Endothelin-1 mediates Aspergillus fumigatus induced airway inflammation and remodelling

Labram, B; Namvar, S; Hussell, T; Herrick, SE

Abstract

BACKGROUND: Asthma is a chronic inflammatory condition of the airways and patients sensitised 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.
OBJECTIVE: We aimed to analyse the production of profibrogenic factors by airway epithelium in response to A. fumigatus, in order to propose novel anti-fibrotic strategies for fungal-induced asthma.
METHODS: We assessed the induction of key profibrogenic factors, TGFβ1, TGFβ2, periostin and endothelin-1, by human airway epithelial cells and in mice exposed to A. fumigatus spores or secreted fungal factors.
RESULTS: A. fumigatus specifically caused production of endothelin-1 by epithelial cells in vitro but not any of the other profibrogenic factors assessed. A. fumigatus also induced endothelin-1 in murine lungs, associated with extensive inflammation and airway wall remodelling. Using a selective endothelin-1 receptor antagonist, we demonstrated for the first time, that endothelin-1 drives many features of airway wall remodelling and inflammation elicited by A. fumigatus.
CONCLUSION: Our 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.

Citation

Labram, B., Namvar, S., Hussell, T., & Herrick, S. (2019). Endothelin-1 mediates Aspergillus fumigatus induced airway inflammation and remodelling. Clinical and Experimental Allergy, 49(6), 861-873. https://doi.org/10.1111/cea.13367

• Journal Article Type: Article
• Acceptance Date: Jan 31, 2019
• Online Publication Date: Feb 8, 2019
• Publication Date: Feb 8, 2019
• Deposit Date: Feb 25, 2019
• Publicly Available Date: Feb 8, 2020
• Journal: Clinical and Experimental Allergy
• Print ISSN: 0954-7894
• Electronic ISSN: 1365-2222
• Publisher: Wiley
• Volume: 49
• Issue: 6
• Pages: 861-873
• DOI: https://doi.org/10.1111/cea.13367
• Publisher URL: https://doi.org/10.1111/cea.13367
• Related Public URLs: https://onlinelibrary.wiley.com/journal/13652222