Joshua A. Boyce, MD

This laboratory focuses on the mechanisms by which allergic pulmonary inflammation is controlled by lipid mediators of inflammation, their cellular sources, and their receptors. We use a combination of strategies, including studies using transgenic mice, RNA interference in primary cells, and benchside approaches to carefully characterized human subjects. We have shown that leukotiene E4, the most abundant metabolite of the cysteinyl leukotrienes (cys-LTs), is a potent inducer/amplifier of pulmonary eosinophil recruitment by a pathway that is independent of the known receptors for cys-LTs (CysLT1R and CysLT2R), but instead depends on the present of platelets and the P2Y12 receptor for adenosine diphosphate (ADP). LTE4 is very abudant in the urine of subjects with aspirin-exacerbated respiratory disease (AERD), a distinctive asthma phenotype that is associated with marked tissue eosinophilia, severe nasal polyposis, and difficult-to-control asthma. We have recently found that platelet adherent leukocytes are markedly increased in the circulation and nasal polyp tissue of patients with AERD. These adherent platelets express leukotriene C4 synthase, and account for ~60% of the capacity of granulocytes to generate cys-LTs in AERD. These observations imply a "feed forward" system in which platelets are both effectors of and sources of cys-LTs. In collaboration with our pulmonary colleagues, we conducting a placebo controlled trial of a P2Y12 receptor antagonist as a potential therapy for AERD.