Endothelin-1 Mediates Fibrocyte Differentiation in Chronic Obstructive Asthma

The airway remodeling is one of the pathophysiological characteristics of chronic obstructive asthma, and its main pathological changes include subepithelial fibrosis formation, submucosal gland hyperplasia, hyperplasia and hypertrophy of airway smooth muscle, and fragility of airway epithelial cells. Subepithelial fibrosis is characterized by extensive deposition of extracellular matrix and connective tissue components such as collagens on airway wall, which may lead to loss of lung function and the development of progressive airflow obstruction. Several reports demonstrated that the serum level of ET-1 is increased in asthmatic patients. ET-1 has shown to be an inducer of connective tissue growth factor (CTGF) production in lung fibroblasts, which in turns promotes progression of lung fibrosis. Fibrocytes are unique bone marrow-derived mesenchymal progenitor cells found in circulation. Fibrocytes have been shown to play an important role in wound healing following injury and in the generation of lung fibrosis. Previous studies have shown that TGF-β is a key inducer of lung fibrosis by stimulating the release of growth factors and by inducing the differentiation of fibrocytes into myofibroblast-like cells. However, the role of ET-1 in fibrocyte differentiation to myofibroblasts in chronic obstructive asthma is still unknown. In our previous study has shown that JNK/AP-1 pathway is involved in thrombin-induced CTGF expression in human lung fibroblasts. Data from our preliminary study showed that the expression of CTGF is significantly increased in fibrocytes from chronic obstructive asthma patients. The Central Hypothesis is that ET-1 plays an important role in fibrocyte differentiation to myofibroblasts, which in turns causes lung fibrosis in chronic obstructive asthma. The overall objective of this sub-project 1 is to elucidate the molecular mechanism of ET-1-induced fibrocyte differentiation in chronic obstructive asthma. The hypotheses and specific aims are described below: Specific Aim 1 (1st year): To study the role of ET-1 in fibrocyte differentiation to myofibroblast in chronic obstructive asthma Hypothesis 1: ET-1 mediates fibrocyte differentiation to myofibroblast in chronic obstructive asthma Specific Aim 2 (2nd year): To characterize signaling pathway in fibrocyte differentiation in chronic obstructive asthma Hypothesis 2: JAK/STAT、MAPKs and transcription factors AP-1/NF-κB mediate fibrocyte differentiation uctive asthma Specific Aim 3 (2nd~3rd years): To confirm the role of ET-1 in fibrocyte differentiation in bleomycin-induced lung fibrosis Hypothesis 3: ETAR mediates fibrocyte differentiation in bleomycin-induced lung fibrosis