title: Inhibition of airway epithelial-to-mesenchymal transition and fibrosis by kaempferol in endotoxin-induced epithelial cells and ovalbumin-sensitized mice.
abstract: Chronic airway remodeling is characterized by structural changes within the airway wall, including smooth muscle hypertrophy, submucosal fibrosis and epithelial shedding. Epithelial-to-mesenchymal transition (EMT) is a fundamental mechanism of organ fibrosis, which can be induced by TGF-β. In the in vitro study, we investigated whether 1-20 μM kaempferol inhibited lipopolysaccharide (LPS)-induced bronchial EMT in BEAS-2B cells. The in vivo study explored demoting effects of 10-20 mg/kg kaempferol on airway fibrosis in BALB/c mice sensitized with ovalbumin (OVA). LPS induced airway epithelial TGF-β1 signaling that promoted EMT with concurrent loss of E-cadherin and induction of α-smooth muscle actin (α-SMA). Nontoxic kaempferol significantly inhibited TGF-β-induced EMT process through reversing E-cadherin expression and retarding the induction of N-cadherin and α-SMA. Consistently, OVA inhalation resulted in a striking loss of epithelial morphology by displaying myofibroblast appearance, which led to bronchial fibrosis with submucosal accumulation of collagen fibers. Oral administration of kaempferol suppressed collagen deposition, epithelial excrescency and goblet hyperplasia observed in the lung of OVA-challenged mice. The specific inhibition of TGF-β entailed epithelial protease-activated receptor-1 (PAR-1) as with 20 μM kaempferol. The epithelial PAR-1 inhibition by SCH-79797 restored E-cadherin induction and deterred α-SMA induction, indicating that epithelial PAR-1 localization was responsible for resulting in airway EMT. These results demonstrate that dietary kaempferol alleviated fibrotic airway remodeling via bronchial EMT by modulating PAR1 activation. Therefore, kaempferol may be a potential therapeutic agent targeting asthmatic airway constriction.
authors.affiliation: Department of Food and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Ju-Hyun
authors.initials: JH
authors.lastname: Gong
authors.affiliation: Department of Food and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: In-Hee
authors.initials: IH
authors.lastname: Cho
authors.affiliation: Department of Food and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Daekeun
authors.initials: D
authors.lastname: Shin
authors.affiliation: Department of Food and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Seon-Young
authors.initials: SY
authors.lastname: Han
authors.affiliation: Department of Food and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Sin-Hye
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Food and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Young-Hee
authors.initials: YH
authors.lastname: Kang
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D024141:Collagen Type IV / Q000096:biosynthesis; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D044949:Kaempferols / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D044463:Receptor, PAR-1 / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
chemical_list: D024141:Collagen Type IV; D044949:Kaempferols; D008070:Lipopolysaccharides; D044463:Receptor, PAR-1; D053773:Transforming Growth Factor beta1; C006552:kaempferol; D010047:Ovalbumin; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14