Journal
JOURNAL OF IMMUNOLOGY
Volume 191, Issue 11, Pages 5359-5370Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1301596
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Funding
- National Institutes of Health [5R03 ES014690, 5R15 AI101973-01, 5R03 AI097532-01A1]
- Flight Attendant Medical Research Institute [103007]
- Chinese National Science Foundation [81170032]
- Chinese Scholar Council
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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-beta 3 rather than TGF-beta 1 was observed in Lyn(-/-) use lungs compared with lungs in wild-type mice. Furthermore, TGF-beta 3 neutralizing Abs not only inhibited the expression of STAT6 and Smad2/3 but also decreased phosphorylation of Smad2 and NF-kB in Lyn(-/-) mouse lungs. In addition, both recombinant and adenoviral TGF-beta 3 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-beta 3. Collectively, these findings revealed that Lyn regulates TGF-beta 3 isoform and modulates the development of airway remodeling, which may have therapeutic implications for severe chronic asthma.
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