Airway remodeling in asthma is a process of permanent structural changes occurring over time, resulting in a component of fixed airway obstruction that can lead to reduced lung function and reduced responsiveness to medications. We have shown that airway inflammation occurs in both the proximal and distal lung in asthma, and we propose that remodeling occurs in both lung compartments. The overall goal of this proposal is to examine critical pathways resulting in dysregulation of airway fibroblast growth and matrix expression throughout the lung that lead to airway remodeling in asthma. A cell type that links inflammation to structural airway changes is the airway fibroblast. Platelet-derived growth factor (PDGF) is a mediator produced by fibroblasts that is induced by IL-13 and is instrumental in tissue repair. In preliminary studies, we demonstrate important differences in primary fibroblasts cultured from the airways of normal and asthmatic subjects. Primary fibroblasts isolated from the asthmatic airways exhibit major disturbances in the critical mitogenic PDGF pathway. We show increased production of PDGF in response to TH2 cytokines, altered expression of PDGF receptor isoforms and changes in matrix expression in response to PDGF. In addition, corticosteroids augment growth in fibroblasts isolated from mild and severe asthmatics as compared to fibroblasts from normal controls; this effect is abrogated when PDGF is inhibited. The hypothesis to be tested is that the TH2 environment induces expression of platelet-derived growth factor (PDGF); PDGF enhances the airway remodeling process in asthma by increasing airway fibroblast growth and collagen expression and by decreasing elastin expression in both the proximal and distal lung. These processes result in a reduction in lung function, airway collapsibility and loss of elastic recoil. Corticosteroids, the mainstay of therapy for asthma, do not suppress but enhance these processes. To test this hypothesis, we will recruit subjects with mild and severe asthma and normal controls who will undergo bronchoscopy with proximal (endobronchial) and distal (transbronchial) lung biopsy. We will determine PDGF expression in the lung, and whether its expression is modulated by IL- 13 (Specific Aim 1).
In Specific Aim 2 we will determine that PDGF modulates fibroblast collagen and elastin expression throughout the lung, and that this modulation predicts lung function.
In Aim 3, we will determine if IL-13 inhibition reduces PDGF expression in the lung and ultimately improves lung function as compared to corticosteroids. The strength of this work is that we will relate the pathologic airway changes determined ex vivo to measures of large and small airway function in vivo in order to predict which asthmatic subjects will suffer the greatest physiological consequences of airway remodeling. This proposal will also determine whether PDGF inhibition could provide important adjuvant therapy for the treatment of severe asthmatics by limiting structural changes that result from activity of this pathway. ? ? ?
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