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Background and purpose <p>acute respiratory distress syndrome (ARDS) is a severe pulmonary condition characterized by alveolar-capillary damage and refractory hypoxemia. Alveolar macrophages (AMs) play a crucial role in regulating inflammation and repair processes during acute lung injury (ALI)/ARDS. However, the transcriptional and functional changes in AMs during ALI/ARDS remain poorly understood, especially when considering species-specific differences between murine models and human pathophysiology. This study aims to elucidate these changes in AMs during ALI/ARDS by integrating in vitro and cross-species transcriptomic analyses.</p> Methods <p>We conducted RNA sequencing on LPS-stimulated MH-S cells and integrated the data with publicly available murine (GSE225406) and human (GSE40885) AM datasets to identify conserved differentially expressed genes (DEGs). Functional enrichment analysis and protein-protein interaction (PPI) network analysis were performed to explore the underlying mechanisms. Core genes were identified and validated using qRT-PCR, Western blot, immunohistochemical staining, and immunofluorescence staining. Additionally, we analyzed the diagnostic potential of these core genes using clinical datasets (GSE121871 and GSE243066).</p> Results <p>We identified 45 conserved upregulated genes and 4 downregulated genes across species, highlighting core transcriptional regulators of LPS-induced Macrophage activation. Functional enrichment analysis revealed significant involvement of immune-inflammatory pathways. PPI network analysis identified 10 core genes potentially central to AM-mediated ALI/ARDS pathogenesis. Experimental validation confirmed the upregulation of key genes and demonstrated that LPS treatment significantly impaired the efferocytosis capacity of AMs with dysregulated expression of stabilin-2, suggesting a potential association with this functional defect. Furthermore, the core gene set showed diagnostic potential in ARDS patient samples (AUC = 0.86).</p> Conclusion <p>This analysis identifies cross-species conserved core genes and inflammatory pathways in AMs during ALI/ARDS. Our findings provide insights into AM-mediated inflammatory mechanisms and highlight candidate genes for further functional studies to explore their potential as therapeutic targets.</p>

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Integrative transcriptomic analysis reveals cross-species conserved core genes and pathways in alveolar macrophages during ALI/ARDS

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月2日

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  • Aguo Li,
  • Kenqi Zhang,
  • Hongyan Wang,
  • Jianhua Li,
  • Yeping Yao,
  • Yong-Sheng Tu

摘要

Background and purpose

acute respiratory distress syndrome (ARDS) is a severe pulmonary condition characterized by alveolar-capillary damage and refractory hypoxemia. Alveolar macrophages (AMs) play a crucial role in regulating inflammation and repair processes during acute lung injury (ALI)/ARDS. However, the transcriptional and functional changes in AMs during ALI/ARDS remain poorly understood, especially when considering species-specific differences between murine models and human pathophysiology. This study aims to elucidate these changes in AMs during ALI/ARDS by integrating in vitro and cross-species transcriptomic analyses.

Methods

We conducted RNA sequencing on LPS-stimulated MH-S cells and integrated the data with publicly available murine (GSE225406) and human (GSE40885) AM datasets to identify conserved differentially expressed genes (DEGs). Functional enrichment analysis and protein-protein interaction (PPI) network analysis were performed to explore the underlying mechanisms. Core genes were identified and validated using qRT-PCR, Western blot, immunohistochemical staining, and immunofluorescence staining. Additionally, we analyzed the diagnostic potential of these core genes using clinical datasets (GSE121871 and GSE243066).

Results

We identified 45 conserved upregulated genes and 4 downregulated genes across species, highlighting core transcriptional regulators of LPS-induced Macrophage activation. Functional enrichment analysis revealed significant involvement of immune-inflammatory pathways. PPI network analysis identified 10 core genes potentially central to AM-mediated ALI/ARDS pathogenesis. Experimental validation confirmed the upregulation of key genes and demonstrated that LPS treatment significantly impaired the efferocytosis capacity of AMs with dysregulated expression of stabilin-2, suggesting a potential association with this functional defect. Furthermore, the core gene set showed diagnostic potential in ARDS patient samples (AUC = 0.86).

Conclusion

This analysis identifies cross-species conserved core genes and inflammatory pathways in AMs during ALI/ARDS. Our findings provide insights into AM-mediated inflammatory mechanisms and highlight candidate genes for further functional studies to explore their potential as therapeutic targets.