Background: Nothing is known about the mechanisms by which increased ceramide levels in the lung contribute to allergic responses and asthma severity. Objective: We sought to investigate the functional role of ceramide in mouse models of allergic airway disease that recapitulate the cardinal clinical features of human allergic asthma. Methods: Allergic airway disease was induced in mice by repeated intranasal administration of house dust mite or the fungal allergen Alternaria alternata. Processes that can be regulated by ceramide and are important for severity of allergic asthma were correlated with ceramide levels measured by mass spectrometry. Results: Both allergens induced massive pulmonary apoptosis and also significantly increased reactive oxygen species in the lung. Prevention of increases in lung ceramide levels mitigated allergen-induced apoptosis, reactive oxygen species, and neutrophil infiltration. In contrast, dietary supplementation of the antioxidant α-tocopherol decreased reactive oxygen species but had no significant effects on elevation of ceramide level or apoptosis, indicating that the increases in lung ceramide levels in allergen-challenged mice are not mediated by oxidative stress. Moreover, specific ceramide species were altered in bronchoalveolar lavage fluid from patients with severe asthma compared with in bronchoalveolar lavage fluid from individuals without asthma. Conclusion: Our data suggest that elevation of ceramide level after allergen challenge contributes to the apoptosis, reactive oxygen species generation, and neutrophilic infiltrate that characterize the severe asthmatic phenotype. Ceramide might be the trigger of formation of Creola bodies found in the sputum of patients with severe asthma and could be a biomarker to optimize diagnosis and to monitor and improve clinical outcomes in this disease.
|Journal||Journal of Allergy and Clinical Immunology|
|State||Published - May 2021|
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health (grant R01AI125433 [to S.S.]). The fluorescence microscopy studies were supported by grant R01NS095215 (to E.B.). J.S. was supported by an Institutional Development Award (P20GM103527.) The Virginia Commonwealth University Lipidomics/Metabolomics , Flow Cytometry, and Microscopy Shared Resources are supported in part by funding from the National Institutes of Health – National Cancer Institute Cancer Center (grant P30 CA016059 ).
© 2020 American Academy of Allergy, Asthma & Immunology
- oxidative stress
ASJC Scopus subject areas
- Immunology and Allergy