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. We have shownthat airway inflammation occurs in both the proximal and distal lung in asthma and that collagen expressionis increased and airway elastin expression is reduced. The mechanisms by which Th2 inflammation leads tothe subsequent host response of remodeling are poorly understood. Interleukin (IL)-13, a Th2 cytokinecritical to the asthma phenotype in murine models, also causes fibrosis by effects on the airway fibroblast. Amediator induced by IL-13 that links inflammation to the structural changes in the proximal and distal lung isplatelet-derived growth factor (PDGF) a potent chemoattractant and mitogen for fibroblasts. PDGF isoformsand receptors are expressed in the lung, induced by IL-13 and expression is inceased by corticosteroids inanimal models. We hypothesize that interleukin-13 modulates airway fibroblast function in humanasthma via increased expression of platelet-derived growth factor and subsequent airway fibroblastproliferation, collagen expression and decreased elastin expression. Corticosteroids, the mainstay oftherapy for asthma, do not suppress and may enhance these processes. These processes result in areduction in lung function, airway collapsibility and loss of elastic recoil. Corticosteroids, the mainstay oftherapy for asthma, do not suppress and may enhance these processes.To test this hypothesis, subjectswith mild and severe asthma and normal controls will undergo bronchoscopy with proximal (endobronchial)and distal (transbronchial) lung biopsy (asthmatic subjects only) and bronchoalveolar lavage. We will firstdetermine that IL-13 induces PDGF expression by the airway fibroblast in human asthma, and that thisrequires activation of STAT-6 and Egr-1 (specific aim 1).
In specific aim 2, we will determine that PDGFmodulates fibroblast collagen and elastin expression throughout the lung via activation of PIS kinase.
In specific aim 3, we will determine that neutralization of IL-13 in vivo will result in improved lung function anddecreased PDGF and airway fibroblast activation ex vivo. We will relate the pathologic airway changes andex vivo fibroblast function to measures of large and small airway function in asthmatic human subjects invivo in hopes of predicting in the laboratory who will suffer the greatest physiological consequences of airwayremodeling. This proposal will shed light on the physiologic and pathologic consequences of airwayremodeling in asthma, the host response to Th2 inflammation that lead to remodeling and whether our maintherapy for asthma, corticosteroids, modulate and possibly enhance this process. This project will evaluatehost responses leading to airway remodeling in asthma in conjunction with projects 1 and 4, provide humansamples for projects 1 and 4 and interact with all the Cores.
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