严重哮喘中细胞衰老通路的临床特征
2026/07/31
摘要
背景 ：哮喘严重程度随年龄增长而增加，提示可能存在加速的生物学衰老。我们假设细胞衰老通路（如衰老相关分泌表型（SASP）和p53-细胞衰老通路）在重症哮喘患者的气道中富集。
方法：我们利用U-BIOPRED队列的转录组数据，通过基因集变异分析评估不同气道分区中p53和SASP通路的富集评分（ES）。支气管活检中的发现在独立NOVA队列中得到验证。我们检验了衰老ES与临床参数及其他哮喘相关基因特征之间的关联，并探索了SASP基因集的功能聚类。
结果：在U-BIOPRED队列中，与轻中度哮喘患者和健康志愿者相比，重症哮喘患者支气管活检中的p53和SASP ES显著升高，且SASP富集在NOVA队列中得到验证。在支气管活检中，较高的衰老ES与频繁急性发作、口服糖皮质激素使用、合并鼻息肉及较低的FEV1%预测值相关。其他气道样本中未发现按哮喘严重程度分组的显著富集。在鼻刷样本中，合并鼻息肉参与者的SASP ES显著更高。一个与肺损伤和修复相关的独特SASP功能聚类（聚类2）与临床严重程度和鼻息肉密切相关。衰老特征与氧化磷酸化和巨噬细胞活化特征呈正相关，但与嗜酸性粒细胞特征无关。
结论：细胞衰老通路在重症哮喘支气管组织中富集，并与疾病严重程度、气道重塑和鼻息肉相关。这些发现值得进一步研究其治疗意义。
Clinical Features of Cellular Senescence Pathways in Severe Asthma
Song WJ, Kermani NZ, Versi A, Guo Y, Sanchez-Ovando S, Simpson JL, Wark PA, Baines KJ, Dahlén SE, Adcock IM, Chung KF, et al.
Abstract
BACKGROUND:
Asthma severity increases with age, suggesting a role for accelerated biological ageing. We hypothesised that cellular senescence pathways such as the senescence- associated secretory pathway (SASP) and the p53- cellular senescence pathway are enriched in the airways of patients with severe asthma.
METHODS:
We utilised transcriptomic data from the U- BIOPRED cohort to analyse enrichment scores (ES) of p53 and SASP pathways in different airway compartments using gene set variation analysis. Findings in bronchial biopsies were validated in the independent NOVA cohort. We examined associations between senescence ES, clinical parameters and other asthma- related gene signatures. Functional clusters of the SASP gene set were also explored.
RESULTS:
In the U- BIOPRED cohort, p53 and SASP ES were significantly elevated in bronchial biopsies of severe asthmatics compared to mild- to- moderate asthmatics and healthy volunteers, with SASP enrichment validated in the NOVA cohort. In bronchial biopsies, higher senescence ES correlated with frequent exacerbations, oral corticosteroid use, comorbid nasal polyps and lower FEV1%. No significant enrichment was found in other airway samples according to asthma severity. In nasal brushings, SASP ES was significantly higher in participants with comorbid nasal polyps. A distinct SASP functional cluster related to lung injury and repair (Cluster 2) was strongly associated with clinical severity and nasal polyps. Senescence signatures correlated positively with oxidative phosphorylation and macrophage activation signatures, but not with eosinophil signatures.
CONCLUSIONS:
Cellular senescence pathways are enriched in severe asthmatic bronchial tissues and correlate with disease severity, remodelling and nasal polyps. These findings warrant further investigation into their therapeutic implications.
背景 ：哮喘严重程度随年龄增长而增加，提示可能存在加速的生物学衰老。我们假设细胞衰老通路（如衰老相关分泌表型（SASP）和p53-细胞衰老通路）在重症哮喘患者的气道中富集。
方法：我们利用U-BIOPRED队列的转录组数据，通过基因集变异分析评估不同气道分区中p53和SASP通路的富集评分（ES）。支气管活检中的发现在独立NOVA队列中得到验证。我们检验了衰老ES与临床参数及其他哮喘相关基因特征之间的关联，并探索了SASP基因集的功能聚类。
结果：在U-BIOPRED队列中，与轻中度哮喘患者和健康志愿者相比，重症哮喘患者支气管活检中的p53和SASP ES显著升高，且SASP富集在NOVA队列中得到验证。在支气管活检中，较高的衰老ES与频繁急性发作、口服糖皮质激素使用、合并鼻息肉及较低的FEV1%预测值相关。其他气道样本中未发现按哮喘严重程度分组的显著富集。在鼻刷样本中，合并鼻息肉参与者的SASP ES显著更高。一个与肺损伤和修复相关的独特SASP功能聚类（聚类2）与临床严重程度和鼻息肉密切相关。衰老特征与氧化磷酸化和巨噬细胞活化特征呈正相关，但与嗜酸性粒细胞特征无关。
结论：细胞衰老通路在重症哮喘支气管组织中富集，并与疾病严重程度、气道重塑和鼻息肉相关。这些发现值得进一步研究其治疗意义。
（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）
（Allergy. 2026.DOI: 10.1111/all.70416）
（Allergy. 2026.DOI: 10.1111/all.70416）
Clinical Features of Cellular Senescence Pathways in Severe Asthma
Song WJ, Kermani NZ, Versi A, Guo Y, Sanchez-Ovando S, Simpson JL, Wark PA, Baines KJ, Dahlén SE, Adcock IM, Chung KF, et al.
Abstract
BACKGROUND:
Asthma severity increases with age, suggesting a role for accelerated biological ageing. We hypothesised that cellular senescence pathways such as the senescence- associated secretory pathway (SASP) and the p53- cellular senescence pathway are enriched in the airways of patients with severe asthma.
METHODS:
We utilised transcriptomic data from the U- BIOPRED cohort to analyse enrichment scores (ES) of p53 and SASP pathways in different airway compartments using gene set variation analysis. Findings in bronchial biopsies were validated in the independent NOVA cohort. We examined associations between senescence ES, clinical parameters and other asthma- related gene signatures. Functional clusters of the SASP gene set were also explored.
RESULTS:
In the U- BIOPRED cohort, p53 and SASP ES were significantly elevated in bronchial biopsies of severe asthmatics compared to mild- to- moderate asthmatics and healthy volunteers, with SASP enrichment validated in the NOVA cohort. In bronchial biopsies, higher senescence ES correlated with frequent exacerbations, oral corticosteroid use, comorbid nasal polyps and lower FEV1%. No significant enrichment was found in other airway samples according to asthma severity. In nasal brushings, SASP ES was significantly higher in participants with comorbid nasal polyps. A distinct SASP functional cluster related to lung injury and repair (Cluster 2) was strongly associated with clinical severity and nasal polyps. Senescence signatures correlated positively with oxidative phosphorylation and macrophage activation signatures, but not with eosinophil signatures.
CONCLUSIONS:
Cellular senescence pathways are enriched in severe asthmatic bronchial tissues and correlate with disease severity, remodelling and nasal polyps. These findings warrant further investigation into their therapeutic implications.
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