Daily Sepsis Research Analysis

Sepsis-induced lung injury, characterized by unregulated inflammation and impaired alveolar epithelial integrity, significantly contributes to sepsis-related mortality. Although receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is critical in regulating necroptosis and inflammation, its precise contribution to sepsis-induced lung injury remains poorly understood. In this study, selective activation of RIPK1 in type II alveolar epithelial cells (AECs) is observed during sepsis. CXCL1 is identified as a critical downstream target of RIPK1 through integrative transcriptomic and proteomic analyses. Mechanistically, RIPK1 interacts with JAK1 to induce STAT3 phosphorylation, facilitate its nuclear translocation, and promote its binding to the Cxcl1 promoter, thereby upregulating its expression and driving excessive neutrophil recruitment. Genetic or pharmacological inhibition of RIPK1 attenuated CXCL1 production, neutrophil infiltration, and alveolar damage, improving survival in septic mice. Compound 62, a selective RIPK1 inhibitor, has demonstrated efficacy in attenuating systemic inflammatory cascades, preserving epithelial barrier integrity, and improving survival rates in mice. These findings establish RIPK1 as a therapeutic target in sepsis-induced lung injury and redefine alveolar epithelial cells as positive contributors to inflammatory amplification. This work advances precision strategies to mitigate sepsis-induced lung injury, addressing a critical unmet need in critical care medicine.

NLRP3 inflammasome is a multiple protein complex sensing exogenous or endogenous stimuli, and aberrant activation of the NLRP3 inflammasome is implicated in various inflammatory disorders. While numerous small-molecule compounds targeting NLRP3 inflammasome activity have been developed, most have encountered limited success in clinical translation. Through screening of a kinase compound library, GSK461364 is identified as a potent and selective NLRP3 inflammasome inhibitor. Notably, GSK461364 confers significant protective effects in murine models of LPS-induced endotoxemia and DSS-induced colitis. Mechanistic study reveals that GSK461364 exerts its inhibitory effects via targeting Polo-like Kinase 1(PLK1). Specifically, that PLK1-mediated phosphorylation of NEK7, likely occurring at evolutionarily conserved serine residues (Ser221 and Ser260), is shown to enhance NEK7-NLRP3 binding, a critical step for NLRP3 inflammasome assembly. These findings not only establish GSK461364 as a novel therapeutic candidate for NLRP3-driven inflammatory diseases but also provide new insights into the regulatory mechanisms governing inflammasome activation through post-translational modification.

OBJECTIVE: To determine the impact of using dynamic measures of fluid responsiveness in guiding the resuscitation of adult patients with sepsis and septic shock. DATA SOURCE: We searched MEDLINE, Embase, and unpublished sources from inception to February 3, 2025. STUDY SELECTION: We included randomized controlled trials (RCTs) that evaluated the use of dynamic measures of fluid responsiveness to guide resuscitation compared with any other method in patients with sepsis and septic shock. DATA EXTRACTION: We collected data regarding study and patient characteristics, definitions of fluid responsiveness, modality for assessing fluid responsiveness, and outcome data. We performed a random-effects meta-analysis and rated the certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation framework. DATA SYNTHESIS: We included nine eligible RCTs (n = 698 patients). The use of dynamic measures of fluid responsiveness to guide IV fluid (IVF) administration of patients with septic shock probably reduces 28-day mortality (relative risk] 0.61; 95% CI, 0.42-0.90, moderate certainty), may reduce the risk of acute kidney injury (AKI) (RR 0.66; 95% CI, 0.44-0.98, low certainty), and cumulative fluid balance on day 3 (mean difference -1.57L; 95% CI, -2.44 L to -0.69 L, low certainty). The use of dynamic measures of fluid responsiveness has an uncertain effect on ICU mortality, ICU and hospital length of stay, need for and duration of mechanical ventilation, need for renal replacement therapy, vasoactive medication administration, duration of vasopressor use, and IVF administration on day 1. CONCLUSIONS: In adult patients with sepsis and septic shock, using dynamic measures of fluid responsiveness may improve survival and reduce the risk of AKI. Future studies should evaluate the impact of this intervention on other important clinical outcomes and determine the comparative efficacy of specific modalities for assessing fluid responsiveness.