Patients with asthma can express clinically significant airway responses to challenge with very low doses of relevant allergen. We hypothesize that mast cells, through their ability to amplify the local expression of allergen-induced inflammatory responses and to produce many mediators, cytokines, chemokines and growth factors, can contribute importantly to the development of the airway hyperreactivity (AHR), chronic inflammation, and tissue remodeling associated with asthma. In experiments using genetically mast cell-deficient WBB6Fl-Kitw/Kitw-v mice and the congenic +/+ mice, we already have found that, in mice sensitized to ovalbumin (OVA) without adjuvant and then challenged via the airways, mast cells have a critical role in significantly enhancing allergen-induced AHR to aerosolized methacholine, eosinophil infiltration, and numbers of proliferating cells within the airway epithelium. However, the specific mechanisms by which mast cells promote the inflammatory, structural and functional changes associated with this asthma model are very incompletely understood. We therefore will develop further and characterize in detail """"""""mast cell-dependent"""""""" models of asthma, and compare them to a """"""""mast cell-independent"""""""" model of the disease, focusing on the patterns of allergen-induced inflammation, structural tissue changes, and AHR, and alterations in tissue- and cell-specific gene expression, that are induced in these settings. To define the specific mast cell-dependent mechanisms that contribute to these changes, we will investigate their expression in mast cell-deficient Kitw/Kitw-v mice, congenic wild type mice, and Kitw/Kitw-v mice that have been selectively reconstituted with in vitro-derived wild type mast cells or mast cells that express genetically-determined alterations in activation and/or mediator/cytokine growth factor production.
The specific aims will test 3 hypotheses: 1. Mast cells can significantly amplify the expression of multiple phenotypic characteristics of asthma; 2. Mast cells can express such function via distinct mechanisms, including the IgE-dependent production of diverse mediators, cytokines, chemokines and growth factors; 3. Mast cells can influence the expression of multiple phenotypic characteristics of asthma by inducing distinct patterns of qualitative and/or quantitative changes in gene expression in the surrounding target cells and tissues.
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