期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 146, 期 4, 页码 884-+出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2020.02.032
关键词
Food allergy; anaphylaxis; mast cell; omeprazole; proton pump inhibitor
资金
- National Institutes of Health (NIH) [1R01AI119918-05, DK097112-05, 5T32AI007512-33]
- Fonds de recherche du Quebec -Sante
- Bridge Grant from the Research Council of Boston Children's Hospital
- Emerging Investigator Award from Food Allergy Research& Education (FARE)
- Crohn's and Colitis Foundation
- NIH grant of the Harvard Digestive Diseases Center [P30DK034854]
- Sean N. Parker Center Seed Grant
- Bunning Family Foundation
- Nanji Family Fund for Food Allergy Research
- Rao Chakravorti Family Fund
- Christine Olsen and Robert Small Food Allergy Research Fund
Background: Patients with eosinophilic esophagitis have increased numbers of mucosal mast cells. Administration of the proton pump inhibitor omeprazole can reduce both esophageal mast cell and eosinophil numbers and attenuate type 2 inflammation in these subjects. Objective: Given that maintenance of an acidic environment within granules is important for mast cell homeostasis, we sought to evaluate the effects of omeprazole on mast cell functions including development, IgE:FceRI-mediated activation, and responses to food allergen. Methods: Mast cell degranulation, cytokine secretion, and early signaling events in the FceRI pathway, including protein kinase phosphorylation and Ca2+ flux, were measured after IgE crosslinking in murine bone marrow-derived mast cells and human cord blood-derived mast cells. The effects of omeprazole on these responses were investigated as was its impact on mast cell-dependent anaphylaxis and food allergy phenotypes in vivo. Results: Murine and human mast cells treated with omeprazole exhibited diminished degranulation and release of cytokines and histamine in response to allergen. In murine mast cells, phosphorylation of protein kinases, ERK and SYK, was decreased. Differentiation of mast cells from bone marrow progenitors was also inhibited. IgE-mediated passive anaphylaxis was blunted in mice treated with omeprazole as was allergen-induced mast cell expansion and mast cell activation in the intestine in a model of food allergy. Conclusions: Our findings suggest that omeprazole targets pathways important for the differentiation and activation of murine mast cells and for the manifestations of food allergy and anaphylaxis.
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