Mast cell and eosinophil activation during allergic airway inflammation has been linked to several aspects of pulmonary disease. Although IgE- mediated pathways are initially responsible for mast cell degranulation during allergic response. C-kit ligand or stem cell factor (SCF), has been identified as a key molecular component of mast cell activation. SCF is not only an important hematopoietic factor which drives terminal differentiation of mast cells, but it also been shown to have mother important roles in regulating mast cell biology, such as survival, activation and degranulation of mature mast cells. In addition, SCF has also been shown to have an activating effect on eosinophils. These observations identify SCF as a central molecule in allergic inflammation. In the present proposal, we will examine the role of SCF as an activating cytokine, capable of augmenting allergic airway inflammation airway inflammation via mast cell activation and eosinophil survival. In addition, because SCF is found in two different forms, soluble and transmembrane, we will specifically examine whether differential activation in two different forms, soluble and transmembrane, we will specifically examine whether differential activation mechanisms exist between these two forms. We hypothesize that SCF expression during an allergen-specific pulmonary response augments mast cell-dependent inflammation that leads to increased peribronchial eosinophil accumulation and airway hyper-reactivity. To test this postulate, we will focus on mechanisms of antigen-specific, SCF-induced mast cell activation leading to airway inflammation. Our studies will include the following: 1) To characterize the level of Stem Cell Factor (SCF) mRNA and protein expression, and identify its specific role during allergic airway responses; 2) To characterize the ability of soluble versus transmembrane SCF to augment mast cell and eosinophil activation; 3) To identify the expression of soluble and/or transmembrane (cell- associated) SCF in specific pulmonary cell populations; 4) To determine the role of soluble versus transmembrane SCF in mediating pulmonary mast cell activation, degranulation, and production of chemokines; 5) To elucidate the contribution of SCF-induced responses to airway hyper- reactivity. The allergic eosinophilic airway inflammation will be generated using an established model of a TH2-type hyper-eosinophilic response. This response is characterized by high levels of allergen- specific serum IgE and airway histamine release after challenge and is an appropriate model for the investigation of mast cell mediated events in allergic airway inflammatory responses. To assess the mechanisms of SCF-induced mast cell activation leading to eosinophilic airway infiltration, we will address a number of previously unexplored mechanisms, especially those pertaining to soluble versus transmembrane SCF leading to mast cell/eosinophil activation and specific chemokine production. In addition, we will assess changes in airway physiology in normal and deficient allergic mice and elucidate the mechanism of SCF- induced mast cell activation.
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