Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland.
Int J Mol Sci. 2021 Nov 26;22(23):12790. doi: 10.3390/ijms222312790.
Subepithelial fibrosis is a component of the remodeling observed in the bronchial wall of patients diagnosed with asthma. In this process, human bronchial fibroblasts (HBFs) drive the fibroblast-to-myofibroblast transition (FMT) in response to transforming growth factor-β (TGF-β), which activates the canonical Smad-dependent signaling. However, the pleiotropic properties of TGF-β also promote the activation of non-canonical signaling pathways which can affect the FMT. In this study we investigated the effect of p38 mitogen-activated protein kinase (MAPK) inhibition by SB203580 on the FMT potential of HBFs derived from asthmatic patients using immunocytofluorescence, real-time PCR and Western blotting methods. Our results demonstrate for the first time the strong effect of p38 MAPK inhibition on the TGF-β-induced FMT potential throughout the strong attenuation of myofibroblast-related markers: α-smooth muscle actin (α-SMA), collagen I, fibronectin and connexin 43 in HBFs. We suggest the pleiotropic mechanism of SB203580 on FMT impairment in HBF populations by the diminishing of TGF-β/Smad signaling activation and disturbances in the actin cytoskeleton architecture along with the maturation of focal adhesion sites. These observations justify future research on the role of p38 kinase in FMT efficiency and bronchial wall remodeling in asthma.
黏膜下纤维化是哮喘患者支气管壁重塑的一个组成部分。在这个过程中，人支气管成纤维细胞（HBFs）在转化生长因子-β（TGF-β）的作用下驱动成纤维细胞向肌成纤维细胞的转化（FMT），从而激活经典的 Smad 依赖性信号通路。然而，TGF-β的多效性也促进了非经典信号通路的激活，从而影响 FMT。在这项研究中，我们使用免疫细胞荧光、实时 PCR 和 Western blot 方法，研究了 p38 丝裂原活化蛋白激酶（MAPK）抑制剂 SB203580 对哮喘患者来源的 HBFs 的 FMT 潜能的影响。我们的结果首次证明了 p38 MAPK 抑制在 TGF-β诱导的 FMT 潜能方面的强烈作用，通过强烈减弱肌成纤维细胞相关标志物：HBFs 中的α-平滑肌肌动蛋白（α-SMA）、胶原 I、纤连蛋白和连接蛋白 43。我们认为，SB203580 通过减少 TGF-β/Smad 信号通路的激活以及肌动蛋白细胞骨架结构的紊乱和粘着斑位点的成熟，对 HBF 群体的 FMT 损伤具有多效性机制。这些观察结果证明了 p38 激酶在哮喘中 FMT 效率和支气管壁重塑中的作用的未来研究的合理性。
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