Abstract
BackgroundChronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is progressive and not fully reversible. Cigarette smoking is one of the most commonly and important risk factors for COPD, which contributes to airway remodeling, the outstanding pathological changes in COPD. One potential mechanism which might be important for airway remodeling is the process called epithelial–mesenchymal transition (EMT). However, the underlying molecular mechanisms of EMT in CS-induced COPD are still poorly understood.MethodsTwo Gene Expression Omnibus (GEO) datasets (GSE108134 and GSE5058) were combined to identify the key genes involved in COPD. Then, single-gene analysis of Lyn was performed. Lyn expression was confirmed in patients with COPD. 16HBE cells were treated with cigarette smoking extracts (CSE). Wild type (WT) C57BL/6 J mice and Lyn+/+ transgenic mice were exposed to CSE to establish CS-exposed model. Pathological changes were observed by hematoxylin-eosin staining. The expression levels of EMT markers were examined by using western blot and immunofluorescence. The expression and phosphorylation levels of Lyn and Smad2/3 were detected as well.ResultsThe gain of mesenchymal markers vimentin and α-SMA with a concomitant loss of E-cadherin was observed in both in vivo and in vitro studies. Meanwhile, cigarette smoking extracts (CSE) induced EMT in 16HBE cells in a time- and dose- dependent manner. Furthermore, by analyzing GEO datasets and using molecular methods, we explored a kinase, Lyn, its expression correlated with the expression of E-cadherin, vimentin and α-SMA in CS-exposed model. Moreover, we found that EMT induced by CSE was regulated by activated Lyn through phosphorylation of Smad2/3.ConclusionsIn summary, we found that Lyn regulates epithelial–mesenchymal transition in CS-exposed model through Smad2/3 signaling. As a kinase, Lyn is “druggable”, and might provide a therapeutic opportunity for targeting EMT. Therefore, our research might provide a new method to treat COPD by targeting Lyn kinase specifically.
Highlights
Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is progressive and not fully reversible
The expression levels of epithelial–mesenchymal transition (EMT) makers correlate with Lyn in COPD-smoker patients We combined two Gene Expression Omnibus (GEO) datasets (GSE108134 and GSE5058) to identify the key genes involved in COPD
We found that the expression level of Lyn was significantly up-regulated in COPD-smoker patients compared with Non-smoker (p = 0.007, Fig. 1c)
Summary
Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is progressive and not fully reversible. Cigarette smoking is one of the most commonly and important risk factors for COPD, which contributes to airway remodeling, the outstanding pathological changes in COPD. One potential mechanism which might be important for airway remodeling is the process called epithelial–mesenchymal transition (EMT). The underlying molecular mechanisms of EMT in CS-induced COPD are still poorly understood. Chronic obstructive pulmonary disease (COPD), which is characterized by continuous limitation of airflow, is a chronic inflammatory pulmonary disease. Cigarette smoking is one of the most commonly and important risk factors for COPD. The underlying molecular mechanisms of cigarette smoking in COPD development are still poorly understood
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