Daily Sepsis Research Analysis

BACKGROUND: Sepsis-associated encephalopathy (SAE) often results from neuroinflammation. Recent studies have shown that brain platelet-derived growth factor receptor β (PDGFRβ) cells, including pericytes, may act as early sensors of infection by secreting monocyte chemoattractant protein-1 (MCP-1), which transmits inflammatory signals to the central nervous system. The erythroblast transformation-specific (ETS) transcription factor Friend leukemia virus integration 1 (Fli-1) plays a critical role in inflammation by regulating the expression of key cytokines, including MCP-1. However, the role of pericyte Fli-1 in neuroinflammation during sepsis remains largely unknown. METHODS: WT and pericyte-specific Fli-1 knockout mice were subjected to endotoxemia through LPS injection or sepsis via cecal ligation and puncture (CLP). In vitro, Fli-1 was knocked down using small interfering RNA in cultured mouse brain pericytes, followed by LPS stimulation. RESULTS: Elevated Fli-1 levels were observed in isolated brain pericytes 2 h after LPS administration, in brain tissues 4 h after CLP, and in cultured mouse brain pericytes 2 h after LPS stimulation in vitro. In endotoxemic mice, pericyte-specific Fli-1 knockout reduced expression of MCP-1 and IL-6 in brain tissue 2 h after LPS injection. At 24 h post-LPS administration, protein levels of MCP-1 and IL-6, and microglia activation were suppressed in pericyte-Fli-1 knockout mice. Additionally, Fli-1 deficiency in pericytes significantly reduced MCP-1 and IL-6 mRNA levels in the brain tissue 4 h after CLP. Moreover, in cultured brain pericytes, Fli-1 knockdown markedly decreased MCP-1 and IL-6 levels after LPS stimulation. Notably, LPS stimulation increased Fli-1 levels via TLR4-Myd88 signaling, which subsequently led to elevated production of MCP-1 in brain pericytes. CONCLUSIONS: Fli-1 in pericytes may serve as a crucial mediator of neuroinflammation during sepsis by directly regulating pivotal cytokines such as MCP-1 and IL-6. Therefore, Fli-1 has the potential to serve as a therapeutic target in SAE and other neuroinflammatory disorders.

Sepsis-induced acute kidney injury (SI-AKI) is the most common organ dysfunction of sepsis, characterized with prolonged hospitalization periods and significantly elevated mortality rates. Piplartine (PLG), an alkaloid extracted from Piper longum within the Piperaceae family, has exhibited diverse pharmacological activities, including anti-inflammatory, anti-atherosclerotic, and anti-tumor effects. Herein, we investigated whether the PLG could reverse SI-AKI and explore its possible anti-inflammatory mechanisms. We constructed an SI-AKI model using cecal ligation and puncture (CLP) and systematically evaluated the protective effect of PLG administered by gavage in the SI-AKI mice. Subsequently, we performed proteomic sequencing of the kidney and integrated data from the GeneCards and SwissTargetPrediction databases to identify potential targets and mechanisms. Immunofluorescence and western blotting were used to examine the expression of relevant targets and pathways in vivo and in vitro. The influence of PLG on the predicted target and pathway was verified using an agonist of the target protein and a series of biochemical experiments. PLG exhibited significant efficacy against pathological damage, neutrophil and macrophage infiltration, and macrophage pyroptosis in kidneys at 30 mg/kg. An integrated analysis of proteomic data identified the translocator protein (TSPO) as a potential target for the renoprotective effects of PLG. Moreover, a TSPO agonist (RO5-4864) prominently reversed the protective effect of PLG in SI-AKI mice, as manifested by a deterioration in renal function, histopathological lesions and macrophage pyroptosis in the kidneys. Our results suggest that PLG may ameliorate SI-AKI, potentially through partial inhibition of the TSPO-macrophage pyroptosis pathway.

PURPOSE: Mortality and morbidity of patients with bloodstream infection (BSI) remain high despite advances in diagnostic methods and efforts to speed up reporting. This study investigated the impact of reporting rapid Minimum Inhibitory Concentration (MIC)-results in Gram negative BSIs with the ASTar system (Q-linea, Uppsala, Sweden) on the adaptation of empirically started antimicrobial therapy. We performed a real-world study during which antimicrobial susceptibility testing (AST) results were instantly reported to the treating physician in an established multidisciplinary antimicrobial stewardship setting. METHODS: Consecutive patients with Gram negative bacteremia were included in the study (monomicrobial Gram stain, life expectancy of at least 48 h and flagging positive before 2 PM). Rapid AST (RAST) reporting with ASTar was added on top of the standard workflow. Technical performance of the system was evaluated as well as the impact on antimicrobial treatment and timelines of achieving effective and optimal antimicrobial therapy. RESULTS: A total of 79 analyses were performed in 77 patients, of which 68 episodes were eligible for analysis. A categorical agreement was observed in 97,5% of 1160 MIC results without false susceptible results. All patients on ineffective empirical therapy (12/68) were switched after a median time of approximately one hour (5 min - 15 h) after communication of the result. Furthermore, 20/55 non-optimal therapies were adapted within a median period of 3 h after communication. CONCLUSION: The implementation of rapid MICs, measured by the ASTar system, in our low antimicrobial resistance setting with elaborate antimicrobial guidelines, was easy and led to early adaptation of empirical treatment in 32/55 instances (12 ineffective and 20 non-optimal therapy). TRIAL REGISTRATION NUMBER: NCT06218277 (date of registration: 18-12-2023).