title: Lyn mitigates mouse airway remodeling by downregulating the TGF-β3 isoform in house dust mite models.
abstract: Chronic airway remodeling is a serious consequence of asthma, which is caused by complex but largely unknown mechanisms. Despite versatile functions, the role of Lyn in chronic airway remodeling remains undefined. Using Lyn(-/-) mice, we show that continual exposure (for 8 wk) of house dust mite extracts induced a severe phenotype of chronic airway remodeling, including exacerbated mucus production, collagen deposition, dysregulated cytokine secretion, and elevated inflammation. Strikingly, a significant increase in TGF-β3 rather than TGF-β1 was observed in Lyn(-/-) mouse lungs compared with lungs in wild-type mice. Furthermore, TGF-β3 neutralizing Abs not only inhibited the expression of STAT6 and Smad2/3 but also decreased phosphorylation of Smad2 and NF-κB in Lyn(-/-) mouse lungs. In addition, both recombinant and adenoviral TGF-β3 significantly promoted epithelial-to-mesenchymal transition and intensified collagen I production and MUC5AC expression. Further examination of chronic asthma patients showed that a decreased Lyn correlated with the severity of airway inflammation and mucus hypersecretion. Finally, Lyn may critically regulate airway remodeling by directly interacting with TGF-β3. Collectively, these findings revealed that Lyn regulates TGF-β3 isoform and modulates the development of airway remodeling, which may have therapeutic implications for severe chronic asthma.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of North Dakota, Grand Forks, ND 58203;
authors.forename: Guoping
authors.initials: G
authors.lastname: Li
authors.forename: John
authors.initials: J
authors.lastname: Fox
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: George F
authors.initials: GF
authors.lastname: Gao
authors.forename: Yang
authors.initials: Y
authors.lastname: Jin
authors.forename: Hongwei
authors.initials: H
authors.lastname: Gao
authors.forename: Min
authors.initials: M
authors.lastname: Wu
mesh_terms: D000328:Adult; D056151:Airway Remodeling / Q000187:drug effects / Q000235:genetics; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D039741:Antigens, Dermatophagoides / Q000276:immunology*; D002460:Cell Line; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology* / Q000628:therapy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D039981:Pyroglyphidae; D034741:RNA, Small Interfering / Q000235:genetics; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D053782:Transforming Growth Factor beta3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics; D055815:Young Adult; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D039741:Antigens, Dermatophagoides; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D053782:Transforming Growth Factor beta3; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases