Low Prostaglandin E2 but High Prostaglandin D2, a Paradoxical Dissociation in Arachidonic Acid Metabolism in Aspirin-Exacerbated Airway Disease: Role of Airway Epithelium

In patients with aspirin-exacerbated respiratory disease (AERD), there is disparate regulation of prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2). Both prostanoids are synthesised by cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). However, while the basal synthesis of PGE2 tends to decrease, that of PGD2 increases in patients with AERD. Furthermore, both behave differently in response to the inhibitory action of NSAIDs on COX-1: PGE2 levels decrease while PGD2 increases. Increased PGD2 release correlates with nasal, bronchial, and extra-pulmonary symptoms caused by aspirin in AERD. The proposed hypothesis establishes that the answer to this paradoxical dissociation can be found in the airway epithelium. This is based on the observation that reduced COX-2 mRNA and/or protein expression is associated with reduced PGE2 synthesis in cultured fibroblast and epithelial cells from AERD compared to patients with asthma who are aspirin-tolerant and healthy subjects. The low production of PGE2 by the airway epithelium in AERD results in an excessive release of alarmins (TSLP, IL-33), which in turn contributes to activating group 2 innate lymphoid cells (ILC2s) and PGD2 synthesis by mast cells and eosinophils. Aspirin, by further increasing the diminished PGE2 regulation capacity in AERD, leads to respiratory reactions associated with the surge in PGD2 from mast cells and eosinophils. In summary, the downregulation of COX-2 and the subsequent low production of PGE2 by airway cells account for the apparently paradoxical increased production of PGD2 by mast cells and eosinophils at the baseline and after aspirin provocation in patients with AERD. A better understanding of the role of the airway epithelium would contribute to elucidating the mechanism of AERD.