title: Fluorofenidone attenuates bleomycin-induced pulmonary inflammation and fibrosis in mice via restoring caveolin 1 expression and inhibiting mitogen-activated protein kinase signaling pathway.
abstract: Idiopathic pulmonary fibrosis is a progressive, life-threatening, interstitial lung disease with no effective therapy. In this study, we evaluated the effects of fluorofenidone (FD), a novel pyridone agent, on a murine model of bleomycin-induced pulmonary inflammation and fibrosis. Institute for Cancer Research mice were intravenously injected with BLM or saline for 14 consecutive days. Fluorofenidone, pirfenidone (500 mg · kg · d, respectively), or vehicle was administered throughout the course of the experiment. Animals were killed on day 28, and various parameters reflecting pulmonary vascular permeability, influx of inflammatory cells, and levels of transforming growth factor β in the bronchoalveolar lavage fluid were assessed. Collagen I, α-smooth muscle actin, and fibronectin were measured by real-time reverse transcriptase-polymerase chain reaction or Western blot. Furthermore, caveolin 1 and activation of P38, extracellular signal-regulated kinase, and c-Jun N-terminal kinase were detected by Western blot. Fluorofenidone treatment significantly attenuated the increased pulmonary damage index score, the levels of proteins, transforming growth factor β, and the influx of cells in bronchoalveolar lavage fluid. Fluorofenidone also markedly reduced the expression of fibronectin, α-smooth muscle actin, and collagen I in mouse lung tissues. Inversely, FD restored caveolin 1 protein and mRNA expression, which was significantly downregulated in BLM-induced lung fibrosis. Fluorofenidone also inhibited phosphorylation of extracellular signal-regulated kinase, P38, and c-Jun N-terminal kinase. These findings collectively suggest that FD is an effective agent with antifibrotic and anti-inflammatory properties, and the mechanisms of its antifibrotic effect include regulating caveolin 1 expression and blocking mitogen-activated protein kinase signaling pathways.
authors.affiliation: Department of Pulmonary Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China. mj0377@163.com
authors.forename: Jie
authors.initials: J
authors.lastname: Meng
authors.forename: Yeqiang
authors.initials: Y
authors.lastname: Zou
authors.forename: Chengping
authors.initials: C
authors.lastname: Hu
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Zhu
authors.forename: Zhangzhe
authors.initials: Z
authors.lastname: Peng
authors.forename: Gaoyun
authors.initials: G
authors.lastname: Hu
authors.forename: Zhaohe
authors.initials: Z
authors.lastname: Wang
authors.forename: Lijian
authors.initials: L
authors.lastname: Tao
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology; D001761:Bleomycin / Q000009:adverse effects* / Q000494:pharmacology; D018893:Bronchoalveolar Lavage; D002199:Capillary Permeability / Q000187:drug effects; D051242:Caveolin 1 / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects; D005353:Fibronectins / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects*; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010766:Phosphorylation / Q000187:drug effects; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011728:Pyridones / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C511655:5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone; D000199:Actins; D000903:Antibiotics, Antineoplastic; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D005353:Fibronectins; D011728:Pyridones; D001761:Bleomycin; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases