There was up-reg-ulation of transforming growth factor-β in bilia

There was up-reg-ulation of transforming growth factor-β in biliary epithelial cells and blocking OPN, transforming GSK126 growth factor-β or both reduced collagen-I expression in hepatic stellate cells. Conclusion: OPN emerges as a key matricellular cytokine driving ductular reaction and

contributing to scarring and liver fibrosis via transforming growth factor-β. Disclosures: The following people have nothing to disclose: Xiaodong Wang, Aritz Lopategi, Yongke Lu, Naoto Kitamura, Xiaodong Ge, Raquel Urtasun, Tung Ming Leung, M. Isabel Fiel, Natalia Nieto Congenital hepatic fibrosis (CHF), the most common extra-hepatic manifestation of autosomal recessive polycystic kidney disease (ARPKD), is associated with excessive extracellular matrix (ECM) deposition which encapsulates ductal plate cell-derived cysts. The precise mechanisms of hepatic cystogenesis and associated CHF are not known. Therapeutic options for ARPKD/CHF are extremely limited. Here, making use BYL719 clinical trial of the polycystic kidney (PCK) rat which harbors the same mutation found in ARPKD patients, we characterized the development of hepatic fibrosis from post natal day (PND) 0 to 3 months after birth.

Sprague-Dawley (SD) rats were used as controls. Liver to body weight ratios were greater in PCK rats compared to controls, consistent with the development and growth of intrahep-atic cysts. At three months, PCK rats had increased hepatic mRNA accumulation of αSMA (myofibroblast marker), type I collagen, elastin (portal fibroblast marker), desmin (hepatic stellate cell marker) and connective tissue growth factor (CTGF) compared to SD rats. Consistent with those findings, 3-month old PCK rats exhibited increased type 1 collagen, Sirius red staining and CTGF protein relative to SD rats. Time

course analysis revealed that the peak hepatic mRNA accumulation of αSMA, Col 1a 1, CTGF and elastin was at PND 10-20. Hepatic αSMA protein also peaked at PND find more 10. Hepatic CTGF mRNA and protein was induced in PCK rats at PND5, peaked at PND10 and remained increased throughout the time course. While cysts were observable PND 0, diffuse ECM deposition around hepatic cysts revealed by Sirius red staining began PND 5 in PCK rats; diffuse Sirius red staining increased until PND 20. In PND 30 and 3-month old PCK rats, Sirius red staining became intense and compressed around proliferating cysts. The increased hepatic fibrosis observed in PCK rat livers was corroborated by observations made in human PKD liver samples. Collectively, these data suggest that initiation of fibrogenesis in PCK rats occurs during early postnatal period and involves both portal fibroblast- and hepatic stellate cell-derived myofibroblasts. Furthermore, these data suggest that CTGF may be a driving force behind CHF in the PKC rat and reveal CTGF as a potential therapeutic target. These studies were supported by grants to U.A. and D.P.W. (P50 DK057301-11) and M.T.P (P20 GM103549 and R00 AA017918).

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