Abstract
Airway remodelling with subepithelial fibrosis, which abolishes the physiological functions of the bronchial wall, is a major issue in bronchial asthma. Human bronchial fibroblasts (HBFs) derived from patients diagnosed with asthma display in vitro predestination towards TGF-β1-induced fibroblast-to-myofibroblast transition (FMT), a key event in subepithelial fibrosis. As commonly used anti-asthmatic drugs do not reverse the structural changes of the airways, and the molecular mechanism of enhanced asthma-related TGF-β1-induced FMT is poorly understood, we investigated the balance between the profibrotic TGF-β/Smad2/3 and the antifibrotic TGF-β/Smad1/5/9 signalling pathways and its role in the myofibroblast formation of HBF populations derived from asthmatic and non-asthmatic donors. Our findings showed for the first time that TGF-β-induced activation of the profibrotic Smad2/3 signalling pathway was enhanced, but the activation of the antifibrotic Smad1/5/(8)9 pathway by TGF-β1 was significantly diminished in fibroblasts from asthmatic donors compared to those from their healthy counterparts. The impairment of the antifibrotic TGF-β/Smad1/5/(8)9 pathway in HBFs derived from asthmatic donors was correlated with enhanced FMT. Furthermore, we showed that Smad1 silencing in HBFs from non-asthmatic donors increased the FMT potential in these cells. Additionally, we demonstrated that activation of antifibrotic Smad signalling via BMP7 or isoliquiritigenin [a small-molecule activator of the TGF-β/Smad1/5/(8)9 pathway] administration prevents FMT in HBFs from asthmatic donors through downregulation of profibrotic genes, e.g., α-SMA and fibronectin. Our data suggest that influencing the balance between the antifibrotic and profibrotic TGF-β/Smad signalling pathways using BMP7-mimetic compounds presents an unprecedented opportunity to inhibit subepithelial fibrosis during airway remodelling in asthma.
Highlights
The airway tracts of patients diagnosed with asthma are characterized by chronic inflammation along with remodelling of the bronchial w all[1, 2]
We showed that the architecture of the actin cytoskeleton, which was associated with N-cadherin function[14, 15], Cx43 signalling activity[16] and the functional status of TGF-β1 and connective tissue growth factor (CTGF)[17, 18] as the main stimulators of fibroblast to myofibroblast transition (FMT) through the Smad2/3 signalling pathway, participated in the efficient myofibroblast transition increase in fibroblasts from asthmatic patients[12, 16]
The results revealed that Human bronchial fibroblasts (HBFs) from asthmatic donors displayed significantly higher gene expression of α-smooth muscle actin (α-SMA) and extra domain A of fibronectin (EDA-fibronectin), especially after TGF-β1 stimulation, compared with those from their non-asthmatic counterparts (Fig. 1C–E)
Summary
The airway tracts of patients diagnosed with asthma are characterized by chronic inflammation along with remodelling of the bronchial w all[1, 2] This phenomenon is a complex process involving damage to the epithelial layer, hypertrophy and hyperplasia of the smooth muscles, enhanced vasculature and the key phenomenon subepithelial fibrosis[3]. In 2009, we were the first to show that the local resident bronchial fibroblasts isolated from biopsies derived from asthmatic patients had a substantially higher potential for transforming growth factor β (TGF-β)-induced fibroblast to myofibroblast transition (FMT) than those from their non-asthmatic c ounterparts[12] These cells displayed some inherent features that facilitate their differentiation into myofibroblasts[4, 13, 14]. It was shown that in fibroblasts, Smurf 2 preferentially targets Smad[1] for ubiquitination and proteasome-mediated degradation.This protein has a much weaker effect on Smad[2] levels, but does not affect Smad[3] levels[29]
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