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.


OBJECTIVE
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) (LTC(4))? (2) Can LTC(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(2+)) imaging to address these questions on cultured and acutely isolated human mast cells from patients with polyposis.


RESULTS
Ca(2+) entry through store-operated Ca(2+) release-activated Ca(2+) (CRAC) channels in polyps produced LTC(4) in a manner dependent on protein kinase C. LTC(4) thus generated activated mast cells through cysteinyl leukotriene type I receptors. Hence Ca(2+) influx into mast cells stimulates LTC(4) production, which then acts as a paracrine signal to activate further Ca(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.


CONCLUSIONS
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.
Di Capite
Joseph
J
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Nelson
Charmaine
C
Bates
Grant
G
Parekh
Anant B
AB
D000085:Acetates / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D003521:Cyclopropanes; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D020024:Leukotriene Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D017997:Leukotriene C4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D009298:Nasal Polyps / Q000188:drug therapy* / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology; D018077:Receptors, Leukotriene / Q000187:drug effects / Q000378:metabolism*; D013440:Sulfides; D019284:Thapsigargin / Q000494:pharmacology
D000085:Acetates; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; D017997:Leukotriene C4; D019284:Thapsigargin; D001094:Arachidonate 5-Lipoxygenase; C093875:montelukast; D002118:Calcium; C063449:zileuton; D006918:Hydroxyurea