Prolyl 4-hydroxylase inhibitor (HOE 077) inhibits pig serum-induced rat liver fibrosis by preventing stellate cell activation

Background/Aims: The aim of this study was to investigate the effect and mechanism of fibrosuppression by a newly synthesized prolyl 4-hydroxylase inhibitor {HOE 077, 2, 4-pyridine dicarboxylic acids bis [(2-methoxyethyl) amide]} on pig serum-induced liver fibrosis in the rat. Methods: Male Wistar rats received 0.5 ml of pig serum twice a week for 10 weeks with 0, 100 or 200 ppm of HOE 077. At the end of the experiment, the hydroxyproline content of the liver, and alanine aminostransferase were measured. Histological stains used were HE, azan and a stain for α-smooth muscle actin (α-SMA). Electron microscopy was also performed. Messenger RNA expressions of type I and III procollagen were examined by Northern blot analysis. α-SMA positive cells and fibers with azan staining were assessed as percent area of the tissue specimen, using an image analysis system. Results: Rats that received pig serum for 10 weeks showed an increased liver hydroxyproline content of 318±39 μg/g we weight (n=15). HOE 077 at doses up to 200 ppm significantly (p<0.01) reduced this increase of liver hydroxyproline content (181±39 μg/g wet weight, n=15) in accordance with imporved histological findings. 200 ppm of HOE 077 significantly reduced mRNA expressions of α2(I) (486±102 vs 151±36, p<0.01) and α1(III) (276±127 vs 160±67, p<0.05) procollagen and percent area of α-SMA positive cells (2.94±2.14 vs 1.17±0.88%). Electron microscopy revealed that 200 ppm of HOE 077 prevented the loss of fat droplets. Conclusions: A prolyl 4-hydroxylase inhibitor (HOE 077) prevented pig serum-induced rat liver fibrosis by inhibiting stellate cell activation.