Daily Sepsis Research Analysis

INTRODUCTION: Sepsis-induced cardiomyopathy (SIC) is a rapidly advancing condition associated with a poor prognosis due to the lack of effective treatments. Neutrophil extracellular traps (NETs), however, act as a double-edged sword in the innate immune response during sepsis. N-formyl methionine (fMet) has been documented to induce NETs in inflammatory conditions, yet its clinical significance and biological function in SIC remain unclear. In this study, we investigated whether fMet induces excessive NETs, thereby promoting SIC. METHODS AND RESULTS: Clinically, serum fMet levels were quantified using ELISA, revealing a significant elevation in patients with SIC compared to non-sepsis patients and healthy controls. The fMet levels were positively correlated with the NETs-related markers myeloperoxidase (MPO) and double-stranded DNA (dsDNA) in patients with SIC. Treatment with lipopolysaccharide and fMet increased NET formation in human neutrophils and upregulated the expression of formyl peptide receptor 1 (FPR1) and hypoxia-inducible factor 1-alpha (HIF-1α). Furthermore, bone marrow-derived neutrophils (BMDNs) were isolated from global FPR1 knockout mice, and FPR1 deficiency in BMDNs was found to suppress NETosis. The cecal ligation and puncture (CLP) model was employed to induce SIC in mice and we found knockout of FPR1 improved outcomes in CLP mice, as evidenced by survival benefit, increased cardiac function, attenuated cytokine storm, reduced neutrophil infiltration, improved mitochondrial function and suppressed NETosis, compared with those of wild-type (WT) mice. In addition, treatment with FPR1 inhibitor HCH6-1 improved cardiac outcome and inhibits NETosis in CLP mice. CONCLUSION: These data reveal the role of fMet-mediated FPR1/HIF-1α activation in promoting SIC through the NETosis, indicating novel therapeutic strategy for SIC.

INTRODUCTION: Bloodstream infections (BSIs) are a major cause of neonatal morbidity and mortality in low-resource settings, yet most are preventable. However, few studies evaluated the effectiveness of multimodal interventions in preventing healthcare-associated BSIs (HA-BSIs) in neonatal intensive care units (NICUs) in low- and middle-income countries (LMICs). METHODS: We conducted an implementation study in a NICU in Northern Ethiopia from January to June 2024, using a pre-and post-intervention design. Multimodal prevention strategies consisted of infection prevention and control (IPC) training, the appointment of an IPC expert, in-house production of alcohol-based hand rub (ABHR), HA-BSI surveillance, and online IPC meetings. Follow-up interventions were implemented based on feedback from these meetings. Logistic regression analysis was used to assess the associations between variables. RESULTS: Among 151 clinically suspected HA-BSI episodes, 58.3 % were culture-positive. The baseline rate of HA-BSI was 333 episodes per 1000 hospital admissions. This rate significantly declined to 74 within two months (p < 0.0001) and 96 episodes per 1000 by the end of the study (p < 0.0001). HA-BSI-associated mortality decreased by 80 % (p < 0.0001). Each additional hospital day increased HA-BSI risk by 10.5 % (odds ratio [OR]: 1.105, 95 % confidence interval [CI]: 1.018-1.200; p < 0.05), while a 100-g increase in birth weight improved the odds of successful antibiotic treatment by 15.2 % (OR: 1.152, 95 % CI: 1.055-1.257; p < 0.01). CONCLUSION: Cost-effective, multimodal IPC interventions can significantly reduce HA-BSIs and associated mortality in NICUs in low-resource settings. Further research is needed to evaluate the long-term sustainability of these measures in LMICs.

OBJECTIVES: Sepsis-associated acute lung injury (S-ALI) is one of the major causes of death in intensive care unit (ICU) patients, yet its mechanisms remain incompletely understood and effective therapies are lacking. Lytic cell death of macrophages is a key driver of the inflammatory cascade in S-ALI. PANoptosis, a newly recognized form of lytic cell death characterized by PANoptosome assembly and activation, involves plasma membrane rupture (PMR) mediated by ninjurin-1 (NINJ1), a recently identified pore-forming protein. Itaconic acid is known for its anti-inflammatory effects, but its role in macrophage PANoptosis during S-ALI is unclear. This study aims to investigate the protective effect of itaconic acid on macrophage PANoptosis in S-ALI to provide new therapeutic insights. METHODS: Male specific-pathogen-free C57BL/6J mice (6-8 weeks, 18-20 g) received intraperitoneal lipopolysaccharide (LPS) to establish a classical S-ALI model. Western blotting was used to assess PANoptosome-related proteins and enzymes involved in the itaconic acid metabolic pathway, while real-time reverse transcription polymerase chain reaction and metabolomics quantified itaconic acid levels. Primary peritoneal macrophages (PMs) were pretreated with the itaconate derivative 4-octyl itaconate (4-OI) and then exposed to tumor necrosis factor alpha (TNF-α) plus interferon gamma (IFN-γ) to induce PANoptosis. Cell viability was evaluated by cell counting kit-8 (CCK-8) assay. Western blotting was employed to quantify enzymes of the itaconate-metabolic pathway in PANoptotic macrophages, to evaluate the impact of 4-OI on PANoptosome-associated proteins, and to determine NINJ1 abundance in lung tissues from S-ALI mice and in PANoptotic macrophages. Fluorescent dye FM RESULTS: In S-ALI mouse lungs, PANoptosome components [NOD-like receptor thermal protein domain associated protein 3 (NLRP3), Gasdermin D (GSDMD), Caspase-1, Z-DNA binding protein (ZBP1), and Caspase-3] and phosphorylated mixed lineage kinase domain-like protein (MLKL) S345 were significantly upregulated (all CONCLUSIONS: Itaconic acid may alleviate macrophage PANoptosis in S-ALI by inhibiting NINJ1-mediated plasma membrane rupture. Targeting NINJ1 or enhancing itaconate pathways may offer a novel therapeutic strategy for S-ALI.