Autophagy plays a role in FSTL1-induced epithelial mesenchymal transition and airway remodeling in asthma
Autophagy plays a role in FSTL1-induced epithelial mesenchymal transition and airway remodeling in asthma
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DOI：
10.1152/ajplung.00510.2016
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发表时间：
2017-07-01
影响因子：
4.9
通讯作者：
Dong, Liang
中科院分区：
文献类型：
--
作者：
Liu, Tian;Liu, Yahui;Dong, Liang
哮喘是一种与气道高反应性和气道重塑相关的慢性疾病。气道重塑是难治性哮喘的重要原因，并且与气道上皮细胞通过上皮 - 间质转化（EMT）分化为肌成纤维细胞相关，从而增加上皮下纤维化进程。越来越多的证据表明自噬调节重塑。然而，这些作用的潜在分子机制仍不清楚。在本研究中，我们假设卵泡抑素样蛋白1（FSTL1）通过增强自噬促进EMT和气道重塑。通过透射电子显微镜（TEM），在患者和小鼠的气道中检测到双膜自噬体。与健康对照组相比，哮喘患者和卵清蛋白（OVA）激发的小鼠中有更多的自噬体。FSTL1和beclin - 1在哮喘患者和OVA激发的小鼠的气道中表达上调，同时伴有气道EMT和重塑。在OVA激发的Fstl1（+/-）小鼠中，与对照小鼠相比，气道重塑和自噬程度降低。还在体外16HBE细胞中测试了FSTL1对自噬和EMT的影响。此外，通过使用LY - 294002和siRNA - ATG5抑制自噬，可降低16HBE细胞中FSTL1诱导的EMT，这通过E - 钙粘蛋白、N - 钙粘蛋白和波形蛋白的表达来衡量。与此一致，给予LY - 294002可降低FSTL1激发的野生型小鼠中自噬、EMT和气道重塑标志物的表达。综上所述，我们的研究表明FSTL1可能通过激活自噬诱导EMT和气道重塑。这些发现可能为针对自噬和FSTL1途径的治疗研究提供新的途径，这可能对难治性哮喘患者有益。
Asthma is a chronic disease related to airway hyperresponsiveness and airway remodeling. Airway remodeling is the important reason of refractory asthma and is associated with differentiation of airway epithelia into myofibroblasts via epithelial-mesenchymal transition (EMT) to increase the process of subepithelial fibrosis. There is growing evidence that autophagy modulates remodeling. However, the underlying molecular mechanisms of these effects are still unclear. In this study, we hypothesized that Follistatin-like 1 (FSTL1) promotes EMT and airway remodeling by intensifying autophagy. With the use of transmission electron microscopy (TEM), double-membrane autophago-somes were detected in the airways of patients and mice. More autophagosomes were in patients with asthma and OVA-challenged mice compared with healthy controls. The expression of FSTL1 and beclin-1 was upregulated in the airways of patients with asthma and OVA-challenged mice, accompanied by airway EMT and remodeling. In OVA-challenged Fstl1(+/-) mice, the degree of airway remodeling and autophagy was decreased compared with control mice. The effects of FSTL1 on autophagy and EMT were also tested in 16HBE cells in vitro. Additionally, inhibition of autophagy by using LY-294002 and siRNA-ATG5 reduced the FSTL1-induced EMT in 16HBE cells, as measured by E-cadherin, N-cadherin, and vimentin expression. In line herewith, administration of LY-294002 reduced the expression of autophagy, EMT, and airway remodeling markers in FSTL1-challenged WT mice. Taken together, our study suggests that FSTL1 may induce EMT and airway remodeling by activating autophagy. These findings may provide novel avenues for therapeutic research targeting the autophagy and FSTL1 pathway, which may be beneficial to patients with refractory asthma.