Daily Sepsis Research Analysis

BACKGROUND: This study aimed to identify a key target gene in proximal tubule cells (PTCs) of sepsis-induced acute kidney injury (S-AKI) and elucidate the underlying mechanisms. METHODS: We screened and analyzed GEO datasets and identified a key gene, GATM, in S-AKI. An S-AKI mouse model was established via intraperitoneal injection of lipopolysaccharide (LPS), and HK-2 cells were used for in vitro experiments. The role of GATM was evaluated using adeno-associated virus (AAV)-mediated overexpression in mice and plasmid-mediated overexpression in HK-2 cells. To identify the downstream target genes of GATM, transcriptome sequencing was conducted. Pathological evaluation was performed using hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) staining. Protein levels were determined by Western blotting (WB), immunohistochemistry (IHC), and immunofluorescence (IF) assays; Apoptosis was evaluated by TUNEL staining; Mitochondrial morphology and function were assessed by transmission electron microscopy (TEM), JC-1 and MitoSOX assays. Lactate concentration and cellular ATP levels were measured. RESULTS: Through analysis of four datasets (GSE151658, GSE247727, GSE220812, and GSE139061), GATM was identified as a key gene in PTCs during S-AKI. GATM expression was downregulated in both S-AKI mice and LPS-stimulated HK-2 cells. In vivo, GATM overexpression improved renal function, alleviated tubular damage, decreased the expression of KIM-1, IL-6, Caspase-3, and 4-HNE, and reduced mitochondrial injury. In vitro, HK-2 cell viability was enhanced, TUNEL-positive cells were reduced, and damaged mitochondria were decreased. Transcriptome sequencing revealed that the PDK4-mediated glycolysis pathway was a downstream target of GATM. GATM overexpression downregulated PDK4 expression, reduced glycolytic enzyme levels (p-PDHA, HK2, LDHA, GLUT1) and lactate, and increased ATP production. However, PDK4 overexpression in HK-2 cells abolished the protective effects of GATM, enhanced glycolysis, increased lactate levels, and reduced ATP production. CONCLUSION: GATM plays a protective role in S-AKI by inhibiting PDK4-mediated aerobic glycolysis, enhancing ATP production, and restoring energy metabolism and mitochondrial function in PTCs.

BACKGROUND: The optimal parameter to assess cardiovascular function in sepsis is currently unknown. We investigated whether echocardiography-derived cardiac index offers superior haemodynamic monitoring and prognostic value compared to left ventricular ejection fraction (LVEF) in ICU patients with sepsis. METHODS: We conducted a retrospective, single-centre cohort study in ICU patients with sepsis admitted between April 2016 and December 2021 that received a transthoracic echocardiogram (TTE) within seven days of sepsis onset. Correlation between CI and LVEF was assessed using the Spearman rank test. The 90-day mortality rates of normal, low and high CI and LVEF subgroups were compared. Multivariable logistic regression analysis was performed to determine the association of CI and LVEF phenotypes with mortality. RESULTS: 1731 patients were included and were aged 62 years (IQR 47-72), with 21% (n = 367) having septic shock. Ninety-day mortality was 32.5% (n = 561). Although CI and LVEF demonstrated moderate correlation (r = 0.51 (0.47-0.54), one-third of patients in a given CI subgroup were classified into a discordant LVEF subgroup. The 90-day mortality rates of low and high CI (54%, 54%) and low and high LVEF subgroups (43%, 59%) were broadly comparable and were higher than their normal CI (20%) and LVEF (23%) counterparts respectively. After regression analysis, low and high CI independently associated with mortality (OR 2.6 (1.8-3.7; p < 0.001), (OR 3.4 (2.7-4.4; p < 0.001), as did low and high LVEF subgroups (OR 1.6 (1.2-2.3; p = 0.004), OR 3.2 (2.4-4.3; p < 0.001). Stratifying CI subgroups into low, normal and high LVEF (and vice-versa) was associated with significantly different mortality rates. CONCLUSIONS: Although CI and LVEF were modestly correlated, this association weakened when either parameter was abnormal, highlighting their non-equivalence as haemodynamic parameters. While both markers exhibited comparable associations with mortality, their combination substantially improved prognostic accuracy.

BACKGROUND: Sepsis is a life-threatening condition caused by a dysregulated host response to infection, with significant biological heterogeneity. Transcriptomic profiling offers insights into immune-related gene expression patterns that may inform patient stratification. This study aimed to identify transcriptomic signatures of sepsis or septic shock. METHOD: Eleven adult patients who presented to the emergency department with sepsis or septic shock were enrolled at a tertiary hospital in Korea. Serial whole-blood samples were collected on days 1, 3, and 7. RNA sequencing was performed using Illumina paired-end protocols. Principal component analysis (PCA) was performed on normalized transcriptomic data to derive a gene signature. Enrichment scores were calculated using single-sample gene set enrichment analysis and validated in external bulk and single-cell RNA-seq datasets. RESULTS: PCA identified first principal component (PC1) as the major axis of variation, separating samples by sepsis severity and timepoint. Clustering of the top 50 PC1 contributing genes identified three transcriptomic subgroups with distinct expression patterns. Enrichment scores for this gene set increased with severity and declined over time. In multiple external sepsis cohorts, enrichment scores showed consistent trends and were significantly associated with 28-day mortality. Functional analysis revealed predominant neutrophil-associated pathways, as further supported by external single-cell RNA-seq validation. CONCLUSIONS: We identified a neutrophil-driven transcriptomic signature associated with sepsis severity and temporal immune dynamics. These findings suggest that longitudinal transcriptomic profiling may provide additional insight into the evolving host immune response during sepsis.