24 HGF might be a key element in the process leading to improvement of liver cirrhosis because this molecule is a powerful hepatoprotective factor and an inducer of hepatocellular differentiation endowed with antifibrogenic activities.17, 25 HGF strongly inhibits the expression of profibrogenic factors such as TGFβ and CTGF, whereas it activates MMP2, MMP9, and MMP14 and reduces TIMP-1 and TIM-2 expression in different cells (reviewed25). These changes were found in SVIGF-I-treated livers making possible a participation of HGF/c-met induction in the antifibrogenic effect Protease Inhibitor Library price of IGF-I (Figs. 5, 6, Supporting Fig. 3). MMP1, MMP2, and MMP14

act as efficient collagen proteases, which could account for the fibrolysis observed with IGF-I therapy. Reduced activation

of HSCs could also result from decreased expression of PDGF, VEGF, and TGFβ (Fig. 6), which have been involved in activation, proliferation, migration, and increased extracellular matrix deposition from HSCs.14, 15 Therefore, IGF-I may favor resolution of the cirrhotic lesion by activation of fibrolysis and reduction of fibrogenesis. This is similar to what has been described for spontaneous reversion of cirrhosis in rats26 and opposite to the mechanisms involved in cirrhosis progression in humans,27 opening the possibility that IGF-I treatment could also decrease fibrosis progression in patients. Although the presence of cross-linking of collagen can make long-standing liver cirrhosis Pritelivir nmr in humans more difficult to revert than in experimental animals, still IGF-I-based therapy may have a role in these cases as it may exert

hepatoprotective activities, halt fibrogenesis, and partially revert liver fibrosis. Activated HSCs decrease in SVIGF-I-treated livers (Fig. 4). We could not determine with certainty whether activated HSCs undergo apoptosis and/or deactivation. Although we could not clearly detect HSC apoptosis at the time of the sacrifice, this process might have occurred at an earlier timepoint taking into account the marked reduction in fibrous septa observed in SVIGF-I-treated rats. However, as mentioned above, up-regulation of neurotrimin and the presence of vimentin-positive, αSMA-negative cells in the 上海皓元 remaining septa of cirrhotic rats given SVIGF-I argue in favor of HSC deactivation (Supporting Fig. 2). Importantly, IGF-I-based therapy also leads to improvement of liver function probably due to the induction of hepatoprotective factors, such as HGF, together with up-regulation of HNF4α, which stimulates differentiated hepatocellular functions (Fig. 7).20 Up-regulation of HNF4α is paralleled by down-regulation of WT-1 (Fig. 7), a nuclear factor that mediates the loss of differentiated hepatocellular functions.19 WT-1 is up-regulated by TGFβ and it seems possible that the reduction in the expression of this cytokine may contribute to diminish WT-1 and to increase HNF4α abundance.