Brain-derived neurotrophic factor and airway fibrosis in asthma
Brain-derived neurotrophic factor and airway fibrosis in asthma
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DOI：
10.1152/ajplung.00580.2016
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发表时间：
2017-08-01
影响因子：
4.9
通讯作者：
Prakash, Y. S.
中科院分区：
文献类型：
--
作者：
Freeman, Michelle R.;Sathish, Venkatachalem;Prakash, Y. S.
由炎症驱动的哮喘中的气道重塑涉及上皮细胞和气道平滑肌（ASM）的增殖，以及增强的细胞外基质（ECM）生成和沉积，即，纤维化因此，了解促纤维化机制对于开发哮喘新治疗策略非常重要。最近的研究，包括我们自己的研究，表明了局部产生的生长因子如脑源性神经营养因子（BDNF）在介导和调节炎症反应中的作用。在这项研究中，我们探讨了促纤维化的影响，BDNF在哮喘的背景下，通过检查表达，活性和ECM蛋白沉积在原代ASM细胞分离哮喘与非哮喘患者。哮喘ASM中基础脑源性神经营养因子的表达和分泌以及高亲和力脑源性神经营养因子受体TrkB的水平较高。外源性BDNF可显著增加ECM的生成和沉积，尤其是胶原-1和胶原-3（纤维连接蛋白较少）以及基质金属蛋白酶（MMP-2，MMP-9）的活性。暴露于促炎细胞因子TNF α显著增加BDNF分泌，特别是在哮喘ASM中，而IL-13没有观察到显著变化。使用TrkB-Fc螯合BDNF逆转TNF α诱导的ECM沉积增加。哮喘ASM的条件培养基增强了非哮喘ASM的ECM生成，这是由BDNF螯合钝化。炎症诱导的MMP-2、MMP-9和组织抑制剂金属蛋白酶（TIMP-1、TIMP-2）的变化在TrkB-Fc存在下逆转。这些新的数据表明，ASM是人类气道内BDNF的炎症敏感来源，对哮喘相关的纤维化具有自分泌作用。
Airway remodeling in asthma driven by inflammation involves proliferation of epithelial cells and airway smooth muscle (ASM), as well as enhanced extracellular matrix (ECM) generation and deposition, i.e., fibrosis. Accordingly, understanding profibrotic mechanisms is important for developing novel therapeutic strategies in asthma. Recent studies, including our own, have suggested a role for locally produced growth factors such as brain-derived neurotrophic factor (BDNF) in mediating and modulating inflammation effects. In this study, we explored the profibrotic influence of BDNF in the context of asthma by examining expression, activity, and deposition of ECM proteins in primary ASM cells isolated from asthmatic vs. nonasthmatic patients. Basal BDNF expression and secretion, and levels of the high-affinity BDNF receptor TrkB, were higher in asthmatic ASM. Exogenous BDNF significantly increased ECM production and deposition, especially of collagen-1 and collagen-3 (less so fibronectin) and the activity of matrix metalloproteinases (MMP-2, MMP-9). Exposure to the proinflammatory cytokine TNF alpha significantly increased BDNF secretion, particularly in asthmatic ASM, whereas no significant changes were observed with IL-13. Chelation of BDNF using TrkB-Fc reversed TNF alpha-induced increase in ECM deposition. Conditioned media from asthmatic ASM enhanced ECM generation in nonasthmatic ASM, which was blunted by BDNF chelation. Inflammation-induced changes in MMP-2, MMP-9, and tissue inhibitor metalloproteinases (TIMP-1, TIMP-2) were reversed in the presence of TrkB-Fc. These novel data suggest ASM as an inflammation-sensitive source of BDNF within human airways, with autocrine effects on fibrosis relevant to asthma.