Endothelin-1 mediates Aspergillus fumigatus-induced airway inflammation and remodelling

BackgroundAsthma is a chronic inflammatory condition of the airways and patients sensitized to airborne fungi such as Aspergillus fumigatus have more severe asthma. Thickening of the bronchial subepithelial layer is a contributing factor to asthma severity for which no current treatment exists. Airway epithelium acts as an initial defence barrier to inhaled spores, orchestrating an inflammatory response and contributing to subepithelial fibrosis. ObjectiveWe aimed to analyse the production of pro-fibrogenic factors by airway epithelium in response to Afumigatus, in order to propose novel anti-fibrotic strategies for fungal-induced asthma. MethodsWe assessed the induction of key pro-fibrogenic factors, TGF-beta 1, TGF-beta 2, periostin and endothelin-1, by human airway epithelial cells and in mice exposed to Afumigatus spores or secreted fungal factors. ResultsAspergillus fumigatus specifically caused production of endothelin-1 by epithelial cells in vitro but not any of the other pro-fibrogenic factors assessed. Afumigatus also induced endothelin-1 in murine lungs, associated with extensive inflammation and airway remodelling. Using a selective endothelin-1 receptor antagonist, we demonstrated for the first time that endothelin-1 drives many features of airway remodelling and inflammation elicited by Afumigatus. ConclusionOur findings are consistent with the hypothesis that elevated endothelin-1 levels contribute to subepithelial thickening and highlight this factor as a possible therapeutic target for difficult-to-treat fungal-induced asthma.