Project Summary Aspirin-exacerbated respiratory disease (AERD) is a common, severe idiopathic disorder characterized by asthma, recurrent nasal polyposis, and marked eosinophilic inflammation of the sinonasal and bronchial mucosa. The disease is consistently associated with markedly dysregulated cysteinyl leukotriene production, and with cryptic over-activation of platelets. This proposal will focus on understanding how these two features drive the pathophysiology of the disease. The central hypothesis is that an autocrine, LTC4-mediated platelet activation pathway plays a critical role in driving the exaggerated type 2 immunopathology associated with AERD, and is central to pathognomonic reactions to ASA. Platelet-associated CysLT2R and HMGB1 are each necessary for these features. A corollary hypothesis is that neutralization of platelet HMGB1 by salicylic acid (SA) contributes to the therapeutic effect of ASA therapy in AERD. We will use newly created transgenic mice, a novel model of AERD, and cells and tissues from carefully characterized human subjects to test the hypothesis. The studies proposed will reveal potential causative mechanisms in AERD and identify therapeutic targets that could restore normal homeostasis, and are the first to integrate CysLT2R into AERD pathophysiology.