Lyn Mitigates Mouse Airway Remodeling by Downregulating the TGF-b3 Isoform in House Dust Mite Models

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 2/2 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-b3 rather than TGF-b1 was observed in Lyn 2/2 mouse lungs compared with lungs in wild-type mice. Furthermore, TGF-b3 neutralizing Abs not only inhibited the expression of STAT6 and Smad2/3 but also decreased phosphorylation of Smad2 and NF-kB in Lyn 2/2 mouse lungs. In addition, both recombinant and adenoviral TGF-b3 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-b3. Collectively, these findings revealed that Lyn regulates TGF-b3 isoform and modulates the development of airway remodeling, which may have therapeutic implications for severe chronic asthma. A irway remodeling is a key feature of severe asthma, which affects 300 million people worldwide (1) and is associated with significant morbidity and health costs (2). Airway remodeling is characterized as epithelial detachment, subepithelial fibrosis, increased smooth muscle mass, goblet cell hyperplasia, and angiogenesis (3). Further, airway remodeling is currently incurable and presents a serious problem in asthma management. Interactions between the immune system and lung structural cells are critical for initiation and development of airway inflammation and remodeling (4). The airway epithelium secretes multiple cytokines, chemokines, and growth factors during exposure to inhaled allergens. In addition, epithelial-to-mesenchymal transition (EMT) is a process whereby epithelial cells lose their markers while gaining mesenchymal symbolic molecules, which may contribute to pathophysiological alterations during airway remodeling. Chronic respiratory aeroallergen exposure in mice induces EMT in the large airways (5). Airway epithelium is critically involved in airway remodeling through the process of EMT following environmental toxicant or allergen challenge. Lasting and dynamic airway epithelial alterations may contribute to airway remodeling via EMT in asthma (6). TGF-b is one of the major mediators involved in airway remod-eling in asthma. Previous studies suggest that TGF-b could be a target for therapeutic intervention for airway remodeling in chronic asthma (5, 7). TGF-b isoforms …