Structural changes in the airways of asthmatics, including subepithelial fibrosis, are thought to play an important role in the physiologic changes characteristic of asthma. Mesenchymal cells, including lung fibroblasts or a subcategory of them called myofibroblasts, appear to be important sources of collagen III, fibronectin, and tenascin, components of the asthmatic subepithelium. Fibrogenic events appear to be coordinated by bronchial epithelial cells in asthmatics. The overall hypothesis for this project states that epithelial cells from asthmatics secrete substance(s) that act on mesenchymal cells (lung fibroblasts and airway smooth muscle cells) to produce the structural changes characteristic of asthmatic airways. We have developed an experimental approach at the interface of cell biology/biochemistry and clinical asthma in which specific elements present in vivo that produce these pathological effects can be identified. This approach has 3 key elements: 1) a 2 week, 4 bronchoscopy protocol (""""""""Recovery from Inflammation,"""""""" or RFI protocol) in which human asthmatics undergo airway sampling (broncholaveolar lavage, bronchial brush biopsy to obtain epithelial cells, endobronchial forceps biopsy) and segmental antigen challenge (SAC) so that inflammatory events before challenge (at baseline), at the height of the inflammatory response (24 hrs after challenge), and during its repair and resolution phases (1 wk and 2 wks after challenge) can be characterized; 2) ex vivo, short term, air-fluid interface culture of epithelial cells from asthmatics and controls in which the asthmatic cells retain important aspects of their asthma phenotype; and 3) a bioassay for epithelial cell-derived fibrogenic factors in which epithelial cell supernatants are tested for their ability to stimulate production of collagen type III and other extracellular matrix (ECM) components from mesenchymal cells, including lung fibroblasts and airway smooth muscle cells, thus allowing us to characterize and identify important fibrogenic mediators. Using these tools we will: 1) Determine the kinetics of the secretion of fibrogenic growth factors from epithelial cells which stimulate lung fibroblasts and airway smooth muscle cells to produce ECM after an in vivo immunologic trigger (SAC), and determine whether these events are restricted to asthmatics and not present in nonasthmatic rhinitics and nonallergic, nonasthmatic controls; 2) Identify the active principle(s) secreted by asthmatic epithelial cells; 3) Determine whether an acute airway eosinophilic response is necessary for asthmatic epithelial cells to secrete fibrogenic factors and whether mechanical, as well as an immunologic injury, can trigger their synthesis; and 4) Identify whether elements of signal transduction pathways involving NF-kB, MAP kinases, and/or Smad pathways are involved in ECM secretion by lung fibroblasts and airway smooth muscle cells triggered with active factors derived from asthmatic epithelial cells. These studies will provide novel information concerning airway remodeling in asthma.
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