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Cells in the Liver—Functions in Health and Disease

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Chronic Liver Failure

Part of the book series: Clinical Gastroenterology ((CG))

Abstract

The liver lobule is formed by hepatocytes and cholangiocytes, constituting the two hepatic epithelial cell populations, as well as by cells that are collectively defined as nonparenchymal cells (1–4). Morphometric and functional analyses indicate that hepatocytes occupy almost 80% of the total liver volume and perform the majority of liver functions.

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References

  1. Braet F, Wisse E. Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review. Comp Hepatol 2002;1:1.

    PubMed  Google Scholar 

  2. Hubbard A, Barr VA, Scott LJ. Hepatocyte surface polarity. In: Arias IM, Boyer JL, Fausto N, Jakoby WB, Schachter D, Shafritz DA, eds. The Liver: Biology and Pathobiology. 3rd ed. New York, NY: Raven Press, 1994; 189–213.

    Google Scholar 

  3. Braet F, Luo D, Spector I, et al. Endothelial and pit cells. In: Arias IM, Boyer JL, Chisari FV, Fausto N, Schachter D, Shafritz DA, eds. The Liver: Biology and Pathobiology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2001; 437–453.

    Google Scholar 

  4. Gumucio JJ, Bilir BM, Moseley RH., et al. The biology of liver cell plate. In: Arias IM, Boyer JL, Fausto N, Jakoby WB, Schachter D, Shafritz DA, eds. The Liver: Biology and Pathobiology. 3rd ed. New York, NY: Raven Press, 1994; 1143–1163.

    Google Scholar 

  5. Arias IM, Boyer JL, Chisari FV, Fausto N, Schachter D, Shafritz DA. The Liver: Biology and Pathobiology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2001.

    Google Scholar 

  6. Matsumura H, Shimizu Y, Ohsawa Y, Kawahara A, Uchiyama Y, Nagata S. Necrotic death pathway in Fas receptor signaling. J Cell Biol 2000;151:1247–1256.

    PubMed  Google Scholar 

  7. Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, Itoh N, et al. Lethal effect of the anti-Fas antibody in mice. Nature 1993;364:806–809.

    PubMed  Google Scholar 

  8. Malhi H, Gores GJ. Cellular and molecular mechanisms of liver injury. Gastroenterology 2008;134:1641–1654.

    PubMed  Google Scholar 

  9. Natori S, Rust C, Stadheim LM, Srinivasan A, Burgart LJ, Gores GJ. Hepatocyte apoptosis is a pathologic feature of human alcoholic hepatitis. J Hepatol 2001;34:248–253.

    PubMed  Google Scholar 

  10. Papakyriakou P, Tzardi M, Valatas V, Kanavaros P, Karydi E, Notas G, Xidakis C, et al. Apoptosis and apoptosis related proteins in chronic viral liver disease. Apoptosis 2002;7:133–141.

    PubMed  Google Scholar 

  11. Hetz H, Hoetzenecker K, Hacker S, Faybik P, Pollreisz A, Moser B, Roth G, et al. Caspase-cleaved cytokeratin 18 and 20 S proteasome in liver degeneration. J Clin Lab Anal 2007;21:277–281.

    PubMed  Google Scholar 

  12. Luft T, Conzelmann M, Benner A, Rieger M, Hess M, Strohhaecker U, Gorner M, et al. Serum cytokeratin-18 fragments as quantitative markers of epithelial apoptosis in liver and intestinal graft-versus-host disease. Blood 2007;110:4535–4542.

    PubMed  Google Scholar 

  13. Yagmur E, Trautwein C, Leers MP, Gressner AM, Tacke F. Elevated apoptosis-associated cytokeratin 18 fragments (CK18Asp386) in serum of patients with chronic liver diseases indicate hepatic and biliary inflammation. Clin Biochem 2007;40:651–655.

    PubMed  Google Scholar 

  14. Wieckowska A, Zein NN, Yerian LM, Lopez AR, McCullough AJ, Feldstein AE. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology 2006;44:27–33.

    PubMed  Google Scholar 

  15. Liu ZX, Govindarajan S, Kaplowitz N. Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity. Gastroenterology 2004;127:1760–1774.

    PubMed  Google Scholar 

  16. Volkmann X, Fischer U, Bahr MJ, Ott M, Lehner F, Macfarlane M, Cohen GM, et al. Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver. Hepatology 2007;46:1498–1508.

    PubMed  Google Scholar 

  17. Malhi H, Barreyro FJ, Isomoto H, Bronk SF, Gores GJ. Free fatty acids sensitise hepatocytes to TRAIL mediated cytotoxicity. Gut 2007;56:1124–1131.

    PubMed  Google Scholar 

  18. Feldstein AE, Canbay A, Guicciardi ME, Higuchi H, Bronk SF, Gores GJ. Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice. J Hepatol 2003;39:978–983.

    PubMed  Google Scholar 

  19. Feldstein A, Gores GJ. Steatohepatitis and apoptosis: therapeutic implications. Am J Gastroenterol 2004;99:1718–1719.

    PubMed  Google Scholar 

  20. Yin M, Wheeler MD, Kono H, Bradford BU, Gallucci RM, Luster MI, Thurman RG. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology 1999;117:942–952.

    PubMed  Google Scholar 

  21. Ribeiro PS, Cortez-Pinto H, Sola S, Castro RE, Ramalho RM, Baptista A, Moura MC, et al. Hepatocyte apoptosis, expression of death receptors, and activation of NF-kappaB in the liver of nonalcoholic and alcoholic steatohepatitis patients. Am J Gastroenterol 2004;99:1708–1717.

    PubMed  Google Scholar 

  22. Lluis JM, Colell A, Garcia-Ruiz C, Kaplowitz N, Fernandez-Checa JC. Acetaldehyde impairs mitochondrial glutathione transport in HepG2 cells through endoplasmic reticulum stress. Gastroenterology 2003;124:708–724.

    PubMed  Google Scholar 

  23. Ji C, Mehrian-Shai R, Chan C, Hsu YH, Kaplowitz N. Role of CHOP in hepatic apoptosis in the murine model of intragastric ethanol feeding. Alcohol Clin Exp Res 2005;29:1496–1503.

    PubMed  Google Scholar 

  24. Pianko S, Patella S, Ostapowicz G, Desmond P, Sievert W. Fas-mediated hepatocyte apoptosis is increased by hepatitis C virus infection and alcohol consumption, and may be associated with hepatic fibrosis: mechanisms of liver cell injury in chronic hepatitis C virus infection. J Viral Hepat 2001;8:406–413.

    PubMed  Google Scholar 

  25. Takaku S, Nakagawa Y, Shimizu M, Norose Y, Maruyama I, Wakita T, Takano T, et al. Induction of hepatic injury by hepatitis C virus-specific CD8+ murine cytotoxic T lymphocytes in transgenic mice expressing the viral structural genes. Biochem Biophys Res Commun 2003;301:330–337.

    PubMed  Google Scholar 

  26. Dunn C, Brunetto M, Reynolds G, Christophides T, Kennedy PT, Lampertico P, Das A, et al. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med 2007;204:667–680.

    PubMed  Google Scholar 

  27. Miyoshi H, Rust C, Roberts PJ, Burgart LJ, Gores GJ. Hepatocyte apoptosis after bile duct ligation in the mouse involves Fas. Gastroenterology 1999;117:669–677.

    PubMed  Google Scholar 

  28. Faubion WA, Guicciardi ME, Miyoshi H, Bronk SF, Roberts PJ, Svingen PA, Kaufmann SH, et al. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. J Clin Invest 1999;103:137–145.

    PubMed  Google Scholar 

  29. Sodeman T, Bronk SF, Roberts PJ, Miyoshi H, Gores GJ. Bile salts mediate hepatocyte apoptosis by increasing cell surface trafficking of Fas. Am J Physiol Gastrointest Liver Physiol 2000;278:G992–999.

    PubMed  Google Scholar 

  30. Reinehr R, Becker S, Wettstein M, Haussinger D. Involvement of the Src family kinase yes in bile salt-induced apoptosis. Gastroenterology 2004;127:1540–1557.

    PubMed  Google Scholar 

  31. Higuchi H, Yoon JH, Grambihler A, Werneburg N, Bronk SF, Gores GJ. Bile acids stimulate cFLIP phosphorylation enhancing TRAIL-mediated apoptosis. J Biol Chem 2003;278:454–461.

    PubMed  Google Scholar 

  32. Higuchi H, Bronk SF, Takikawa Y, Werneburg N, Takimoto R, El-Deiry W, Gores GJ. The bile acid glycochenodeoxycholate induces trail-receptor 2/DR5 expression and apoptosis. J Biol Chem 2001;276:38610–38618.

    PubMed  Google Scholar 

  33. Canbay A, Taimr P, Torok N, Higuchi H, Friedman S, Gores GJ. Apoptotic body engulfment by a human stellate cell line is profibrogenic. Lab Invest 2003;83:655–663.

    PubMed  Google Scholar 

  34. Zhong Z, Theruvath TP, Currin RT, Waldmeier PC, Lemasters JJ. NIM811, a mitochondrial permeability transition inhibitor, prevents mitochondrial depolarization in small-for-size rat liver grafts. Am J Transplant 2007;7:1103–1111.

    PubMed  Google Scholar 

  35. Pockros PJ, Schiff ER, Shiffman ML, McHutchison JG, Gish RG, Afdhal NH, Makhviladze M, et al. Oral IDN-6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C. Hepatology 2007;46:324–329.

    PubMed  Google Scholar 

  36. Botla R, Spivey JR, Aguilar H, Bronk SF, Gores GJ. Ursodeoxycholate (UDCA) inhibits the mitochondrial membrane permeability transition induced by glycochenodeoxycholate: a mechanism of UDCA cytoprotection. J Pharmacol Exp Ther 1995;272:930–938.

    PubMed  Google Scholar 

  37. Rodrigues CM, Fan G, Ma X, Kren BT, Steer CJ. A novel role for ursodeoxycholic acid in inhibiting apoptosis by modulating mitochondrial membrane perturbation. J Clin Invest 1998;101:2790–2799.

    PubMed  Google Scholar 

  38. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009;119:1420–1428.

    PubMed  Google Scholar 

  39. Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003;112:1776–1784.

    PubMed  Google Scholar 

  40. Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 2006;7:131–142.

    PubMed  Google Scholar 

  41. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 2009;119:1429–1437.

    PubMed  Google Scholar 

  42. Cannito S, Novo E, Valfre di Bonzo L, Busletta C, Colombatto S, Parola M. Epithelial-Mesenchymal Transition: from Molecular Mechanisms, Redox Regulation to Implications in Human Health and Disease. Antioxid Redox Signal 2010;12:1383–1430.

    Google Scholar 

  43. Pagan R, Sanchez A, Martin I, Llobera M, Fabregat I, Vilaro S. Effects of growth and differentiation factors on the epithelial-mesenchymal transition in cultured neonatal rat hepatocytes. J Hepatol 1999;31:895–904.

    PubMed  Google Scholar 

  44. Pagan R, Llobera M, Vilaro S. Epithelial-mesenchymal transition in cultured neonatal hepatocytes. Hepatology 1995;21:820–831.

    PubMed  Google Scholar 

  45. Kaimori A, Potter J, Kaimori JY, Wang C, Mezey E, Koteish A. Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro. J Biol Chem 2007;282:22089–22101.

    PubMed  Google Scholar 

  46. Zeisberg M, Yang C, Martino M, Duncan MB, Rieder F, Tanjore H, Kalluri R. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem 2007;282:23337–23347.

    PubMed  Google Scholar 

  47. Cicchini C, Laudadio I, Citarella F, Corazzari M, Steindler C, Conigliaro A, Fantoni A, et al. TGFbeta-induced EMT requires focal adhesion kinase (FAK) signaling. Exp Cell Res 2008;314:143–152.

    PubMed  Google Scholar 

  48. Dooley S, Hamzavi J, Ciuclan L, Godoy P, Ilkavets I, Ehnert S, Ueberham E, et al. Hepatocyte-specific Smad7 expression attenuates TGF-beta-mediated fibrogenesis and protects against liver damage. Gastroenterology 2008;135:642–659.

    PubMed  Google Scholar 

  49. Wake K. Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinusoids, and vitamin A-storing cells in extrahepatic organs. Int Rev Cytol 1980;66:303–353.

    PubMed  Google Scholar 

  50. Bouwens L, Baekeland M, De Zanger R, Wisse E. Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver. Hepatology 1986;6:718–722.

    PubMed  Google Scholar 

  51. MacPhee PJ, Schmidt EE, Groom AC. Evidence for Kupffer cell migration along liver sinusoids, from high-resolution in vivo microscopy. Am J Physiol 1992;263:G17–23.

    PubMed  Google Scholar 

  52. Naito M, Hasegawa G, Takahashi K. Development, differentiation, and maturation of Kupffer cells. Microsc Res Tech 1997;39:350–364.

    PubMed  Google Scholar 

  53. Steinhoff G, Wonigeit K, Sorg C, Behrend M, Mues B, Pichlmayr R. Patterns of macrophage immigration and differentiation in human liver grafts. Transplant Proc 1989;21:398–400.

    PubMed  Google Scholar 

  54. Nolan JP. Endotoxin, reticuloendothelial function, and liver injury. Hepatology 1981;1:458–465.

    PubMed  Google Scholar 

  55. Crispe IN. Hepatic T cells and liver tolerance. Nat Rev Immunol 2003;3:51–62.

    PubMed  Google Scholar 

  56. Terpstra V, van Berkel TJ. Scavenger receptors on liver Kupffer cells mediate the in vivo uptake of oxidatively damaged red blood cells in mice. Blood 2000;95:2157–2163.

    PubMed  Google Scholar 

  57. Suematsu M, Ishimura Y. The heme oxygenase-carbon monoxide system: a regulator of hepatobiliary function. Hepatology 2000;31:3–6.

    PubMed  Google Scholar 

  58. Schwabe RF, Seki E, Brenner DA. Toll-like receptor signaling in the liver. Gastroenterology 2006;130:1886–1900.

    PubMed  Google Scholar 

  59. Karck U, Peters T, Decker K. The release of tumor necrosis factor from endotoxin-stimulated rat Kupffer cells is regulated by prostaglandin E2 and dexamethasone. J Hepatol 1988;7:352–361.

    PubMed  Google Scholar 

  60. Kawada N, Tran-Thi TA, Klein H, Decker K. The contraction of hepatic stellate (Ito) cells stimulated with vasoactive substances. Possible involvement of endothelin 1 and nitric oxide in the regulation of the sinusoidal tonus. Eur J Biochem 1993;213:815–823.

    PubMed  Google Scholar 

  61. Arthur MJ, Kowalski-Saunders P, Wright R. Effect of endotoxin on release of reactive oxygen intermediates by rat hepatic macrophages. Gastroenterology 1988;95:1588–1594.

    PubMed  Google Scholar 

  62. Luckey SW, Petersen DR. Activation of Kupffer cells during the course of carbon tetrachloride-induced liver injury and fibrosis in rats. Exp Mol Pathol 2001;71:226–240.

    PubMed  Google Scholar 

  63. Arthur MJ, Bentley IS, Tanner AR, Saunders PK, Millward-Sadler GH, Wright R. Oxygen-derived free radicals promote hepatic injury in the rat. Gastroenterology 1985;89:1114–1122.

    PubMed  Google Scholar 

  64. Laskin DL. Nonparenchymal cells and hepatotoxicity. Semin Liver Dis 1990;10:293–304.

    PubMed  Google Scholar 

  65. Shiratori Y, Takikawa H, Kawase T, Sugimoto T. Superoxide anion generating capacity and lysosomal enzyme activities of Kupffer cells in galactosamine induced hepatitis. Gastroenterol Jpn 1986;21:135–144.

    PubMed  Google Scholar 

  66. Sass G, Koerber K, Bang R, Guehring H, Tiegs G. Inducible nitric oxide synthase is critical for immune-mediated liver injury in mice. J Clin Invest 2001;107:439–447.

    PubMed  Google Scholar 

  67. Gehring S, Dickson EM, San Martin ME, van Rooijen N, Papa EF, Harty MW, Tracy TF, Jr., et al. Kupffer cells abrogate cholestatic liver injury in mice. Gastroenterology 2006;130:810–822.

    PubMed  Google Scholar 

  68. Thurman RG. II. Alcoholic liver injury involves activation of Kupffer cells by endotoxin. Am J Physiol 1998;275:G605–611.

    PubMed  Google Scholar 

  69. Mochida S, Ogata I, Hirata K, Ohta Y, Yamada S, Fujiwara K. Provocation of massive hepatic necrosis by endotoxin after partial hepatectomy in rats. Gastroenterology 1990;99:771–777.

    PubMed  Google Scholar 

  70. Meyer DH, Bachem MG, Gressner AM. Modulation of hepatic lipocyte proteoglycan synthesis and proliferation by Kupffer cell-derived transforming growth factors type beta 1 and type alpha. Biochem Biophys Res Commun 1990;171:1122–1129.

    PubMed  Google Scholar 

  71. Friedman S, Arthur M. Activation of cultured rat hepatic lipocytes by Kupffer cell conditioned medium. Direct enhancement of matrix synthesis and stimulation of cell proliferation via induction of platelet-derived growth factor receptors. J Clin Invest 1989;84:1780–1785.

    PubMed  Google Scholar 

  72. Winwood PJ, Arthur MJ. Kupffer cells: their activation and role in animal models of liver injury and human liver disease. Semin Liver Dis 1993;13:50–59.

    PubMed  Google Scholar 

  73. Rakhmilevich AL. Neutrophils are essential for resolution of primary and secondary infection with Listeria monocytogenes. J Leukoc Biol 1995;57:827–831.

    PubMed  Google Scholar 

  74. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 1998;101:890–898.

    PubMed  Google Scholar 

  75. Lehner MD, Ittner J, Bundschuh DS, van Rooijen N, Wendel A, Hartung T. Improved innate immunity of endotoxin-tolerant mice increases resistance to Salmonella enterica serovar typhimurium infection despite attenuated cytokine response. Infect Immun 2001;69:463–471.

    PubMed  Google Scholar 

  76. Tomioka M, Iinuma H, Okinaga K. Impaired Kupffer cell function and effect of immunotherapy in obstructive jaundice. J Surg Res 2000;92:276–282.

    PubMed  Google Scholar 

  77. Cousens LP, Wing EJ. Innate defenses in the liver during Listeria infection. Immunol Rev 2000;174:150–159.

    PubMed  Google Scholar 

  78. Barsig J, Flesch IE, Kaufmann SH. Macrophages and hepatocytic cells as chemokine producers in murine listeriosis. Immunobiology 1998;199:87–104.

    PubMed  Google Scholar 

  79. Henson D, Smith RD, Gehrke J. Non-fatal mouse cytomegalovirus hepatitis. Combined morphologic, virologic and immunologic observations. Am J Pathol 1966;49:871–888.

    PubMed  Google Scholar 

  80. Afford SC, Randhawa S, Eliopoulos AG, Hubscher SG, Young LS, Adams DH. CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection. J Exp Med 1999;189:441–446.

    PubMed  Google Scholar 

  81. Gobejishvili L, Barve S, Joshi-Barve S, Uriarte S, Song Z, McClain C. Chronic ethanol-mediated decrease in cAMP primes macrophages to enhanced LPS-inducible NF-kappaB activity and TNF expression: relevance to alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 2006;291:G681–688.

    PubMed  Google Scholar 

  82. Bezugla Y, Kolada A, Kamionka S, Bernard B, Scheibe R, Dieter P. COX-1 and COX-2 contribute differentially to the LPS-induced release of PGE2 and TxA2 in liver macrophages. Prostaglandins Other Lipid Mediat 2006;79:93–100.

    PubMed  Google Scholar 

  83. Eguchi H, McCuskey PA, McCuskey RS. Kupffer cell activity and hepatic microvascular events after acute ethanol ingestion in mice. Hepatology 1991;13:751–757.

    PubMed  Google Scholar 

  84. Enomoto N, Ikejima K, Bradford B, Rivera C, Kono H, Brenner DA, Thurman RG. Alcohol causes both tolerance and sensitization of rat Kupffer cells via mechanisms dependent on endotoxin. Gastroenterology 1998;115:443–451.

    PubMed  Google Scholar 

  85. Caixas A, Bashore C, Nash W, Pi-Sunyer F, Laferrere B. Insulin, unlike food intake, does not suppress ghrelin in human subjects. J Clin Endocrinol Metab 2002;87:1902.

    PubMed  Google Scholar 

  86. Tomita K, Tamiya G, Ando S, Ohsumi K, Chiyo T, Mizutani A, Kitamura N, et al. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut 2006;55:415–424.

    PubMed  Google Scholar 

  87. Kodama Y, Kisseleva T, Iwaisako K, Miura K, Taura K, De Minicis S, Osterreicher CH, et al. c-Jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis to steatohepatitis and fibrosis in mice. Gastroenterology 2009;137:1467–1477 e1465.

    PubMed  Google Scholar 

  88. Malaguarnera L, Rosa MD, Zambito AM, dell’Ombra N, Marco RD, Malaguarnera M. Potential role of chitotriosidase gene in nonalcoholic fatty liver disease evolution. Am J Gastroenterol 2006;101:2060–2069.

    PubMed  Google Scholar 

  89. Czaja MJ, Weiner FR, Flanders KC, Giambrone MA, Wind R, Biempica L, Zern MA. In vitro and in vivo association of transforming growth factor-beta 1 with hepatic fibrosis. J Cell Biol 1989;108:2477–2482.

    PubMed  Google Scholar 

  90. Nagy LE. Recent insights into the role of the innate immune system in the development of alcoholic liver disease. Exp Biol Med (Maywood) 2003;228:882–890.

    Google Scholar 

  91. Zhao XJ, Dong Q, Bindas J, Piganelli JD, Magill A, Reiser J, Kolls JK. TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol. J Immunol 2008;181:3049–3056.

    PubMed  Google Scholar 

  92. Huang H, Park PH, McMullen MR, Nagy LE. Mechanisms for the anti-inflammatory effects of adiponectin in macrophages. J Gastroenterol Hepatol 2008;23(Suppl 1):S50–53.

    PubMed  Google Scholar 

  93. Marra F, Bertolani C. Adipokines in liver diseases. Hepatology 2009;50:957–969.

    PubMed  Google Scholar 

  94. Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters JJ. Mechanisms of hepatotoxicity. Toxicol Sci 2002;65:166–176.

    PubMed  Google Scholar 

  95. Ju C, Reilly TP, Bourdi M, Radonovich MF, Brady JN, George JW, Pohl LR. Protective role of Kupffer cells in acetaminophen-induced hepatic injury in mice. Chem Res Toxicol 2002;15:1504–1513.

    PubMed  Google Scholar 

  96. Harbrecht BG, Billiar TR. The role of nitric oxide in Kupffer cell-hepatocyte interactions. Shock 1995;3:79–87.

    PubMed  Google Scholar 

  97. Bone-Larson CL, Simpson KJ, Colletti LM, Lukacs NW, Chen SC, Lira S, Kunkel SL, et al. The role of chemokines in the immunopathology of the liver. Immunol Rev 2000;177:8–20.

    PubMed  Google Scholar 

  98. Ruttinger D, Vollmar B, Wanner GA, Messmer K. In vivo assessment of hepatic alterations following gadolinium chloride-induced Kupffer cell blockade. J Hepatol 1996;25:960–967.

    PubMed  Google Scholar 

  99. Bilzer M, Roggel F, Gerbes AL. Role of Kupffer cells in host defense and liver disease. Liver Int 2006;26:1175–1186.

    PubMed  Google Scholar 

  100. Jaeschke H, Farhood A, Bautista AP, Spolarics Z, Spitzer JJ. Complement activates Kupffer cells and neutrophils during reperfusion after hepatic ischemia. Am J Physiol 1993;264:G801–809.

    PubMed  Google Scholar 

  101. Kiemer AK, Baron A, Gerbes AL, Bilzer M, Vollmar AM. The atrial natriuretic peptide as a regulator of Kupffer cell functions. Shock 2002;17:365–371.

    PubMed  Google Scholar 

  102. Jaeschke H. Role of reactive oxygen species in hepatic ischemia-reperfusion injury and preconditioning. J Invest Surg 2003;16:127–140.

    PubMed  Google Scholar 

  103. Rogoff TM, Lipsky PE. Role of the Kupffer cells in local and systemic immune responses. Gastroenterology 1981;80:854–860.

    PubMed  Google Scholar 

  104. Donaldson PT, Alexander GJ, O’Grady J, Neuberger J, Portmann B, Thick M, Davis H, et al. Evidence for an immune response to HLA class I antigens in the vanishing-bileduct syndrome after liver transplantation. Lancet 1987;1:945–951.

    PubMed  Google Scholar 

  105. Brass CA, Roberts TG. Hepatic free radical production after cold storage: Kupffer cell-dependent and -independent mechanisms in rats. Gastroenterology 1995;108:1167–1175.

    PubMed  Google Scholar 

  106. Crispe IN, Dao T, Klugewitz K, Mehal WZ, Metz DP. The liver as a site of T-cell apoptosis: graveyard, or killing field? Immunol Rev 2000;174:47–62.

    PubMed  Google Scholar 

  107. Michalopoulos GK. Liver regeneration. J Cell Physiol 2007;213:286–300.

    PubMed  Google Scholar 

  108. Xu H, Korneszczuk K, Karaa A, Lin T, Clemens MG, Zhang JX. Thromboxane A2 from Kupffer cells contributes to the hyperresponsiveness of hepatic portal circulation to endothelin-1 in endotoxemic rats. Am J Physiol Gastrointest Liver Physiol 2005;288:G277–283.

    PubMed  Google Scholar 

  109. Bayon LG, Izquierdo MA, Sirovich I, van Rooijen N, Beelen RH, Meijer S. Role of Kupffer cells in arresting circulating tumor cells and controlling metastatic growth in the liver. Hepatology 1996;23:1224–1231.

    PubMed  Google Scholar 

  110. Kan Z, Ivancev K, Lunderquist A, McCuskey PA, McCuskey RS, Wallace S. In vivo microscopy of hepatic metastases: dynamic observation of tumor cell invasion and interaction with Kupffer cells. Hepatology 1995;21:487–494.

    PubMed  Google Scholar 

  111. Heuff G, van de Loosdrecht AA, Betjes MG, Beelen RH, Meijer S. Isolation and purification of large quantities of fresh human Kupffer cells, which are cytotoxic against colon carcinoma. Hepatology 1995;21:740–745.

    PubMed  Google Scholar 

  112. Hepatic stellate cell nomenclature. Hepatology 1996;23:193.

    Google Scholar 

  113. Kent G, Gay S, Inouye T, Bahu R, Minick OT, Popper H. Vitamin A-containing lipocytes and formation of type III collagen in liver injury. Proc Natl Acad Sci USA 1976;73:3719–3722.

    PubMed  Google Scholar 

  114. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008;88:125–172.

    PubMed  Google Scholar 

  115. Friedman SL, Roll FJ. Isolation and culture of hepatic lipocytes, Kupffer cells, and sinusoidal endothelial cells by density gradient centrifugation with Stractan. Anal Biochem 1987;161:207–218.

    PubMed  Google Scholar 

  116. Geerts A. On the origin of stellate cells: mesodermal, endodermal or neuro-ectodermal? J Hepatol 2004;40:331–334.

    PubMed  Google Scholar 

  117. Kiassov AP, Van Eyken P, van Pelt JF, Depla E, Fevery J, Desmet VJ, Yap SH. Desmin expressing nonhematopoietic liver cells during rat liver development: an immunohistochemical and morphometric study. Differentiation 1995;59:253–258.

    PubMed  Google Scholar 

  118. Novo E, di Bonzo LV, Cannito S, Colombatto S, Parola M. Hepatic myofibroblasts: a heterogeneous population of multifunctional cells in liver fibrogenesis. Int J Biochem Cell Biol 2009;41:2089–2093.

    PubMed  Google Scholar 

  119. Blomhoff R, Wake K. Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis. Faseb J 1991;5:271–277.

    PubMed  Google Scholar 

  120. Ulven SM, Natarajan V, Holven KB, Lovdal T, Berg T, Blomhoff R. Expression of retinoic acid receptor and retinoid X receptor subtypes in rat liver cells: implications for retinoid signalling in parenchymal, endothelial, Kupffer and stellate cells. Eur J Cell Biol 1998;77:111–116.

    PubMed  Google Scholar 

  121. Milani S, Herbst H, Schuppan D, Hahn EG, Stein H. In situ hybridization for procollagen types I, III and IV mRNA in normal and fibrotic rat liver: evidence for predominant expression in nonparenchymal liver cells. Hepatology 1989;10:84–92.

    PubMed  Google Scholar 

  122. Milani S, Herbst H, Schuppan D, Grappone C, Pellegrini G, Pinzani M, Casini A, et al. Differential expression of matrix-metalloproteinase-1 and -2 genes in normal and fibrotic human liver. Am J Pathol 1994;144:528–537.

    PubMed  Google Scholar 

  123. Pinzani M, Failli P, Ruocco C, Casini A, Milani S, Baldi E, Giotti A, et al. Fat-storing cells as liver-specific pericytes. Spatial dynamics of agonist-stimulated intracellular calcium transients. J Clin Invest 1992;90:642–646.

    PubMed  Google Scholar 

  124. Ekataksin W, Kaneda K. Liver microvascular architecture: an insight into the pathophysiology of portal hypertension. Semin Liver Dis 1999;19:359–382.

    PubMed  Google Scholar 

  125. Zhang JX, Pegoli W, Jr., Clemens MG. Endothelin-1 induces direct constriction of hepatic sinusoids. Am J Physiol 1994;266:G624–632.

    PubMed  Google Scholar 

  126. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008;134:1655–1669.

    PubMed  Google Scholar 

  127. Cassiman D, Roskams T. Beauty is in the eye of the beholder: emerging concepts and pitfalls in hepatic stellate cell research. Journal of Hepatology 2002;37:527–535.

    PubMed  Google Scholar 

  128. Mann DA, Smart DE. Transcriptional regulation of hepatic stellate cell activation. Gut 2002;50:891–896.

    PubMed  Google Scholar 

  129. Inagaki Y, Okazaki I. Emerging insights into Transforming growth factor beta Smad signal in hepatic fibrogenesis. Gut 2007;56:284–292.

    PubMed  Google Scholar 

  130. Bonacchi A, Petrai I, Defranco RM, Lazzeri E, Annunziato F, Efsen E, Cosmi L, et al. The chemokine CCL21 modulates lymphocyte recruitment and fibrosis in chronic hepatitis C. Gastroenterology 2003;125:1060–1076.

    PubMed  Google Scholar 

  131. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007;316:889–894.

    PubMed  Google Scholar 

  132. Arthur MJ. Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 2000;279:G245–249.

    PubMed  Google Scholar 

  133. Knittel T, Fellmer P, Ramadori G. Gene expression and regulation of plasminogen activator inhibitor type I in hepatic stellate cells of rat liver. Gastroenterology 1996;111:745–754.

    PubMed  Google Scholar 

  134. Rockey DC. Hepatic fibrosis, stellate cells, and portal hypertension. Clin Liver Dis 2006;10:459–479, vii–viii.

    PubMed  Google Scholar 

  135. Rockey DC. Vascular mediators in the injured liver. Hepatology 2003;37:4–12.

    PubMed  Google Scholar 

  136. Marra F, Valente AJ, Pinzani M, Abboud HE. Cultured human liver fat-storing cells produce monocyte chemotactic protein-1. Regulation by proinflammatory cytokines. J Clin Invest 1993;92:1674–1680.

    PubMed  Google Scholar 

  137. Medina J, Arroyo AG, Sanchez-Madrid F, Moreno-Otero R. Angiogenesis in chronic inflammatory liver disease. Hepatology 2004;39:1185–1195.

    PubMed  Google Scholar 

  138. Aleffi S, Petrai I, Bertolani C, Parola M, Colombatto S, Novo E, Vizzutti F, et al. Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells. Hepatology 2005;42:1339–1348.

    PubMed  Google Scholar 

  139. Roskams T. Relationships among stellate cell activation, progenitor cells, and hepatic regeneration. Clin Liver Dis 2008;12:853–860, ix.

    PubMed  Google Scholar 

  140. Wisse E. An ultrastructural characterization of the endothelial cell in the rat liver sinusoid under normal and various experimental conditions, as a contribution to the distinction between endothelial and Kupffer cells. J Ultrastruct Res 1972;38:528–562.

    PubMed  Google Scholar 

  141. Wisse E, De Zanger RB, Charels K, Van Der Smissen P, McCuskey RS. The liver sieve: considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of Disse. Hepatology 1985;5:683–692.

    PubMed  Google Scholar 

  142. McCuskey RS, Reilly FD. Hepatic microvasculature: dynamic structure and its regulation. Semin Liver Dis 1993;13:1–12.

    PubMed  Google Scholar 

  143. Smedsrod B, De Bleser PJ, Braet F, Lovisetti P, Vanderkerken K, Wisse E, Geerts A. Cell biology of liver endothelial and Kupffer cells. Gut 1994;35:1509–1516.

    PubMed  Google Scholar 

  144. Le Couteur DG, Warren A, Cogger VC, Smedsrod B, Sorensen KK, De Cabo R, Fraser R, et al. Old age and the hepatic sinusoid. Anat Rec (Hoboken) 2008;291:672–683.

    Google Scholar 

  145. Elvevold K, Smedsrod B, Martinez I. The liver sinusoidal endothelial cell: a cell type of controversial and confusing identity. Am J Physiol Gastrointest Liver Physiol 2008;294:G391–400.

    PubMed  Google Scholar 

  146. Seternes T, Sorensen K, Smedsrod B. Scavenger endothelial cells of vertebrates: a nonperipheral leukocyte system for high-capacity elimination of waste macromolecules. Proc Natl Acad Sci U S A 2002;99:7594–7597.

    PubMed  Google Scholar 

  147. Smedsrod B. Clearance function of scavenger endothelial cells. Comp Hepatol 2004;3(Suppl 1):S22.

    PubMed  Google Scholar 

  148. Fraser JR, Alcorn D, Laurent TC, Robinson AD, Ryan GB. Uptake of circulating hyaluronic acid by the rat liver. Cellular localization in situ. Cell Tissue Res 1985;242:505–510.

    Google Scholar 

  149. DeLeve LD. Hepatic microvasculature in liver injury. Semin Liver Dis 2007;27:390–400.

    PubMed  Google Scholar 

  150. Rieder H, Meyer zum Buschenfelde KH, Ramadori G. Functional spectrum of sinusoidal endothelial liver cells. Filtration, endocytosis, synthetic capacities and intercellular communication. J Hepatol 1992;15:237–250.

    PubMed  Google Scholar 

  151. Ohira H, Ueno T, Tanikawa K, et al. Changes in adhesion molecules of sinusoidal endothelial cells in liver injury. In: Tanikawa K, Ueno T, eds. Liver diseases and hepatic sinusoidal cells. Tokyo: Springer, 1999; 91–100.

    Google Scholar 

  152. Maher JJ. Cell-specific expression of hepatocyte growth factor in liver. Upregulation in sinusoidal endothelial cells after carbon tetrachloride. J Clin Invest 1993;91:2244–2252.

    PubMed  Google Scholar 

  153. Ross MA, Sander CM, Kleeb TB, Watkins SC, Stolz DB. Spatiotemporal expression of angiogenesis growth factor receptors during the revascularization of regenerating rat liver. Hepatology 2001;34:1135–1148.

    PubMed  Google Scholar 

  154. Fernandez M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol 2009;50:604–620.

    PubMed  Google Scholar 

  155. Valfre di Bonzo L, Novo E, Cannito S, Busletta C, Paternostro C, Povero D, Parola M. Angiogenesis and liver fibrogenesis. Histol Histopathol 2009;24:1323–1341.

    PubMed  Google Scholar 

  156. Phng LK, Gerhardt H. Angiogenesis: a team effort coordinated by notch. Dev Cell 2009;16:196–208.

    PubMed  Google Scholar 

  157. Knolle PA, Gerken G. Local control of the immune response in the liver. Immunol Rev 2000;174:21–34.

    PubMed  Google Scholar 

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Marra, F., Parola, M. (2011). Cells in the Liver—Functions in Health and Disease. In: Ginès, P., Kamath, P., Arroyo, V. (eds) Chronic Liver Failure. Clinical Gastroenterology. Humana Press. https://doi.org/10.1007/978-1-60761-866-9_1

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