Suppression of aspirin-mediated eosinophil activation by prostaglandin E 2 : Relevance to aspirin and nonsteroidal anti-inflammatory drug hypersensitivity.

Background: Aspirin-exacerbated respiratory disease (AERD) is characterized by severe, sometimes life-threatening reactions to nonsteroidal anti-inflammatory drugs (NSAIDs). Mechanisms driving the disease include overproduction of leukotrienes and loss of anti-inflammatory prostaglandin E ₂ (PGE ₂ ) production. Many cell types contribute to the disease; however, eosinophils are markedly elevated and are important drivers of pathologic findings.
Objective: To investigate the capacity of aspirin and NSAIDs to drive eosinophil activation and the ability of PGE ₂ to inhibit this activation.
Methods: Eosinophils were purified from blood of healthy individuals without AERD and stimulated with lysine aspirin, ketorolac, or sodium salicylate. The role of PGE ₂ in altering activation was determined by incubating eosinophils with increasing doses of PGE ₂ before lysine aspirin stimulation. Specific PGE ₂ receptor use was determined by incubating eosinophils with receptor agonists and antagonists before aspirin stimulation. Cysteinyl leukotrienes (CysLTs), leukotriene B ₄ (LTB ₄ ), and eosinophil-derived neurotoxin (EDN) were quantified by enzyme-linked immunosorbent assay.
Results: Stimulation of eosinophils with lysine aspirin, ketorolac, or sodium salicylate resulted in secretion of CysLTs and LTB ₄ in the absence of EDN release. Low doses of PGE ₂ inhibited LTB ₄ and CysLT release, an effect lost at higher PGE ₂ concentrations. Use of butaprost, an EP ₂ receptor agonist, suppressed lysine aspirin stimulation. This mechanism was supported by blocking activity of the EP ₁ and EP ₃ receptors.
Conclusion: Eosinophils can be directly activated by NSAIDs via cyclooxygenase-independent pathways to produce CysLTs and LTB ₄ . This effect can be inhibited by PGE ₂ acting through the EP ₂ receptor. The recognized loss of EP ₂ receptor expression combined with low PGE ₂ levels explains in part the sensitivity to NSAIDs.
(Copyright © 2019 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)