Endothelial dysfunction is a major contributor to multi-organ failure and mortality in sepsis, with the lungs being particularly susceptible to vascular leakage. Previous studies have implicated matrix metalloproteinase 8 (MMP8) in sepsis pathogenesis. However, the role of MMP8 in maintaining endothelial barrier integrity during sepsis remains unclear. This study aimed to investigate the role of MMP8 in sepsis-induced vascular leakage and the underlying mechanisms. A significant increase in MMP8 expression was observed in lipopolysaccharide (LPS)-treated endothelial cells and lung tissues from mice with cecum ligation and puncture-induced sepsis. In vitro, loss- or gain-of-function of MMP8 in endothelial cells modulated LPS- or Cytomix (TNF-α, IL-1β and IFN-γ)-induced endothelial hyperpermeability, without inducing cell apoptosis or affecting cell viability. In vivo, pharmacologic inhibition of MMP8 alleviated pulmonary vascular leakage, multi-organ injury, and mortality in septic mice. Mechanistically, MMP8 interacted with ERK, promoting its phosphorylation, and consequently activated calpains, leading to membrane VE-cadherin proteolysis. This induced VE-cadherin internalisation through clathrin- and caveolin 1-mediated endocytosis. Clinically, serum MMP8 levels were elevated in patients with sepsis, with the highest levels observed in those with pleural effusion. A nomogram incorporating albumin, blood urea nitrogen, lactate, Acute Physiology and Chronic Health Evaluation II score, and serum MMP8 levels showed favourable prediction accuracy and clinical utility for pleural effusion risk. These findings suggest the critical role of MMP8 in sepsis and its potential as a promising biomarker of sepsis-induced pulmonary vascular leakage.
Yao-Jun Peng, Qiyan Wu, Yu-Yu Liu et al.· Molecular Biomedicine· 0 citations
Background Mitochondrial dysfunction has been implicated in the pathophysiology of sepsis. However, human genetic evidence linking mitochondria-related genes to sepsis susceptibility remains limited. This study aimed to identify mitochondria-related genes associated with sepsis risk using a multi-omics Mendelian randomization framework. Methods Summary-data-based Mendelian randomization (SMR) was applied using sepsis genome-wide association study (GWAS) summary statistics from the UK Biobank and FinnGen databases. Expression, methylation, single-cell, and protein quantitative trait loci (QTLs) were used as genetic instruments. Colocalization analyses were conducted to evaluate whether SMR associations were driven by shared genetic variants. Expression of prioritized candidate genes was further examined in clinical septic samples, and correlations with disease severity (SOFA scores) were assessed. Results SMR analysis prioritized 13 mitochondria-related genes associated with sepsis risk. Immune cell-specific eQTL analysis suggested that genetically predicted SURF1 expression in memory B cells and naïve T cells was associated with sepsis risk. Differential expression of 12 candidate genes was confirmed in septic patients by qPCR, and PPOX expression showed a negative correlation with SOFA scores. Integration of mQTL and eQTL data supported a regulatory relationship between methylation at cg06661924 and AK4 expression. Increased genetically predicted AK4 expression was associated with higher sepsis risk (OR = 1.21, 95% CI 1.02-1.42). Protein-level analysis identified DUT as a potential sepsis-associated candidate, with consistent evidence across streptococcal and pneumococcal septicemia subtypes. Subtype analyses also suggested heterogeneous genetic signals across different sepsis subtypes. Conclusion This study prioritized several mitochondria-related genes associated with sepsis susceptibility based on human genetic evidence. These findings provide candidate targets for further mechanistic and translational investigation.
Lu Wang, Zhen Gao, Chengjin Wang et al.· Frontiers in Immunology· 0 citations
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