Eosinophils are central to the pathogenesis of asthma. Activated eosinophils release several polycationic protein substances, which are associated with an increase in airway smooth muscle (ASM) contractile response. The long-term goal of the proposed studies is to understand the mechanism(s) by which eosinophil-derived proteins alter ASM contractile responses. Deposits of polycationic proteins released from activated eosinophils, including MBP, are found within both airway epithelial and smooth muscle layers of airways of patients dying from status asthmaticus. Recent studies by others indicate that MBP increases force in airways indirectly through an effect on airway epithelium or by inhibiting airway muscarinic M2 receptors. In addition, recent work in our laboratory indicates that MBP and other model polycationic proteins directly elevate intracellular calcium concentration ([Ca2+]i) in cultured ASM cells in a concentration-dependent manner and increase basal force generation in an epithelium-independent manner in ASM strips. It is possible that alteration in both epithelial and myocyte [Ca2+]i mobilization induced by eosinophil-derived polycationic proteins may indirectly and/or directly influence clinical disease states of altered airway force, such as asthma and viral bronchiolitis. The overall hypothesis of the proposed studies is that MBP causes an increase in airway cell [Ca2+]i that in airway epithelium elicits epithelial broncho-constrictor release and in ASM elicits smooth muscle contraction. In the proposed studies, human airway epithelium and human airway smooth muscle strips and freshly dissociated human airway myocytes will be used to examine the effects of MBP on epithelial broncho-constrictor release and ASM force generation, [Ca2+]i regulation and Ca2+ sensitivity.
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