Abstract
Kupffer cells may be involved in liver fibrogenesis through production of TGF-β1. Their role in fibrinolysis is less clear. Octreotide, a synthetic analogue of somatostatin, is often used in cirrhotic patients. Its effect on Kupffer cells was studied. Isolated rat Kupffer cells were cultured in the presence of lipopolysaccharide and/or octreotide. TGF-β1, leptin, collagenase (MMP-1), and urokinase-type plasminogen activator (uPA) were assessed in supernatants by ELISA, and MMP-2 and MMP-9 by zymography. Kupffer cells produced large amounts of MMP-1 and lipopolysaccharide induced a significant (P < 0.02) early increase. Octreotide and lipopolysaccharide caused a synergistic effect on MMP-1 secretion. By contrast, MMP-9 production stimulated by lipopolysaccharide was suppressed by octreotide. Kupffer cells produced a basal amount of uPA, significantly increased after lipopolysaccharide or octreotide incubation (P < 0.001). Large amounts of TGF-β1 were produced in a time-dependent manner by unstimulated Kupffer cells. Lipopolysaccharide and octreotide, alone or in combination, induced a significant inhibition of this production (P < 0.01). Kupffer cells did not produce leptin, a recently identified mediator of liver fibrosis, or MMP-2. Kupffer cells may play a significant role in liver fibrinolysis. Octreotide, acting on TGF-β1, uPA, and MMP-1 production, may be a useful agent for fibrosis resolution.
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Arthur MJ: Degradation of matrix proteins in liver fibrosis. Pathol Res Pract 190:825–833, 1994
Ikejima K, Takei Y, Honda H, Hirose M, Yoshikawa M, Zhang YJ, Lang T, Fukuda T, Yamashina S, Kitamura T, Sato N: Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology 122:1399–1410, 2002
De Bleser PJ, Niki T, Rogiers V, Geerts A: Transforming growth factor-beta gene expression in normal and fibrotic rat liver. J Hepatol 26:886–893, 1997
Zhang LP, Takahara T, Yata Y, Furui K, Jin B, Kawada N, Watanabe A: Increased expression of plasminogen activator and plasminogen activator inhibitor during liver fibrogenesis of rats: role of stellate cells. J Hepatol 31:703–711, 1999
Knolle PA, Gerken G: Local control of the immune response in the liver. Immunol Rev 174:21–34, 2000
Bautista AP: Acute alcohol intoxication and endotoxemia desensitize HIV-1 gp120-induced CC-chemokine production by Kupffer cells. Life Sci 68:1939–1949, 2001
Su GL: Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation. Am J Physiol Gastrointest Liver Physiol 283:G256–G265, 2002
Gregory SH, Wing EJ: Neutrophil-Kupffer cell interaction: a critical component of host defenses to systemic bacterial infections. J Leukoc Biol 72:239–248, 2002
Reichlin S: Somatostatin. N Engl J Med 309:1495–1501, 1983
Lamberts SW: The role of somatostatin in the regulation of anterior pituitary hormone secretion and the use of its analogs in the treatment of human pituitary tumors. Endocr Rev 9:417–436, 1988
Kvols LK, Buck M, Moertel CG, Schutt AJ, Rubin J, O’Connell MJ, Hahn RG: Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 201-995). Ann Intern Med 107:162–168, 1987
Farthing MJ: The role of somatostatin analogues in the treatment of refractory diarrhoea. Digestion 57(Suppl 1):107–113, 1996
Goulis J, Burroughs AK: Role of vasoactive drugs in the treatment of bleeding oesophageal varices. Digestion 60(Suppl 3):25–34, 1999
Kouroumalis E, Skordilis P, Thermos K, Vasilaki A, Moschandrea J, Manousos ON: Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut 42:442–447, 1998
Samonakis DN, Moschandreas J, Arnaoutis T, Skordilis P, Leontidis C, Vafiades I, Kouroumalis E: Treatment of hepatocellular carcinoma with long acting somatostatin analogues. Oncol Rep 9:903–907, 2002
Valatas V, Kolios G, Notas G, Xidakis C, Diamantis I, Kouroumalis EA: Octreotide regulates CC but not CXC LPS-induced chemokine secretion in rat Kupffer cells. Br J Pharmacol 141:477–487, 2004
Valatas V, Xidakis C, Roumpaki H, Kolios G, Kouroumalis EA: Isolation of rat Kupffer cells: a combined methodology for highly purified primary cultures. Cell Biol Int 27:67–73, 2003
Knook DL, Sleyster EC: Separation of Kupffer and endothelial cells of the rat liver by centrifugal elutriation. Exp Cell Res 99:444–449, 1976
Kolios G, Valatas V, Psilopoulos D, Petraki K, Kouroumalis E: Depletion of non specific esterase activity in the colonic mucosa of patients with ulcerative colitis. Eur J Clin Invest 32:265–273, 2002
Leyland H, Gentry J, Arthur MJ, Benyon RC: The plasminogen-activating system in hepatic stellate cells. Hepatology 24:1172–1178, 1996
Benyon RC, Arthur MJ: Extracellular matrix degradation and the role of hepatic stellate cells. Semin Liver Dis 21:373–384, 2001
Brodsky S, Chen J, Lee A, Akassoglou K, Norman J, Goligorsky MS: Plasmin-dependent and -independent effects of plasminogen activators and inhibitor-1 on ex vivo angiogenesis. Am J Physiol Heart Circ Physiol 281:H1784–H1792, 2001
Fibbi G, Pucci M, Grappone C, Pellegrini G, Salzano R, Casini A, Milani S, Del Rosso M: Functions of the fibrinolytic system in human Ito cells and its control by basic fibroblast and platelet-derived growth factor. Hepatology 29:868–878, 1999
Okazaki I, Watanabe T, Hozawa S, Arai M, Maruyama K: Molecular mechanism of the reversibility of hepatic fibrosis: with special reference to the role of matrix metalloproteinases. J Gastroenterol Hepatol 15 (Suppl):D26–D32, 2000
Sakaida I, Hironaka K, Terai S, Okita K: Gadolinium chloride reverses dimethylnitrosamine (DMN)-induced rat liver fibrosis with increased matrix metalloproteinases (MMPs) of Kupffer cells. Life Sci 72:943–959, 2003
Melgert BN, Weert B, Schellekens H, Meijer DK, Poelstra K: The pharmacokinetic and biological activity profile of dexamethasone targeted to sinusoidal endothelial and Kupffer cells. J Drug Target 11:1–10, 2003
Melgert BN, Olinga P, Van Der Laan JM, Weert B, Cho J, Schuppan D, Groothuis GM, Meijer DK, Poelstra K: Targeting dexamethasone to Kupffer cells: effects on liver inflammation and fibrosis in rats. Hepatology 34:719–728, 2001
Hata J, Ikeda E, Uno H, Asano S: Expression of hepatocyte growth factor mRNA in rat liver cirrhosis induced by N-nitrosodimethylamine as evidenced by in situ RT-PCR. J Histochem Cytochem 50:1461–1468, 2002
Luckey SW, Petersen DR: Activation of Kupffer cells during the course of carbon tetrachloride-induced liver injury and fibrosis in rats. Exp Mol Pathol 71:226–240, 2001
Akita K, Okuno M, Enya M, Imai S, Moriwaki H, Kawada N, Suzuki Y, Kojima S: Impaired liver regeneration in mice by lipopolysaccharide via TNF-alpha/kallikrein-mediated activation of latent TGF-beta. Gastroenterology 123:352–364, 2002
Rivera CA, Bradford BU, Hunt KJ, Adachi Y, Schrum LW, Koop DR, Burchardt ER, Rippe RA, Thurman RG: Attenuation of CCl(4)-induced hepatic fibrosis by GdCl(3) treatment or dietary glycine. Am J Physiol Gastrointest Liver Physiol 281:G200–G207, 2001
Shimizu I: Antifibrogenic therapies in chronic HCV infection. Curr Drug Targets Infect Disord 1:227–240, 2001
De Bleser PJ, Niki T, Rogiers V, Geerts A: Transforming growth factor-beta gene expression in normal and fibrotic rat liver. J Hepatol 26:886–893, 1997
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Xidakis, C., Ljumovic, D., Manousou, P. et al. Production of Pro- and Anti-fibrotic Agents by Rat Kupffer Cells; The Effect of Octreotide. Dig Dis Sci 50, 935–941 (2005). https://doi.org/10.1007/s10620-005-2668-8
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DOI: https://doi.org/10.1007/s10620-005-2668-8