Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, tissue eosinophilia, overproduction of cysteinyl leukotrienes (cysLTs), and respiratory reactions to nonselective cyclooxygenase (COX) inhibitors. Ex vivo studies suggest that functional abnormalities of the COX-2/microsomal prostaglandin (PG)E_2 synthase-1 system may underlie AERD. We demonstrate that microsomal PGE_2 synthase-1 null mice develop a remarkably AERD-like phenotype in a model of eosinophilic pulmonary inflammation. Lysine aspirin (Lys- ASA)-challenged PGE_2 synthase-1 nullmice exhibit sustained increases in airway resistance, along with lung mast cell (MC) activation and cysLT overproduction. A stable PGE_2 analog and a selective E prostanoid(EP)2 receptor agonist blocked the responses to Lys-ASA by~90; EP_3 and EP_4 agonists were also active. The increases in airway resistance andMCproductswere blockedby antagonistsof the type 1 cysLT receptor or 5-lipoxygenase, implying that bronchoconstriction andMC activation were both cysLT dependent. Lys-ASA-induced cysLT generation and MC activation depended on platelet-adherent granulocytes and T-prostanoid (TP) receptors. Thus, lesions that impair the inducible generation of PGE_2 remove control of platelet/granulocyte interactions and TP-receptor-dependent cysLT production, permitting MC activation in response to COX-1 inhibition. The findings suggest applications of antiplatelet drugs or TP receptor antagonists for the treatment of AERD.
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