Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, 21224, USA.
Department of Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Respir Res. 2024 Apr 20;25(1):174. doi: 10.1186/s12931-024-02790-6.
Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) represents a complex condition characterized by shared clinical and pathophysiological features of asthma and COPD in older individuals. However, the pathophysiology of ACO remains unexplored. We aimed to identify the major inflammatory cells in ACO, examine senescence within these cells, and elucidate the genes responsible for regulating senescence.
Bioinformatic analyses were performed to investigate major cell types and cellular senescence signatures in a public single-cell RNA sequencing (scRNA-Seq) dataset derived from the lung tissues of patients with ACO. Similar analyses were carried out in an independent cohort study Immune Mechanisms Severe Asthma (IMSA), which included bulk RNA-Seq and CyTOF data from bronchoalveolar lavage fluid (BALF) samples.
The analysis of the scRNA-Seq data revealed that monocytes/ macrophages were the predominant cell type in the lung tissues of ACO patients, constituting more than 50% of the cells analyzed. Lung monocytes/macrophages from patients with ACO exhibited a lower prevalence of senescence as defined by lower enrichment scores of SenMayo and expression levels of cellular senescence markers. Intriguingly, analysis of the IMSA dataset showed similar results in patients with severe asthma. They also exhibited a lower prevalence of senescence, particularly in airway CD206 + macrophages, along with increased cytokine expression (e.g., IL-4, IL-13, and IL-22). Further exploration identified alveolar macrophages as a major subtype of monocytes/macrophages driving cellular senescence in ACO. Differentially expressed genes related to oxidation-reduction, cytokines, and growth factors were implicated in regulating senescence in alveolar macrophages. PPARγ (Peroxisome Proliferator-Activated Receptor Gamma) emerged as one of the predominant regulators modulating the senescent signature of alveolar macrophages in ACO.
The findings suggest that senescence in macrophages, particularly alveolar macrophages, plays a crucial role in the pathophysiology of ACO. Furthermore, PPARγ may represent a potential therapeutic target for interventions aimed at modulating senescence-associated processes in ACO.Key words ACO, Asthma, COPD, Macrophages, Senescence, PPARγ.
哮喘-慢性阻塞性肺疾病（COPD）重叠（ACO）代表一种复杂的病症，其特征是老年人中哮喘和 COPD 的临床和病理生理学特征共同存在。然而，ACO 的病理生理学仍未得到探索。我们旨在确定 ACO 中的主要炎症细胞，检查这些细胞中的衰老，并阐明调节衰老的基因。
我们进行了生物信息学分析，以研究来自 ACO 患者肺部组织的公共单细胞 RNA 测序（scRNA-Seq）数据集的主要细胞类型和细胞衰老特征。在独立的免疫机制严重哮喘（IMSA）队列研究中进行了类似的分析，该研究包括来自支气管肺泡灌洗液（BALF）样本的批量 RNA-Seq 和 CyTOF 数据。
scRNA-Seq 数据分析显示，单核细胞/巨噬细胞是 ACO 患者肺部组织中的主要细胞类型，占分析细胞的 50%以上。ACO 患者的肺单核细胞/巨噬细胞的衰老程度较低，根据 SenMayo 的富集评分和细胞衰老标志物的表达水平来定义。有趣的是，IMSA 数据集的分析在严重哮喘患者中也显示出类似的结果。他们的衰老程度也较低，特别是在气道 CD206+巨噬细胞中，同时细胞因子表达增加（例如，IL-4、IL-13 和 IL-22）。进一步的探索确定肺泡巨噬细胞是驱动 ACO 中细胞衰老的单核细胞/巨噬细胞的主要亚型。与氧化还原、细胞因子和生长因子相关的差异表达基因被认为参与调节肺泡巨噬细胞的衰老。过氧化物酶体增殖物激活受体γ（PPARγ）是调节 ACO 中肺泡巨噬细胞衰老特征的主要调节因子之一。
这些发现表明，巨噬细胞，特别是肺泡巨噬细胞的衰老在 ACO 的病理生理学中起着关键作用。此外，PPARγ 可能代表一种有潜力的治疗靶点，可用于干预 ACO 中与衰老相关的过程。关键词：ACO、哮喘、COPD、巨噬细胞、衰老、PPARγ。
