01 Set Effects of the treatment with Maraviroc, a CCR5 inhibitor, on a human hepatic stellate cell line

Maria Aurora Carleo

After an acute liver damage, tissue regeneration repairs lesions with degradation of deposed fibrotic material, while mechanisms of tissue restoration are persistently activated following several repeated injuries, inducing deposition of extracellular matrix (ECM). Factors responsible for ECM remodeling have been identified in a pathway involving a family of zinc-dependent enzyme matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs) and several converting enzymes. Recent experimental models suggested a role of CCR5 receptor in the genesis of liver fibrosis. We evaluated the effects of the treatment with the CCR5 inhibitor Maraviroc on LX-2, a human hepatic stellate cell line (HSC). Treatment with Maraviroc resulted in: a block in S phase of LX-2 cells, an increased expression levels of cyclin D1 and p21, a reduced expression of p53, a decrease of specific markers as Collagen type I, α-SMA and TGF-β1, a down regulation of both metalloproteins (MMP-2, MMP-9), used for the degradation of the ECM and their inhibitors (TIMP-1, TIMP-2). In this way Maraviroc could interfere with the generation of liver fibrosis and could be crucial in all chronic liver diseases, also in HCV chronic infection. In fact, even following HCV eradication, liver damage does not regress. Maraviroc could play an important role because, in addition to its own anti-HIV activity, it could reduce the release of pro-inflammatory citokynes implicated in liver fibrogenesis.