Fluorofenidone attenuates bleomycin-induced pulmonary fibrosis by inhibiting eukaryotic translation initiation factor 3a (eIF3a) in rats

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• 作者：Yue-Han Wu^b ; ¹ ; Xian-Wei Li^c ; ¹ ; Wen-Qun Li^b ; Xiao-Hui Li^b ; Yuan-Jian Li^b ; Gao-Yun Hu^d ; Zhao-Qian Liu^e ; Dai Li^a ; ^{lid2002@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Fluorofenidone ; Pulmonary fibrosis ; Pulmonary fibroblasts ; Eukaryotic translation initiation factor 3a
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：773
• 期：Complete
• 页码：42-50
• 全文大小：3387 K

文摘

Fluorofenidone is a novel derivative of l-mimosine. It has remarkable anti-fibrotic properties. In this study, we established that fluorofenidone ameliorates pulmonary fibrosis (PF) both in vivo and in vitro by specifically inhibiting the expression of eukaryotic translation initiation factor 3a (eIF3a). eIF3a plays an important role in the development and progression of PF. An animal model of PF was induced by intratracheal instillation of bleomycin (5 mg/kg) in rats. Rats were orally administered with fluorofenidone (250, 500 mg/kg/d·[i.g.]) and pirfenidone (500 mg/kg/d·[i.g.]) for 28 days. Primary pulmonary fibroblasts were cultured to determine the effect of fluorofenidone on TGF-β₁-induced (5 ng/ml) proliferation and differentiation of fibroblasts. The expression/level of eIF3a, TGF-β₁, α-SMA, collagen I, and collagen III were analyzed by ELISA, real-time PCR, and western blot. The cell proliferation rate was determined by MTS assay. The results indicate that fluorofenidone significantly improves the pathological changes in lung tissues and reduces the deposition of collagen by inhibiting eIF3a in rats with bleomycin-induced PF. Moreover, in a culture of pulmonary fibroblasts, fluorofenidone decreased the up-regulation of TGF-β₁-induced eIF3a by inhibiting the proliferation of cells and reducing the expression of α-SMA, collagen I, and collagen III. These findings suggest that eIF3a is a new and special target of fluorofenidone, which could be potentially used in the development of a drug that treats PF.