Mast cells (MCs) are important effector cells in type 1 hypersensitivity and asthma as indicated by the efficacy of treatments directed to the MC and its mediators. Bronchial biopsies from asthmatic individuals contain substantially more MCs than do biopsies from nonasthmatic controls yet essentially nothing is known about the mechanisms responsible for this increase. The overall goal of this project is to further characterize the pathways that regulate the recruitment, maturation, survival, and expansion of MC populations in pulmonary tissues with allergic inflammation using mouse models. Although MCs and MC progenitors (MCp) are sparse in mouse lung at baseline, the appearance of mature MCs in tracheobronchial epithelium (intraepithelial (IE) MC hyperplasia) is a characteristic of allergic, T-cell dependent inflammation. We find a rapid increase in the number of MCp in the allergen-challenged lung that depends on CD4+ cells and the cytokines interleukin (IL)-9 and tumor necrosis factor alpha (TNFa) although not on Th1 or Th2 cells. Using antibody-mediated depletion, null mice, and selective reconstitution, this project will test the hypotheses that: 1. IL-9 (through proliferation and cytoprotection) and TNFa (through induction of VCAM-1) are necessary for the early accumulation of MCp in the allergen-challenged lung, and;2. IL-9 is provided by Th17 cells. Further, as the number of IE MC increases at time when MCp numbers have returned to baseline, we suspect that the development of the IE MC hyperplasia depends on Th2-derived cytokines and cysteinyl leukotrienes (based on analyses of mice lacking leukotriene C4 synthase (LTC4S)).
The second aim of this project then will test the hypotheses that: 3. The accumulation of pulmonary MCp is a necessary prerequisite for the development of tracheobronchial IE MC hyperplasia and;4. IE MC hyperplasia in the tracheobronchial mucosa requires cytokines derived from Th2 cells (IL-3, IL-10, IL-4, and possibly IL-9) that facilitate the in situ proliferation and maturation of MCp and that cys-LTs can act as secondary messengers in these processes. Thus, this project will define the pathways and mechanisms involved in the appearance of the pulmonary MC implicated in the pathogenesis of allergic pulmonary diseases.
The appearance of a pulmonary mast cell hyperplasia is characteristic of allergic inflammation in this organ. The immunological and developmental pathways leading to this increase in the number of pulmonary mast cells will be further defined in this project which in turn should lead to novel therapeutic possibilities for the amelioration of mast cell mediated pathologies in the lung.
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