The prolyl 4-hydroxylase inhibitor HOE 077 prevents activation of Ito cells, reducing procollagen gene expression in rat liver fibrosis induced by choline-deficient L-amino acid-defined diet
The prolyl 4-hydroxylase inhibitor HOE 077 prevents activation of Ito cells, reducing procollagen gene expression in rat liver fibrosis induced by choline-deficient L-amino acid-defined diet
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DOI：
10.1002/hep.510230416
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发表时间：
1996-04-01
期刊：
影响因子：
13.5
通讯作者：
Okita, K
中科院分区：
文献类型：
--
作者：
Sakaida, I;Matsumura, Y;Okita, K
目前尚无通过抑制细胞外基质积累来治疗肝纤维化的有效方法。新合成的脯氨酰4-羟化酶（PH）抑制剂ho077（吡啶-2,4-二羧基-二（2-甲氧基乙基）酰胺）对16周龄雄性Wistar大鼠胆碱缺乏l -氨基酸（CDAA）饮食诱导肝纤维化的影响进行了研究。剂量高达200ppm的HOE 077以剂量依赖的方式预防纤维化，如肝脏中羟脯氨酸含量降低以及血清纤维化标志物（PIIIP, 7S，透明质酸）升高的抑制所示。在200 ppm下，ho077降低肝脏中III型前胶原α 1信使RNA （mRNA）的表达，与血清PIIIP和肝脏羟脯氨酸含量有良好的相关性。组织学上，200ppm的ho077也减少了肌成纤维样细胞（激活的Ito细胞）的增殖。这些结果表明，PH抑制剂不仅可以通过抑制脯氨酸的羟基化，还可以通过抑制Ito细胞的活化来预防纤维化，Ito细胞被认为是主要的胶原生成细胞，导致前胶原mRNA的表达减少。
No effective therapy has yet developed for liver fibrosis by directory inhibiting the accumulation of extracellular matrix. The effect of a newly synthesized prolyl 4-hydroxylase (PH) inhibitor, HOE 077 (pyridine-2,4-dicarboxylic-di(2-methoxyethyl)amide), was examined using the model of choline-deficient L-camino acid (CDAA) defined diet-induced liver fibrosis in l6-week-old male Wistar rats. HOE 077 at doses up to 200 ppm prevented fibrosis in a dose-dependent manner, as indicated by reduced hydroxyproline content in liver as well as inhibition of increased serum fibrotic markers (PIIIP, 7S, hyaluronic acid). HOE 077 at 200 ppm reduced expression of type III procollagen alpha 1 messenger RNA (mRNA) in the liver, with a good correlation with serum PIIIP and hydroxyproline content of the liver. Histologically, HOE 077 at 200 ppm also reduced proliferation of myofibroblastlike cells (activated Ito cells). These results indicate that a PH inhibitor can prevent fibrosis by inhibiting not only the hydroxylation of proline but also the activation of Ito cells, which are considered the main collagen-producing cells, resulting in reduced expression of procollagen mRNA.