Sphingosine-1-phosphate/TGF-beta axis drives epithelial mesenchymal transition in asthma-like disease

Background and Purpose Airway remodelling is a critical feature of chronic lung diseases. Epithelial-mesenchymal transition (EMT) represents an important source of myofibroblasts, contributing to airway remodelling. Here, we investigated the sphingosine-1-phosphate (S1P) role in EMT and its involvement in asthma-related airway dysfunction. Experimental Approach A549 cells were used to assess the S1P effect on EMT and its interaction with TGF-beta signalling. To assess the S1P role in vivo and its impact on lung function, two experimental models of asthma were used by exposing BALB/c mice to subcutaneous administration of either S1P or ovalbumin (OVA). Key Results Following incubation with TGF-beta or S1P, A549 acquire a fibroblast-like morphology associated with an increase of mesenchymal markers and down-regulation of the epithelial. These effects are reversed by treatment with the TGF-beta receptor antagonist LY2109761. Systemic administration of S1P to BALB/c mice induces asthma-like disease characterized by mucous cell metaplasia and increased levels of TGF-beta, IL-33 and FGF-2 within the lung. The bronchi harvested from S1P-treated mice display bronchial hyperresponsiveness associated with overexpression of the mesenchymal and fibrosis markers and reduction of the epithelial.The S1P-induced switch from the epithelial toward the mesenchymal pattern correlates to a significant increase of lung resistance and fibroblast activation. TGF-beta blockade, in S1P-treated mice, abrogates these effects. Finally, inhibition of sphingosine kinases by SK1-II in OVA-sensitized mice, abrogates EMT, pulmonary TGF-beta up-regulation, fibroblasts recruitment and airway hyperresponsiveness. Conclusion and Implications Targeting S1P/TGF-beta axis may hold promise as a feasible therapeutic target to control airway dysfunction in asthma.

Automated summary

This study found that S1P is involved in the EMT process of airway remodeling and plays a role in asthma-related airway dysfunction. Targeting the S1P/TGF-beta axis may hold promise as a therapeutic target for controlling airway dysfunction in asthma.