TGF-{beta}1-Mediated CTGF Upregulation Through Transactivation of EGFR in Fibrocytes of Chronic Obstructive Asthma

Circulating fibrocytes are increased in chronic obstructive asthma (COA) with a higher capacity of proliferation and differentiation by TGF-β1. Our previous study highlighted a potential involvement of connective tissue growth factor (CTGF) in fibrocyte transformation. We evaluated the role of epidermal growth factor receptor (EGFR) and a disintegrin and metalloproteinase 17 (ADAM17) in mediating TGF-β1-induced CTGF activation of fibrocytes. Fibrocytes were isolated from asthmatics with normal pulmonary function (NPF) (n=14) and COA (n=13). Fibrocytes expressing CD45, collagen I, EGFR, ADAM17, CTGF, or α-SMA were determined by flowcytometry. Expression of EGFR, ADAM17 and CTGF was increased in fibrocytes from COA. TGF-β1 dose-dependently increased expression of CTGF, EGFR and ADAM17 on fibrocytes from asthma NPF after 24-h culture. TGF-β1 increased the number of CTGF+fibrocytes (13.8±2.1x104cells/ml, n=6, p<0.05) and fibrocytes transformed into myofibroblasts were reduced by an EGFR tyrosine kinase inhibitor, gefitinib (5.8±1.3x10<4cells/ml), blocking ADAM17 with TNF protease inhibitor-1(TAPI-1, 6.7±1.5x104cells/ml), and anti-CTGF Ab (3.7±1.3x104cells/ml) in asthma NPF at 14 days. In COA patients, higher expression of CTGF+fibrocytes and TGF-β1-induced fibrocyte proliferation were suppressed by gefitinib and TAPI-1, but not affected by ALK5 (SB43154) and Smad3 (SIS3) inhibitors. Overexpression or knockout ADAM17...
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Airway Cell Biology and Immunopathology Source Type: research