Daily Sepsis Research Analysis

BACKGROUND: Patients with sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) commonly suffer from severe pulmonary thrombosis, but clinical trials of anticoagulant therapies in patients with sepsis and ARDS have failed. Patients with ARDS with thrombocytopenia also exhibit increased mortality, and widespread pulmonary thrombosis is often seen in patients with COVID-19 ARDS. METHODS: Different amounts of microbeads were administered intravenously to adult mice to induce various levels of pulmonary thrombosis. ALI was induced by either intraperitoneal lipopolysaccharide or cecal ligation and puncture. Endothelial cell (EC)-targeted nanoparticles were used to deliver plasmid DNA expressing the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) system for EC-specific gene knockout of Alox15 (arachidonate 15-lipoxygenase) or plasmid DNA expressing Alox15 for EC-specific overexpression. Lipidomic profiling and in vivo rescue studies with the identified Alox15-regulated lipids were performed. In addition, thrombocytopenia was induced by genetic depletion of platelets using RESULTS: We show that although severe pulmonary thrombosis or thrombocytopenia augments sepsis-induced ALI, the induction of mild pulmonary thrombosis conversely reduces EC apoptosis, ALI, and mortality via sustained expression of endothelial Alox15. Endothelial CONCLUSIONS: We have demonstrated that moderate levels of lung thrombosis protect against sepsis-induced inflammatory lung injury via endothelial Alox15. Overexpression of endothelial Alox15 inhibits severe pulmonary thrombosis-induced increases in ALI. Thus, upregulation of ALOX15 expression or treatment with ALOX15-dependent protective lipid(s) represents a promising therapeutic strategy for treatment of ARDS, especially in subpopulations of patients with thrombocytopenia and widespread pulmonary thrombosis.

Sepsis-induced liver injury is closely associated with poor prognosis in septic patients. In this study, through integrated approaches including high-throughput virtual screening, target fishing technology, and atomic force microscopy (AFM) analysis, Forsythiaside E (FE) is first identified as a novel allosteric activator of pyruvate kinase M2 (PKM2) that promotes tetramer formation. Mutant protein construction combined with dynamic light scattering (DLS) and fluorescence resonance energy transfer (FRET) reveals FE binds to PKM2 K311 to promote tetramer formation. Employing Seahorse XF metabolic analyzers, real-time single-cell multi-modal analysis systems, and transcriptome sequencing, it is revealed that FE-mediated PKM2 tetramerization induces metabolic reprogramming in macrophages while suppressing STAT3 phosphorylation and subsequent NLRP3 transcriptional activation. In vivo assessments indicate that FE exhibited no significant multi-organ toxicity. FE alleviates sepsis-induced liver injury by promoting macrophage polarization toward the M2 anti-inflammatory phenotype. Further validation through macrophage-specific overexpression of PKM2 WT/K311A in mice confirms FE's mechanism of action. Collectively, this study elucidates the molecular mechanism by which FE alleviates sepsis-associated liver injury through targeted PKM2 tetramerization and proposes an innovative metabolic-epigenetic coordinated regulation strategy for sepsis-related liver injury treatment.

OBJECTIVE: These European Society of Intensive Care Medicine (ESICM) guidelines provide recommendations for the diagnosis of shock and hemodynamic monitoring for adult critically ill patients. METHODS: An international panel of experts formulated PICO-formatted questions, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was applied to assess evidence and formulate recommendations. In the absence of strong evidence, panelists issued ungraded good practice statements (UGPS). RESULTS: Panelists issued 50 statements. Among others, skin perfusion should be monitored using the assessment of capillary refill time, and this may be complemented by the assessment of skin temperature and mottling (UGPS). In patients with a central venous catheter, serial measurements of (central) venous oxygen saturation and of the veno-arterial difference in carbon dioxide partial pressure should be performed (UGPS). In patients with persistent shock after initial fluid resuscitation, fluid responsiveness should be assessed before continuing fluid resuscitation (UGPS). It is recommended to use dynamic variables over static markers of preload for predicting fluid responsiveness, when applicable (graded statement). Cardiac output (CO) and/or stroke volume should be monitored in patients who do not respond to initial therapy (UGPS). Arterial pressure should be monitored with an arterial catheter in shock that is not responsive to initial therapy and/or requiring vasopressor infusion (UGPS), and central venous pressure should be measured in patients who have a central venous catheter (UGPS). Panelists suggest using echocardiography as the first-line imaging modality to assess the type of shock (graded statement). Echocardiographically defined phenotypes of left and right ventricular dysfunction may be of prognostic significance (UGPS). CONCLUSIONS: The panel made 50 recommendations on shock diagnosis and hemodynamic monitoring.