Regulation and Function of Epithelial Secreted Phospholipase A2 Group X in Asthma

Rationale: Indirect airway hyperresponsiveness (AHR) is a fundamental feature of asthma that is manifest as exercise-induced broncho-constriction (EIB). Secreted phospholipase A(2) group X (sPLA(2)-X) plays a key role in regulating eicosanoid formation and the development of inflammation and AHR in murine models. Objectives: We sought to examine sPLA(2)-X in the airway epithelium and airway wall of patients with asthma, the relationship to AHR in humans, and the regulation and function of sPLA(2)-X within the epithelium. Methods: We precisely phenotyped 34 patients with asthma (19 with and 15 without EIB) and 10 normal control subjects to examine in vivo differences in epithelial gene expression, quantitative morphometry of endobronchial biopsies, and levels of secreted protein. The regulation of sPLA(2)-X gene (PLA2G10) expression was examined in primary airway epithelial cell cultures. The function of epithelial sPLA(2)-X in eicosanoid formation was examined using PLA(2) inhibitors and murine tracheal epithelial cells with Pla2g10 deletion. Measurements and Main Results: We found that sPLA(2)-X protein is increased in the airways of patients with asthma and that epithelial-derived sPLA(2)-X may be increased in association with indirect AHR. The expression of sPLA(2)-X increases during in vitro epithelial differentiation; is regulated by inflammatory signals including tumor necrosis factor, IL-13, and IL-17; and is both secreted from the epitheliumand directly participates in the release of arachidonic acid by epithelial cells. Conclusions: These data reveal a relationship between epithelial-derived sPLA(2)-X and indirect AHR in asthma and that sPLA(2)-X serves as an epithelial regulator of inflammatory eicosanoid formation. Therapies targeting epithelial sPLA(2)-X may be useful in asthma.