THE ROLE OF ENDOTHELIUM IN THE FORMATION OF LIVER FIBROSIS

Chronic liver disease is a worldwide health problem. A significant proportion of the manifestations and complications of chronic liver diseases is due to liver fibrosis and its subsequent transition to liver cirrhosis. The initial and the key link in the formation of fibrotic changes in the liver are liver sinusoidal endothelial cells (LSEC). In view of the unique structure and central position of the liver endothelial tissue in the pathogenesis of fibrosis, it seems relevant to present current data in the form of this review. LSECs are the only endothelial cells in the body that lack a basement membrane and contain transcellular pores called fenestrae. At the initial stages of the fibrogenesis process, LSECs change their phenotype: they lose fenestrae and develop a basement membrane, turning into a continuous endothelium. LSECs are involved in fibrosis through the secretion of angiocrine signals that act as paracrine factors that balance the liver’s response to injury towards fibrosis or regeneration. LSEC cells are very sensitive to the slightest changes in the microenvironment, with prolonged exposure they quickly change their phenotype, their numerous functions are disrupted, including vasodilator, anti-inflammatory, antithrombotic and antifibrotic, as well as the regulation of angiogenesis and regeneration, and prevention of HSC activation. Such changes in the phenotype are called endothelial dysfunction. Loss of fenestres (capillaryization) by LSEC cells is the initial event in liver fibrosis. It precedes HSC activation and promotes fibrosis and progression to cirrhosis. Fenestra maintains liver homeostasis, promotes efficient transport of lipoproteins, regulates liver regeneration and immune tolerance. LSEC fenestra are approximately 50-200 nm in diameter, and most of them are clustered into several dozen ultrastructures called sieve plates. Chronic liver injury leads to deep dedifferentiation of LSECs, which lose their vasoprotective properties and become vasoconstrictive, proinflammatory, and prothrombotic. Major molecular dysregulations seen in LSEC in chronic liver disease 

include fenestra loss and basement membrane development that interfere with the exchange of molecules such as lipoproteins and oxygen with hepatocytes, promoting steatosis and parenchymal apoptosis; reduction of NO by suppression of KLF2 and endothelial NO synthase (eNOS) activity, together with an increase in ROS-mediated NO uptake, leading to activation of hepatic stellate cells and deposition of extracellular matrix; increased production of vasoconstrictors (such as endothelin 1 or thromboxane A2) and pro-inflammatory cytokines, further exacerbating sinusoidal constriction. These pathological changes lead to sinusoidal vasoconstriction, microvascular dysfunction, fibrosis, and ultimately portal hypertension. Thus, LSECs play complex interrelated roles in maintaining liver homeostasis and are involved as factors in inflammation and fibrogenesis in liver diseases. Their unique position, phenotype, and function make them attractive candidates for organ-specific therapies, and it is likely that more therapies targeting these cells will be tested in the future as novel therapies to reduce liver damage and inflammation, and to prevent or reversal of fibrogenesis.

1. Parola M., Pinzani M. Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues // Mol Aspects Med. – 2019. – № 65 – P. 37-55. doi: 10.1016/j.mam.2018.09.002.

2. Ginès P., Castera L., Lammert F. et al. LiverScreen Consortium Investigators. Population screening for liver fibrosis: Toward early diagnosis and intervention for chronic liver diseases // Hepatology. – 2022. – № 75(1). – P. 219-228. doi: 10.1002/hep.32163.

3. Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study // Lancet Gastroenterol Hepatol. – 2018. – № 3(6). – P. 383-403. doi: 10.1016/S2468-1253(18)30056-6.

4. Spearman C.W., Dusheiko G.M., Hellard M., Sonderup M. Hepatitis C // Lancet. – 2019. – № 394(10207). – P. 1451-1466. doi: 10.1016/S0140-6736(19)32320-7.

5. Seitz H.K., Bataller R., Cortez-Pinto H. et al. Alcoholic liver disease // Nat Rev Dis Primers. – 2018. – № 4(1). – P. 16. doi: 10.1038/s41572-018-0014-7.

6. Powell E.E., Wong V.W., Rinella M. Non-alcoholic fatty liver disease // Lancet. – 2021. – № 397(10290). – P. 2212-2224. doi: 10.1016/S0140-6736(20)32511-3.

7. Tanaka A. Current understanding of primary biliary cholangitis // Clin Mol Hepatol. – 2021. – № 27(1). – P. 1-21. doi: 10.3350/cmh.2020.0028.

8. Sarcognato S., Sacchi D., Grillo F., et al. Autoimmune biliary diseases: primary biliary cholangitis and primary sclerosing cholangitis // Pathologica. – 2021. – № 113(3). – P. 170-184. doi: 10.32074/1591-951X-245.

9. Sucher E., Sucher R., Gradistanac T., Brandacher G., Schneeberger S., Berg T. Autoimmune HepatitisImmunologically Triggered Liver Pathogenesis-Diagnostic and Therapeutic Strategies // J Immunol Res. – 2019. – № 2019. P.9437043. doi: 10.1155/2019/9437043.

10. Sandahl T.D., Laursen T.L., Munk D.E., Vilstrup H., Weiss K.H., Ott P. The Prevalence of Wilson’s Disease: An Update // Hepatology. – 2020. – № 71(2). – P. 722-732. doi: 10.1002/hep.30911.

11. Brissot P., Pietrangelo A., Adams P.C., de Graaff B., McLaren C.E., Loréal O. Haemochromatosis // Nat Rev Dis Primers. – 2018. – № 4. P. 18016. doi: 10.1038/nrdp.2018.16.

12. Craig T.J., Henao M.P. Advances in managing COPD related to α1 -antitrypsin deficiency: An underrecognized genetic disorder // Allergy. – 2018. – № 73(11). – P. 2110-2121. doi: 10.1111/all.13558.

13. Sun M., Kisseleva T. Reversibility of liver fibrosis // Clin Res Hepatol Gastroenterol. – 2015. – № 39. – P. S 60–3.

14. Bataller R., Brenner D.A. Liver fibrosis // J Clin Invest. – 2005. – № 115. – P. 209–18. https://doi.org/10.1172/JCI24282

15. World Health Organization (WHO). Viral Hepatitis B Fact Sheet June 24, 2022 [Electronic resource] URL: https://www.who.int/news-room/fact-sheets/detail/hepatitis-b

16. Aydın M.M., Akçalı K.C. Liver fibrosis // Turk J Gastroenterol. – 2018. – № (1). – P. 14-21. doi: 10.5152/tjg.2018.17330.

17. Maurizio P., Massimo P. Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues // Molecular Aspects of Medicine. – 2019. – № 65. P. 37-55. doi: 10.1016/j.mam.2018.09.002.

18. Povero D., Busletta C., Novo E., di Bonzo L.V., Cannito S., Paternostro C., Parola M. Liver fibrosis: a dynamic and potentially reversible process // Histol Histopathol. – 2010. – № 25(8). – P. 1075-91. doi: 10.14670/HH-25.1075.

19. Lafoz E., Ruart M., Anton A., Oncins A., Hernández-Gea V. The Endothelium as a Driver of Liver Fibrosis and Regeneration // Cells. – 2020. – № 9(4). – P. 929. doi: 10.3390/cells9040929.

20. Gracia-Sancho J., Caparrós E., Fernández-Iglesias A., Francés R. Role of liver sinusoidal endothelial cells in liver diseases // Nat Rev Gastroenterol Hepatol. – 2021. – № 18(6). – P. 411-431. doi: 10.1038/s41575-020-00411-3.

21. Gracia-Sancho J., Marrone G., Fernández-Iglesias. A. Hepatic microcirculation and mechanisms of portal hypertension // Nat. Rev. Gastroenterol. Hepatol. – 2019. – № 16. – P. 221–234.

22. Smedsrød B. et al. Cell biology of liver endothelial and Kupffer cells. – 1994. – № 35. – P. 1509–1516.

23. Couvelard A., Scoazec J.Y., Dauge M.C., Bringuier A.F., Potet F., Feldmann G. Structural and Functional Differentiation of Sinusoidal Endothelial Cells during Liver Organogenesis in Humans // Blood. –1996. – № 87. – P. 4568–4580. doi: 10.1182/blood.V87.11.4568.bloodjournal87114568

24. McCuskey R.S. Morphological Mechanisms for Regulating Blood Flow through Hepatic Sinusoids // Liver Int. – 2000. – № 20. – P. 3–7. doi: 10.1034/j.1600-0676.2000.020001003.x.

25. Szafranska K., Kruse L.D., Holte C.F., McCourt P., Zapotoczny B. The wHole Story About Fenestrations in LSEC // Front Physiol. – 2021. – № 12. – P. 735573. doi: 10.3389/fphys.2021.735573.

26. Tanoi T., Tamura T., Sano N., Nakayama K., Fukunaga K., Zheng Y.-W., Akhter A., Sakurai Y., Hayashi Y., Harashima H., et al. Protecting Liver Sinusoidal Endothelial Cells Suppresses Apoptosis in Acute Liver Damage // Hepatol. Res. – 2016. – № 46. – P. 697–706. doi: 10.1111/hepr.12607.

27. Golse N., Bucur P.O., Adam R., Castaing D., Sa Cunha A., Vibert E. New Paradigms in Post-Hepatectomy Liver Failure // J. Gastrointest. Surg. – 2013. – № 17. – P. 593–605. doi: 10.1007/s11605-012-2048-6.

28. Pellicoro A., Ramachandran P., Iredale J.P., Fallowfield J.A. Liver Fibrosis and Repair: Immune Regulation of Wound Healing in a Solid Organ // Nat. Rev. Immunol. – 2014. – № 14. – P.181–194. doi: 10.1038/nri3623.

29. Xie G., Wang X., Wang L.L., Wang L.L., Atkinson R.D., Kanel G.C., Gaarde W.A., Deleve L.D. Role of Differentiation of Liver Sinusoidal Endothelial Cells in Progression and Regression of Hepatic Fibrosis in Rats // Gastroenterology. – 2012. – № 142. – P. 918–927 doi: 10.1053/j.gastro.2011.12.017.

30. Smedsrød B., Pertoft H., Gustafson S., Laurent T.C. Scavenger Functions of the Liver Endothelial Cell // Biochem. J. –1990. – № 266. – P. 313. doi: 10.1042/bj2660313.

31. De Rudder M., Dili A., Stärkel P., Leclercq I.A. Critical Role of LSEC in Post-Hepatectomy Liver Regeneration and Failure // Int J Mol Sci. – 2021. – № (15). – P. 8053. doi: 10.3390/ijms22158053.

32. Hunt N.J., Kang S.W.S., Lockwood G.P., Le Couteur D.G., Cogger V.C. Hallmarks of Aging in the Liver // Comput Struct Biotechnol J. – 2019. – № 17. – P. 1151-1161. doi: 10.1016/j.csbj.2019.07.021.

33. Ramos-Tovar E., Muriel P. Molecular Mechanisms That Link Oxidative Stress, Inflammation, and Fibrosis in the Liver. Antioxidants (Basel). – 2020. – № 9(12). – P. 1279. doi: 10.3390/antiox9121279.

34. Forman H.J., Zhang H. Targeting oxidative stress in disease: promise and limitations of antioxidant therapy // Nat Rev Drug Discov. – 2021. – № 20(9). – P. 689-709. doi: 10.1038/s41573-021-00233-1.

35. Chen Z., Tian R., She Z., Cai J., Li H. Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease // Free Radic Biol Med. – 2020. – № 152. – P.116-141. doi: 10.1016/j.freeradbiomed.2020.02.025.

36. Luangmonkong T., Suriguga S., Mutsaers H.A.M., Groothuis G.M.M., Olinga P., Boersema M. Targeting Oxidative Stress for the Treatment of Liver Fibrosis // Rev Physiol Biochem Pharmacol. – 2018. – № 175. P. 71102. doi: 10.1007/112_2018_10.

37. Temkin V., Karin M. From Death Receptor to Reactive Oxygen Species and C-Jun N-Terminal Protein Kinase: The Receptor-Interacting Protein 1 Odyssey // Immunol. Rev. – 2007. – № :8–21. doi: 10.1111/j.1600065X.2007.00560.x.

38. Friedman S.L., Neuschwander-Tetri B.A., Rinella M., Sanyal A.J. Mechanisms of NAFLD Development and Therapeutic Strategies // Nat. Med. –2018. –138. doi: 10.1038/s41591-018-0104-9.

39. Sprague A.H., Khalil R.A. Inflammatory Cytokines in Vascular Dysfunction and Vascular Disease // Biochem. Pharmacol. – 2009. – № 4. – P.539–552. doi: 10.1016/j.bcp.2009.04.029.

40. Hammoutene A., Rautou P.E. Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease // J Hepatol. – 2019. – № 70(6). – P. 1278-1291. doi: 10.1016/j.jhep.2019.02.012.

41. Li P., Zhou J., Li W. et al. Characterizing liver sinusoidal endothelial cell fenestrae on soft substrates upon AFM imaging and deep learning // Biochim Biophys Acta Gen Subj. – 2020. – № 1864(12). – P. 129702. doi: 10.1016/j.bbagen.2020.129702.

42. Ruart M., Chavarria L., Campreciós G., Suárez-Herrera N., Montironi C., Guixé-Muntet S., Bosch J., Friedman S.L., Garcia-Pagán J.C., Hernández-Gea V. Impaired endothelial autophagy promotes liver fibrosis by aggravating the oxidative stress response during acute liver injury // J Hepatol. – 2019. – № 70(3) – P. 458-469. doi: 10.1016/j.jhep.2018.10.015.

43. Rockey D.C., Chung J.J. Reduced Nitric Oxide Production by Endothelial Cells in Cirrhotic Rat Liver: Endothelial Dysfunction in Portal Hypertension // Gastroenterology. – 1998. – № 114. – P. 344–351. doi: 10.1016/S0016-5085(98)70487-1.

44. Gracia-Sancho J., Laviña B., Rodríguez-Vilarrupla A., García-Calderó H., Bosch J., García-Pagán J.C. Enhanced Vasoconstrictor Prostanoid Production by Sinusoidal Endothelial Cells Increases Portal Perfusion Pressure in Cirrhotic Rat Livers // J. Hepatol. – 2007. – № 47 – P. 220–227. doi: 10.1016/j.jhep.2007.03.014.

45. Shchyokotova A.P, Shchekotov V.V, Popov A.V et al. Indicators of endothelial dysfunction and liver impedancemetry in chronic hepatitis and liver cirrhosis [Pokazateli disfunkcii endoteliya i impedansometriya pecheni pri hronicheskom gepatite i cirroze pecheni] // Permskij medicinskij zhurnal. – 2009. – № 4. – S. 77-79.

46. Falero-Perez J., Song Y.S., Zhao Y. et al. Cyp1b1 expression impacts the angiogenic and inflammatory properties of liver sinusoidal endothelial cells // PLoS One. – 2018. – № 13(10). – P. e0206756. doi: 10.1371/journal.pone.0206756.