Advertisement

Signaling Pathways in Liver Diseases Kupffer Cells

  • Christian J. Steib
  • Alexander L. GerbesEmail author
Chapter

Abstract

Kupffer cells (KC) constitute 80–90% of tissue ­macrophages present in the body. These liver macrophages are named after the pathologist C. von Kupffer, who apparently first recognized this nonparenchymal cell type [1]. KC represents about 35% of the nonparenchymal liver cells in normal adult mice [2]. They reside within the lumen of the liver sinusoids, adherent to the endothelial cells that compose the blood vessel walls. KC, found in greatest number in the periportal area, constitute the first macrophage population of the body to come in contact with bacteria, bacterial endotoxins, and microbial debris derived from the gastrointestinal tract and transported to the liver via the portal vein [3]. Consequently, KC are constantly exposed to proinflammatory factors, e.g., bacterial endotoxins, known to activate macrophages. Upon activation, KC release various products including cytokines, prostanoides, nitric oxide, and reactive oxygen species [4]. These factors regulate the phenotype of the KC that produce them, as well as the phenotypes of neighboring cells, such as hepatocytes, stellate cells, and endothelial cells and other immune cells that traffic through the liver [5]. Therefore, KC are intimately involved in the liver’s response to infection, toxins, ischemia, resection, and various other stresses. This review will summarize established basic concepts of KC function as well as their role in the pathogenesis of various liver diseases. Due to the complexity of processes mediated by KC, this review focuses on selected aspects of the pathophysiology.

Keywords

Kupffer Cell Atrial Natriuretic Peptide Liver Regeneration Alcoholic Liver Disease Apoptotic Neutrophil 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Wake K (1980) 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 66:303–353CrossRefPubMedGoogle Scholar
  2. 2.
    Phillips MJ, Poucell S, Patterson J et al (1987) The liver: an atlas and text of ultrastructural pathology. Raven, New York, pp 1–32Google Scholar
  3. 3.
    Fox ES, Thomas P, Broitman SA (1987) Comparative studies of endotoxin uptake by isolated rat Kupffer and peritoneal cells. Infect Immun 55:2962–2966PubMedGoogle Scholar
  4. 4.
    Decker K (1990) Biologically active products of stimulated liver macrophages (Kupffer cells). Eur J Biochem 192: 245–261CrossRefPubMedGoogle Scholar
  5. 5.
    Laskin DL, Weinberger B, Laskin JC (2001) Functional heterogeneity of liver and lung macrophages. J Leukoc Biol 70:163–170PubMedGoogle Scholar
  6. 6.
    Schieferdecker HL, Schlaf G, Jungermann K, Gotze O (2001) Functions of anaphylatoxin C5a in rat liver: direct and indirect actions on nonparenchymal and parenchymal cells. Int Immunopharmacol 1:469–481CrossRefPubMedGoogle Scholar
  7. 7.
    Thornton BP, Vetvicka V, Pitman M et al (1996) Analysis of the sugar specificity and molecular location of the β-Glucan-binding lectin site of complement receptor type 3 (CD11b/CD18). J Immunol 156:1235–1246PubMedGoogle Scholar
  8. 8.
    Su GL (2002) Lipopylysaccharides in liver injury:molecular mechanisms of Kupffer cell activation. Am J Physiol Gastrointest Liver Physiol 283:G256–G265Google Scholar
  9. 9.
    Seki E, Tsutsui H, Nakano H, Tsuji N, Hoshino K, Adachi O (2001) Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1beta. J Immunol 166: 2651–2657PubMedGoogle Scholar
  10. 10.
    Thobe BM, Frink M, Hildebrand F, Schwacha MG, Hubbard WJ, Choudhry MA (2007) The role of MAPK in Kupffer cell toll-like receptor (TLR) 2, TLR4-, and TLR9-mediated signaling following trauma-hemorrhage. J Cell Physiol 210:667–675CrossRefPubMedGoogle Scholar
  11. 11.
    Jaeschke H, Farhood A, Smith CW (1994) Contribution of complement-stimulated hepatic macrophages and neutrophils to endotoxin-induced liver injury in rats. Hepatology 19:973–979CrossRefPubMedGoogle Scholar
  12. 12.
    Ember JA, Hugli TE (1997) Complement factors and their receptors. Immunopharm 38:3–15CrossRefGoogle Scholar
  13. 13.
    Dieter P, Schulze-Specking A, Decker K (1998) Ca2+ requirement of prostanoid but not of superoxide production by rat Kupffer cells. Eur J Biochem 177:61–67Google Scholar
  14. 14.
    Dieter P, Altin JG, Decker K et al (1987) Possible involvement of eicosanoids in zymosan and arachidonic-acid-induced oxygen uptake, glycogenolysis and Ca2+ mobilization in the perfused rat liver. Eur J Biochem 165: 455–460CrossRefPubMedGoogle Scholar
  15. 15.
    Häussinger D, Stehle T, Gerok W (1988) Effects of leukotrienes and the thromboxane A2 analogue U-46619 in isolated perfused rat liver. Metabolic, hemodynamic and ion-flux responses. Biol Chem Hoppe Seyler 369:97–107PubMedGoogle Scholar
  16. 16.
    Kawada N, Tran-Thi TA, Klein H et al (1993) The concentration of hepatic stellate (Ito) cell stimulated with vasoactive substances. Possible involvement of endothelin 1 and nitric oxide in the regulation of the sinusoidal tonus. Eur J Biochem 213:815–823CrossRefPubMedGoogle Scholar
  17. 17.
    Karck U, Peters T, Decker K (1988) The release of tumor necrosis factor from endotoxin-stimulated rat Kupffer cells is regulated by prostaglandin E2 and dexamethasone. J Hepatol 7:352–361CrossRefPubMedGoogle Scholar
  18. 18.
    Peters T, Karck U, Decker K (1990) Interdependence of tumor necrosis factor, prostaglandin E2, and protein synthesis in lipopolysaccharide-exposed rat Kupffer cells. Eur J Biochem 191:583–589CrossRefPubMedGoogle Scholar
  19. 19.
    Arai M, Peng XX, Currin RT et al (1999) Protection of sinusoidal endothelial cells against storage/reperfusion injury by prostaglandin E2 derived from Kupffer cells. Transplantation 68:440–445CrossRefPubMedGoogle Scholar
  20. 20.
    Schumann RR, Leong SR, Flaggs GW et al (1990) Structure and function of lipopolysaccharide binding protein. Science 249:1429–1431CrossRefPubMedGoogle Scholar
  21. 21.
    Schumann RR (1992) Function of lipopolysaccharide (LPS)-binding protein (LBP) and CD14, the receptor for LPS/LBP complexes: a short review. Res Immunol 143:11–15CrossRefPubMedGoogle Scholar
  22. 22.
    Takai N, Kataoka M, Higuchi Y et al (1997) Primary structure of rat CD14 and characteristics of rat CD14, cytokine, and NO synthase mRNA expression in mononuclear phagocyte system cells in response to LPS. J Leuk Biol 61:736–744Google Scholar
  23. 23.
    Matsuura K, Ishida T, Setoguchi M et al (1994) Upregulation of mouse CD14 expression in Kupffer cells by lipopolysaccharide. J Exp Med 179:1671–1676CrossRefPubMedGoogle Scholar
  24. 24.
    Shimazu R, Akashi S, Ogata H et al (1999) MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med 189:1777–1782CrossRefPubMedGoogle Scholar
  25. 25.
    Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immun 2:675–680CrossRefGoogle Scholar
  26. 26.
    Hoffmann F, Sass G, Zillies J, Zahler S, Tiegs G, Hartkorn A, Fuchs S, Wagner J, Winter G, Coester C, Gerbes AL, Vollmar AM: A novel technique for selective NFkB inhibition in Kupffer cells - contrary effects in fulminant hepatitis and ischemia/reperfusion. Gut 2009 May 25, Epub ahead of print).Google Scholar
  27. 27.
    Marra F. Selective inhibition of NF-kB in Kupffer cells: good, but not for everything. Gut 2009, in press)Google Scholar
  28. 28.
    Klein A, Zhadkewich M, Margolick J et al (1994) Quantitative discrimination of hepatic reticuloendothelial clearance and phagocytic killing. J Leuk Biol 55:248–252Google Scholar
  29. 29.
    Gregory SH, Cousens LP, van Rooijen N et al (2002) Complementary adhesion molecules promote neutrophil-Kupffer cell interaction and the elimination of bacteria taken up by the liver. J Immunol 268:308–315Google Scholar
  30. 30.
    Gregory SH, Wing EJ (2002) Neutrophil–Kupffer cell interaction: a critical component of host defenses to systemic bacterial infections. J Leukoc Biol 72:239–248PubMedGoogle Scholar
  31. 31.
    Ofek I, Sharon N (1988) Lectinophagocytosis: a molecular mechanism of recognition between cell surface sugars and lectins in the phagocytosis of bacteria. Infect Immun 56: 539–547PubMedGoogle Scholar
  32. 32.
    Perry A, Ofek I (1984) Inhibition of blood clearance and hepatic tissue binding of Escherichia coli by liver lectin-specific sugars and glycoproteins. Infect Immun 43: 257–262PubMedGoogle Scholar
  33. 33.
    Rosen H, Gordon S, North RJ (1989) Exacerbation of murine listeriosis by a monoclonal antibody specific for the type 3 complement receptor of myelomonocytic cells. Absence of monocytes at infective foci allows Listeria to multiply in nonphagocytic cells. J Exp Med 170:27–37CrossRefPubMedGoogle Scholar
  34. 34.
    van Oosten M, van de Bilt E, de Vries HE et al (1995) Vascular adhesion molecule-1 and intercellular adhesion molecule-1 expression on rat liver cells after lipopolysaccharide administration in vivo. Hepatology 22:1538–1546CrossRefPubMedGoogle Scholar
  35. 35.
    Rakhmilevich AL (1995) Neutrophils are essential for resolution of primary and secondary infection with Listeria monocytogenes. J Leuk Biol 57:827–831Google Scholar
  36. 36.
    Brown KE, Brunt EM, Heinecke JW (2001) Immuno-histochemical detection of myeloperoxidase and its oxidation products in Kupffer cells of human liver. Am J Pathol 159:2081–2088PubMedGoogle Scholar
  37. 37.
    Shi J, Fujieda H, Kokubo Y et al (1996) Apoptosis of neutrophils and their elimination by Kupffer cells in rat liver. Hepatology 24:1256–1263CrossRefPubMedGoogle Scholar
  38. 38.
    Shi J, Gilbert GE, Kokubo Y et al (2001) Role of the liver in regulating numbers of circulating neutrophils. Blood 98:1226–1230CrossRefPubMedGoogle Scholar
  39. 39.
    Fadok VA, Bratton DL, Konowal A et al (1998) Macro­phages that have ingested apoptotic cells in vitro inhibit ­proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2, and PAF. J Clin Investig 101:890–898CrossRefPubMedGoogle Scholar
  40. 40.
    Crispe IN, Dao T, Klugewitz K et al (2000) The liver as a site of T-cell apoptosis: graveyard or killing field? Immunol Rev 174:47–62CrossRefPubMedGoogle Scholar
  41. 41.
    Liu ZX, Govindarajan S, Okamoto S et al (2001) Fas-mediated apoptosis causes elimination of virus-specific cytotoxic T cells in the virus-infected liver. J Immunol 166:3035–3041PubMedGoogle Scholar
  42. 42.
    Sun Z, Wada T, Maemura K et al (2003) Hepatic allograft-derived Kupffer cells regulate T cell response in rats. Liver Transplant 9:489–497CrossRefGoogle Scholar
  43. 43.
    Bellone M, Iezzi G, Rovere P et al (1997) Processing of engulfed apoptotic bodies yields T cell epitopes. J Immunol 159:5391–5399PubMedGoogle Scholar
  44. 44.
    Albert ML, Sauter B, Bhardwaj N (1998) Dendritic cell acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392:86–89CrossRefPubMedGoogle Scholar
  45. 45.
    You Q, Cheng L, Kedl RM, Ju C (2008) Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology 48:978–990CrossRefPubMedGoogle Scholar
  46. 46.
    Akerman P, Cote P, Yang SQ et al (1992) Antibodies to tumor necrosis factor inhibit liver regeneration after partial hepatectomy. Am J Physiol 263:G579–G585Google Scholar
  47. 47.
    Loffreda S, Rai RM, Yang SQ et al (1997) Bile ducts and portal and central veins are major producers of tumor ­necrosis factor alpha in regenerating rat liver. Gastroenterology 112:2089–2098CrossRefPubMedGoogle Scholar
  48. 48.
    Yamada Y, Kirillova I, Peschon J et al (1997) Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I TNF receptor. Proc Natl Acad Sci USA 94:1441–1446CrossRefPubMedGoogle Scholar
  49. 49.
    Cressman D, Greenbaum L, DeAngelis R et al (1996) Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 274:1379–1383CrossRefPubMedGoogle Scholar
  50. 50.
    Selzner N, Selzner M, Odermatt B et al (2003) ICAM-1 triggers liver regeneration through leukocyte recruitment and Kupffer cell-dependent release of TNF-alpha/IL-6 in mice. Gastroenterology 124:692–700CrossRefPubMedGoogle Scholar
  51. 51.
    Strey CW, Markiewski M, Mastellos D et al (2003) The proinflammatory mediators C3a and C5a are essential for liver regeneration. J Exp Med 198:913–923CrossRefPubMedGoogle Scholar
  52. 52.
    Tsukamoto H, Lu CS (2001) Current concepts in the pathogenesis of alcoholic liver injury. FASEB 15: 1335–1348CrossRefGoogle Scholar
  53. 53.
    Solga SF, Diehl AM (2003) Non-alcoholic fatty liver diseases: lumen-liver interactions and possible role for probiotics. J Hepatol 38:681–687CrossRefPubMedGoogle Scholar
  54. 54.
    Jaeschke H, Gores GJ, Cederbaum AI et al (2002) Mech-anisms of hepatotoxicity. Toxicol Sci 65:166–176CrossRefPubMedGoogle Scholar
  55. 55.
    Videla AL, Fernandez V, Tapia G et al (2003) Oxidative stress-mediated hepatotoxicity of iron and copper: role of Kupffer cells. Biometals 16:103–111CrossRefPubMedGoogle Scholar
  56. 56.
    Bilzer M, Gerbes AL (2000) Preservation injury of the liver: mechanisms and novel therapeutic strategies. J Hepatol 32: 508–515CrossRefPubMedGoogle Scholar
  57. 57.
    Selzner N, Rudiger H, Graf R et al (2003) Protective strategies against ischemic injury of the liver. Gastroenterology 125:917–936CrossRefPubMedGoogle Scholar
  58. 58.
    Rivera CA, Bradford BU, Hunt KJ et al (2001) Attenuation of CCl(4)-induced hepatic fibrosis by GdCl(3) treatment of dietary glycine. Am J Physiol Gastrointest Liver Physiol 281:G200–G207Google Scholar
  59. 59.
    Czaja MJ, Xy J, Yue J et al (1994) Lipopolysaccharide-neutralizing antibody reduces hepatocyte injury from acute hepatotoxin administration. Hepatology 19:1282–1289CrossRefPubMedGoogle Scholar
  60. 60.
    Graupera M, Garcia-Pagan JC, Titos E et al (2002) 5-lipoxygenase inhibition reduces intrahepatic vascular resistance of cirrhotic rat livers: a possibile role of cysteinyl-leukotrienes. Gastroenterology 122:387–393CrossRefPubMedGoogle Scholar
  61. 61.
    Yokoyama Y, Xu H, Kresge N et al (2003) Role of thromboxane A2 in early BDL-induced portal hypertension. Am J Physiol Gastrointest Liver Physiol 284:G453–G460Google Scholar
  62. 62.
    Goulis J, Patch D, Burroughs AK (1999) Bacterial infection in the pathogenesis of variceal bleeding. Lancet 353: 139–142CrossRefPubMedGoogle Scholar
  63. 63.
    Hinson JA, Pike SL, Pumford NR et al (1998) Nitrotyrosine-protein adducts in hepatic centrilobular areas following toxic doses of acetaminophen in mice. Chem Res Toxicol 11:604–607CrossRefPubMedGoogle Scholar
  64. 64.
    James LP, McCullough SS, Knight TR et al (2003) Acetaminophen toxicity in mice lacking NADPH oxidase activity: role of peroxynitrite formation and mitochondrial oxidant stress. Free Radical Res 37:1289–1297CrossRefGoogle Scholar
  65. 65.
    Goldin RD, Ratnayka ID, Breach CS et al (1996) Role of macrophages in acetaminophen (paracetamol)-induced hepatotoxicity. J Pathol 179:432–435CrossRefPubMedGoogle Scholar
  66. 66.
    Jaeschke H (2003) Role of reactive oxygen species in hepatic ischemia-reperfusion injury and preconditioning. J Invest Surg 16:127–140PubMedGoogle Scholar
  67. 67.
    Jaeschke H, Farhood A (1991) Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver in vivo. Am J Physiol Gastrointest Liver Physiol 260:G355–G362Google Scholar
  68. 68.
    Rymsa B, Wang JF, de Groot H (1991) O2-release by activated Kupffer cells upon hypoxia-reoxygenation. Am J Physiol Gastrointest Liver Physiol 261:G602–G607Google Scholar
  69. 69.
    Yokoyama I, Todo S, Miyata T et al (1989) Endotoxemia and human liver transplantation. Transplant Proc 21:3833–3841PubMedGoogle Scholar
  70. 70.
    Jaeschke H, Farhood A, Bautista AP et al (1993) Complement activates Kupffer cells and neutrophils during reperfusion after hepatic ischemia. Am J Physiol Gastrointest Liver Physiol 264:G801–G809Google Scholar
  71. 71.
    Jaeschke H (2003) Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 284:G15–G26Google Scholar
  72. 72.
    Bilzer M, Baron A, Schauer R et al (2002) Glutathione treatment protects the rat liver against injury after warm ischemia and Kupffer cell activation. Digestion 66:49–57CrossRefPubMedGoogle Scholar
  73. 73.
    Bilzer M, Paumgartner G, Gerbes AL (1999) Glutathione protects the rat liver against reperfusion injury after hypothermic preservation. Gastroenterology 117:200–210CrossRefPubMedGoogle Scholar
  74. 74.
    Liu P, Fisher MA, Farhood A et al (1995) Beneficial effects of extracellular glutathione against endotoxin-induced liver injury during ischemia and reperfusion. Shock 43:64–70Google Scholar
  75. 75.
    Schauer RJ, Gerbes AL, Vonier D et al (2004) Glutathione protects the rat liver against reperfusion injury after prolonged warm ischemia. Ann Surg 239:220–231CrossRefPubMedGoogle Scholar
  76. 76.
    Bilzer M, Witthaut R, Paumgartner G et al (1994) Prevention of ischemia/reperfusion injury in the rat liver by atrial natriuretic peptide. Gastroenterology 106:143–151PubMedGoogle Scholar
  77. 77.
    Gerbes AL, Vollmar AM, Kiemer AK et al (1998) The guanylate cyclase-coupled natriuretic peptide receptor: a new target for prevention of cold ischemia-reperfusion damage of the rat liver. Hepatology 28:1309–1317CrossRefPubMedGoogle Scholar
  78. 78.
    Bilzer M, Jaeschke H, Vollmar AM et al (1999) Prevention of Kupffer cell-induced oxidant injury in rat liver by atrial natriuretic peptide. Am J Physiol 276:G1137–G1144Google Scholar
  79. 79.
    von Ruecker AA, Wild M, Rao GS et al (1989) Atrial natriuretic peptide protects hepatocytes against damage induced by hypoxia and reactive oxygen: possible role of intracellular free ionized calcium. J Clin Chem Clin Biochem 27: 531–537Google Scholar
  80. 80.
    Kiemer AK, Baron A, Gerbes AL et al (2002) The atrial natriuretic peptide as a regulator of Kupffer cell functions. Shock 17:365–371CrossRefPubMedGoogle Scholar
  81. 81.
    Kiemer AK, Gerwig T, Gerbes AL et al (2003) Kupffer-cell specific induction of heme oxygenase 1 (hsp32) by the atrial natriuretic peptide-role of cGMP. J Hepatol 38:490–498CrossRefPubMedGoogle Scholar
  82. 82.
    Adachi Y, Bradford BU, Gao W et al (1994) Inactivation of Kupffer cells prevents early alcohol-induced liver injury. Hepatology 20:453–460CrossRefPubMedGoogle Scholar
  83. 83.
    Enomoto M, Ikejima K, Yamashima S et al (2001) Kupffer cell sensitization by alcohol involves increased permeability to gut-derived endotoxin. Alcohol Clin Exp Res 25:51–54CrossRefGoogle Scholar
  84. 84.
    Adachi Y, Moore LE, Bradford BU et al (1995) Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology 108:218–224CrossRefPubMedGoogle Scholar
  85. 85.
    Nanji AA, Khettry U, Sadrzadeh SM (1994) Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver disease. Proc Soc Exp Boil Med 205: 243–247Google Scholar
  86. 86.
    Iimuro Y, Gallucci RM, Luster MI et al (1997) Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. Hepatology 26:1530–1537CrossRefPubMedGoogle Scholar
  87. 87.
    Yin M, Wheeler MD, Kono H et al (1999) Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology 117:942–952CrossRefPubMedGoogle Scholar
  88. 88.
    McClain CJ, Hill DB, Schmidt J et al (1993) Cytokines and alcoholic liver disease. Semin Liv Dis 13:170–182CrossRefGoogle Scholar
  89. 89.
    Kamimura S, Tsukamoto H (1995) Cytokine gene expression by Kupffer cells in experimental alcoholic liver disease. Hepatology 22:1304–1309PubMedGoogle Scholar
  90. 90.
    Hritz I, Mandrekar P, Velayudham A, Catalano D, Dolganiuc A, Kodys K, Kurt-Jones E, Szabo G (2008) The critical role of TLR4 in alcoholic liver disease is independent of the common TLR adapter MyD88. Hepatology 48: 1224–1231CrossRefPubMedGoogle Scholar
  91. 91.
    Hill DB, Devalaraja R, Joshi-Barve S et al (1999) Antioxidants attenuate nuclear factor-kappa B activation and tumor necrosis factor-alpha production in a alcoholic hepatitis patient monocytes and rat Kupffer cells, in vitro. Clin Biochem 32:563–570CrossRefPubMedGoogle Scholar
  92. 92.
    Tsukamoto H, Lin M, Ohata M et al (1999) Iron primes hepatic macrophages for NF-κB activation in alcoholic liver injury. Am J Physiol 277:G1240–G1250Google Scholar
  93. 93.
    Zhao XJ, Dong Q, Bindas J, Piganelli JD, Magill A, Reiser J, Kolls JK (2008) TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol. J Immunol 181: 3049–3056PubMedGoogle Scholar
  94. 94.
    Xu H, Korneszczuk K, Karaa A, Lin T, Clemens MG, Zhang JX (2005) 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 288(2):G277–G283CrossRefGoogle Scholar
  95. 95.
    Steib CJ, Gerbes AL, Bystron M, Op den Winkel M, Härtl J, Roggel F, Prüfer T, Göke B, Bilzer M (2007) Kupffer cell activation in normal and fibrotic livers increases portal pressure via thromboxane A(2). J Hepatol 47(2): 228–238CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Department of Medicine IILudwig-Maximilians-UniversityMunichGermany

Personalised recommendations