支气管热成形术治疗哮喘:对不同哮喘内型/表型的探索性组织病理学评估
2021/08/24
摘要
背景：支气管热成形术调节哮喘气道狭窄的结构异常。在目前的研究中，我们旨在研究支气管热成形术对不同哮喘内型/表型的组织病理学支气管结构的影响。
方法：从30例严重不受控哮喘患者中收集支气管热成形术前和3次连续支气管热成形术后的支气管内活检(n=450)。根据血液嗜酸性粒细胞、特应性、过敏和烟雾暴露对患者进行分类。组织切片评估组织病理学参数和热休克蛋白和糖皮质激素受体的表达。ki67染色检测细胞增殖情况。
结果：在所有患者中，支气管热成形术改善了哮喘控制(p＜0.001)，气道平滑肌减少(p=0.014)，增殖(Ki67+)上皮细胞增多(p=0.014)。支气管热成形术后，T2高支气管型哮喘患者气道平滑肌明显减少。低血嗜酸性粒细胞患者(p=0.016)、无过敏患者(p=0.028)和无烟雾暴露患者(p=0.034)支气管热成形术后上皮细胞增殖增加。在所有患者中，支气管热成形术增加了上皮细胞(p=0.018)和上皮下间充质细胞(p=0.033)中糖皮质激素受体的表达和细胞核中糖皮质激素受体的易位(p=0.036)。此外，支气管热成形术提高了上皮细胞热休克蛋白70 (p=0.002)和热休克蛋白90 (p=0.001)的表达，降低了上皮下间充质细胞热休克蛋白70 (p=0.009)和热休克蛋白90 (p=0.002)的表达。支气管热成形术对热休克蛋白70和90表达的影响在不同的哮喘内生型/表型中是不同的。
结论：支气管热成形术导致气道平滑肌减少，上皮细胞再生，气道糖皮质激素受体表达和激活增加，上皮细胞热休克蛋白表达增加。组织病理学效应在不同的内型/表型中表现不同，这表明支气管热成形术的有益作用是通过与哮喘内型/表型相关的不同分子靶点实现的。
Bronchial thermoplasty in asthma: an exploratory histopathological evaluation in distinct asthma endotypes/phenotypes
Papakonstantinou E, Koletsa T, Zhou L, et al.
Abstract
BACKGRUND:Bronchial thermoplasty regulates structural abnormalities involved in airway narrowing in asthma. In the present study we aimed to investigate the effect of bronchial thermoplasty on histopathological bronchial structures in distinct asthma endotypes/phenotypes.
METHODS:Endobronchial biopsies (n=450) were collected from 30 patients with severe uncontrolled asthma before bronchial thermoplasty and after 3 sequential bronchial thermoplasties. Patients were classified based on blood eosinophils, atopy, allergy and smoke exposure. Tissue sections were assessed for histopathological parameters and expression of heat-shock proteins and glucocorticoid receptor. Proliferating cells were determined by Ki67-staining.
RESULTS:In all patients, bronchial thermoplasty improved asthma control (p<0.001), reduced airway smooth muscle (p=0.014) and increased proliferative (Ki67+) epithelial cells (p=0.014). After bronchial thermoplasty, airway smooth muscle decreased predominantly in patients with T2 high asthma endotype. Epithelial cell proliferation was increased after bronchial thermoplasty in patients with low blood eosinophils (p=0.016), patients with no allergy (p=0.028) and patients without smoke exposure (p=0.034). In all patients, bronchial thermoplasty increased the expression of glucocorticoid receptor in epithelial cells (p=0.018) and subepithelial mesenchymal cells (p=0.033) and the translocation of glucocorticoid receptor in the nucleus (p=0.036). Furthermore, bronchial thermoplasty increased the expression of heat shock protein-70 (p=0.002) and heat shock protein-90 (p=0.001) in epithelial cells and decreased the expression of heat shock protein-70 (p=0.009) and heat shock protein-90 (p=0.002) in subepithelial mesenchymal cells. The effect of bronchial thermoplasty on the expression of heat shock proteins -70 and -90 was distinctive across different asthma endotypes/phenotypes.
Conclusions:Bronchial thermoplasty leads to a diminishment of airway smooth muscle, to epithelial cell regeneration, increased expression and activation of glucocorticoid receptor in the airways and increased expression of heat shock proteins in the epithelium. Histopathological effects appear to be distinct in different endotypes/phenotypes indicating that the beneficial effects of bronchial thermoplasty are achieved by diverse molecular targets associated with asthma endotypes/phenotypes.
背景：支气管热成形术调节哮喘气道狭窄的结构异常。在目前的研究中，我们旨在研究支气管热成形术对不同哮喘内型/表型的组织病理学支气管结构的影响。
方法：从30例严重不受控哮喘患者中收集支气管热成形术前和3次连续支气管热成形术后的支气管内活检(n=450)。根据血液嗜酸性粒细胞、特应性、过敏和烟雾暴露对患者进行分类。组织切片评估组织病理学参数和热休克蛋白和糖皮质激素受体的表达。ki67染色检测细胞增殖情况。
结果：在所有患者中，支气管热成形术改善了哮喘控制(p＜0.001)，气道平滑肌减少(p=0.014)，增殖(Ki67+)上皮细胞增多(p=0.014)。支气管热成形术后，T2高支气管型哮喘患者气道平滑肌明显减少。低血嗜酸性粒细胞患者(p=0.016)、无过敏患者(p=0.028)和无烟雾暴露患者(p=0.034)支气管热成形术后上皮细胞增殖增加。在所有患者中，支气管热成形术增加了上皮细胞(p=0.018)和上皮下间充质细胞(p=0.033)中糖皮质激素受体的表达和细胞核中糖皮质激素受体的易位(p=0.036)。此外，支气管热成形术提高了上皮细胞热休克蛋白70 (p=0.002)和热休克蛋白90 (p=0.001)的表达，降低了上皮下间充质细胞热休克蛋白70 (p=0.009)和热休克蛋白90 (p=0.002)的表达。支气管热成形术对热休克蛋白70和90表达的影响在不同的哮喘内生型/表型中是不同的。
结论：支气管热成形术导致气道平滑肌减少，上皮细胞再生，气道糖皮质激素受体表达和激活增加，上皮细胞热休克蛋白表达增加。组织病理学效应在不同的内型/表型中表现不同，这表明支气管热成形术的有益作用是通过与哮喘内型/表型相关的不同分子靶点实现的。
（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）
（Respir Res, 2021, 22(1): 186.）
（Respir Res, 2021, 22(1): 186.）
Bronchial thermoplasty in asthma: an exploratory histopathological evaluation in distinct asthma endotypes/phenotypes
Papakonstantinou E, Koletsa T, Zhou L, et al.
Abstract
BACKGRUND:Bronchial thermoplasty regulates structural abnormalities involved in airway narrowing in asthma. In the present study we aimed to investigate the effect of bronchial thermoplasty on histopathological bronchial structures in distinct asthma endotypes/phenotypes.
METHODS:Endobronchial biopsies (n=450) were collected from 30 patients with severe uncontrolled asthma before bronchial thermoplasty and after 3 sequential bronchial thermoplasties. Patients were classified based on blood eosinophils, atopy, allergy and smoke exposure. Tissue sections were assessed for histopathological parameters and expression of heat-shock proteins and glucocorticoid receptor. Proliferating cells were determined by Ki67-staining.
RESULTS:In all patients, bronchial thermoplasty improved asthma control (p<0.001), reduced airway smooth muscle (p=0.014) and increased proliferative (Ki67+) epithelial cells (p=0.014). After bronchial thermoplasty, airway smooth muscle decreased predominantly in patients with T2 high asthma endotype. Epithelial cell proliferation was increased after bronchial thermoplasty in patients with low blood eosinophils (p=0.016), patients with no allergy (p=0.028) and patients without smoke exposure (p=0.034). In all patients, bronchial thermoplasty increased the expression of glucocorticoid receptor in epithelial cells (p=0.018) and subepithelial mesenchymal cells (p=0.033) and the translocation of glucocorticoid receptor in the nucleus (p=0.036). Furthermore, bronchial thermoplasty increased the expression of heat shock protein-70 (p=0.002) and heat shock protein-90 (p=0.001) in epithelial cells and decreased the expression of heat shock protein-70 (p=0.009) and heat shock protein-90 (p=0.002) in subepithelial mesenchymal cells. The effect of bronchial thermoplasty on the expression of heat shock proteins -70 and -90 was distinctive across different asthma endotypes/phenotypes.
Conclusions:Bronchial thermoplasty leads to a diminishment of airway smooth muscle, to epithelial cell regeneration, increased expression and activation of glucocorticoid receptor in the airways and increased expression of heat shock proteins in the epithelium. Histopathological effects appear to be distinct in different endotypes/phenotypes indicating that the beneficial effects of bronchial thermoplasty are achieved by diverse molecular targets associated with asthma endotypes/phenotypes.
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