Role of Circulating Bone Marrow Derived Fibrocytes in Chronic Obstructive Asthma

Chronic obstructive asthma is characterized by persistent airway inflammation and subepithelial fibrosis, leading to airway wall remodeling. These processes of subepithelial fibrosis may result in an increased amount of connective tissue components such as collagens, tenascin, fibronectin and proteoglycans. Fibroblasts are considered to be important key cells in this mechanism since they migrate to sites of injury where they acquire a myofibroblast phenotype, upon activation by factors such as TGF-β1, which is followed by production of a new extracellular matrix. Circulating fibrocytes, that express fibroblast products as well as the hemopoietic stem cell Ag CD34, enter sites of tissue injury, and localize to areas of extracellular matrix deposition. These cells express a specific pattern of both mesenchymal and hematopoetic markers including procollagen I, alpha-smooth muscle actin (α-SMA), CXCR4, CD34, and CD45. Circulating fibrocytes may function as myofibroblast precursors and may contribute to the genesis of subepithelial fibrosis in allergen-induced asthma and mice model. It is therefore crucial to elucidate the mechanisms involved in the accumulation of these cells in the airways of chronic asthma. To investigate the proliferative capacity and regulatory mechanisms of circulating fibrocytes in patients with chronic obstructive asthma, rather than in allergen-induced asthma, to provide direct evidence to delineate the role of bone marrow derived fibrocytes as important key cells in airway remodeling, circulating fibrocytes will be retrieved from peripheral venous blood of 40 chronic asthmatics with rapid decline of FEV1 in 5 years, 40 asthmatics with acute exacerbation, and 40 normal controls. The cell number and surface expression of chemotaxis receptors (CXCR4, CCR3, CCR5, CCR7) will be quantitated by flow cytometry. The influence of T cell interaction and cytokines (IL-3, IL-4, IL-13, TGF-β1) on fibrocyte proliferation and differentiation into myofibroblasts will be examined after cultured for 7-14 days. The intracellular signal pathways for regulation of cell proliferation, cell differentiation and delayed apoptosis will be also studied. Anti-asthma drugs, including corticosteroids, long acting β2-agonists, antileukotrienes, will be explored their inhibitory activities on circulating fibrocytes, and the related underlying mechanisms. Bronchial biopsy will be done to explore the presence of bone marrow derived fibrocytes and chemokines (stromal derived factor, secondary lymphoid chemokine). Based on our preliminary results, we anticipate this study may elucidate the role of circulating fibrocytes in the development of airway remodeling in chronic obstructive asthma, and then shed light on a new therapeutic direction in modifying subepithelial fibrosis in chronic asthma.

Project ID:PC9801-1750
External Project ID:NSC96-2628-B182-022-MY3