The Mechanisms Underlying the Enhanced Capacity of Fibrocyte Proliferation and Myofibroblast Transformation with High Output of Connective Tissue Matrix in Patients with Chronic Obstructive Asthma

Fibrocytes are cells that circulate in the peripheral blood and produce connective tissue proteins. Our recently published work (Wang et al, Am J Respir Crit Care Med. 2008;178:583-91.) has shown that increased numbers of circulating fibrocytes expressing CD34/collagen 1 in patients with chronic obstructive asthma (COA). In our preliminary results, we have found these fibrocytes from COA have distinct cell biological features, including a higher proliferative capacity, mainly attributed to up-regulation of epidermal growth factor receptors (EGFR) and ADAM17 on those fibrocytes (Wang et al, Am J Respir Crit Care Med 2011 in revision); a distinct chemotaxis with CCL19/CCR7 compared to CCL12/CXCR4 for fibrocytes chemotaxis in acute asthma response; and upregulated ET-1 and ET receptor, ETAR related to myofibroblast transformation and production of pro-fibrogenic mediators, connective tissue growth factor (CTGF), α-SMA and collagen. In this study proposal, we would like to continue to in-depth investigate fibrocytes in COA, based on the following hypotheses: 1) increased oxidative stress in COA potentiates TGF-­‐β1 transactivation of ADAM17/EGFR and ET-­‐1/ETAR through G-­‐protein coupled receptors (GPCR); 2) up-­‐regulated expression of ETAR/CTGF increases and mediates production of fibrogenic products, collagen I and α-SMA; 3) interaction with TH2 cytokines, such as IL-4, IL-13, or IL-17E induces fibrocyte transformation into myofibroblast and synthesis of pro-inflammatory mediators; 4) expression of CCL19 in airways and up-regulation of CCR7 in fibrocytes are responsible for fibrocyte recruitment from bone marrow and migration into airways of COA; 5) PI3K is essential for up-regulaion of ADAM17/EGFR, ETAR through GPCR transactivation, and for cytokine, chemokine, connective tissue products synthesis, as well as chemotaxis of fibrocytes; 6) mast cells with presence of tryptase and chymase, are contributory to the increased serum level of ET-1 and airway CCL19 expression in COA. Therefore, this 3-year research project aims to 1) investigate the mechanisms underlying the enhanced capacity of proliferation and transformation into myofibroblasts with high output of connective tissue matrix from fibrocytes of COA; 2) examine the contribution of fibrocytes to airway inflammation in COA patients by release of pro-inflammatory mediators through an interaction with TH2 cytokines or IL-17E; 3) explore the chemotactic receptors and cognate ligands responsible for recruitment and migration of fibrocytes in COA, and the regulatory mechanisms; 4) study the role of mast cell in recruitment, proliferation, transformation and synthesis of pro-inflammatory mediators of fibrocytes. Those novel findings of fibrocytes not only shed light on the pathogenesis of airway remodeling in COA but also provide a new therapeutic direction to prevent airway remodeling in severe asthma. In the 1st year of this study, we will continue our exploration of mechanisms underlying the enhanced proliferation capacity and transformation into myofibroblast with connective tissue matrix production of fibrocytes from COA. In the 2nd year of this study, we will explore the chemotactic receptors and cognate ligands responsible for fibrocyte migration and recruitment from bone marrow. The difference in fibrocyte chemotaxis between COA patients and asthmatics with acute exacerbation will be examined. The chemotactic receptors and the cognate ligands will be confirmed by migration assay, and will be studied the stimuli responsible for their expression. In the 3rd year of this study, we will determine the role of airway mast cells in activation and chemotaxis of fibrocytes in COA patients.

Project ID:PC10009-0039
External Project ID:NSC100-2314-B182A-085-MY3