(1113) Small molecule inhibitors have been developed that suppress tumor angiogenesis in several animal experimental tumor models via inhibition of integrins v3/v5. infiltration by macrophages/Kupffer cells was not affected, although increases in TNF-, IL-18 and COX-2 mRNA indicated modest macrophage activation. == Conclusion == Specific inhibition of integrin v3 (v5)in vivodecreased angiogenesis but worsened biliary (BDL) and septal (TAA) fibrosis, despite its antifibrogenic effect on HSC in vitro. Angiogenesis inhibitors should be used with caution in patients with hepatic fibrosis. (248 words). Keywords:Angiogenesis, collagen, liver fibrosis, rat model, vitronectin receptor == INTRODUCTORY STATEMENT == Liver fibrosis is a typical complication of many chronic liver diseases and characterized by an excessive synthesis and deposition of extracellular matrix (ECM) that consists mainly of collagens, proteoglycans, and non-collagenous glycoproteins. (1) When damaged chronically, e.g. by viruses, autoimmunity or toxins like alcohol, the liver initiates a would healing reaction that results in hepatic fibrosis and cirrhosis. (24) The fibrogenic effector cells are activated hepatic stellate cells and (myo-) fibroblasts that proliferate and produce GW 501516 excess amounts of ECM components, which is unbalanced by fibrolysis. While mechanisms of hepatic fibrosis progression are fairly GW 501516 well understood, it remains a challenge to alter the balance of hepatic fibrogenesis and fibrolysis in favour of fibrolysis, and to develop safe and effective antifibrotic therapies for patients with chronic liver diseases. The integrin v3 is an adhesion receptor that is expressed mainly on endothelial cells (EC), but also on some tumor cells, HSC and inflammatory cells, especially monocytes and macrophages. (57) It plays an important role in EC migration, proliferation and blood vessel formation, and its dysregulation is involved in the pathogenesis of many diseases, especially of cancers, promoting metastasis and tumor-induced neovascularization. (810) Engagement of v3 and its close relative v5 upregulates ECM-degrading protease activities, such as that of matrix metalloprotease (MMP) -2, -3 and -9. (1113) Small molecule inhibitors have been developed that suppress tumor angiogenesis in several animal experimental tumor models via inhibition of integrins v3/v5. (1416) Aberrant angiogenesis is clearly implicated in the progression of hepatic fibrosis and is considered a major determinant of hepatic dysfunction and irreversibility in cirrhosis. (3,1719) However, results regarding the benefit of anti-angiogenic therapy in fibrosis are controversial. GW 501516 (20) Thus, in leptin-deficient Zucker rats fed with a choline-and amino acid-defined diet hepatic neovascularization was identified as a prerequisite for fibrosis progression, (21) and inhibition of new vessel growth by angiostatin or inhibitors of vascular endothelial growth factor (VEGF) in the CCl4model resulted in alleviation of liver fibrosis. (22,23) In contrast, in the remnant kidney model of progressive renal failure inhibition of angiogenesis worsened renal scaring, while application of proangiogenic VEGF reduced fibrosis and stabilized renal function. (24,25) In order to assess the effect of antiangiogenic treatment in hepatic fibrosis, we selected Cilengitide (EMD121974), a specific inhibitor of integrins v3 and v5, that isused in human cancer studies. (26) Cilengitide was expected to be beneficial both due to its specific anti-angiogenic effect in vitro and in vivo (27,28) and to its antiproliferative and antifibrotic activity on HSC in vitro. (6) To allow more Rabbit polyclonal to PELI1 general conclusions, we chose two different animal models, secondary biliary fibrosis due to bile duct ligation (BDL) and panlobular fibrosis due to thioacetamide. == EXPERIMENTAL PROCEDURES == == Materials == Cilengitide (EMD121974) was obtained from Merck (Darmstadt, Germany). Cilengitide (cyclo-Arg-Gly-Asp-D-Phe-(N-methyl)-Val) is an antagonist GW 501516 selective for integrins v3 and v5, with IC50values of 3nM.