Abstract

Liver fibrosis is a chronic and complex pathological process, occuring in patients with chronic liver diseases. The most common cause of liver fibrosis is the alcoholic liver disease, viral hepatitis type B, C and D, as well as autoimmune diseases. Other causes include metabolic dysfunctions like hemachromatosis and Wilson’s disease, biliary duct disorders, damaging effects of medicine and parasite infections. Fibrosis’ dynamics and progres speed depend on the nature of underlying mechanisms and are characterized by accumulation of ECM elements. They vary from patient to patient and are directly correlated to aberrations of homeostasis degradation and production of liver connective tissue. In liver fibrosis the main source of ECM are hepatic stellate cells (HSCS), although other cells are also able to produce ECM such as: portal fibroblasts, narrow-derived cells, biliary duct epithelial cells and epithelial mesenchymal transition hepatocytes. The HSCS activity is stimulated by proinflammatory cytokines, oxidative and nitrosative stress which lead to different pathologies such as: inflammation, steatosis, fibrosis, cirrhosis, liver-cell cancer. Alcohol, the main fibrotic agents is metabolized almost entirely in the liver, so the organ is extremely sensitive to its negative intermediate and mediate influence. Factors influencing alcoholic liver failure are not only oxidative and nitrosative stress and proinflammatory cytokines activity, but also reductive stress, hepatocytes; hypoxia, mucous membranę dysfunction and intestine flora influence, as well as genetic and immunological factors. Though in last several yers there has been a great advancement in our knowledge of liver fibrosis mechanisms, it remains tough to diagnose the proces in its early stages and consequently apply an efficient therapy. The challenge for the futur is finding useful biomarkers and new therapeutic goals.

References

• 1. Arthur M.J.: Fibrosis and altered matrix degradation. Digestion, 1998; 59(4): 376–80
  Google Scholar
• 2. Aydin M.M., Akçali K.C.: Liver fibrosis. Turk. J. Gastroenterol., 2018; 29: 14–21
  Google Scholar
• 3. Bartosz G.: Druga twarz tlenu. Wolne rodniki w przyrodzie. Wydawnictwo Naukowe PWN, Warszawa 2013
  Google Scholar
• 4. Baszczuk A., Kęsy L., Kopczyński Z.: Wartość badań laboratoryjnych w diagnostyce włóknienia wątroby. Nowiny Lekarskie, 2012; 81: 175–81
  Google Scholar
• 5. Bataller R., Brenner D.A.: Liver fibrosis. J. Clin. Invest., 2005; 115(2): 209–18
  Google Scholar
• 6. Batandier C., Leverve X., Fontaine E.: Opening of the mitochondrial permeability transition pore induces reactive oxygen species production at the level of the respiratory chain complex I. J. Biol. Chem., 2004; 279(17): 17197–204
  Google Scholar
• 7. Bonis P.A., Friedman S.J., Kaplan M.M.: Is liver fibrosis reversible? N. Engl. J. Med., 2001; 344(6): 452–4
  Google Scholar
• 8. Cahill A., Cunnigham C.C., Adachi M., Ishii H., Bailey S.M., Fromenty B., Davies A.: Effects of alcohol and oxidative stress on liver pathology: the role of the mitochondrion. Alcohol Clin. Exp. Res., 2002; 26(6): 907–15
  Google Scholar
• 9. Chen C.H., Chern C.L., Lin C.C., Lu F.J., Shih M.K., Hisieh P.Y., Liu T.Z.: Involvement of reactive oxygen species but not mitochondrial permeability transition in the apoptic induction of human SK-Hep-1 hepatoma cells by shikonin. Planta Med., 2003; 69(12): 1119–24
  Google Scholar
• 10. Crosas-Molist E., Fabregat I.: Role of NADPH oxidases in the redox biology of liver fibrosis. Redox Biol., 2015; 6: 106–11
  Google Scholar
• 11. Desmet V.J., Roskams T.: Cirrhosis reversal: a duel between dogma and myth. J. Hepatol., 2004, 40(5): 860–7
  Google Scholar
• 12. Diesen D.L., Kuo P.C.: Nitric oxide and redox regulation in the liver: part II. Redox biology in pathologic hepatocytes and implications for intervention. J. Surg. Res., 2011; 167(1): 96–112
  Google Scholar
• 13. Friedman S.L.: Liver fibrosis from bench to bedside. J. Hepatol., 2003; 38(Suppl 1): S38–S53
  Google Scholar
• 14. Friedman S.L.: Mechanism of hepatic fibrogenesis. Gastroenterology, 2008; 134(6): 1655–69
  Google Scholar
• 15. Friedman S.L.: Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J. Biol. Chem., 2000; 275(4): 2247–50
  Google Scholar
• 16. Gandhi C.R.: Hepatic stellate cell activation and pro-fibrogenic signals. J. Hepatol., 2017; 67(5): 1104–5
  Google Scholar
• 17. Gandhi C.R.: Oxidative stress and hepatic stellate cells. A paradoxical relationship. Trends Cell. Moll. Biol., 2012; 7: 1–10
  Google Scholar
• 18. Grattagliano I., Calamita G., Cocco T., Wang D.Q., Portincasa P.: Pathogenic role of oxidative and nitrosative stress in primary biliary cirrhosis. World J. Gastroenterol., 2014; 20(19): 5746–59
  Google Scholar
• 19. Gressner A.M., Weiskirchen R.: Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-β as major players and therapeutic targets. J. Cell. Moll. Med., 2006; 10(1): 76–99
  Google Scholar
• 20. Guo J., Friedman S.L.: Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis. Fibrogenesis Tissue Repair, 2010; 3: 21
  Google Scholar
• 21. Haghgoo S.M., Sharafi H., Alavian S.M.: Serum cytokines, adipokines and ferritin for non-invasive assessment of liver fibrosis in chronic liver disease: a systematic review. Clin. Chem. Lab. Med., 2019; 57(5): 577–610
  Google Scholar
• 22. Hayyan M., Hashim M.A., Ainashef I.M.: Superoxide ion: generation and chemical implications. Chem. Rev., 2016; 116(5): 3029–85
  Google Scholar
• 23. Henderson N.C., Forbes S.J.: Hepatic fibrogenesis from within and outwith. Toxicology, 2008; 254(3): 130–5
  Google Scholar
• 24. Higashi T., Friedman S.L., Hoshida Y.: Hepatic stellate cells as key target in liver fibrosis. Adv. Drug Deliv. Rev., 2017; 121: 27–42
  Google Scholar
• 25. Hopkins P.A., Sriskandan S.: Mammalian toll-like receptors: to immunity and beyond. Clin. Exp. Immunol., 2005; 140(3): 395–407
  Google Scholar
• 26. Inagaki Y., Mamura M., Kanamaru Y., Greenwel P., Nemoto T., Takehara K., Ten Dijke P., Nakao A.: Constitutive phosphorylation and nuclear localization of Smad3 are correlated with increased collagen gene transcription in activated hepatitc stellate cells. J. Cell. Physiol., 2001; 187(1): 117–23
  Google Scholar
• 27. Iredale J.P., Thompson A., Henderson N.C.: Extracellular matrix degradation in liver fibrosis: Biochemistry and regulation. Biochim. Biophys. Acta, 2013; 1832(7): 876–83
  Google Scholar
• 28. Kanno T., Sato E.E., Muranaka S., Fujita H., Fujiwara T., Utsumi T., Inoue M., Utsumi K.: Oxidative stress underlies the mechanism for Ca2+-induced permeability transition of mitochondria. Free Radic. Res., 2004; 38(1): 27–35
  Google Scholar
• 29. Klaas M., Kangur T., Viil J., Mäemets-Allas K., Minajeva A., Vadi K., Antsov M., Lapidus N., Järvekülg M., Jaks V.: The alterations in the extracellular matrix composition guide the repair of damaged liver tissue. Sci. Rep., 2016; 6: 27398
  Google Scholar
• 30. Koyama Y., Xu J., Liu X., Brenner D.A.: New developments on the treatment of liver fibrosis. Dig. Dis., 2016; 34(5): 589–96
  Google Scholar
• 31. Lintart K., Bartsch H., Seitz H.K.: The role of reactive oxygen species (ROS) and cytochrome P-450 2E1 in the generation of carcinogenic etheno-DNA adducts. Redox Biol., 2014; 3: 56–62
  Google Scholar
• 32. Marnett L.J.: Oxy radicals, lipid peroxidation and DNA damage. Toxicology, 2002; 181–2: 219–22
  Google Scholar
• 33. Masarone M., Rosato V., Dallio M., Gravina A.G., Aglitti A., Loguercio C., Federico A., Persico M.: Role of oxidative stress in pathophysiology of nonalcoholic fatty liver disease. Oxid. Med. Cell. Longev., 2018; 2018: 9547613
  Google Scholar
• 34. Milkiewicz P.: Elastografia wątroby w codziennej praktce klinicznej. Gastroenterol. Klin., 2017; 9(1): 1–6
  Google Scholar
• 35. Mohamed S.Y., Mostafa E.F., Hanafy A.S., Atia H., Metwally A., Marei A.M.: The relationship between expression of Toll-like receptor 4 in chronic hepatitis C patients and different stages of liver fibrosis. Gastroenterol. Hepatol. Bed Bench, 2017; 10(4): 278–83
  Google Scholar
• 36. Moreira R.K.: Hepatic stellate cells and liver fibrosis. Arch. Pathol. Lab. Med., 2007; 131(11): 1728–34
  Google Scholar
• 37. Mormone E., George J., Nieto N.: Molecular pathogenesis of hepatic fibrosis and current therapeutic approaches. Chem. Biol. Interact., 2011; 193(3): 225–31
  Google Scholar
• 38. Munker S., Wu Y.L., Ding H.G., Liebe R., Weng H.L.: Can a fibrotic liver afford epithelial- mesenchymal transition? World J. Gastroenterol., 2017; 23(26); 4661–8
  Google Scholar
• 39. Plewka K., Szuster-Ciesielska A., Kandefer-Szerszeń M.: Rola komórek gwiaździstych w procesie alkoholowego włóknienia wątroby. Postępy Hig. Med. Dośw., 2009; 63: 303–17
  Google Scholar
• 40. Ramirez A., Vázquez-Sánchez A.Y., Carrión-Robalino N., Camacho J.: Ion channels and oxidative stress as a potential link for the diagnosis or treatment of liver diseases. Oxid. Med. Cell. Longev., 2016; 2016: 3928714
  Google Scholar
• 41. Rizzuto R., De Stefani A., Raffaello A., Mammucari C.: Mitochondria as sensors and regulators of calcium signaling. Nat. Rev. Mol. Cell. Biol., 2012; 13(9): 566–78
  Google Scholar
• 42. Schuppan D., Ruehl M., Somasundaram R., Hahn E.G.: Matrix as a modulator of hepatic fibrogenesis. Semin. Liver Dis., 2001; 21(3): 351–72
  Google Scholar
• 43. Sies H.: Oxidative stress: a concept in redox biology and medicine. Redox Biol., 2015; 4: 180–3
  Google Scholar
• 44. Simon F., Varela D., Cabello-Verrugio C.: Oxidative stress-modulated TRPM ion channels in cell dysfunction and pathological conditions in humans. Cell. Signal., 2013; 25(7): 1614–24
  Google Scholar
• 45. Spengler U., Natermann J.: Immunopathogenesis in hepatitis C virus cirrhosis. Clin. Sci., 2007: 112: 141–55
  Google Scholar
• 46. Stalmiokowitz D.K., Weissbrod A.B.: Liver fibrosis and inflammation. Ann. Hepatol., 2004; 40: 860–7
  Google Scholar
• 47. Tacke F., Trautwein C.: Mechanisms of liver fibrosis resolution. J. Hepatol., 2015; 63(4): 1038–39
  Google Scholar
• 48. Torok N.J.: Dysregulation of redox pathways in liver fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol., 2016; 311(4): G667–G674
  Google Scholar
• 49. Trautwein C., Friedman S.L., Schuppan D., Pinzani M.: Hepatic fibrosis: Concept to treatment. J. Hepatol., 2015; 62(Suppl 1): S15–S24
  Google Scholar
• 50. Tsuchida T., Friedman S.L.: Mechanisms of hepatic stellate cell activation. Nat. Rev. Gastroenterol. Hepatol., 2017, 14(7): 397–411
  Google Scholar
• 51. Tuma D.J.: Role of malondialdehyde-acetaldehyde adducts in liver injury. Free Radic. Biol. Med., 2002; 32(4): 303–8
  Google Scholar
• 52. Urtasun R., Conde de la Rosa L., Nieto N.: Oxidative and nitrosative stress and fibrogenic response. Clin. Liver Dis., 2008; 12(4): 769–90
  Google Scholar
• 53. Valko M., Izakovic M., Mazur M., Rhodes C.J., Telser J.: Role of oxygen radicals in DNA damage and cancer incidence. Mol. Cell. Biochem., 2004; 266(1–2): 37–56
  Google Scholar
• 54. Weber S.N., Bohner A., Dapito D.H., Schwabe R.F., Lammert F.: TLR4 deficiency protects against hepatic fibrosis and diethylnitrosamine-induced precarcinogenic liver injury in fibrotic liver. PLoS One, 2016; 11(7): e0158819
  Google Scholar
• 55. Wynn T.A.: Cellular and molecular mechanism of fibrosis. J. Pathol., 2008; 214(2): 199–210
  Google Scholar
• 56. Yoshikawa T., Naito Y.: What is oxidative stress? JMAJ, 2002; 45(7): 271–6
  Google Scholar
• 57. Yu K., Li Q., Shi G., Li N.: Involvement of epithelial-mesenchymal transition in liver fibrosis. Saudi J. Gastroenterol., 2018; 24: 5–11
  Google Scholar
• 58. Zbodakova O., Chelupsky K., Tureckova J., Sedlacek R.: Metalloproteinases in liver fibrosis: Current insights. Dovepress, 2017; 2017: 25–35
  Google Scholar
• 59. Zhang C.Y., Yuan W.G., He P., Lei J.H., Wang C.X.: Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets. World J. Gastroenterol., 2016; 22(48): 10512–22
  Google Scholar
• 60. Zhao Y.L., Zhu R.T., Sun Y.L.: Epithelial-mesenchymal transition in liver fibrosis. Biomed. Rep., 2016; 4(3): 269–74
  Google Scholar

Full text