脯氨酰4-羟化酶抑制剂（HOE 077）通过阻止星状细胞活化来抑制猪血清诱导的大鼠肝纤维化。

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

作者信息

Matsumura Y, Sakaida I, Uchida K, Kimura T, Ishihara T, Okita K

机构信息

First Department of Internal Medicine, Yamaguchi University, School of Medicine, Japan.

出版信息

J Hepatol. 1997 Jul;27(1):185-92. doi: 10.1016/s0168-8278(97)80300-5.

DOI:10.1016/s0168-8278(97)80300-5

PMID:9252094

Abstract

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 acid 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 aminotransferase were measured. Histological stains used were HE, azan and a stain for alpha-smooth muscle actin (alpha-SMA). Electron microscopy was also performed. Messenger RNA expressions of type I and III procollagen were examined by Northern blot analysis. alpha-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 microg/g wet weight (n=15). HOE 077 at doses up to 200 ppm significantly (p<0.01) reduced this increase of liver hydroxyproline content (181+/-39 microg/g wet weight, n=15) in accordance with improved histological findings. 200 ppm of HOE 077 significantly reduced mRNA expressions of alpha2(I) (486+/-102 vs 151+/-36, p<0.01) and alpha1(III) (276+/-127 vs 160+/-67, p<0.05) procollagen and percent area of alpha-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.

摘要

背景/目的：本研究旨在探讨一种新合成的脯氨酰4-羟化酶抑制剂[HOE 077，2,4-吡啶二甲酸双[(2-甲氧基乙基)酰胺]]对猪血清诱导的大鼠肝纤维化的作用及其机制。

方法

雄性Wistar大鼠每周两次接受0.5 ml猪血清，共10周，同时分别给予0、100或200 ppm的HOE 077。实验结束时，测定肝脏羟脯氨酸含量和丙氨酸转氨酶水平。使用的组织学染色方法包括苏木精-伊红染色（HE）、偶氮卡红染色（azan）和α-平滑肌肌动蛋白（α-SMA）染色。还进行了电子显微镜检查。通过Northern印迹分析检测I型和III型前胶原的信使核糖核酸（mRNA）表达。使用图像分析系统，将经偶氮卡红染色的α-SMA阳性细胞和纤维评估为组织标本的面积百分比。

结果

接受猪血清10周的大鼠肝脏羟脯氨酸含量增加至318±39 μg/g湿重（n = 15）。高达200 ppm的HOE 077显著（p<0.01）降低了肝脏羟脯氨酸含量的这种增加（181±39 μg/g湿重，n = 15），同时组织学结果有所改善。200 ppm的HOE 077显著降低了α2（I）（486±102对151±36，p<0.01）和α1（III）（276±127对160±67，p<0.05）前胶原的mRNA表达以及α-SMA阳性细胞的面积百分比（2.94±2.14对1.17±0.88%）。电子显微镜检查显示，200 ppm的HOE 077可防止脂肪滴的丢失。