Lin Ching-Huei, Shen Mei-Lin, Kao Shung-Te, Wu Dong Chuan
Graduate Institute of Chinese Medicine, China Medical University, Taichung, Taiwan; Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.
Graduate Institute of Chinese Medicine, China Medical University, Taichung, Taiwan.
Int Immunopharmacol. 2014 Sep;22(1):141-50. doi: 10.1016/j.intimp.2014.06.031. Epub 2014 Jun 27.
Airway fibrosis, which is a crucial pathological condition occurring in various types of pulmonary disorders, is characterized by accumulation and activation of fibroblast cells, deposition of extracellular matrix (ECM) proteins, and increase of airway basement membrane. Transforming growth factor beta 1 (TGF-β1) is the principal profibrogenic cytokine that is responsible for fibrotic responses. In the present study, we aimed to investigate the antifibrotic effects of the natural polyphenolic compound, sesamin, on TGF-β1-induced fibroblast proliferation and activation, epithelial-mesenchymal transition (EMT), and ovalbumin (OVA)-induced airway fibrosis in vivo. We found that sesamin attenuated TGF-β1-induced proliferation of cultured lung fibroblasts. Sesamin inhibited TGF-β1-stimulated expression of alpha smooth muscle actin (α-SMA), suggesting that sesamin plays an inhibitory role in fibroblast activation. Sesamin blocked upregulation of the mesenchymal markers (fibronectin and vimentin) and downregulation of the epithelial marker (E-cadherin), indicating an inhibitory effect on TGF-β1-induced EMT in A549 cells. TGF-β1-induced Smad3 phosphorylation was also significantly reduced by sesamin in both cultured fibroblast and A549 cells. In the airway fibrosis induced by OVA in mice, sesamin inhibited the accumulation of α-SMA-positive cells and expression of collagen I in the airway. Histological studies revealed that sesamin protected against subepithelial fibrosis by reducing myofibroblast activation and collagen accumulation in the ECM. OVA-induced thickening of basement membrane was significantly alleviated in animals receiving sesamin treatments. These results suggest a therapeutic potential of sesamin as an antifibrotic agent.
气道纤维化是发生在各种肺部疾病中的一种关键病理状况，其特征在于成纤维细胞的积累和活化、细胞外基质（ECM）蛋白的沉积以及气道基底膜的增厚。转化生长因子β1（TGF-β1）是负责纤维化反应的主要促纤维化细胞因子。在本研究中，我们旨在研究天然多酚化合物芝麻素对TGF-β1诱导的成纤维细胞增殖和活化、上皮-间质转化（EMT）以及卵清蛋白（OVA）诱导的体内气道纤维化的抗纤维化作用。我们发现芝麻素可减弱TGF-β1诱导的培养肺成纤维细胞的增殖。芝麻素抑制TGF-β1刺激的α平滑肌肌动蛋白（α-SMA）的表达，表明芝麻素在成纤维细胞活化中起抑制作用。芝麻素阻断间充质标志物（纤连蛋白和波形蛋白）的上调以及上皮标志物（E-钙黏蛋白）的下调，表明对TGF-β1诱导的A549细胞EMT具有抑制作用。在培养的成纤维细胞和A549细胞中，芝麻素还显著降低了TGF-β1诱导的Smad3磷酸化。在OVA诱导的小鼠气道纤维化中，芝麻素抑制了气道中α-SMA阳性细胞的积累和I型胶原蛋白的表达。组织学研究表明，芝麻素通过减少肌成纤维细胞活化和ECM中胶原蛋白的积累来预防上皮下纤维化。接受芝麻素治疗的动物中，OVA诱导的基底膜增厚得到显著缓解。这些结果表明芝麻素作为抗纤维化药物具有治疗潜力。
