Department of Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Department of Critical Care Medicine, The First Affiliated Hospital, Ningbo University, Ningbo, Zhejiang, China.
Front Immunol. 2024 Apr 30;15:1382449. doi: 10.3389/fimmu.2024.1382449. eCollection 2024.
Acute Respiratory Distress Syndrome (ARDS) or its earlier stage Acute lung injury (ALI), is a worldwide health concern that jeopardizes human well-being. Currently, the treatment strategies to mitigate the incidence and mortality of ARDS are severely restricted. This limitation can be attributed, at least in part, to the substantial variations in immunity observed in individuals with this syndrome.
Bulk and single cell RNA sequencing from ALI mice and single cell RNA sequencing from ARDS patients were analyzed. We utilized the Seurat program package in R and cellmarker 2.0 to cluster and annotate the data. The differential, enrichment, protein interaction, and cell-cell communication analysis were conducted.
The mice with ALI caused by pulmonary and extrapulmonary factors demonstrated differential expression including Clec4e, Retnlg, S100a9, Coro1a, and Lars2. We have determined that inflammatory factors have a greater significance in extrapulmonary ALI, while multiple pathways collaborate in the development of pulmonary ALI. Clustering analysis revealed significant heterogeneity in the relative abundance of immune cells in different ALI models. The autocrine action of neutrophils plays a crucial role in pulmonary ALI. Additionally, there was a significant increase in signaling intensity between B cells and M1 macrophages, NKT cells and M1 macrophages in extrapulmonary ALI. The CXCL, CSF3 and MIF, TGFβ signaling pathways play a vital role in pulmonary and extrapulmonary ALI, respectively. Moreover, the analysis of human single-cell revealed DCs signaling to monocytes and neutrophils in COVID-19-associated ARDS is stronger compared to sepsis-related ARDS. In sepsis-related ARDS, CD8+ T and Th cells exhibit more prominent signaling to B-cell nucleated DCs. Meanwhile, both MIF and CXCL signaling pathways are specific to sepsis-related ARDS.
This study has identified specific gene signatures and signaling pathways in animal models and human samples that facilitate the interaction between immune cells, which could be targeted therapeutically in ARDS patients of various etiologies.
急性呼吸窘迫综合征（ARDS）或其早期阶段急性肺损伤（ALI）是一个全球性的健康问题，危及人类福祉。目前，减轻 ARDS 发病率和死亡率的治疗策略受到严重限制。这种限制至少部分归因于该综合征个体中观察到的免疫差异很大。
分析了 ALI 小鼠的 bulk 和单细胞 RNA 测序以及 ARDS 患者的单细胞 RNA 测序。我们使用 R 中的 Seurat 程序包和 cellmarker 2.0 对数据进行聚类和注释。进行了差异表达、富集、蛋白质相互作用和细胞间通讯分析。
由肺外因素引起的 ALI 小鼠表现出差异表达，包括 Clec4e、Retnlg、S100a9、Coro1a 和 Lars2。我们已经确定炎症因子在外肺性 ALI 中更为重要，而多个途径共同参与肺性 ALI 的发展。聚类分析显示不同 ALI 模型中免疫细胞相对丰度存在显著异质性。中性粒细胞的自分泌作用在肺性 ALI 中起关键作用。此外，在外肺性 ALI 中，B 细胞和 M1 巨噬细胞、NKT 细胞和 M1 巨噬细胞之间的信号强度显著增加。CXCL、CSF3 和 MIF、TGFβ 信号通路分别在肺性和肺外性 ALI 中发挥重要作用。此外，对人类单细胞的分析表明，COVID-19 相关 ARDS 中 DC 向单核细胞和中性粒细胞的信号传递强于脓毒症相关 ARDS。在脓毒症相关 ARDS 中，CD8+T 和 Th 细胞向 B 细胞有核 DC 的信号传递更为显著。同时，MIF 和 CXCL 信号通路均为脓毒症相关 ARDS 所特有。
本研究在动物模型和人类样本中鉴定了特定的基因特征和信号通路，促进了免疫细胞之间的相互作用，这可能为不同病因的 ARDS 患者提供治疗靶点。
