Mechanisms and control of epithelial to mesenchymal transition in chronic asthma

University Of California, San Diego, La Jolla CA

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Linked publications & trials

Abstract

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