Evidence that Mast Cells Regulate the Cough Hypersensitivity Associated with Eosinophilic Bronchitis

Eosinophils have been implicated as key effectors in the emergence of chronic cough. But causality has not been firmly established, and many patients with cough secondary to eosinophilic bronchitis (EB) are likely misdiagnosed as asthmatics based on successful empiric trials using inhaled corticosteroids. Better diagnostics and more precise therapeutic strategies for EB and other diseases that lead to chronic cough remain important but unmet clinical needs.

With the goal of better defining the mechanisms of cough in disease, we established a model of EB in guinea pigs using allergen challenges that induce a cough hypersensitivity responsive to steroid therapy.

The heightened cough responsiveness associated with the eosinophilic inflammation was mimicked by LTD₄ inhalation and prevented by cysLT₁ receptor blockade with pranlukast or montelukast. But cysLT₁ receptor antagonism failed to prevent the eosinophilic infiltration of the airways evoked by allergen challenge. Additionally, inhalation of the mast cell selective stimulant Compound 48/80 mimicked the effects of allergen challenge on cough but failed to significantly increase eosinophilic infiltration of the airways. We also observed that thromboxane A2, through TP receptor engagement, acts downstream from and simultaneously with the leukotrienes to promote cough hypersensitivity in EB.

These results suggest that mast cells and not eosinophils may be essential to the emergence of cough hypersensitivity in EB. We speculate that therapeutic strategies targeting mast cells, cysLT₁ receptors, and TP receptors may represent endotype-specific treatments for chronic cough.