title: Fluorofenidone attenuates bleomycin-induced pulmonary fibrosis by inhibiting eukaryotic translation initiation factor 3a (eIF3a) in rats.
abstract: 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 (5mg/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.
authors.affiliation: Hunan Provincial Key Laboratory of Cardiovascular Research, School of Pharmaceutical Sciences, Central South University, Changsha, China.
authors.forename: Yue-Han
authors.initials: YH
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Wannan Medical College, Wuhu, Anhui Province, China.
authors.forename: Xian-Wei
authors.initials: XW
authors.lastname: Li
authors.affiliation: Hunan Provincial Key Laboratory of Cardiovascular Research, School of Pharmaceutical Sciences, Central South University, Changsha, China.
authors.forename: Wen-Qun
authors.initials: WQ
authors.lastname: Li
authors.affiliation: Hunan Provincial Key Laboratory of Cardiovascular Research, School of Pharmaceutical Sciences, Central South University, Changsha, China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Li
authors.affiliation: Hunan Provincial Key Laboratory of Cardiovascular Research, School of Pharmaceutical Sciences, Central South University, Changsha, China.
authors.forename: Yuan-Jian
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Central South University, Changsha, China.
authors.forename: Gao-Yun
authors.initials: GY
authors.lastname: Hu
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Zhao-Qian
authors.initials: ZQ
authors.lastname: Liu
authors.affiliation: National Institution of Drug Clinical Trial, Xiangya Hospital, Central South University, Changsha, China. Electronic address: lid2002@163.com.
authors.forename: Dai
authors.initials: D
authors.lastname: Li
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000009:adverse effects*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D039621:Eukaryotic Initiation Factor-3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000097:blood / Q000378:metabolism
chemical_list: C511655:5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone; D039621:Eukaryotic Initiation Factor-3; D011728:Pyridones; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D003094:Collagen
keywords: Eukaryotic translation initiation factor 3a; Fluorofenidone; Pulmonary fibroblasts; Pulmonary fibrosis