Allergic asthma is now widely considerred to represent a disorder of chronic inflammation of the airways. Indeed, much of the clinical benefit of inhaled corticosteroids in asthma is though to reflect the ability of these drugs to suppress the persistent airways inflammation that is characteristic of this disease. Because much of the inflammation in asthma is thought to be cytokine-driven, and because T cells, monocytes/macrophages and other leukocytes present in the inflammatory infiltrates of asthma represent potential sources of cytokines/growth factors, considerable attention has focused on the role of these infiltrating leukocytes in the pathogenesis of allergic asthma. Yet the factors that account for the initiation and persistence of airways inflammation in asthma remain poorly understood. We hypothesize that allergen- & IgE-dependent activation of mast cells (MCs) through the high affinity IgE receptor (Fc epsilonRI), and the release of tumor necrosis factor-alpha (TNF-alpha) and other cytokines by these MCs, importantly contribute to the initiation and perpetuation of inflammation in allergic asthma. We also propose that the ability of MCs to express and release cytokines is subject to regulation by microenvironmental factors, such as tissue-or leukocyte-derived cytokines, whose expression may be altered in the airways of asthmatics. To test these hypotheses, and to explore the extent to which effects on MC cytokine production might contribute to the clinical benefit of certain types of therapeutic intervention in asthma, we propose: ] 1. To analyze the regulation and pharmacological modulation of human MC cytokine expression and secretion in vitro, focusing initially on the IgE- dependent production of two representative pro-inflammatory cytokines (TNF- alpha and macrophage inflammatory protein-alpha [MIP-1alpha) that can be produced by MCs and that have been implicated in allergic inflammation: 2. To analyze MC cytokine production and its pharmacological modulation i situ, using excised human lung specimens; we will also assess whether IgE- dependent MC cytokine secretion can either augment the expression of molecules, such as P- and E-selectin, VCAM-1 and ICAM-1, that contribute to leukocyte recruitment in allergic inflammation, or augment epithelial cell inducible nitric oxide synthase (iNOS); and 3. To analyze MC cytokine production in vivo, by assessing both the patterns of expression of MC cytokines and the local consequences of MC activation and cytokine production (i.e., P and E-selectin, VCAM-1, ICAM-1, iNOS expression; leukocyte recruitment) in the airways of subjects with allergic asthma and (to establish whether the findings are specific for allergic asthma) in the airways of normal subjects, subjects with intrinsic, non-atopic asthma, or atopic subjects without asthma.
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