Abstract
The activation of human bronchial fibroblasts by transforming growth factor-β1 (TGF-β1) leads to the formation of highly contractile myofibroblasts in the process of the fibroblast–myofibroblast transition (FMT). This process is crucial for subepithelial fibrosis and bronchial wall remodeling in asthma. However, this process evades current therapeutic asthma treatment strategies. Since our previous studies showed the attenuation of the TGF-β1-induced FMT in response to lipid-lowering agents (e.g., statins), we were interested to see whether a corresponding effect could be obtained upon administration of hypolipidemic agents. In this study, we investigated the effect of fenofibrate on FMT efficiency in populations of bronchial fibroblasts derived from asthmatic patients. Fenofibrate exerted a dose-dependent inhibitory effect on the FMT, even though it did not efficiently affect the expression of α-smooth muscle actin (α-SMA; marker of myofibroblasts); however, it considerably reduced its incorporation into stress fibers through connexin 43 regulation. This effect was accompanied by disturbances in the actin cytoskeleton architecture, impairments in the maturation of focal adhesions, and the fenofibrate-induced deactivation of TGF-β1/Smad2/3 signaling. These data suggest that fenofibrate interferes with myofibroblastic differentiation during asthma-related subepithelial fibrosis. The data indicate the potential application of fenofibrate in the therapy and prevention of bronchial remodeling during the asthmatic process.
Highlights
Contemporary views on asthma pathophysiology suggest that the asthmatic process in proximal bronchi is associated with chronic inflammation-induced bronchial wall remodeling [1,2]
Collagen is predominantly deposited by bronchial fibroblasts and myofibroblasts; we estimated the effect of fenofibrate on myofibroblastic differentiation of human bronchial fibroblasts (HBFs) derived from asthmatics
Note that fenofibrate efficiently attenuates the transforming growth factor-β1 (TGF-β1)-induced Smad signaling, but not the ERK-dependent pathway. This phenomenon was confirmed by immunofluorescence studies and with cytofluorimetric analyses of HBFs (Figure 5C,D). These results clearly show the inhibitory effect of fenofibrate on connexin 43 (Cx43) levels in the TGF-β1-treated bronchial fibroblasts, which corresponds to the attenuation of the TGF-β1/Smad2/3 signaling pathway and fibroblast–myofibroblast transition (FMT) efficiency
Summary
Contemporary views on asthma pathophysiology suggest that the asthmatic process in proximal bronchi is associated with chronic inflammation-induced bronchial wall remodeling [1,2]. Bronchial asthma is manifested by a wide range of histopathological changes in the bronchial wall. These changes comprise epithelial dysfunction and an unbalanced increase in the airway smooth muscle mass and subepithelial fibrosis, which is associated with the abnormal activation of bronchial fibroblasts [3]. Because of the bronchial wall remodeling, a functional impairment of asthmatic bronchi and chronic airflow obstruction occurs. This impairment is accompanied by chronic inflammation that further promotes pro-fibrotic changes in the bronchial airway walls [4]. The asthmatic bronchi microenvironment is rich in locally secreted pro-inflammatory cytokines and growth factors (especially TGF-β1), which favor the myofibroblastic differentiation of bronchial fibroblasts
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