Briana N James1, Clement Oyeniran1, Jamie L Sturgill2, Jason Newton1, Rebecca K Martin3, Erhard Bieberich4, Cynthia Weigel1, Melissa A Maczis1, Elisa N D Palladino1, Joseph C Lownik3, John B Trudeau5, Joan M Cook-Mills6, Sally Wenzel5, Sheldon Milstien1, Sarah Spiegel7. 1. Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Va. 2. Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kentucky College of Medicine, Lexington, Ky. 3. Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Va. 4. Department of Physiology, University of Kentucky College of Medicine, Lexington, Ky. 5. Department of Medicine, University of Pittsburgh, Pittsburgh, Pa. 6. Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana School of Medicine, Indianapolis, Ind. 7. Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Va. Electronic address: sarah.spiegel@vcuhealth.org.
Abstract
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.
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.
Authors: Araceli Díaz-Perales; Maria M Escribese; María Garrido-Arandia; David Obeso; Elena Izquierdo-Alvarez; Jaime Tome-Amat; Domingo Barber Journal: Front Allergy Date: 2021-06-14
Authors: Aki Hoji; Rajesh Kumar; James E Gern; Casper G Bendixsen; Christine M Seroogy; Joan M Cook-Mills Journal: J Allergy Clin Immunol Glob Date: 2022-04-07
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