综合多组学分析揭示了急性高原病中与炎症相关的分子网络
Integrative multi-omics analysis reveals inflammation-related molecular networks in acute mountain sickness.
摘要(中文译文)
高原脑水肿（HACE）是快速进入高海拔地区后发生的一种危及生命的疾病，急性高山病（AMS）是其关键前驱阶段。越来越多的证据表明炎症参与其发病机制，但分子调控网络仍不清楚。我们整合了批量RNA测序（GSE75665）、非编码RNA测序（GSE90500）和单细胞RNA测序数据集，以探索AMS中炎症相关机制。鉴定差异表达基因（DEGs），并采用基因本体论（GO）、京都基因与基因组百科全书（KEGG）和基因集富集分析（GSEA）进行分析。构建了蛋白质-蛋白质相互作用、miRNA-mRNA、转录因子和药物-基因网络。单细胞和去卷积分析确定了细胞类型特异性表达和免疫组成。建立低压低氧诱导的HACE小鼠模型进行实验验证，以评估肝素结合EGF样生长因子（HBEGF）表达及相关神经炎症和病理变化。我们鉴定了323个DEGs，包括5个炎症相关基因，这些基因在AMS中均下调，并富集于上皮细胞生长、迁移和ErbB信号通路。预测hsa-miR-375调控多个关键基因，药物基因分析提示HBEGF为潜在治疗靶点。单细胞数据显示单核细胞是关键基因表达的主要来源，且AMS中CD4单核细胞增加。在HACE小鼠中，HBEGF表达显著降低，而腺相关病毒（AAV）介导的HBEGF过表达减轻了脑水肿、血脑屏障破坏、神经元损伤和促炎细胞因子释放。这项整合多组学研究确定单核细胞介导的炎症和ErbB通路是HACE的关键机制。HBEGF有望成为预防高海拔条件下神经炎症和脑损伤的治疗靶点。
Abstract
High-altitude cerebral edema (HACE) is a life-threatening condition following rapid ascent to high altitude, with acute mountain sickness (AMS) as a key precursor. Increasing evidence implicates inflammation in its pathogenesis, yet the molecular regulatory networks remain unclear. We integrated bulk RNA-seq (GSE75665), non-coding RNA-seq (GSE90500), and single-cell RNA-seq datasets to explore inflammation-related mechanisms in AMS. Differentially expressed genes (DEGs) were identified and analyzed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). Protein-protein interaction, miRNA-mRNA, transcription factor, and drug-gene networks were constructed. Single-cell and deconvolution analyses determined cell-type-specific expression and immune composition. A hypobaric hypoxia-induced HACE mouse model was established for experimental validation to assess heparin-binding EGF-like growth factor (HBEGF) expression and associated neuroinflammatory and pathological changes. We identified 323 DEGs, including five 5 inflammation-related genes, all downregulated in AMS and enriched in epithelial cell growth, migration, and the ErbB signaling pathway. hsa-miR-375 was predicted to regulate multiple key genes, and drug gene analysis highlighted HBEGF as a potential therapeutic target. Single-cell data revealed monocytes as the major source of key gene expression and increased CD4 monocytes in AMS. , HBEGF expression was significantly reduced in HACE mice, while Adeno-associated virus (AAV)-mediated HBEGF overexpression mitigated cerebral edema, blood-brain barrier disruption, neuronal injury, and proinflammatory cytokine release. This integrative multi-omics study identifies monocyte-mediated inflammation and the ErbB pathway as critical mechanisms in HACE. HBEGF emerges as a promising therapeutic target for preventing neuroinflammation and cerebral injury in high-altitude conditions.
如何引用
AMA
Zhicheng Xiang, Haifeng Ma, Dahai Cao, Fei Zhang, Chunqing Yang, Taijian Cao, et al. Integrative multi-omics analysis reveals inflammation-related molecular networks in acute mountain sickness.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1745433.
APA
Zhicheng Xiang, Haifeng Ma, Dahai Cao, Fei Zhang, Chunqing Yang, Taijian Cao, et al (2026). Integrative multi-omics analysis reveals inflammation-related molecular networks in acute mountain sickness.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1745433
GB/T 7714
Zhicheng Xiang, Haifeng Ma, Dahai Cao, Fei Zhang, Chunqing Yang, Taijian Cao, et al. Integrative multi-omics analysis reveals inflammation-related molecular networks in acute mountain sickness.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1745433.
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