Regulation of arachidonate remodeling enzymes impacts eosinophil survival during allergic asthma

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 α(cPLA₂-α, gIVαPLA₂) 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 gIVαPLA₂ phosphorylation, and increased both gIVαPLA₂ 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-inducedeosinophil 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 gIVαPLA₂ activity, and increased CoA-IT activity. These findings indicate that both in vitro and in vivo challenge of eosinophils activated gIVαPLA₂ and CoA-IT, which may play a key role in enhanced eosinophil survival.