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Updated: Jul 20, 2025
Bronchoalveolar Lavage Exosomes in Lipopolysaccharide-induced Septic Lung Injury
Published on: May 21, 2018
Prognostic implication of downregulated exosomal miRNAs in patients with sepsis: a cross-sectional study with
Beomsu Shin1, Jin Young Lee2, Yunjoo Im2
1Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Republic of Korea.
Background:
Despite the understanding of sepsis-induced extracellular vesicles (EVs), such as exosomes, and their role in intercellular communication during sepsis, little is known about EV contents such as microRNA (miRNA), which modulate important cellular processes contributing to sepsis in body fluids. This study aimed to analyze the differential expression of exosomal miRNAs in plasma samples collected from sepsis patients and healthy controls, and to identify potential miRNA regulatory pathways contributing to sepsis pathogenesis.
Methods:
Quantitative real-time PCR-based microarrays were used to profile plasma exosomal miRNA expression levels in 135 patients with sepsis and 11 healthy controls from an ongoing prospective registry of critically ill adult patients admitted to the intensive care unit. The identified exosomal miRNAs were tested in an external validation cohort (35 sepsis patients and 10 healthy controls). And then, functional enrichment analyses of gene ontology, KEGG pathway analysis, and protein-protein interaction network and cluster analyses were performed based on the potential target genes of the grouped miRNAs. Finally, to evaluate the performance of the identified exosomal miRNAs in predicting in-hospital and 90-day mortalities of sepsis patients, receiver operating characteristic curve (ROC) and Kaplan-Meier analyses were performed.
Results:
Compared with healthy controls, plasma exosomes from sepsis patients showed significant changes in 25 miRNAs; eight miRNAs were upregulated and 17 downregulated. Additionally, the levels of hsa-let-7f-5p, miR-331-3p miR-301a-3p, and miR-335-5p were significantly lower in sepsis patients than in healthy controls (p < 0.0001). These four miRNAs were confirmed in an external validation cohort. In addition, the most common pathway for these four miRNAs were PI3K-Akt and mitogen-activated protein kinase (MAPK) signaling pathways based on the KEGG analysis. The area under the ROC of hsa-let-7f-5p, miR-331-3p, miR-301a-3p, and miR-335-5p level for in-hospital mortality was 0.913, 0.931, 0.929, and 0.957, respectively (p < 0.001), as confirmed in an external validation cohort. Also, the Kaplan-Meier analysis showed a significant difference in 90-day mortality between sepsis patients with high and low miR-335-5p, miR-301a-3p, hsa-let-7f-5p, and miR-331-3p levels (p < 0.001, log-rank test).
Conclusion:
Among the differentially-expressed miRNAs detected in microarrays, the top four downregulated exosomal miRNAs (hsa-let-7f-5p, miR-331-3p miR-301a-3p, and miR-335-5p) were identified as independent prognostic factors for in-hospital and 90-day mortalities among sepsis patients. Bioinformatics analysis demonstrated that these four microRNAs might provide a significant contribution to sepsis pathogenesis through PI3K-Akt and MAPK signaling pathway.
Insights
This study identified four specific exosomal microRNAs (miRNAs) that are significantly downregulated in sepsis patients. These miRNAs are promising biomarkers for predicting sepsis-related mortality and may play a role in disease pathogenesis.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Extracellular vesicles (EVs), including exosomes, are crucial for intercellular communication in sepsis.
- MicroRNAs (miRNAs) within EVs modulate cellular processes, but their role in sepsis pathogenesis remains underexplored.
- This study investigates exosomal miRNA profiles in sepsis patients' plasma.
Purpose of the Study:
- To analyze differential expression of exosomal miRNAs in sepsis patients compared to healthy controls.
- To identify potential miRNA regulatory pathways involved in sepsis pathogenesis.
- To evaluate the prognostic value of identified exosomal miRNAs for sepsis mortality.
Main Methods:
- Plasma exosomal miRNA expression was profiled using quantitative real-time PCR-based microarrays in 135 sepsis patients and 11 controls.
- Differential expression analysis identified 25 miRNAs, with four specific miRNAs (hsa-let-7f-5p, miR-331-3p, miR-301a-3p, miR-335-5p) being significantly downregulated in sepsis.
- Functional enrichment analyses (GO, KEGG, PPI) and survival analyses (ROC, Kaplan-Meier) were performed.
Main Results:
- Twenty-five differentially expressed miRNAs were found, with 17 downregulated and 8 upregulated in sepsis patients.
- Four specific miRNAs (hsa-let-7f-5p, miR-331-3p, miR-301a-3p, miR-335-5p) were significantly downregulated and validated in an external cohort.
- These miRNAs are associated with PI3K-Akt and MAPK signaling pathways and show high accuracy in predicting in-hospital and 90-day mortality.
Conclusions:
- The four downregulated exosomal miRNAs (hsa-let-7f-5p, miR-331-3p, miR-301a-3p, miR-335-5p) are independent prognostic factors for sepsis mortality.
- These miRNAs may contribute to sepsis pathogenesis via PI3K-Akt and MAPK signaling pathways.
- Exosomal miRNAs represent potential diagnostic and prognostic biomarkers for sepsis.
