Targeting Ca2+ release–activated Ca2+ channel channels and leukotriene receptors provides a novel combination strategy for treating nasal polyposis

Background Nasal polyposis is a chronic inflammatory disease of the upper respiratory tract that affects around 2% of the population and almost 67% of patients with aspirin-intolerant asthma. Polyps are rich in mast cells and eosinophils, resulting in high levels of the proinflammatory cysteinyl leukotrienes. Objectives To better understand the role of the proinflammatory leukotrienes in nasal polyposis, we asked the following questions: (1) How do nasal polyps produce leukotriene C4 (LTC4 )? (2) Can LTC4 feed back in a paracrine way to maintain mast cell activation? (3) Could a combination therapy targeting the elements of this feed-forward loop provide a novel therapy for allergic disease? Methods We have used immunohistochemistry, enzyme immunoassay, and cytoplasmic calcium ion (Ca2+ ) imaging to address these questions on cultured and acutely isolated human mast cells from patients with polyposis. Results Ca2+ entry through store-operated Ca2+ release–activated Ca2+ (CRAC) channels in polyps produced LTC4 in a manner dependent on protein kinase C. LTC4 thus generated activated mast cells through cysteinyl leukotriene type I receptors. Hence Ca2+ influx into mast cells stimulates LTC4 production, which then acts as a paracrine signal to activate further Ca2+ influx. A combination of a low concentration of both a CRAC channel blocker and a leukotriene receptor antagonist was as effective at suppressing mast cell activation as a high concentration of either antagonist alone. Conclusion A drug combination directed against CRAC channels and leukotriene receptor antagonist suppresses the feed-forward loop that leads to aberrant mast cell activation. Hence our results identify a new potential strategy for combating polyposis and mast cell–dependent allergies.