Epithelial regulation of eicosanoid production in asthma

Alterations in the airway epithelium have been associated with the development of asthma in elite athletes and in subjects that are susceptible to exercise-induced bronchoconstriction (EIB). The syndrome of EIB refers to acute airflow obstruction that is triggered by a period of physical exertion. Asthmatics who are susceptible to EIB have increased levels of cysteinyl leukotrienes (CysLTs, i.e., LTs C4, D4, and E4) in induced sputum and exhaled breath condensate, and greater shedding of epithelial cells into the airway lumen. Exercise challenge in individuals susceptible to this disorder initiates a sustained increase in CysLTs in the airways, and secreted mucin release and smooth muscle constriction, which may be mediated in part through activation of sensory nerves. We have identified a secreted phospholipase A2 (sPLA2) with increased levels in the airways of patients with EIB called sPLA2 group X (sPLA2-X). We have found that sPLA2-X is strongly expressed in the airway epithelium in asthma. Further, we discovered that transglutaminase 2 (TGM2) is expressed at increased levels in asthma and serves as a regulator of sPLA2-X. Finally, we demonstrated that sPLA2-X acts on target cells such as eosinophils to initiate cellular eicosanoid synthesis. Collectively, these studies identify a novel mechanism linking the airway epithelium to the production of inflammatory eicosanoids by leukocytes.