Peribronchial leukocyte accumulation and activation is a major disease factor during development of asthmatic airway responses that leads to chronic airway disease. In particular, eosinophils have been reported to be primary populations associated with induction of bronchial injury, and are thought to participate in epithelial cell damage, mucus production, bronchial obstruction, and airway hyperreactivity. Over the past several years our laboratory has been investigating the novel role of stem cell factor (SCF) produced in the airway during cockroach allergen-induced responses. Our data has provided novel findings related directly to the induction of the allergic responses. When SCF is neutralized within the airway long-term changes can be observed related directly to eosinophil accumulation, eosinophil activation, and mucus production. This latter aspect will be the focus of this renewal application with studies centered on a principal concept. Our hypothesis is that airway epithelial cell production of SCF within the airway after cockroach allergen challenge activates recruited eosinophils upregulating inflammatory and growth factors that induce increased airway hyperreactivity and production of mucus. This complex interaction between SCF producing epithelial cells and infiltrating eosinophils will be investigated using both an established in vivo model of allergic airway disease and in vitro analysis to better identify the mechanism of the responses. To test this hypothesis we will focus on mechanisms involved in the ability of airway epithelial cell-derived SCF to induce specific eosinophil related functions. Our studies will 1) establish that SCF contributes to the development of chronic airway disease and define its relation to eosinophil accumulation and activation as well as mucus production, 2) define by what signal transduction pathways SCF influences eosinophil activation leading to subsequent mucus production in the airway, 3) determine that particular pathways have a specific role for SCF-induced functions leading to activation of mucus production 4) investigate how epithelial cell-derived SCF impacts on eosinophil activation, and 5) define by what mechanism SCF-activated eosinophils alter development of mucus-related genes and protein. To assess the mechanisms of SCF-induced eosinophil activation leading to airway damage, mucus production, and pathophysiology, we will address a number of previously unexplored mechanisms. We will especially concentrate on those pertaining to differential SCF signaling leading to eosinophil activation and specific inflammatory and mucus producing cytokines. In addition, we will assess changes in airway physiology in normal and SCF deficient allergic mice and elucidate the mechanism of SCF-induced eosinophil activation during chronic disease development leading to mucus overproduction. Our studies will also utilize new technology with siRNA constructs for inhibition of specific aspects of SCF-induced eosinophil activation.
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