{"title":"免疫失调和中枢基因鉴定在非肺败血症诱导的急性肺损伤：来自转录组学和实验分析的见解。","authors":"Chen Yan, Wen Li, Yang-Ming Cai, Wei-Yi Cai, Nian-Dan Hu, Yang-Yi-Yan Song, Wen-Qiang Li, Zhou Sun, Qing Geng","doi":"10.1007/s11596-025-00083-7","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>Sepsis-induced acute lung injury (ALI) poses a critical challenge in critical care, yet its immunoregulatory mechanisms remain poorly defined. This study aimed to delineate immune dysregulation networks and identify therapeutic targets through multiomics data integration.</p><p><strong>Methods: </strong>Transcriptomic datasets (GSE40180 and GSE165226) were analyzed through a multiphase bioinformatics workflow, including gene set enrichment analysis (GSEA), immune cell deconvolution (CIBERSORT), differential gene expression profiling (|log2FC|> 1.5, P.adj < 0.05), and pathway annotation (GO/KEGG). Protein-protein interaction (PPI) networks were constructed to identify hub genes. Experimental validation was done using a murine cecal ligation and puncture (CLP) model with histopathological lung injury scoring and RT-qPCR-based hub gene verification.</p><p><strong>Results: </strong>Integrated analysis revealed 26 consensus biological processes (24 upregulated, 2 downregulated) dominated by innate immune activation. CIBERSORT revealed significant infiltration of M1 macrophages, neutrophils, activated dendritic cells (DCs), and activated natural killer (NK) cells in septic lungs, which was concurrent with Th17/naive CD8+ T-cell dysregulation. Among the 58 differentially expressed genes (DEG), 7 hub genes (Cxcl1, Cxcl2, Ccl3, Cd14, Saa3, Timp1, and Socs3) were significantly correlated with immune cell dynamics. CLP modeling confirmed severe alveolar damage (lung injury score: 8.11 ± 1.17 vs. 1.97 ± 0.29; P < 0.0001) and upregulated hub gene expression (all P < 0.01) in septic lungs, with hub gene expression levels strongly correlated with the lung injury score (Pearson's r > 0.85, P < 0.001).</p><p><strong>Conclusion: </strong>Innate adaptive immune crosstalk, particularly dysregulated immune cell infiltration, drives sepsis-induced ALI pathogenesis. The 7 hub genes mechanistically connect immune dyshomeostasis to tissue injury, suggesting novel targets for precision immunomodulation and biomarker development in critical care.</p>","PeriodicalId":10820,"journal":{"name":"Current Medical Science","volume":" ","pages":""},"PeriodicalIF":2.0000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Immune Dysregulation and Hub Gene Identification in Non-Pulmonary Sepsis-Induced Acute Lung Injury: Insights from Transcriptomic and Experimental Analyses.\",\"authors\":\"Chen Yan, Wen Li, Yang-Ming Cai, Wei-Yi Cai, Nian-Dan Hu, Yang-Yi-Yan Song, Wen-Qiang Li, Zhou Sun, Qing Geng\",\"doi\":\"10.1007/s11596-025-00083-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>Sepsis-induced acute lung injury (ALI) poses a critical challenge in critical care, yet its immunoregulatory mechanisms remain poorly defined. This study aimed to delineate immune dysregulation networks and identify therapeutic targets through multiomics data integration.</p><p><strong>Methods: </strong>Transcriptomic datasets (GSE40180 and GSE165226) were analyzed through a multiphase bioinformatics workflow, including gene set enrichment analysis (GSEA), immune cell deconvolution (CIBERSORT), differential gene expression profiling (|log2FC|> 1.5, P.adj < 0.05), and pathway annotation (GO/KEGG). Protein-protein interaction (PPI) networks were constructed to identify hub genes. Experimental validation was done using a murine cecal ligation and puncture (CLP) model with histopathological lung injury scoring and RT-qPCR-based hub gene verification.</p><p><strong>Results: </strong>Integrated analysis revealed 26 consensus biological processes (24 upregulated, 2 downregulated) dominated by innate immune activation. CIBERSORT revealed significant infiltration of M1 macrophages, neutrophils, activated dendritic cells (DCs), and activated natural killer (NK) cells in septic lungs, which was concurrent with Th17/naive CD8+ T-cell dysregulation. Among the 58 differentially expressed genes (DEG), 7 hub genes (Cxcl1, Cxcl2, Ccl3, Cd14, Saa3, Timp1, and Socs3) were significantly correlated with immune cell dynamics. CLP modeling confirmed severe alveolar damage (lung injury score: 8.11 ± 1.17 vs. 1.97 ± 0.29; P < 0.0001) and upregulated hub gene expression (all P < 0.01) in septic lungs, with hub gene expression levels strongly correlated with the lung injury score (Pearson's r > 0.85, P < 0.001).</p><p><strong>Conclusion: </strong>Innate adaptive immune crosstalk, particularly dysregulated immune cell infiltration, drives sepsis-induced ALI pathogenesis. The 7 hub genes mechanistically connect immune dyshomeostasis to tissue injury, suggesting novel targets for precision immunomodulation and biomarker development in critical care.</p>\",\"PeriodicalId\":10820,\"journal\":{\"name\":\"Current Medical Science\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.0000,\"publicationDate\":\"2025-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Current Medical Science\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s11596-025-00083-7\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current Medical Science","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s11596-025-00083-7","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Immune Dysregulation and Hub Gene Identification in Non-Pulmonary Sepsis-Induced Acute Lung Injury: Insights from Transcriptomic and Experimental Analyses.
Objective: Sepsis-induced acute lung injury (ALI) poses a critical challenge in critical care, yet its immunoregulatory mechanisms remain poorly defined. This study aimed to delineate immune dysregulation networks and identify therapeutic targets through multiomics data integration.
Methods: Transcriptomic datasets (GSE40180 and GSE165226) were analyzed through a multiphase bioinformatics workflow, including gene set enrichment analysis (GSEA), immune cell deconvolution (CIBERSORT), differential gene expression profiling (|log2FC|> 1.5, P.adj < 0.05), and pathway annotation (GO/KEGG). Protein-protein interaction (PPI) networks were constructed to identify hub genes. Experimental validation was done using a murine cecal ligation and puncture (CLP) model with histopathological lung injury scoring and RT-qPCR-based hub gene verification.
Results: Integrated analysis revealed 26 consensus biological processes (24 upregulated, 2 downregulated) dominated by innate immune activation. CIBERSORT revealed significant infiltration of M1 macrophages, neutrophils, activated dendritic cells (DCs), and activated natural killer (NK) cells in septic lungs, which was concurrent with Th17/naive CD8+ T-cell dysregulation. Among the 58 differentially expressed genes (DEG), 7 hub genes (Cxcl1, Cxcl2, Ccl3, Cd14, Saa3, Timp1, and Socs3) were significantly correlated with immune cell dynamics. CLP modeling confirmed severe alveolar damage (lung injury score: 8.11 ± 1.17 vs. 1.97 ± 0.29; P < 0.0001) and upregulated hub gene expression (all P < 0.01) in septic lungs, with hub gene expression levels strongly correlated with the lung injury score (Pearson's r > 0.85, P < 0.001).
Conclusion: Innate adaptive immune crosstalk, particularly dysregulated immune cell infiltration, drives sepsis-induced ALI pathogenesis. The 7 hub genes mechanistically connect immune dyshomeostasis to tissue injury, suggesting novel targets for precision immunomodulation and biomarker development in critical care.
期刊介绍：
Current Medical Science provides a forum for peer-reviewed papers in the medical sciences, to promote academic exchange between Chinese researchers and doctors and their foreign counterparts. The journal covers the subjects of biomedicine such as physiology, biochemistry, molecular biology, pharmacology, pathology and pathophysiology, etc., and clinical research, such as surgery, internal medicine, obstetrics and gynecology, pediatrics and otorhinolaryngology etc. The articles appearing in Current Medical Science are mainly in English, with a very small number of its papers in German, to pay tribute to its German founder. This journal is the only medical periodical in Western languages sponsored by an educational institution located in the central part of China.
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