymal transition in the liver. Am J Physiol Gastrointest Liver Physiol 305:G881–G890

    PubMed Central  CAS  PubMed  Google Scholar 

  19. Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, Pradere JP, Schwabe RF (2013) Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun 4:2823. doi:10.1038/ncomms3823

    PubMed Central  PubMed  Google Scholar 

  20. Watson MR, Wallace K, Gieling RG, Manas DM, Jaffray E, Hay RT, Mann DA, Oakley F (2008) NF-κB is a critical regulator of the survival of rodent and human hepatic myofibroblasts. J Hepatol 48:589–597

    CAS  PubMed  Google Scholar 

  21. Novo E, Marra F, Zamara E, Valfrè di Bonzo L, Monitillo L, Cannito S, Petrai I, Mazzocca A, Bonacchi A, De Franco RS, Colombatto S, Autelli R, Pinzani M, Parola M (2006) Overexpression of Bcl-2 by activated human hepatic stellate cells: resistance to apoptosis as a mechanism of progressive hepatic fibrogenesis in humans. Gut 55:1174–1182

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Kendall TJ, Hennedige S, Aucott RL, Hartland SN, Vernon MA, Benyon RC, Iredale JP (2009) p75 neurotrophin receptor signaling regulates hepatic myofibroblast proliferation and apoptosis in recovery from rodent liver fibrosis. Hepatology 49:901–910

    CAS  PubMed  Google Scholar 

  23. Pinzani M, Rombouts K (2004) Liver fibrosis: from the bench to clinical targets. Dig Liver Dis 36:231–242

    CAS  PubMed  Google Scholar 

  24. Robino G, Parola M (2001) Oxidative stress-related molecules and liver fibrosis. J Hepatol 35:297–306

    PubMed  Google Scholar 

  25. Novo E, Parola M (2008) Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis Tissue Repair 1:5

    PubMed Central  PubMed  Google Scholar 

  26. Ryter SW, Choi AM (2005) Heme oxygenase-1: redox regulation of a stress protein in lung and cell culture models. Antioxid Redox Signal 7:80–91

    CAS  PubMed  Google Scholar 

  27. Novo E, Busletta C, Valfrè di Bonzo L, Povero D, Paternostro C, Mareschi K, Ferrero I, David E, Bertolani C, Caligiuri A, Cannito S, Tamagno E, Compagnone A, Colombatto S, Marra F, Fagioli F, Pinzani M, Parola M (2011) Intracellular reactive oxygen species are required for directional migration of resident and bone marrow-derived hepatic pro-fibrogenic cells. J Hepatol 54:964–974

    CAS  PubMed  Google Scholar 

  28. Novo E, Povero D, Busletta C, Paternostro C, di Bonzo LV, Cannito S, Compagnone A, Bandino A, Marra F, Colombatto S, David E, Pinzani M, Parola M (2012) The biphasic nature of hypoxia-induced directional migration of activated human hepatic stellate cells. J Pathol 226:588–597

    CAS  PubMed  Google Scholar 

  29. Bedossa P, Houglum K, Trautwein C, Holstege A, Chojkier M (1994) Stimulation of collagen α 1(I) gene expression is associated with lipid peroxidation in hepatocellular injury. A link to tissue fibrosis? Hepatology 19:1262–1271

    CAS  PubMed  Google Scholar 

  30. Niemela O, Parkkila S, Yla-Herttuala S, Villanueva J, Ruebner B, Halsted CH (1995) Sequential acetaldehyde production, lipid peroxidation and fibrogenesis in micropig model of alcohol induced disease. Hepatology 22:1208–1214

    CAS  PubMed  Google Scholar 

  31. Tsukamoto H, Horne W, Kamimura S, Niemela O, Parkkila S, Yla-Herttuala S, Brittenham GM (1995) Experimental liver cirrhosis induced by alcohol and iron. J Clin Invest 96:620–630

    PubMed Central  CAS  PubMed  Google Scholar 

  32. Parola M, Pinzani M, Casini A, Albano E, Poli G, Gentilini A, Gentilini P, Dianzani MU (1993) Stimulation of lipid peroxidation or 4-hydroxynonenal treatment increases procollagen α 1(I) gene expression in human liver fat-storing cells. Biochem Biophys Res Commun 194:1044–1050

    CAS  PubMed  Google Scholar 

  33. Casini A, Ceni E, Salzano R, Biondi P, Parola M, Galli A, Foschi M, Caligiuri A, Pinzani M, Surrenti C (1997) Neutrophil-derived superoxide anion induces lipid peroxidation and stimulates collagen synthesis in human hepatic stellate cells: role of nitric oxide. Hepatology 25:361–367

    CAS  PubMed  Google Scholar 

  34. Maher JJ, Tzagarakis C, Gimenez A (1994) Malondialdehyde stimulates collagen production by hepatic lipocytes only upon activation in primary culture. Alcohol Alcohol 29:605–610

    CAS  PubMed  Google Scholar 

  35. Parola M, Pinzani M, Casini A, Leonarduzzi G, Marra F, Caligiuri A, Ceni E, Biondi P, Poli G, Dianzani MU (1996) Induction of procollagen type I gene expression and synthesis in human hepatic stellate cells by 4-hydroxy-2,3-nonenal and other 4-hydroxy-2,3-alkenals is related to their molecular structure. Biochem Biophys Res Commun 1996(222):261–264

    Google Scholar 

  36. Comporti M, Arezzini B, Signorini C, Sgherri C, Monaco B, Gardi C (2005) F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis? Lab Invest 2005(85):1381–1391

    Google Scholar 

  37. Svegliati Baroni G, D'Ambrosio L, Ferretti G, Casini A, Di Sario A, Salzano R, Ridolfi F, Saccomanno S, Jezequel AM, Benedetti A (1998) Fibrogenic effect of oxidative stress on rat hepatic stellate cells. Hepatology 27:720–726

    CAS  PubMed  Google Scholar 

  38. Nieto N, Friedman SL, Cederbaum AI (2002) Cytochrome P502E1-derived reactive oxygen species mediate paracrine stimulation of collagen I protein synthesis by hepatic stellate cells. J Biol Chem 277:9853–9864

    CAS  PubMed  Google Scholar 

  39. Nieto N, Cederbaum AI (2003) Increased Sp1-dependent transactivation of the LAMã promoter in hepatic stellate cells co-cultured with HepG2 cells overexpressing cytochrome P450 2E1. J Biol Chem 278:15360–15372

    CAS  PubMed  Google Scholar 

  40. Parola M, Robino G, Marra F, Pinzani M, Bellomo G, Leonarduzzi G, Chiarugi P, Camandola S, Poli G, Waeg G, Gentilini P, Dianzani MU (1998) HNE interacts directly with JNK isoforms in human hepatic stellate cells. J Clin Invest 102:1942–1950

    PubMed Central  CAS  PubMed  Google Scholar 

  41. Chen A, Davis BH (1999) UV irradiation activates JNK and increases alpha (I) collagen gene expression in rat hepatic stellate cells. J Biol Chem 274:158–164

    CAS  PubMed  Google Scholar 

  42. Greenwel P, Dominguez-Rosales JA, Mavi G, Rivas-Estilla AM, Rojkind M (2000) Hydrogen peroxide: a link between acetaldehyde-elicited alpha1(I) collagen gene up-regulation and oxidative stress in mouse hepatic stellate cells. Hepatology 31:109–116

    CAS  PubMed  Google Scholar 

  43. Chen A, Davis BH (2000) The DNA binding protein BTEB mediates acetaldehyde-induced, Jun N-terminal kinase-dependent alphaI(I) collagen gene expression in rat hepatic stellate cells. Mol Cell Biol 20:2818–2826

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Nieto N, Friedman SL, Greenwel P, Cederbaum AI (1999) Cyp2E1-mediated oxidative stress induces collagen type I expression in rat hepatic stellate cells. Hepatology 30:987–996

    CAS  PubMed  Google Scholar 

  45. Nieto N, Greenwel P, Friedman SL, Zhang F, Dannenberg AJ, Cederbaum AI (2000) Ethanol and arachidonic acid increase α 2 (I) collagen expression in rat hepatic stellate cells overexpressing cytochrome P450 2E1. J Biol Chem 26:20136–20145

    Google Scholar 

  46. Garcia-Trevijano E, Iraburu MJ, Fontana L, Dominguez-Rosales JA, Auster A, Covarrubias-Pinedo A, Rojkind M (1999) Trasforming growth factor β1 induces the expression of α (I) procollagen mRNA by a hydrogen peroxide-C/EBPβ-dependent mechanism in rat hepatic stellate cells. Hepatology 29:960–970

    CAS  PubMed  Google Scholar 

  47. Leonarduzzi G, Scavazza A, Biasi F, Chiarpotto E, Camandola S, Vogel S, Dargel R, Poli G (1997) The lipid peroxidation end product 4-hydroxy-2,3-nonenal up-regulates transforming growth factor β1 expression in the macrophage lineage: a link between oxidative injury and fibrosclerosis. FASEB J 11:851–857

    CAS  PubMed  Google Scholar 

  48. Czaja MJ (2007) Cell signaling in oxidative stress-induced liver injury. Semin Liver Dis 27:378–389

    CAS  PubMed  Google Scholar 

  49. Paik YH, Kim J, Aoyama T, De Minicis S, Bataller R, Brenner DA (2014) Role of NADPH oxidases in liver fibrosis. Antioxid Redox Signal 20:2854–2872

    CAS  PubMed  Google Scholar 

  50. Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313

    CAS  PubMed  Google Scholar 

  51. Bataller R, Schwabe RF, Choi YH, Yang L, Paik YH, Lindquist J, Qian T, Schoonhoven R, Hagedorn CH, Lemasters JJ, Brenner DA (2003) NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest 112:1383–1394

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Bureau C, Bernad J, Chaouche N, Orfila C, Béraud M, Gonindard C, Alric L, Vinel JP, Pipy B (2001) Nonstructural 3 protein of hepatitis C virus triggers an oxidative burst in human monocytes via activation of NADPH oxidase. J Biol Chem 276:23077–23083

    CAS  PubMed  Google Scholar 

  53. Thorén F, Romero A, Lindh M, Dahlgren C, Hellstrand K (2004) A hepatitis C virus-encoded, nonstructural protein (NS3) triggers dysfunction and apoptosis in lymphocytes: role of NADPH oxidase-derived oxygen radicals. J Leukoc Biol 76:1180–1186

    PubMed  Google Scholar 

  54. Bataller R, Paik YH, Lindquist JN, Lemasters JJ, Brenner DA (2004) Hepatitis C virus core and nonstructural proteins induce fibrogenic effects in hepatic stellate cells. Gastroenterology 126:529–540

    CAS  PubMed  Google Scholar 

  55. Boudreau HE, Emerson SU, Korzeniowska A, Jendrysik MA, Leto TL (2009) Hepatitis C virus (HCV) proteins induce NADPH oxidase 4 expression in a transforming growth factor beta-dependent manner: a new contributor to HCV-induced oxidative stress. J Virol 83:12934–12946

    PubMed Central  CAS  PubMed  Google Scholar 

  56. Jiang JX, Chen X, Serizawa N, Szyndralewiez C, Page P, Schröder K, Brandes RP, Devaraj S, Török NJ (2012) Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo. Free Radic Biol Med 53(2):289–296

    PubMed Central  CAS  PubMed  Google Scholar 

  57. Reinehr R, Becker S, Eberle A, Grether-Beck S, Häussinger D (2005) Involvement of NADPH oxidase isoforms and Src family kinases in CD95-dependent hepatocyte apoptosis. J Biol Chem 280:27179–27194

    CAS  PubMed  Google Scholar 

  58. Yang L, Roh YS, Song J, Zhang B, Liu C, Loomba R, Seki E (2014) Transforming growth factor beta signaling in hepatocytes participates in steatohepatitis through regulation of cell death and lipid metabolism in mice. Hepatology 59:483–495

    PubMed Central  CAS  PubMed  Google Scholar 

  59. Lee KS, Buck M, Houglum K, Chojkier M (1995) Activation of hepatic stellate cells by TGF alpha and collagen type I is mediated by oxidative stress through c-myb expression. J Clin Invest 96:2461–2468

    PubMed Central  CAS  PubMed  Google Scholar 

  60. Novo E, Marra F, Zamara E, Valfrè di Bonzo L, Caligiuri A, Cannito S, Antonaci C, Colombatto S, Pinzani M, Parola M (2006) Dose dependent and divergent effects of superoxide anion on cell death, proliferation, and migration of activated human hepatic stellate cells. Gut 55:90–97

    PubMed Central  CAS  PubMed  Google Scholar 

  61. Zamara E, Novo E, Marra F, Gentilini A, Romanelli RG, Caligiuri A, Robino G, Tamagno E, Aragno M, Danni O, Autelli R, Colombatto S, Dianzani MU, Pinzani M, Parola M (2004) 4-Hydroxynonenal as a selective pro-fibrogenic stimulus for activated human hepatic stellate cells. J Hepatol 40:60–68

    CAS  PubMed  Google Scholar 

  62. Novo E, Marra F, Zamara E, Valfrè di Bonzo L, Monitillo L, Cannito S, Petrai I, Mazzocca A, Bonacchi A, De Franco RS, Colombatto S, Autelli R, Pinzani M, Parola M (2006) Overexpression of Bcl-2 by activated human hepatic stellate cells: resistance to apoptosis as a mechanism of progressive hepatic fibrogenesis in humans. Gut 55:1174–1182

    PubMed Central  CAS  PubMed  Google Scholar 

  63. Colmenero J, Bataller R, Sancho-Bru P, Bellot P, Miquel R, Moreno M, Jares P, Bosch J, Arroyo V, Caballeria J, Gines P (2007) Hepatic expression of candidate genes in patients with alcoholic hepatitis: correlation with disease severity. Gastroenterology 132:687–697

    CAS  PubMed  Google Scholar 

  64. de Mochel NS, Seronello S, Wang SH, Ito C, Zheng JX, Liang TJ, Lambeth JD, Choi J (2010) Hepatocyte NAD(P)H oxidases as an endogenous source of reactive oxygen species during hepatitis C virus infection. Hepatology 52:47–59

    PubMed Central  PubMed  Google Scholar 

  65. Paik YH, Iwaisako K, Seki E, Inokuchi S, Schnabl B, Osterreicher CH, Kisseleva T, Brenner DA (2011) The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91(phox) mediate hepatic fibrosis in mice. Hepatology 53:1730–1741

    PubMed Central  CAS  PubMed  Google Scholar 

  66. Adachi T, Togashi H, Suzuki A, Kasai S, Ito J, Sugahara K, Kawata S (2005) NAD(P)H oxidase plays a crucial role in PDGF-induced proliferation of hepatic stellate cells. Hepatology 41:1272–1281

    CAS  PubMed  Google Scholar 

  67. De Minicis S, Seki E, Oesterreicher C, Schnabl B, Schwabe RF, Brenner DA (2008) Reduced nicotinamide adenine dinucleotide phosphate oxidase mediates fibrotic and inflammatory effects of leptin on hepatic stellate cells. Hepatology 48:2016–2026

    PubMed  Google Scholar 

  68. Guimaraes EL, Empsen C, Geerts A, van Grunsven LA (2010) Advanced glycation end products induce production of reactive oxygen species via the activation of NADPH oxidase in murine hepatic stellate cells. J Hepatol 52:389–397

    CAS  PubMed  Google Scholar 

  69. Zhan SS, Jiang JX, Wu J, Halsted C, Friedman SL, Zern MA, Torok NJ (2006) Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo. Hepatology 43:435–443

    CAS  PubMed  Google Scholar 

  70. Aoyama T, Paik YH, Watanabe S, Laleu B, Gaggini F, Fioraso-Cartier L, Molango S, Heitz F, Merlot C, Szyndralewiez C, Page P, Brenner DA (2012) Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology 56:2316–2327

    PubMed Central  CAS  PubMed  Google Scholar 

  71. Cui W, Matsuno K, Iwata K, Ibi M, Matsumoto M, Zhang J, Zhu K, Katsuyama M, Torok NJ, Yabe-Nishimura C (2011) NOX1/nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase promotes proliferation of stellate cells and aggravates liver fibrosis induced by bile duct ligation. Hepatology 54:949–958

    CAS  PubMed  Google Scholar 

  72. Pinzani M, Gesualdo L, Sabbah GM, Abboud HE (1989) Effects of platelet-derived growth factor and other polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat-storing cells. J Clin Invest 84:1786–1793

    PubMed Central  CAS  PubMed  Google Scholar 

  73. Bataller R, Sancho-Bru P, Gines P, Brenner DA (2005) Liver fibrogenesis: a new role for the renin-angiotensin system. Antioxid Redox Signal 7:1346–1355

    CAS  PubMed  Google Scholar 

  74. Paizis G, Cooper ME, Schembri JM, Tikellis C, Burrell LM, Angus PW (2002) Up-regulation of components of the renin angiotensin system in the bile duct-ligated rat liver. Gastroenterology 123:1667–1676

    CAS  PubMed  Google Scholar 

  75. Griendling KK, Ushio-Fukai M (2000) Reactive oxygen species as mediators of angiotensin II signaling. Regul Pept 91:21–27

    CAS  PubMed  Google Scholar 

  76. Bataller R, Gines P, Nicolas JM, Gorbig MN, Garcia-Ramallo E, Gasull X, Bosch J, Arroyo V, Rodes J (2000) Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology 118:1149–1156

    CAS  PubMed  Google Scholar 

  77. Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, Tsujinoue H, Fukui H (2001) Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology 34:745–750

    CAS  PubMed  Google Scholar 

  78. Wang B, Trippler M, Pei R, Lu M, Broering R, Gerken G, Schlaak JF (2009) Toll-like receptor activated human and murine hepatic stellate cells are potent regulators of hepatitis C virus replication. J Hepatol 51:1037–1045

    CAS  PubMed  Google Scholar 

  79. Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA (2003) Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology 37:1043–1055

    CAS  PubMed  Google Scholar 

  80. Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA, Schwabe RF (2007) TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 13(1324–1332):2007

    Google Scholar 

  81. Fernández M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J (2009) Angiogenesis in liver diseases. J Hepatol 50:604–620

    PubMed  Google Scholar 

  82. Valfrè di Bonzo L, Novo E, Cannito S, Busletta C, Paternostro C, Povero D, Parola M (2009) Angiogenesis and liver fibrogenesis. Histol Histopathol 23(2009):1324–1341

    Google Scholar 

  83. Semenza GL (2012) Hypoxia-inducible factors in physiology and medicine. Cell 148:399–408

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307

    PubMed Central  CAS  PubMed  Google Scholar 

  85. Novo E, Cannito S, Zamara E, Valfrè di Bonzo L, Caligiuri A, Cravanzola C, Compagnone A, Colombatto S, Marra F, Pinzani M, Parola M (2007) Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. Am J Pathol 170:1942–1953

    PubMed Central  CAS  PubMed  Google Scholar 

  86. Moon J-K, Welch TP, Gonzalez FJ, Copple BL (2009) Reduced liver fibrosis in hypoxia-inducible factor-1alpha-deficient mice. Am J Physiol Gastrointest Liver Physiol 296:G582–G592

    PubMed Central  CAS  PubMed  Google Scholar 

  87. Novo E, Povero D, Busletta C, Paternostro C, Valfrè di Bonzo L, Cannito S, Compagnone A, Bandino A, Marra F, Colombatto S, David E, Pinzani M, Parola M (2012) The biphasic nature of hypoxia-induced directional migration of activated human hepatic stellate cells. J Pathol 226:588–597

    CAS  PubMed  Google Scholar 

  88. Novo E, Busletta C, Valfrè di Bonzo L, Povero D, Paternostro C, Mareschi K, Ferrero I, David E, Bertolani C, Caligiuri A, Cannito S, Tamagno E, Compagnone A, Colombatto S, Marra F, Fagioli F, Pinzani M, Parola M (2011) Dissection of the biphasic nature of hypoxia-induced motogenic action in bone marrow-derived human mesenchymal stem cells. J Hepatol 54:964–974

    CAS  PubMed  Google Scholar 

  89. Semela D, Das A, Langer D, Kang N, Leof E, Shah V (2008) Platelet-derived growth factor signaling through ephrin-b2 regulates hepatic vascular structure and function. Gastroenterology 135:671–679

    PubMed Central  CAS  PubMed  Google Scholar 

  90. Aleffi S, Petrai I, Bertolani C, Parola M, Colombatto S, Novo E, Vizzutti F, Anania FA, Milani S, Rombouts K, Laffi G, Pinzani M, Marra F (2005) Upregulation of pro-inflammatory and pro-angiogenic cytokines by leptin in human hepatic stellate cells. Hepatology 42:1339–1348

    CAS  PubMed  Google Scholar 

  91. Aleffi S, Navari N, Delogu W, Galastri S, Novo E, Rombouts K, Pinzani M, Parola M, Marra F (2011) Mammalian target of rapamycin mediates the angiogenic effects of leptin in human hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 301:G210–G219

    CAS  PubMed  Google Scholar 

  92. Pinzani M, Rombouts K, Colagrande S (2005) Fibrosis in chronic liver diseases: diagnosis and management. J Hepatol 42(Suppl 1):S22–S36

    PubMed  Google Scholar 

  93. Chang CY, Argo CK, Al-Osaimi AMS, Caldwell SH (2006) Therapy of NAFLD: antioxidants and cytoprotective agents. J Clin Gastroenterol 40(Suppl 1):S51–S60

    CAS  PubMed  Google Scholar 

  94. de Alwis NMW, Day CP (2008) Non-alcoholic fatty liver: the mist gradually clear. J Hepatol 48(Suppl 1):S105–S112

    Google Scholar 

  95. Lieber CS, Weiss DG, Groszmann R, Paronetto F, Schenker S (2003) II. Veterans Affairs Cooperative Study of polyenylphosphatidylcholine in alcoholic liver disease. Alcohol Clin Exp Res 27:1765–1772

    CAS  PubMed  Google Scholar 

  96. Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, Lymp JF, Burgart L, Colin P (2004) Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 39:770–778

    CAS  PubMed  Google Scholar 

  97. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR (2010) Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 362:1675–1685

    PubMed Central  CAS  PubMed  Google Scholar 

  98. Zarski JP, Sturm N, Desmorat H, Melin P, Raabe JJ, Bonny C, Sogni P, Pinta A, Rouanet S, Babany G, Cheveau A, Chevallier M (2010) Non-invasive assessment of liver fibrosis progression in hepatitis C patients retreated for 96 weeks with antiviral therapy: a randomized study. Liver Int 30:1049–1058

    CAS  PubMed  Google Scholar 

  99. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E (2005) Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142:37–46

    CAS  PubMed  Google Scholar 

  100. Colmenero J, Bataller R, Sancho-Bru P, Dominguez M, Moreno M, Forns X, Bruguera M, Arroyo V, Brenner DA, Gines P (2009) Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C. Am J Physiol Gastrointest Liver Physiol 297:G726–G734

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Corey KE, Shah N, Misdraji J, Abu Dayyeh BK, Zheng H, Bhan AK, Chung RT (2009) The effect of angiotensin-blocking agents on liver fibrosis in patients with hepatitis C. Liver Int 29:748–753

    PubMed Central  CAS  PubMed  Google Scholar 

  102. Rimola A, Londono MC, Guevara G, Bruguera M, Navasa M, Forns X, Garcia-Retortillo M, Garcia-Valdecasas JC, Rodes J (2004) Beneficial effect of angiotensin-blocking agents on graft fibrosis in hepatitis C recurrence after liver transplantation. Transplantation 78:686–691

    CAS  PubMed  Google Scholar 

  103. Sookoian S, Fernandez MA, Castano G (2005) Effects of six months losartan administration on liver fibrosis in chronic hepatitis C patients: a pilot study. World J Gastroenterol 11:7560–7563

    CAS  PubMed  Google Scholar 

  104. Zarski JP, Sturm N, Desmorat H, Melin P, Raabe JJ, Bonny C, Sogni P, Pinta A, Rouanet S, Babany G, Cheveau A, Chevallier M (2010) Non-invasive assessment of liver fibrosis progression in hepatitis C patients retreated for 96 weeks with antiviral therapy: a randomized study. Liver Int 30:1049–1058

    CAS  PubMed  Google Scholar 

  105. Kim MY, Cho MY, Baik SK, Jeong PH, Suk KT, Jang YO, Yea CJ, Kim JW, Kim HS, Kwon SO, Yoo BS, Kim JY, Eom MS, Cha SH, Chang SJ (2012) Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis—a randomized open-label controlled study. Liver Int 32:977–987

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical and Biological Sciences, Unit of Experimental Medicine, University of Torino, C.so Raffaello 30, Torino, 10125, Italy

    Erica Novo & Maurizio Parola

  2. Interuniversity Centre for Liver Pathophysiology, University of Torino, C.so Raffaello 30, Torino, 10125, Italy

    Erica Novo & Maurizio Parola

  3. Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, Florence, 50134, Italy

    Fabio Marra

  4. Center for Research, Transfer and Higher Education DenoTHE, University of Florence, Largo Brambilla 3, Florence, 50134, Italy

    Fabio Marra

Authors
  1. Erica Novo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fabio Marra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maurizio Parola
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maurizio Parola .

Editor information

Editors and Affiliations

  1. Department of Health Sciences, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy

    Emanuele Albano

  2. Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, School of Medicine, University of Torino, Torino, Italy

    Maurizio Parola

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Novo, E., Marra, F., Parola, M. (2015). Oxidative Stress and Liver Fibrogenesis. In: Albano, E., Parola, M. (eds) Studies on Hepatic Disorders. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Cham. https://doi.org/10.1007/978-3-319-15539-5_8

Download citation

Publish with us

Policies and ethics

Search

Navigation