Daily Sepsis Research Analysis
Analyzed 48 papers and selected 3 impactful papers.
Summary
Three impactful sepsis studies span mechanisms, diagnostics, and potential therapies. A basic study identifies Smurf1 as a negative regulator of non-canonical inflammasome activation, reducing caspase-11–driven pyroptosis and mortality in murine sepsis. A rapid meta-analysis supports procalcitonin-guided antibiotic discontinuation in critically ill sepsis, while translational work links NETs to endothelial barrier breakdown via the Wnt7a/β-catenin/HDAC5 axis, revealing actionable targets.
Research Themes
- Inflammasome and pyroptosis regulation in sepsis
- Biomarker-guided antibiotic stewardship in critical care
- Endothelial barrier injury pathways and therapeutic targets
Selected Articles
1. ERK/Smurf1 regulates non-canonical pyroptosis by prompting Caspase-11 ubiquitination.
This study reveals Smurf1 as a critical negative regulator of non-canonical inflammasome activation by promoting K48-linked ubiquitination of caspase-11, leading to its proteasomal degradation. ERK phosphorylation enhances Smurf1 activity, and macrophage-specific Smurf1 deficiency worsens sepsis mortality in mice, while macrophage-targeted Smurf1 supplementation mitigates lethality and inflammation.
Impact: It uncovers a novel, targetable mechanism linking ERK–Smurf1 signaling to caspase-11 control and pyroptosis, directly affecting sepsis survival in vivo. This positions Smurf1 as a therapeutic entry point in Gram-negative sepsis.
Clinical Implications: While preclinical, macrophage-targeted augmentation of SMURF1 activity or modulation of ERK–SMURF1 signaling could attenuate hyperinflammation in Gram-negative sepsis. Translation will require validation in human macrophages and alignment with caspase-4/5 biology.
Key Findings
- Smurf1 catalyzes K48-linked polyubiquitination of caspase-11 at K245/K247, promoting 26S proteasomal degradation and restraining non-canonical inflammasome activation.
- ERK phosphorylation at Smurf1 S148 amplifies this regulatory process; conversely, caspase-11 can cleave Smurf1, indicating reciprocal regulation.
- Macrophage-specific Smurf1 deficiency exacerbates sepsis mortality in mice, while macrophage-targeted Smurf1 supplementation mitigates lethality and inflammatory responses.
Methodological Strengths
- Mechanistic depth across biochemical, cellular, and macrophage-specific genetic models with in vivo sepsis mortality readouts.
- Causal inference strengthened by both loss-of-function and targeted supplementation approaches.
Limitations
- Preclinical mouse and cell models may not fully translate to human caspase-4/5 biology and sepsis heterogeneity.
- Drugability, specificity, and safety of modulating SMURF1–ERK axis remain untested.
Future Directions: Validate SMURF1–caspase-4/5 regulation in human macrophages and clinical specimens; develop small-molecule or protein-based modulators; assess efficacy in diverse sepsis models and early-phase trials.
Sepsis, a devastating microbe-induced inflammatory response, culminates in multi-organ dysfunction, with pyroptosis mediated by the non-canonical inflammasome being a pivotal factor. The mouse Caspase-11, central to this pathway, is directly activated by cytoplasmic lipopolysaccharide (LPS). Although ubiquitination is known to tightly regulate the inflammatory response in pyroptosis, its role in modulating the non-canonical inflammasome remains enigmatic. In this study, we unveil that the E3 ubiq
2. Clinical effectiveness of procalcitonin- or C-reactive protein-guided antibiotic discontinuation protocols for adult patients who are critically ill with sepsis: a rapid systematic review and meta-analysis.
Across 21 trials, procalcitonin-guided discontinuation probably shortens antibiotic therapy by about 2 days without increasing mortality in critically ill sepsis patients. Evidence for CRP-guided discontinuation is insufficient or low certainty.
Impact: This synthesis of randomized evidence supports biomarker-guided antimicrobial stewardship in the ICU, balancing therapy duration with safety. It consolidates moderate-certainty evidence for PCT while clarifying uncertainties around CRP.
Clinical Implications: Implementing PCT-guided discontinuation protocols can safely reduce antibiotic exposure in critically ill sepsis patients; institutions should standardize thresholds and workflows. CRP-guided protocols should be used cautiously pending stronger evidence.
Key Findings
- Procalcitonin-guided protocols reduced antibiotic duration by a mean of 2.0 days (95% CI −2.6 to −1.4) versus standard care (moderate certainty, 19 trials; n=6382).
- Procalcitonin guidance was associated with an approximate 5% relative reduction in mortality risk (RR 0.95, 95% CI 0.83–1.07), without clear harm.
- Evidence for CRP-guided discontinuation remains unclear with very low to low certainty.
Methodological Strengths
- Systematic synthesis of randomized controlled trials with moderate certainty evidence for key outcomes.
- Large aggregate sample size across diverse ICU settings, enhancing external validity.
Limitations
- Heterogeneity in PCT thresholds, stopping rules, and clinical contexts; rapid review process may risk omission bias.
- Uncertain effects on reinfection/recurrence and limited high-quality evidence for CRP-guided strategies.
Future Directions: Standardize PCT thresholds and algorithms; conduct pragmatic trials evaluating patient-centered outcomes and antimicrobial resistance; assess cost-effectiveness and implementation strategies.
INTRODUCTION: Antibiotics are a first-line treatment for sepsis, with guidelines recommending a 7- to 10-day course. Prolonged antibiotic use carries significant risks, prompting growing interest in using inflammatory biomarkers, such as procalcitonin or C-reactive protein, to guide clinical decision-making on the duration of antibiotic therapy in patients who are critically ill. This rapid systematic review aims to assess the effectiveness and safety of using procalcitonin- or C-reactive prote
3. Neutrophil extracellular traps exacerbate endothelial tight junction dysfunction via the Wnt7a/β-catenin/HDAC5 pathway in sepsis-associated lung injury.
NETs activate the Wnt7a/β-catenin pathway and upregulate HDAC5 in endothelial cells, downregulating tight junction proteins (Claudin-5, ZO-1, Occludin) and impairing lung microvascular barrier function. In a CLP sepsis model, disrupting NETs or inhibiting Wnt7a/HDAC5 mitigated tight junction loss and improved outcomes.
Impact: It delineates a druggable signaling axis linking NETs to endothelial barrier failure in sepsis-associated lung injury, providing mechanistic rationale for anti-NET or HDAC/Wnt-targeted adjunctive therapies.
Clinical Implications: Targeting NET formation or the Wnt7a/β-catenin/HDAC5 axis may preserve endothelial integrity and reduce pulmonary edema in sepsis. These findings support translational efforts to test HDAC5 or Wnt pathway inhibitors as adjuncts.
Key Findings
- NET-stimulated endothelial cells showed Wnt7a/β-catenin activation with increased HDAC5 and downregulation of Claudin-5, ZO-1, and Occludin.
- In vivo CLP sepsis models linked NETs to lung endothelial barrier dysfunction and worse prognosis.
- NET disruption or Wnt7a/HDAC5 inhibition restored tight junction protein expression and improved outcomes.
Methodological Strengths
- Integration of RNA-seq reanalysis, in vitro validation (qPCR, Western blot, immunofluorescence), and in vivo CLP models.
- Use of targeted inhibition to demonstrate pathway causality.
Limitations
- Use of HUVECs and murine CLP models may limit generalizability to human pulmonary microvascular endothelium.
- Potential off-target effects of inhibitors were not comprehensively addressed.
Future Directions: Validate Wnt7a/HDAC5 signaling changes in human sepsis lung tissue; test selective HDAC5 or Wnt pathway inhibitors in advanced preclinical models; design early-phase adjunctive therapy trials.
Sepsis is a complicated clinical disease caused by an infection-related host response, which results in acute organ dysfunction and a high mortality risk. Among the affected organs, the lungs are particularly susceptible to sepsis. Sepsis-induced acute lung injury (SI-ALI) is a common and severe complication observed among septic patients. Neutrophil extracellular traps (NETs) serve a significant role in immune and inflammatory regulation. Our previous studies have shown a close association betwe