Pharmacological Inhibition of Integrin Alphavbeta3 Aggravates Experimental Liver Fibrosis and Suppresses Hepatic Angiogenesis

Overview

Journal Hepatology

Specialty Gastroenterology

Date 2009 Sep 3

PMID 19725105

Citations 87

Authors

Eleonora Patsenker

Yury Popov

Felix Stickel

Vreni Schneider

Monika Ledermann

Hans Sagesser

Gerald Niedobitek

Simon L Goodman

Detlef Schuppan

Affiliations

Soon will be listed here.

Abstract

Unlabelled: The vitronectin receptor integrin alphavbeta3 promotes angiogenesis by mediating migration and proliferation of endothelial cells, but also drives fibrogenic activation of hepatic stellate cells (HSCs) in vitro. Expecting antifibrotic synergism, we studied the effect of alphavbeta3 inhibition in two in vivo models of liver fibrogenesis. Liver fibrosis was induced in rats by way of bile duct ligation (BDL) for 6 weeks or thioacetamide (TAA) injections for 12 weeks. A specific alphavbeta3 (alphavbeta5) inhibitor (Cilengitide) was given intraperitoneally twice daily at 15 mg/kg during BDL or after TAA administration. Liver collagen was determined as hydroxyproline, and gene expression was quantified by way of quantitative polymerase chain reaction. Liver angiogenesis, macrophage infiltration, and hypoxia were assessed by way of CD31, CD68 and hypoxia-inducible factor-1alpha immunostaining. Cilengitide decreased overall vessel formation. This was significant in portal areas of BDL and septal areas of TAA fibrotic rats and was associated with a significant increase of liver collagen by 31% (BDL) and 27% (TAA), and up-regulation of profibrogenic genes and matrix metalloproteinase-13. Treatment increased gamma glutamyl transpeptidase in both models, while other serum markers remained unchanged. alphavbeta3 inhibition resulted in mild liver hypoxia, as evidenced by up-regulation of hypoxia-inducible genes. Liver infiltration by macrophages/Kupffer cells was not affected, although increases in tumor necrosis factor alpha, interleukin-18, and cyclooxygenase-2 messenger RNA indicated modest macrophage activation.

Conclusion: Specific inhibition of integrin alphavbeta3 (alphavbeta5) in vivo decreased angiogenesis but worsened biliary (BDL) and septal (TAA) fibrosis, despite its antifibrogenic effect on HSCs in vitro. Angiogenesis inhibitors should be used with caution in patients with hepatic fibrosis.

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References

Fabris L, Cadamuro M, Guido M, Spirli C, Fiorotto R, Colledan M . Analysis of liver repair mechanisms in Alagille syndrome and biliary atresia reveals a role for notch signaling. Am J Pathol. 2007; 171(2):641-53. PMC: 1934520. DOI: 10.2353/ajpath.2007.070073. View

Friedman S, Bansal M . Reversal of hepatic fibrosis -- fact or fantasy?. Hepatology. 2006; 43(2 Suppl 1):S82-8. DOI: 10.1002/hep.20974. View

Desmet V, Roskams T . Cirrhosis reversal: a duel between dogma and myth. J Hepatol. 2004; 40(5):860-7. DOI: 10.1016/j.jhep.2004.03.007. View

Zhou X, Murphy F, Gehdu N, Zhang J, Iredale J, Benyon R . Engagement of alphavbeta3 integrin regulates proliferation and apoptosis of hepatic stellate cells. J Biol Chem. 2004; 279(23):23996-4006. DOI: 10.1074/jbc.M311668200. View

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(22):15090-8. DOI: 10.1074/jbc.M600030200. View

Harms J, Welch D, Samant R, Shevde L, Miele M, Babu G . A small molecule antagonist of the alpha(v)beta3 integrin suppresses MDA-MB-435 skeletal metastasis. Clin Exp Metastasis. 2004; 21(2):119-28. DOI: 10.1023/b:clin.0000024763.69809.64. View

Bataller R, Brenner D . Liver fibrosis. J Clin Invest. 2005; 115(2):209-18. PMC: 546435. DOI: 10.1172/JCI24282. View

Hood J, Cheresh D . Role of integrins in cell invasion and migration. Nat Rev Cancer. 2003; 2(2):91-100. DOI: 10.1038/nrc727. View

Neef M, Ledermann M, Saegesser H, Schneider V, Widmer N, Decosterd L . Oral imatinib treatment reduces early fibrogenesis but does not prevent progression in the long term. J Hepatol. 2005; 44(1):167-75. DOI: 10.1016/j.jhep.2005.06.015. View

10.

Corpechot C, Barbu V, Wendum D, Kinnman N, Rey C, Poupon R . Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatology. 2002; 35(5):1010-21. DOI: 10.1053/jhep.2002.32524. View

11.

Schneider J, Zhu Y, Coleman T, Semenkovich C . Macrophage beta3 integrin suppresses hyperlipidemia-induced inflammation by modulating TNFalpha expression. Arterioscler Thromb Vasc Biol. 2007; 27(12):2699-706. DOI: 10.1161/ATVBAHA.107.153650. View

12.

Schuppan D, Afdhal N . Liver cirrhosis. Lancet. 2008; 371(9615):838-51. PMC: 2271178. DOI: 10.1016/S0140-6736(08)60383-9. View

13.

Friedman S . Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008; 134(6):1655-69. PMC: 2888539. DOI: 10.1053/j.gastro.2008.03.003. View

14.

Kitade M, Yoshiji H, Kojima H, Ikenaka Y, Noguchi R, Kaji K . Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats. Hepatology. 2006; 44(4):983-91. DOI: 10.1002/hep.21338. View

15.

Tugues S, Fernandez-Varo G, Munoz-Luque J, Ros J, Arroyo V, Rodes J . Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology. 2007; 46(6):1919-26. DOI: 10.1002/hep.21921. View

16.

Schuppan D, Ruehl M, Somasundaram R, Hahn E . Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis. 2001; 21(3):351-72. DOI: 10.1055/s-2001-17556. View

17.

Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin D . Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut. 2003; 52(9):1347-54. PMC: 1773781. DOI: 10.1136/gut.52.9.1347. View

18.

Hoefs J, Wang F, Lilien D, Walker B, Kanel G . A novel, simple method of functional spleen volume calculation by liver-spleen scan. J Nucl Med. 1999; 40(10):1745-55. View

19.

Horie Y, Wolf R, Russell J, Shanley T, Granger D . Role of Kupffer cells in gut ischemia/reperfusion-induced hepatic microvascular dysfunction in mice. Hepatology. 1997; 26(6):1499-505. DOI: 10.1002/hep.510260617. View

20.

Reardon D, Nabors L, 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(8):1225-35. PMC: 2832832. DOI: 10.1517/13543784.17.8.1225. View