Mechanisms and control of epithelial to mesenchymal transition in chronic asthma

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Chronic persistent asthma has been linked to both ongoing airway inflammation and airway remodeling. The relationship between airway inflammation and remodeling has remained uncertain; but there is evidence that corticosteroid therapy does not prevent the development of airway remodeling. Thus, there is a major impetus to understand the pathogenesis of airway remodeling at a more fundamental level. One of the critical components of airway remodeling is the generation of myofibroblasts. Myofibroblasts contribute both to the enhanced deposition of matrix protein including types I and III collagens as well as to the contractile apparatus. Relatively little is known about the origin of myofibroblasts involved in asthma. Three potential sources of airway myofibroblasts are activation of resident lung fibroblasts, recruitment of bone marrow fibroblast stem cells that differentiate into fibroblasts and transition or transdifferentiation of airway epithelial cell into myofibroblasts. Studies in other organs, particularly the kidney, have shown that epithelial to mesenchymal transition (EMT) is a major source of myofibroblasts following injury or trauma. Our hypothesis is that airway epithelial cells in chronic asthma establish a local milieu that promotes transition of epithelial cells to myofibroblasts, and that this represents a significant component of airway remodeling. An important corollary of this hypothesis is that changing the local milieu can promote myofiblast to epithelial transition, and thereby improve remodeling. To test this hypothesis, we propose the following specific aims: 1: Assess the mechanisms underlying epithelial-mesenchymal transition (EMT) in airway epithelial cells; 2) Analyze the regulation of epithelialmesenchymal transition in airway epithelial cells; and 3) Explore the relationship between epithelialmesenchymal transition and in vivo airway remodeling in patients with chronic asthma. These studies will directly address a fundamental mechanism by which the airway may undergo remodeling during chronic asthma. Because the pathways leading to epithelial to mesenchymal transition are subject to regulation by current and future medications, defining the molecular steps in the process of transition will provide guidance for future efforts to limit remodeling. Finally, development of a biomarker for remodeling will significantly enhance the ability to monitor these therapeutic efforts.