Interaction with IGF-IR leads to activation of mitogen activated protein (MAP) kinase and PI3 kinase cascades that regulate genes involved in cell survival, growth, and differentiation.3 In liver cirrhosis, as result Staurosporine supplier of hepatocellular insufficiency, there is a marked reduction in the levels of IGF-I. This hormonal deficiency may play a role in the systemic metabolic derangement present in liver cirrhosis.4 In fact, treatment of cirrhotic rats with recombinant IGF-I (rIGF-I) promotes weight gain, nitrogen retention, and intestinal absorption of nutrients.5 In addition, rIGF-I has been shown to exert hepatoprotective activities

in cirrhotic rats.6 A recent pilot clinical trial showed that cirrhotic patients treated with a daily dose of rIGF-I (100 μg/kg bw) manifested a significant increase in serum albumin and an improvement of the Child-Pugh score.4 However, restoration of IGF-I ABT 199 levels

in cirrhotic patients using recombinant protein entails consumption of high doses of this molecule, making the treatment exceedingly costly. It may be envisioned that the recombinant protein might be substituted by the use of viral vectors encoding IGF-I that allow sustained expression of the transgene within the cirrhotic liver. Previously, we showed that the transfer of a recombinant Simian virus 40 vector encoding IGF-I (SVIGF-I) to a noncirrhotic liver reduced hepatocellular damage induced by subsequent administration of carbon tetrachloride (CCl4).7 However, it remained to be determined whether the injection of the vector was able to revert established liver cirrhosis. In the present article we show that administration of SVIGF-I to rats with established liver cirrhosis activates a robust tissue repair program characterized by stimulation of fibrolysis, down-regulation of profibrogenic factors, and induction of cytoprotective molecules leading to improved hepatocellular function and reduced liver fibrosis. These findings suggest that IGF-I gene transfer to the cirrhotic liver might be considered for the improvement of liver function

in patients without access to liver transplant or who deteriorate while on the waiting list for transplantation AR, amphiregulin; αSMA, α-smooth muscle actin; CCl4, carbon tetrachloride; CTGF, connective tissue growth factor; HGF, hepatocyte growth factor; HNF4α, hepatocyte nuclear factor 4 alpha; HSC, Dipeptidyl peptidase hepatic stellate cell; IGF-I insulin-like growth factor I; MAP, mitogen activated protein; MMPs, matrix metalloproteases; PDGF, platelet-derived growth factor; rIGF-I, recombinant IGF-I; TAA, thioacetamide; SVIGF-I, Simian virus 40 vectors encoding IGF-I; SVLuc, Simian virus luciferase; TGFβ, transforming growth factor beta; TIMP-1, tissue inhibitor of metalloproteinase 1; VEGF, vascular endothelium growth factor; WT-1, Wilms tumor-1. Hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells were isolated from healthy and cirrhotic male Sprague-Dawley rats as described.