分泌的热激蛋白控制气道重塑：来自支气管热成形术的证据
2021/05/26
摘要
背景：气道平滑肌质量增加是哮喘的关键病理。支气管热成形术是一种基于选择性加热气道的重度哮喘的治疗方法，旨在减少气道平滑肌细胞（ASMC）的质量，从而减少支气管收缩。然而，短时间的热暴露不足以解释其持久的作用，已有研究表明热激蛋白（HSP）在其中的作用。
目的：我们试图确定HSP70和HSP90在通过支气管热成形术控制气道壁重塑中的作用。
方法：在热成形术之前和之后，对20例重度哮喘患者进行了支气管肺泡灌洗液和支气管内活检。将分离的上皮细胞和ASMC暴露在65oC下10秒钟，以模拟热成型。通过免疫组织化学，Western印迹，免疫荧光和ELISA测定蛋白质。通过细胞计数和抗原Ki67（MKI67）表达进行增殖。
结果：热成形术显着增加了HSP70和HSP90在上皮和支气管肺泡灌洗液中的表达。在ASMC中，热成形术可同时降低两种HSP。这些细胞类型特异性作用甚至在组织切片热成型后1个月即可检测到。在上皮细胞中，离体暴露于高温（65oC，10秒）会增加HSP70和HSP90的表达和分泌。另外，通过加热或用人重组HSP70或HSP90处理，上皮细胞增殖被上调。在ASMC中，受热或外源HSP会减少增殖和分化。在这两种细胞类型中，HSP70和HSP90激活了雷帕霉素核糖体蛋白S6激酶1和CCAAT /增强子结合蛋白-β蛋白精氨酸甲基转移酶1线粒体活性的丝氨酸/苏氨酸蛋白激酶哺乳动物靶标的信号级联。
结论：源自上皮细胞的HSP70和HSP90改善了上皮细胞的功能，但阻止了ASMC重塑。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（J Allergy Clin Immunol, 2021.）
Secreted heat shock proteins control airway remodeling: Evidence from bronchial thermoplasty
Fang L, Li J, Papakonstantinou E, et al.
Abstract
BACKGROUND:Increased airway smooth muscle mass is a key pathology in asthma. Bronchial thermoplasty is a treatment for severe asthma based on selective heating of the airways that aims to reduce the mass of airway smooth muscle cells (ASMCs), and thereby bronchoconstriction. However, short heat exposure is insufficient to explain the long-lasting effect, and heat shock proteins (HSPs) have been suggested to play a role.
OBJECTIVE: We sought to determine the role of HSP70 and HSP90 in the control of airway wall remodeling by bronchial thermoplasty.
METHODS: Bronchoalveolar lavage fluid and endobronchial biopsies of 20 patients with severe asthma were obtained before and after thermoplasty. Isolated epithelial cells and ASMCs were exposed to 65oC for 10 seconds, mimicking thermoplasty. Proteins were determined by immunohistochemistry, Western blotting, immunofluorescence, and ELISA; proliferation by cell counts and antigen Ki67 (MKI67) expression.
RESULTS:Thermoplasty significantly increased the expression of HSP70 and HSP90 in the epithelium and bronchoalveolar lavage fluid. In ASMCs, thermoplasty reduced both HSPs. These cell-type-specific effects were detectable even 1 month after thermoplasty in tissue sections. In epithelial cells, exvivo exposure to heat (65oC, 10 seconds) increased the expression and secretion of HSP70 and HSP90. In addition, epithelial cell proliferation was upregulated by heat or treatment with human recombinant HSP70 or HSP90. In ASMCs, heat exposure or exogenous HSPs reduced proliferation and differentiation. In both cell types, HSP70 and HSP90 activated the signaling cascade of serine/threonine-protein kinase mammalian target of rapamycinribosomal protein S6 kinase 1 and CCAAT/enhancer binding protein-betaprotein arginine methyltransferase 1 mitochondria activity.
CONCLUSIONS: Epithelial cell-derived HSP70 and HSP90 improve the function of epithelial cells, but block ASMC remodeling.
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血液中的类胰蛋白酶和胸腺基质淋巴细胞生成素水平可预测严重哮喘加重的风险
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肺功能波动模式揭示与2型炎症无关的哮喘与COPD表型
