Targeting Ca super(2+) release-activated Ca super(2+) 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 sub(4) (LTC sub(4))? (2) Can LTC sub(4) 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 (Ca super(2+)) imaging to address these questions on cultured and acutely isolated human mast cells from patients with polyposis. Results - Ca super(2+) entry through store-operated Ca super(2+) release-activated Ca super(2+) (CRAC) channels in polyps produced LTC sub(4) in a manner dependent on protein kinase C. LTC sub(4) thus generated activated mast cells through cysteinyl leukotriene type I receptors. Hence Ca super(2+) influx into mast cells stimulates LTC sub(4) production, which then acts as a paracrine signal to activate further Ca super(2+) 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.