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 C-4 (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. (J Allergy Clin Immunol 2009;124:1014-21.)