• 1
    Schuppan D, Ruehl M, Somasundaram R, Hahn EG. Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis 2001; 21: 351372.
  • 2
    Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005; 115: 209218.
  • 3
    Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008; 371: 838851.
  • 4
    Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008; 134: 16551669.
  • 5
    Hood JD, Cheresh DA. Role of integrins in cell invasion and migration. Nat Rev Cancer 2002; 2: 91100.
  • 6
    Patsenker E, Popov Y, Wiesner M, Goodman SL, Schuppan D. Pharmacological inhibition of the vitronectin receptor abrogates PDGF-BB-induced hepatic stellate cell migration and activation in vitro. J Hepatol 2007; 46: 878887.
  • 7
    Chung AS, Gao Q, Kao WJ. Either integrin subunit beta1 or beta3 is involved in mediating monocyte adhesion, IL-1beta protein and mRNA expression in response to surfaces functionalized with fibronectin-derived peptides. J Biomater Sci Polym Ed 2007; 18: 713729.
  • 8
    Sato T, Konishi K, Kimura H, Maeda K, Yabushita K, Tsuji M, et al. Vascular integrin beta 3 and its relation to pulmonary metastasis of colorectal carcinoma. Anticancer Res 2001; 21: 643647.
  • 9
    Ruegg C, Mariotti A. Vascular integrins: pleiotropic adhesion and signaling molecules in vascular homeostasis and angiogenesis. Cell Mol Life Sci 2003; 60: 11351157.
  • 10
    Mahabeleshwar GH, Feng W, Phillips DR, Byzova TV. Integrin signaling is critical for pathological angiogenesis. J Exp Med 2006; 203: 24952507.
  • 11
    Bendeck MP, Irvin C, Reidy M, Smith L, Mulholland D, Horton M, et al. Smooth muscle cell matrix metalloproteinase production is stimulated via alpha(v)beta(3) integrin. Arterioscler Thromb Vasc Biol 2000; 20: 14671472.
  • 12
    Jackson C. Matrix metalloproteinases and angiogenesis. Curr Opin Nephrol Hypertens 2002; 11: 295299.
  • 13
    Baum O, Hlushchuk R, Forster A, Greiner R, Clezardin P, Zhao Y, et al. Increased invasive potential and up-regulation of MMP-2 in MDA-MB-231 breast cancer cells expressing the beta3 integrin subunit. Int J Oncol 2007; 30: 325332.
  • 14
    Belvisi L, Riccioni T, Marcellini M, Vesci L, Chiarucci I, Efrati D, et al. Biological and molecular properties of a new alpha(v)beta3/alpha(v)beta5 integrin antagonist. Mol Cancer Ther 2005; 4: 16701680.
  • 15
    Harms JF, Welch DR, Samant RS, Shevde LA, Miele ME, Babu GR, et al. A small molecule antagonist of the alpha(v)beta3 integrin suppresses MDA-MB-435 skeletal metastasis. Clin Exp Metastasis 2004; 21: 119128.
  • 16
    Zhao Y, Bachelier R, Treilleux I, Pujuguet P, Peyruchaud O, Baron R, et al. Tumor alphavbeta3 integrin is a therapeutic target for breast cancer bone metastases. Cancer Res 2007; 67: 58215830.
  • 17
    Friedman SL, Bansal MB. Reversal of hepatic fibrosis—fact or fantasy? HEPATOLOGY 2006; 43: S82S88.
  • 18
    Desmet VJ, Roskams T. Cirrhosis reversal: a duel between dogma and myth. J Hepatol 2004; 40: 860867.
  • 19
    Taura K, De Minicis S, Seki E, Hatano E, Iwaisako K, Osterreicher CH, et al. Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology 2008; 135: 17291738.
  • 20
    Kang DH, Johnson RJ. Vascular endothelial growth factor: a new player in the pathogenesis of renal fibrosis. Curr Opin Nephrol Hypertens 2003; 12: 4349.
  • 21
    Kitade M, Yoshiji H, Kojima H, Ikenaka Y, Noguchi R, Kaji K, et al. Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats. HEPATOLOGY 2006; 44: 983991.
  • 22
    Vogten JM, Drixler TA, te Velde EA, Schipper ME, van Vroonhoven TJ, Voest EE, et al. Angiostatin inhibits experimental liver fibrosis in mice. Int J Colorectal Dis 2004; 19: 387394.
  • 23
    Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, et al. Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut 2003; 52: 13471354.
  • 24
    Kang DH, Hughes J, Mazzali M, Schreiner GF, Johnson RJ. Impaired angiogenesis in the remnant kidney model: II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. J Am Soc Nephrol 2001; 12: 14481457.
  • 25
    Kang DH, Joly AH, Oh SW, Hugo C, Kerjaschki D, Gordon KL, et al. Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1. J Am Soc Nephrol 2001; 12: 14341447.
  • 26
    Hariharan S, Gustafson D, Holden S, McConkey D, Davis D, Morrow M, et al. Assessment of the biological and pharmacological effects of the alpha nu beta3 and alpha nu beta5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors. Ann Oncol 2007; 18: 14001407.
  • 27
    Cai W, Chen X. Anti-angiogenic cancer therapy based on integrin alphavbeta3 antagonism. Anticancer Agents Med Chem 2006; 6: 407428.
  • 28
    Reardon DA, Nabors LB, Stupp R, Mikkelsen T. Cilengitide: an integrin-targeting arginine-glycine-aspartic acid peptide with promising activity for glioblastoma multiforme. Expert Opin Investig Drugs 2008; 17: 12251235.
  • 29
    Goodman SL, Holzemann G, Sulyok GA, Kessler H. Nanomolar small molecule inhibitors for alphav(beta)6, alphav(beta)5, and alphav(beta)3 integrins. J Med Chem 2002; 45: 10451051.
  • 30
    Eskens FA, Dumez H, Hoekstra R, Perschl A, Brindley C, Bottcher S, et al. Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of Cilengitide (EMD 121974), a novel inhibitor of the integrins alphavbeta3 and alphavbeta5 in patients with advanced solid tumours. Eur J Cancer 2003; 39: 917926.
  • 31
    Popov Y, Patsenker E, Bauer M, Niedobitek E, Schulze-Krebs A, Schuppan D. Halofuginone induces matrix metalloproteinases in rat hepatic stellate cells via activation of p38 and NFkappaB. J Biol Chem 2006; 281: 1509015098.
  • 32
    Popov Y, Patsenker E, Fickert P, Trauner M, Schuppan D. Mdr2 (Abcb4)-/- mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes. J Hepatol 2005; 43: 10451054.
  • 33
    Patsenker E, Popov Y, Stickel F, Jonczyk A, Goodman SL, Schuppan D. Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression. Gastroenterology 2008; 135: 660670.
  • 34
    Fabris L, Cadamuro M, Guido M, Spirli C, Fiorotto R, Colledan M, et al. Analysis of liver repair mechanisms in Alagille syndrome and biliary atresia reveals a role for notch signaling. Am J Pathol 2007; 171: 641653.
  • 35
    Foss AJ, Alexander RA, Jefferies LW, Hungerford JL, Harris AL, Lightman S. Microvessel count predicts survival in uveal melanoma. Cancer Res 1996; 56: 29002903.
  • 36
    Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 2005; 115: 5665.
  • 37
    Fallowfield JA, Mizuno M, Kendall TJ, Constandinou CM, Benyon RC, Duffield JS, et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol 2007; 178: 52885295.
  • 38
    Yoshiji H, Kuriyama S, Fukui H. Angiotensin-I-converting enzyme inhibitors may be an alternative anti-angiogenic strategy in the treatment of liver fibrosis and hepatocellular carcinoma. Possible role of vascular endothelial growth factor. Tumour Biol 2002; 23: 348356.
  • 39
    Maubant S, Saint-Dizier D, Boutillon M, Perron-Sierra F, Casara PJ, Hickman JA, et al. Blockade of alpha v beta3 and alpha v beta5 integrins by RGD mimetics induces anoikis and not integrin-mediated death in human endothelial cells. Blood 2006; 108: 30353044.
  • 40
    Zhou X, Murphy FR, Gehdu N, Zhang J, Iredale JP, Benyon RC. Engagement of alphavbeta3 integrin regulates proliferation and apoptosis of hepatic stellate cells. J Biol Chem 2004; 279: 2399624006.
  • 41
    Raguse JD, Gath HJ, Bier J, Riess H, Oettle H. Cilengitide (EMD 121974) arrests the growth of a heavily pretreated highly vascularised head and neck tumour. Oral Oncol 2004; 40: 228230.
  • 42
    Hoefs JC, Wang FW, Lilien DL, Walker B, Kanel G. A novel, simple method of functional spleen volume calculation by liver-spleen scan. J Nucl Med 1999; 40: 17451755.
  • 43
    Nanji AA, Miao L, Thomas P, Rahemtulla A, Khwaja S, Zhao S, et al. Enhanced cyclooxygenase-2 gene expression in alcoholic liver disease in the rat. Gastroenterology 1997; 112: 943951.
  • 44
    Ren J, Avery J, Zhao H, Schneider JG, Ross FP, Muslin AJ. Beta3 integrin deficiency promotes cardiac hypertrophy and inflammation. J Mol Cell Cardiol 2007; 42: 367377.
  • 45
    Schneider JG, Zhu Y, Coleman T, Semenkovich CF. Macrophage beta3 integrin suppresses hyperlipidemia-induced inflammation by modulating TNFalpha expression. Arterioscler Thromb Vasc Biol 2007; 27: 26992706.
  • 46
    Horie Y, Wolf R, Russell J, Shanley TP, Granger DN. Role of Kupffer cells in gut ischemia/reperfusion-induced hepatic microvascular dysfunction in mice. HEPATOLOGY 1997; 26: 14991505.
  • 47
    Siegmund SV, Brenner DA. Molecular pathogenesis of alcohol-induced hepatic fibrosis. Alcohol Clin Exp Res 2005; 29: 102S109S.
  • 48
    Rosmorduc O, Wendum D, Corpechot C, Galy B, Sebbagh N, Raleigh J, et al. Hepatocellular hypoxia-induced vascular endothelial growth factor expression and angiogenesis in experimental biliary cirrhosis. Am J Pathol 1999; 155: 10651073.
  • 49
    Corpechot C, Barbu V, Wendum D, Kinnman N, Rey C, Poupon R, et al. Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. HEPATOLOGY 2002; 35: 10101021.
  • 50
    Jeong WI, Do SH, Yun HS, Song BJ, Kim SJ, Kwak WJ, et al. Hypoxia potentiates transforming growth factor-beta expression of hepatocyte during the cirrhotic condition in rat liver. Liver Int 2004; 24: 658668.
  • 51
    Ueno T, Nakamura T, Torimura T, Sata M. Angiogenic cell therapy for hepatic fibrosis. Med Mol Morphol 2006; 39: 1621.
  • 52
    Taniguchi E, Kin M, Torimura T, Nakamura T, Kumemura H, Hanada S, et al. Endothelial progenitor cell transplantation improves the survival following liver injury in mice. Gastroenterology 2006; 130: 521531.
  • 53
    Tugues S, Fernandez-Varo G, Munoz-Luque J, Ros J, Arroyo V, Rodes J, et al. Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. HEPATOLOGY 2007; 46: 19191926.
  • 54
    Pinzani M, Gesualdo L, Sabbah GM, Abboud HE. Effects of platelet-derived growth factor and other polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat-storing cells. J Clin Invest 1989; 84: 17861793.
  • 55
    Neef M, Ledermann M, Saegesser H, Schneider V, Widmer N, Decosterd LA, et al. Oral imatinib treatment reduces early fibrogenesis but does not prevent progression in the long term. J Hepatol 2006; 44: 167175.