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Regulation of Arachidonate Remodeling Enzymes Impacts Eosinophil Survival during Allergic Asthma

Michael C. Seeds^1,2,*, Kristina K. Peachman^3,*,, David L. Bowton^2,4, Kelly L. Sivertson^3, and Floyd H. Chilton^1,5

¹ Department of Internal Medicine/Sections on Molecular Medicine and ² Pulmonary and Critical Care, ³ Department of Microbiology and Immunology, ⁴ Department of Anesthesiology/Section on Critical Care, and ⁵ Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Correspondence and requests for reprints should be addressed to Michael C. Seeds, Ph.D., Internal Medicine/Molecular Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail: mseeds{at}wfubmc.edu

Although the role of arachidonic acid (AA) metabolism to eicosanoids has been well established in allergy and asthma, recent studies in neoplastic cells have revealed that AA remodeling through phospholipids impacts cell survival. This study tests the hypothesis that regulation of AA/phospholipid-remodeling enzymes, cytosolic phospholipase A₂ (cPLA₂-, gIVPLA₂) and CoA-independent transacylase (CoA-IT), provides a mechanism for altered eosinophil survival during allergic asthma. In vitro incubation of human eosinophils (from donors without asthma) with IL-5 markedly increased cell survival, induced gIVPLA₂ phosphorylation, and increased both gIVPLA₂ and CoA-IT activity. Furthermore, treatment of eosinophils with nonselective (ET18-O-CH₃) and selective (SK&F 98625) inhibitors of CoA-IT triggered apoptosis, measured by changes in morphology, membrane phosphatidylserine exposure, and caspase activation, completely reversing IL-5–induced eosinophil survival. To determine if similar activation occurs in vivo, human blood eosinophils were isolated from either normal individuals at baseline or from subjects with mild asthma, at both baseline and 24 hours after inhaled allergen challenge. Allergen challenge of subjects with allergic asthma induced a marked increase in cPLA₂ phosphorylation, augmented gIVPLA₂ activity, and increased CoA-IT activity. These findings indicate that both in vitro and in vivo challenge of eosinophils activated gIVPLA₂ and CoA-IT, which may play a key role in enhanced eosinophil survival.

Key Words: phospholipase A₂ • coenzyme A–independent transacylase • eosinophil • asthma • enzyme inhibitors

CLINICAL RELEVANCE These findings indicate that both in vitro and in vivo challenge of eosinophils activated gIVaPLA2 and CoA-IT, which may play a key role in enhanced eosinophil survival. Understanding the activation of these inflammatory cells in lung diseases such as asthma may provide insight into therapeutic targets to improve clinical management.