Daily Sepsis Research Analysis

BACKGROUND: Lipid metabolic reprogramming is a key feature of sepsis, with increased lipid storage contributing to disease progression. Although lipid metabolism dysregulation has been implicated in sepsis pathogenesis, how lipid biosynthesis, particularly mediated by sterol regulatory element-binding transcription factor 1 (SREBF1), leads to dendritic cell (DC) immunoparalysis remains unclear. METHODS: Intracellular lipid accumulation was assessed by Oil Red O and BODIPY staining. Gene and protein expression levels were analyzed via qPCR, Western blot, and immunofluorescence. SREBF1 activity was modulated using genetic knockout and siRNA silencing. DC phenotype and CD4 RESULTS: In a cecal ligation and puncture-induced sepsis model, we observed increased lipid biosynthesis and significantly elevated SREBF1 expression in spleen DCs. Increased SREBF1 expression suppressed the expression of costimulatory molecules (e.g., CD40, CD80, and CD86) and MHC II, reduced the secretion of inflammatory cytokines (e.g., TNFα, IL-1β, IL-6, and IL-12), impaired CD4 CONCLUSIONS: Our study identifies SREBF1 as a central regulator of sepsis-induced DC immunoparalysis by coupling lipid metabolic reprogramming to ER stress activation. Targeting this SREBF1-lipid-ER stress axis represents a novel strategy to reverse immunosuppression in septic patients. [Image: see text]

Delay in the initial administration of antimicrobials is one of the strongest predictors for mortality for septic patients in the intensive care unit (ICU). Given the different logistics among hospitals for antibiotic administration, this delay can take hours. As antibiotic administration involves care coordination and the participation of different team members, education and the antimicrobial stewardship (AMS) program play a key role in reducing these times. This study evaluated the time between the initial prescription and the effective administration of antibiotics for ICU patients in seven Latin American hospitals, before (pre-) and after (post-I and post-II) the implementation of a tailored educational approach. After establishing a baseline measurement (pre-), we implemented a tailored educational intervention directed to the ICU team including nurses, specialists, pharmacists, and the members of the AMS team. Then, we conducted a post-intervention measurement after a 3 month period (post-I) and repeated it after a 1 year period (post-II). During the pre-interventional phase, the hang time varied between 88 and 178 min, reporting an adherence to the 1 hour bundle of 33.8%. For the post-I, it significantly reduced with time variations between 46 and 104 min, showing an increase of 54.9% in adherence. After 1 year, in post-II, a persistent effect of shorter administration time was observed, varying between 49 and 109 min, increasing the adherence to 59.6%. Our results highlight that an active and tailored multidisciplinary AMS educational process incorporating antibiotic hang time protocols and including multidisciplinary healthcare teams involved in coordinating sepsis care decreases the administration time of antibiotics in Latin American hospitals with limited resources.

AIM: Sepsis-induced vascular injury is a major contributor to the high mortality rate of sepsis. However, effective treatments remain elusive due to limited knowledge regarding the underlying molecular mechanisms. Itaconic acid, an endogenous metabolite, involved in multiple inflammatory diseases, but its role in sepsis-induced vascular injury remains unclear. The current study investigates the effect of 4-octyl itaconate (4-OI), a cell-permeable derivative of itaconic acid, on sepsis-induced vascular injury and organ damage. METHODS AND RESULTS: An in vitro cell model was established by treating human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) revealed that 4-OI inhibited the LPS-induced increases in TNF-α, IL-6, and IL-1β levels. Cellular reactive oxygen species (ROS) levels, measured using the fluorescent probe DCFH-DA, mitochondrial ROS (mtROS) levels, measured by MitoSOX, and mitochondrial membrane potential (ΔΨ), detected by the fluorescent indicator JC-1, were all reduced following 4-OI treatment. Additionally, mtDNA release, detected by qRT-PCR, were decreased. Mitochondrial morphology, assessed by PK Mito Orange, was preserved by 4-OI treatment. Furthermore, 4-OI suppressed HUVECs apoptosis and pyroptosis, as detected by TUNEL staining and western blotting. 4-OI treatment also significantly inhibited LPS-induced cell adhesion, as shown in THP-1 attachment assay, by decreasing ICAM-1 and VCAM-1 expression. Cell permeability, determined by FITC-Dx-70 leakage, revealed that 4-OI effectively suppressed LPS-induced increases in cell permeability. Furthermore, 4-OI inhibited LPS-induced phosphorylation and internalization of VE-cadherin protein, preserving the adhesion junctions between endothelial cells. Network pharmacology and molecular docking analysis suggested the involvement of TLR4/MAPK/NF-κB signaling pathway as a key mechanism by which 4-OI ameliorated sepsis-induced vascular cell inflammation and injury, which was confirmed by western blotting. The in vitro results were subsequently verified in vivo in an LPS-induced sepsis mouse model. 4-OI pretreatment substantially decreased inflammatory cytokine levels in serum and lung tissues, inhibited pulmonary oedema and pulmonary vascular leakage, as evidenced by the wet-to-dry weight ratio and Evans blue staining of lung tissues, and alleviated tissue damage, as shown by histological analysis. Survival analysis indicated that 4-OI post-sepsis treatment improved the overall survival rate in LPS-induced ALI mice. CONCLUSION: 4-OI protects against sepsis-induced vascular injury and tissue damage by suppressing endothelial inflammation, oxidative stress, and preserving endothelial barrier integrity.