哮喘患者气道高水平TSLP与2型炎症、黏液栓形成及气道重塑密切相关：UCSF与SARP-3队列分析
2025/12/29
摘要
背景：靶向干预胸腺基质淋巴细胞生成素（TSLP）可改善哮喘患者疾病控制水平，然而气道TSLP水平与哮喘患者临床特征和免疫学表型间的关系仍待阐明。
目的：探讨哮喘患者气道TSLP水平与疾病控制及气道重塑的相关性。
方法：共纳入137名轻中度哮喘患者（来自加州大学旧金山分校队列，UCSF）、397名中重度哮喘患者（来自重度哮喘研究项目SARP-3 队列）及95名健康对照人群，检测痰液TSLP蛋白水平，并分析其与肺功能指标、哮喘急性发作、气道炎症及基于肺部CT评估的黏液栓评分、空气潴留和气道重塑之间的关联。
结果：健康对照人群痰TSLP第95百分位上限值浓度为1.6 pg/ml，UCSF队列和SAPR-3队列中分别有16%和33.5%患者TSLP水平超过该阈值。TSLP水平升高主要见于具有典型2型炎症临床特征的重度哮喘患者。亚组分析显示高TSLP水平与嗜酸性炎症及2型免疫反应基因表达谱显著相关，而与1型免疫反应基因表达谱无显著关联。此外，痰TSLP高水平也与痰MUC5AC高表达、CT影像高黏液栓评分、空气潴留及气道重塑指标显著相关。
结论：哮喘患者气道TSLP水平升高与疾病严重程度、以2型免疫炎症表型、黏液栓形成、空气潴留及气道重塑密切相关。
临床意义：部分重度哮喘患者在接受高剂量糖皮质激素治疗后仍呈现气道TSLP升高，其气道炎症以2型免疫反应为主，这为应用抗TSLP或其他靶向2型炎症的生物制剂提供了理论依据。
关键词：TSLP；黏液栓；胸腺基质淋巴细胞生成素；2型免疫反应
Abstract
Background: Inhibition of thymic stromal lymphopoietin (TSLP) improves asthma control but the relationships between airway TSLP levels and clinical and immunologic features of asthma are unclear.
Objective: To determine associations between airway TSLP, disease control, and airway remodeling in asthma.
Methods: We measured TSLP protein in sputum from mild-moderate asthma patients (University of California San Francisco cohort, n=137), moderate-severe patients (Severe Asthma Research Program-3 cohort, n=397), and healthy controls (n=95). We explored how sputum TSLP levels relate to measures of lung function and exacerbations, airway inflammation, and lung image-based measures of mucus plugging and airway remodeling.
Results: The upper 95th centile value for sputum TSLP concentration in health was 1.6 pg/mL, and 16% of the UCSF cohort and 33.5% of the SARP cohort had TSLP concentrations above this value. High sputum TSLP levels occurred most often in severe asthma patients showing clinical traits typical of type 2 inflammation. There was considerable overlap between subgroups who were high for TSLP and high for eosinophilic inflammation. High sputum TSLP levels were associated with a strong sputum cell gene expression profile for type 2 immune responses and a weak expression for type 1 responses. High sputum TSLP levels were also associated with high sputum MUC5AC expression, and high scores for mucus plugging, air trapping and other measures of airway remodeling on CT lung scans.
Conclusion: High levels of airway TSLP in asthma are associated with more severe asthma, predominantly type 2 airway immune responses, and with mucus plugging, air trapping and airway remodeling.
Clinical implication: High airway TSLP levels occur in severe asthma patients with a type 2-high endotype despite treatment with corticosteroids, providing rationale for treatment with anti-TSLP or other type 2 directed biologics.
Capsule summary: A subset of asthma patients with severe disease has high airway TSLP levels despite high-dose inhaled corticosteroids, and these patients have predominant airway type 2 immune responses, increased mucus plugging, air trapping, and airway remodeling.
Keywords: TSLP; mucus plugging; thymic stromal lymphopoietin; type 2 immune responses.
背景：靶向干预胸腺基质淋巴细胞生成素（TSLP）可改善哮喘患者疾病控制水平，然而气道TSLP水平与哮喘患者临床特征和免疫学表型间的关系仍待阐明。
目的：探讨哮喘患者气道TSLP水平与疾病控制及气道重塑的相关性。
方法：共纳入137名轻中度哮喘患者（来自加州大学旧金山分校队列，UCSF）、397名中重度哮喘患者（来自重度哮喘研究项目SARP-3 队列）及95名健康对照人群，检测痰液TSLP蛋白水平，并分析其与肺功能指标、哮喘急性发作、气道炎症及基于肺部CT评估的黏液栓评分、空气潴留和气道重塑之间的关联。
结果：健康对照人群痰TSLP第95百分位上限值浓度为1.6 pg/ml，UCSF队列和SAPR-3队列中分别有16%和33.5%患者TSLP水平超过该阈值。TSLP水平升高主要见于具有典型2型炎症临床特征的重度哮喘患者。亚组分析显示高TSLP水平与嗜酸性炎症及2型免疫反应基因表达谱显著相关，而与1型免疫反应基因表达谱无显著关联。此外，痰TSLP高水平也与痰MUC5AC高表达、CT影像高黏液栓评分、空气潴留及气道重塑指标显著相关。
结论：哮喘患者气道TSLP水平升高与疾病严重程度、以2型免疫炎症表型、黏液栓形成、空气潴留及气道重塑密切相关。
临床意义：部分重度哮喘患者在接受高剂量糖皮质激素治疗后仍呈现气道TSLP升高，其气道炎症以2型免疫反应为主，这为应用抗TSLP或其他靶向2型炎症的生物制剂提供了理论依据。
关键词：TSLP；黏液栓；胸腺基质淋巴细胞生成素；2型免疫反应
（南方医科大学南方医院 倪钰 陈颖 赵海金）
（Kritika Khanna , Monica Tang et al. High airway TSLP in asthma associates with type 2 inflammation, mucus plugging and airway remodeling. J Allergy Clin Immunol. 2025 Dec 13:S0091-6749(25)02175-X. doi: 10.1016/j.jaci.2025.11.014.）
（Kritika Khanna , Monica Tang et al. High airway TSLP in asthma associates with type 2 inflammation, mucus plugging and airway remodeling. J Allergy Clin Immunol. 2025 Dec 13:S0091-6749(25)02175-X. doi: 10.1016/j.jaci.2025.11.014.）
Abstract
Background: Inhibition of thymic stromal lymphopoietin (TSLP) improves asthma control but the relationships between airway TSLP levels and clinical and immunologic features of asthma are unclear.
Objective: To determine associations between airway TSLP, disease control, and airway remodeling in asthma.
Methods: We measured TSLP protein in sputum from mild-moderate asthma patients (University of California San Francisco cohort, n=137), moderate-severe patients (Severe Asthma Research Program-3 cohort, n=397), and healthy controls (n=95). We explored how sputum TSLP levels relate to measures of lung function and exacerbations, airway inflammation, and lung image-based measures of mucus plugging and airway remodeling.
Results: The upper 95th centile value for sputum TSLP concentration in health was 1.6 pg/mL, and 16% of the UCSF cohort and 33.5% of the SARP cohort had TSLP concentrations above this value. High sputum TSLP levels occurred most often in severe asthma patients showing clinical traits typical of type 2 inflammation. There was considerable overlap between subgroups who were high for TSLP and high for eosinophilic inflammation. High sputum TSLP levels were associated with a strong sputum cell gene expression profile for type 2 immune responses and a weak expression for type 1 responses. High sputum TSLP levels were also associated with high sputum MUC5AC expression, and high scores for mucus plugging, air trapping and other measures of airway remodeling on CT lung scans.
Conclusion: High levels of airway TSLP in asthma are associated with more severe asthma, predominantly type 2 airway immune responses, and with mucus plugging, air trapping and airway remodeling.
Clinical implication: High airway TSLP levels occur in severe asthma patients with a type 2-high endotype despite treatment with corticosteroids, providing rationale for treatment with anti-TSLP or other type 2 directed biologics.
Capsule summary: A subset of asthma patients with severe disease has high airway TSLP levels despite high-dose inhaled corticosteroids, and these patients have predominant airway type 2 immune responses, increased mucus plugging, air trapping, and airway remodeling.
Keywords: TSLP; mucus plugging; thymic stromal lymphopoietin; type 2 immune responses.
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靶向谷氨酰胺代谢抑制嗜酸性粒细胞扩增与活化：过敏性气道炎症治疗新策略
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