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-β 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-β 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-β 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-β, 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-β blockade, in S1P-treated mice, abrogates these effects. Finally, inhibition of sphingosine kinases by SK1-II in OVA-sensitized mice, abrogates EMT, pulmonary TGF-β up-regulation, fibroblasts recruitment and airway hyperresponsiveness. Conclusion and Implications: Targeting S1P/TGF-β axis may hold promise as a feasible therapeutic target to control airway dysfunction in asthma.

Sphingosine-1-phosphate/TGF-β axis drives epithelial mesenchymal transition in asthma-like disease / Riemma, M. A.; Cerqua, I.; Romano, B.; Irollo, E.; Bertolino, A.; Camerlingo, R.; Granato, E.; Rea, G.; Scala, S.; Terlizzi, M.; Spaziano, G.; Sorrentino, R.; D'Agostino, B.; Roviezzo, F.; Cirino, G.. - In: BRITISH JOURNAL OF PHARMACOLOGY. - ISSN 0007-1188. - 179:8(2022), pp. 1753-1768. [10.1111/bph.15754]

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

Riemma M. A.;Cerqua I.;Romano B.;Irollo E.;Bertolino A.;Camerlingo R.;Granato E.;Terlizzi M.;Spaziano G.;Roviezzo F.
;
Cirino G.
2022

Abstract

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-β 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-β 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-β 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-β, 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-β blockade, in S1P-treated mice, abrogates these effects. Finally, inhibition of sphingosine kinases by SK1-II in OVA-sensitized mice, abrogates EMT, pulmonary TGF-β up-regulation, fibroblasts recruitment and airway hyperresponsiveness. Conclusion and Implications: Targeting S1P/TGF-β axis may hold promise as a feasible therapeutic target to control airway dysfunction in asthma.
2022
Sphingosine-1-phosphate/TGF-β axis drives epithelial mesenchymal transition in asthma-like disease / Riemma, M. A.; Cerqua, I.; Romano, B.; Irollo, E.; Bertolino, A.; Camerlingo, R.; Granato, E.; Rea, G.; Scala, S.; Terlizzi, M.; Spaziano, G.; Sorrentino, R.; D'Agostino, B.; Roviezzo, F.; Cirino, G.. - In: BRITISH JOURNAL OF PHARMACOLOGY. - ISSN 0007-1188. - 179:8(2022), pp. 1753-1768. [10.1111/bph.15754]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/875410
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