Daily Sepsis Research Analysis
Analyzed 3 papers and selected 3 impactful articles.
Summary
Analyzed 3 papers and selected 3 impactful articles.
Selected Articles
1. DLL4+ neutrophils promote Notch1-mediated endothelial PANoptosis to exacerbate acute lung injury in sepsis.
The study identifies DLL4+ neutrophils as drivers of Notch1-dependent endothelial PANoptosis in sepsis-induced ALI. A novel Notch1–DLL4 inhibitory peptide reduced endothelial PANoptosis, lung injury, inflammation, vascular leak, and improved survival in sepsis models.
Impact: Reveals a previously unrecognized neutrophil–endothelium pathway and provides a tractable therapeutic inhibitor with in vivo efficacy. This mechanistic advance opens a path to targeted therapies for sepsis-induced lung injury.
Clinical Implications: While preclinical, targeting Notch1–DLL4 signaling could inform future trials for sepsis-induced acute lung injury by preventing endothelial PANoptosis and barrier failure.
Key Findings
- eCIRP induces DLL4+ neutrophils that drive ZBP1-initiated endothelial PANoptosis in sepsis.
- DLL4 binds Notch1 on pulmonary endothelium to activate Notch1 intracellular signaling and amplify ZBP1-mediated PANoptosis.
- A novel Notch1–DLL4 inhibitor (NDI) reduced endothelial PANoptosis, decreased lung injury and permeability, lowered inflammatory markers, and improved survival.
Methodological Strengths
- Multimodal validation across in vitro endothelial systems and in vivo sepsis models with survival outcomes.
- Target engagement demonstrated with a rationally designed peptide inhibitor blocking Notch1–DLL4 interaction.
Limitations
- Preclinical models may not fully recapitulate human sepsis heterogeneity.
- Pharmacokinetics, safety, and dosing of the inhibitor in large animals/humans are not assessed.
Future Directions: Evaluate NDI pharmacology and safety, assess biomarkers of DLL4+ neutrophils/PANoptosis in patients, and design early-phase trials targeting Notch1–DLL4 in sepsis-induced ALI.
Neutrophils play a critical role in sepsis-induced acute lung injury (ALI). Extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, promotes neutrophil heterogeneity. While delta-like ligand 4 (DLL4) expression has been studied in various cell populations, its expression in neutrophils and impact on inflammation remain unknown. Here, we discovered that eCIRP induces DLL4+ neutrophils. These neutrophils trigger PANoptosis, a novel proinflammatory form of cell death initiated by Z-DNA-binding protein-1 (ZBP1) in pulmonary vascular endothelial cells (PVECs). In sepsis, DLL4+ neutrophils increase in the blood and lungs, upregulating ZBP1, cleaved gasdermin D, cleaved caspase-3, and phosphorylated MLKL, all of which are markers of PANoptosis, exacerbating ALI. DLL4 binds to Notch1 on PVECs and activates Notch1 intracellular domain to increase ZBP1-mediated endothelial PANoptosis. We discovered what we believe to be a novel Notch1-DLL4 inhibitor (NDI), derived from Notch1 to specifically block this interaction. Our findings reveal that NDI reduced endothelial PANoptosis in vitro and in vivo, attenuated pulmonary injury induced by DLL4+ neutrophils, and decreased lung water content and permeability, indicating improved barrier function. NDI also reduced serum injury and inflammatory markers and improved survival rate in sepsis. These findings underscore the Notch1-DLL4 pathway's critical role in DLL4+ neutrophil-mediated ALI. Targeting the Notch1-DLL4 interaction with an NDI represents a promising therapeutic strategy for sepsis-induced ALI.
2. A Critical Role for MALAT1 in Gram-negative Bacteria-induced Coagulation via Regulation of Caspase-11 signaling.
Plasma IFNβ at admission predicted 48-hour onset of septic DIC, and mechanistically IFNβ induces macrophage MALAT1, which suppresses GPX4, enhances caspase-11 activation, and promotes coagulation. Targeting the IFNβ–MALAT1–caspase-11 axis could enable early DIC risk stratification and novel interventions.
Impact: Bridges human predictive biomarker data with mechanistic validation in gene-edited mice, uncovering a novel immunocoagulation pathway in bacterial sepsis.
Clinical Implications: IFNβ could serve as an early biomarker for DIC risk, and MALAT1/caspase-11 signaling represents a therapeutic target to prevent sepsis-associated coagulopathy.
Key Findings
- Admission plasma IFNβ, but not HMGB1, correlates with 48-hour onset of septic DIC.
- IFNβ induces macrophage MALAT1, which lowers GPX4 activity via YY1/Hba-a1, facilitating LPS internalization and caspase-11 activation.
- Macrophage-specific Malat1 deletion protects against caspase-11/GSDMD–dependent phosphatidylserine exposure and bacteria-induced coagulation.
Methodological Strengths
- Integration of human biomarker association with transcriptomics and mechanistic validation in gene-modified mice.
- Clear signaling cascade delineation linking IFNβ, MALAT1, GPX4, and caspase-11.
Limitations
- Clinical cohort details (size, external validation) are limited in the abstract.
- Translational steps for targeting MALAT1/GPX4/caspase-11 in humans remain to be defined.
Future Directions: Prospective validation of IFNβ for DIC prediction, development of MALAT1/GPX4 modulators, and early-phase trials to prevent sepsis-associated coagulopathy.
BACKGROUND: Our previous animal studies suggested the critical role of type I interferons (IFNβ) and high-mobility group box 1 (HMGB1) axis in coagulation; however, the predictive value of IFNβ/HMGB1 for the clinical onset of septic disseminated intravascular coagulation (DIC) remains unknown. OBJECTIVES: This study aims to further elaborate on the pathogenesis of sepsis-associated DIC and identify potential biomarkers suitable for the early prediction of DIC. METHODS: The plasma levels of IFNβ/HMGB1 were determined in septic patients without DIC at admission. The onset of septic DIC was assessed 48 h thereafter. We subsequently compared the leukocyte transcriptomes of non-DIC with and DIC patients. A series of gene-modified mice, including IFNα/βR1 RESULTS: The plasma level of IFNβ but not HMGB1 in septic patients shows a consistent correlation with the onset of DIC. We identified a HMGB1-bypassing signaling pathway where IFNβ stimulates macrophages to express high levels of the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in response to gram-negative bacteria. Deletion of Malat1 specifically in macrophages restores GSH (glutathione) exhaustion and enhances GPX4 activity by maintaining YY1-mediated Hba-a1 expression, which dampens lipopolysaccharide (LPS) internalization and caspase-11 activation, and suppresses caspase-11/GSDMD-dependent phosphatidylserine (PS) exposure, thereby protecting against bacteria-induced coagulation. CONCLUSION: Our study unveils a novel immunocoagulation pathway: MALAT1 fuels caspase-11-dependent coagulation by inhibiting GPX4 activity, which provides new insights into the coagulation mechanisms in bacterial sepsis.
3. The role of transcranial Doppler in predicting the incidence and prognosis of sepsis-associated encephalopathy.
In a registered prospective cohort of 93 septic ICU patients, daily TCD showed that elevated PI and RI strongly predicted SAE; day-1 PI ≥1.30 achieved AUC 0.963 with 95% sensitivity and 100% specificity. PI also predicted mortality, supporting early bedside neuro-hemodynamic risk stratification.
Impact: Offers a non-invasive, reproducible early predictor for SAE and mortality with actionable cutoffs, supporting implementation in ICU protocols.
Clinical Implications: Incorporating day-1 TCD PI (≥1.30) and day-3 RI (≥0.67) into ICU screening may enable early identification of SAE risk, prioritizing neuroprotective strategies and monitoring.
Key Findings
- Day-1 PI ≥1.30 predicted SAE with AUC 0.963 (95.45% sensitivity, 100% specificity).
- Day-3 RI ≥0.67 predicted SAE with AUC 0.971 (95.45% sensitivity, 95.92% specificity).
- Higher PI/RI and lower mFV were associated with SAE, higher severity scores, and increased 28-day mortality.
Methodological Strengths
- Prospective design with daily standardized TCD assessments and predefined SAE criteria.
- Trial preregistration and strong diagnostic performance with clear cutoffs.
Limitations
- Single-center study with modest sample size may limit generalizability.
- External validation and impact on clinical decision-making were not tested.
Future Directions: Multicenter validation of TCD thresholds, integration into sepsis bundles, and testing whether TCD-guided interventions improve neurological outcomes.
BACKGROUND: Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, contributing to poor outcomes and increased mortality. Early detection remains challenging due to the absence of observable direct brain injury. Transcranial Doppler (TCD) ultrasonography provides a non-invasive, bedside tool for assessing cerebral hemodynamics and may help identify patients at risk. SAE was defined as new-onset delirium (positive CAM-ICU) or unexplained coma (GCS < 8) not attributable to structural or metabolic causes. This study aimed to evaluate the role of TCD in predicting the incidence and prognosis of SAE in septic patients admitted to the ICU. METHODS: This prospective cohort study included 93 patients with sepsis. Demographic, clinical, and laboratory data were recorded upon admission. Daily TCD was performed for seven consecutive days to measure the pulsatility index (PI) and resistive index (RI). Neurological dysfunction was assessed daily using the Confusion Assessment Method for the ICU (CAM-ICU) and the Glasgow Coma Scale (GCS). RESULTS: A total of 93 patients were included, of whom 44 (47.3%) developed SAE. SAE patients showed greater illness severity, with higher median SOFA (6 [5-7] vs. 5 [3-6], p < 0.001) and APACHE II (14 [12-17] vs. 11 [9-14], p < 0.001) scores, and higher 28-day mortality (61.4% vs. 22.4%, p < 0.001). The median PI and RI were consistently higher in SAE patients across all study days, while the mean flow velocity (mFV) was lower. PI on day 1 had the best accuracy for predicting SAE, with a cutoff ≥ 1.30 (AUC: 0.963, sensitivity 95.45%, specificity 100%). RI on day 3 was also highly predictive (AUC: 0.971, cutoff ≥ 0.67, sensitivity 95.45%, specificity 95.92%). CONCLUSIONS: In this sample of septic patients, PI and RI are strong predictors of SAE, with PI serving as a reliable early indicator of both SAE and mortality. Trial Preregistration The study was registered in the Pan African Clinical Trials Registry: PACTR202410707982429, date: 7/10/2024.