Failure of therapeutic trials for Chronic Obstructive Lung Disease (COPD) reflects our poor mechanistic understanding of the disease. The long term goal of this project is to improve the mechanistic understanding of COPD. The two major pathologic features of COPD that contribute to airway obstruction are loss of alveolar walls and wall thickening of small airways (<2mm). Small airway changes progress with increasing severity of COPD and therefore represent a therapeutic target to stabilize or potentially reverse airway obstruction. Recent investigation suggests that TGF? is likely to play a major mechanistic role in wall thickening in COPD by regulating the balanced autocrine and paracrine interactions between airway epithelial and mesenchymal cell types, collectively known as the epithelial-mesenchymal trophic unit (EMTU). These autocrine and paracrine interactions dictate cellular differentiation during lung development. Imbalances in these interactions could result from chronic airway injury (e.g. tobacco smoke) and lead to airway remodeling. TGF? isoforms are expressed by all cell types within the EMTU, but almost entirely in an inactive form. Hence, activation of TGF? is a major point of regulation of TGF? function. We have recently developed one of the first in vitro models of the human EMTU (Araya, et al, Am. J. Path, 2006) and have used it to determine that the integrin av?8 plays a major role in TGF? activation, and subsequent autocrine and paracrine interactions between airway epithelial cells and fibroblasts. Using human COPD samples, we demonstrate increased ?8 expression in both the airway epithelium and small airway fibroblasts, which significantly correlates with declining pulmonary function and airway wall thickening. These findings have led us to our overall hypothesis: Increased av?8-dependent activation of TGF? in COPD airway epithelial cells and fibroblasts leads to inappropriate reactivation of morphogenic programs within the EMTU, which leads to airway remodeling. Using physiologically relevant primary human airway epithelial and fibroblast cell culture systems, we will: 1) determine the mechanism of increased (38 expression in COPD by airway epithelial cells and fibroblasts;2) determine mechanism of increased av?8-mediated activation of TGF? in COPD;3) determine the functional consequence of increased av?8-mediated activation of TGF? in autocrine and paracrine interactions between airway epithelial and fibroblast cell types. TGF? is one of the most fibrogenic cytokines known, but because of its normal homeostatic role in virtually all tissues, therapies targeted at global TGF? neutralization will also have undesired systemic effects. The TGF? activating integrin, av?8, is upregulated in COPD but has a highly restricted pattern of expression in normal human tissues making it a possible therapeutic target to specifically inhibit TGF? in COPD. This proposal is the first step in testing the therapeutic potential of inhibiting av?8 function in COPD.
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