11, 25 An important finding of the current study is that oral losartan given for short periods of time, did not reduce established fibrosis. This is not surprising, since in the vast majority of studies in which losartan reduces the extent of liver fibrosis, losartan is given concomitantly

with the agent causing liver injury, and for prolonged periods of time (i.e., several weeks).26, 27 This finding suggests that antifibrotic drugs may be not as active selleck as expected when administered to rats with established fibrosis, which is in line with the poor clinical usefulness of many preclinical drug-candidates. Here, we demonstrate that the selective delivery of antifibrotic drugs to the main fibrogenic Doxorubicin cell type in the liver (i.e., activated HSCs) markedly increased the antifibrotic effect. Different mechanisms may explain the strong antifibrotic effect achieved with our drug-targeting construct. First, targeting losartan to activated HSCs via the modified albumin, M6PHSA, increases the fraction of the dose that accumulates within the fibrogenic cells. Since HSCs only represent a small fraction of the total liver, the drug levels found in liver homogenates may underestimate the actual accumulation of losartan-M6PHSA within HSCs. However, orally administered losartan resulted in higher hepatic concentrations due to the much higher dose, which however produced weaker

antifibrogenic effects. Thus, the strong effects of losartan-M6PHSA cannot be attributed to an increase in drug concentrations within the liver,

but to the selectivity of losartan to activated HSCs. Secondly, the activity of losartan-M6PHSA may be enhanced by the specific interaction that M6PHSA provides. The M6P/IGFII receptor participates in the activation of latent TGF-β1, which may be affected by M6PHSA.10 However, the finding that treatment with M6PHSA alone did not affect fibrosis or inflammation in bile duct-ligated rats does not support this hypothesis. Thirdly, we show that targeted losartan rapidly reduces the accumulation of activated HSCs in the fibrotic liver. This is consistent with previous reports showing that angiotensin II is find more a powerful mitogen for HSCs.28 And finally, targeted losartan strongly attenuated infiltration of inflammatory cells, a major pathogenic event in liver fibrogenesis.29 This latter effect is consistent with previous reports showing that Ang II exerts pro-inflammatory actions both in cultured cells and in vivo.6, 30 Although the cell type mediating the anti-inflamatory effect is unknown, activated HSCs are potential candidates. In fact, losartan-M6PHSA attenuated the inflammatory effects induced by angiotensin II on cultured HSCs. The beneficial effect of losartan-M6PHSA is not related with increased expression or activity of the collagenolytic enzymes MMP2, MMP3, and MMP9. Our results may have implications for the treatment of chronic liver diseases.