Airway Remondeling in Asthma: Modulation By IL-13

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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 shown that airway inflammation occurs in both the proximal and distal lung in asthma and that collagen expression is increased and airway elastin expression is reduced. The mechanisms by which Th2 inflammation leads to the subsequent host response of remodeling are poorly understood. Interleukin (IL)-13, a Th2 cytokine critical to the asthma phenotype in murine models, also causes fibrosis by effects on the airway fibroblast. A mediator induced by IL-13 that links inflammation to the structural changes in the proximal and distal lung is platelet-derived growth factor (PDGF) a potent chemoattractant and mitogen for fibroblasts. PDGF isoforms and receptors are expressed in the lung, induced by IL-13 and expression is inceased by corticosteroids in animal models. We hypothesize that interleukin-13 modulates airway fibroblast function in human asthma via increased expression of platelet-derived growth factor and subsequent airway fibroblast proliferation, collagen expression and decreased elastin expression. Corticosteroids, the mainstay of therapy for asthma, do not suppress and may enhance these processes. 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 and may enhance these processes.To test this hypothesis, subjects with 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 first determine that IL-13 induces PDGF expression by the airway fibroblast in human asthma, and that this requires activation of STAT-6 and Egr-1 (specific aim 1). In specific aim 2, we will determine that PDGF modulates 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 and decreased PDGF and airway fibroblast activation ex vivo. We will relate the pathologic airway changes and ex vivo fibroblast function to measures of large and small airway function in asthmatic human subjects in vivo in hopes of predicting in the laboratory who will suffer the greatest physiological consequences of airway remodeling. This proposal will shed light on the physiologic and pathologic consequences of airway remodeling in asthma, the host response to Th2 inflammation that lead to remodeling and whether our main therapy for asthma, corticosteroids, modulate and possibly enhance this process. This project will evaluate host responses leading to airway remodeling in asthma in conjunction with projects 1 and 4, provide human samples for projects 1 and 4 and interact with all the Cores.