Daily Sepsis Research Analysis

BACKGROUND: Sepsis-Induced Acute Respiratory Distress Syndrome (SI-ARDS) presents significant diagnostic and prognostic challenges due to its complex clinical manifestations and high mortality rate. METHODS: We developed a deep Knowledge-Driven multi-Modal Fusion (KDMF) framework for the accurate diagnosis and prognosis of SI-ARDS. The model leverages multi-modal data, including CT images, CT reports, and laboratory indicators, alongside a disease-specific knowledge graph. RESULTS: KDMF achieves superior performance in predicting SI-ARDS incidence (AUC 0.930) and time to 28-day mortality (AUC 0.843, C-index 0.833). Comprehensive error analysis and ablation studies demonstrate the critical contributions of each data modality and the integrated knowledge graph. CONCLUSIONS: The results highlight the potential of KDMF to enhance early intervention and treatment strategies, underscoring the robustness and interpretability of the framework in clinical applications. Sepsis is a life-threatening condition that can lead to a serious lung injury called ARDS, which is difficult to diagnose early and has a high risk of death. This study developed a computer model called KDMF to help medical practitioners identify sepsis patients who are likely to develop ARDS and predict their risk of death within 28 days. The model combines multiple types of patient data—including scans of the lungs, text from radiology reports, and routine lab results—along with medical knowledge built into the system. When tested on real patient data, the model was highly accurate at predicting both the onset of ARDS and patient survival. It also helped explain which factors, such as specific symptoms or lab values, were most important for its predictions. This tool could support doctors in making faster and more informed decisions, potentially improving treatment and outcomes for high-risk patients in the intensive care unit.

OBJECTIVE: Sepsis-induced acute lung injury (SALI) is a life-threatening complication characterized by uncontrolled inflammation and alveolar macrophage (AM) activation, and contributes significantly to sepsis-related mortality. Cytidine/uridine monophosphate kinase 2 (CMPK2) has emerged as a potential regulator of inflammatory responses, but its role in SALI remains poorly understood. This study aimed to elucidate the molecular mechanisms by which CMPK2 modulates SALI, focusing on its impact on AM polarization and inflammatory signalling pathways, to identify novel therapeutic targets for improving clinical outcomes. METHODS: The biological impact of CMPK2 on SALI was assessed by evaluating the survival rate and histological appearance of lung tissue from a cecal ligation and puncture (CLP)-induced sepsis mouse model. The concentrations of inflammatory factors and oxidative stress indicators were subsequently assessed via enzyme-linked immunosorbent assay (ELISA) and biochemical kits. Flow cytometry and real-time quantitative PCR were utilized to evaluate the polarization types of AMs. RNA sequencing was conducted on AMs from wild-type and CMPK2-deficient mice to explore potential molecular mechanisms involved. Transmission electron microscopy (TEM) was used to examine the mitochondrial ultrastructure in lipopolysaccharide (LPS)-stimulated macrophages. The subcellular localization of CMPK2 in RAW264.7 macrophages was mapped via high-resolution confocal microscopy. Dual-luciferase reporter assays and coimmunoprecipitation (co-IP) were used to investigate the interaction of CMPK2 with NF-κB signalling components. RESULTS: CMPK2 was significantly upregulated in the lung tissue of CLP-induced septic mice, which correlated with increased systemic and pulmonary inflammation, as evidenced by elevated IL-1β, IL-6, and TNF-α levels and a higher lung wet-dry (W-D) ratio. RNA sequencing revealed 2843 DEGs in CLP versus sham mice, with enrichment in Th1/Th2 cell differentiation, NF-κB, NOD-like receptor, and B-cell receptor signalling pathways. CMPK2 deficiency significantly improved survival; reduced lung edema, inflammatory cell infiltration, and microvascular leakage; and decreased cytokine levels in the BALF. TEM revealed that CMPK2 knockdown in LPS-stimulated macrophages mitigated mitochondrial edema and cristae disruption, restoring the mitochondrial membrane potential and ATP levels. Flow cytometry and RT-qPCR confirmed reduced M1 macrophage polarization in CMPK2^-/-^ mice, with decreased expression of M1-specific markers. Mechanistically, CMPK2 interacts with IKKα/β via its C-terminal domain, enhancing NF-κB phosphorylation and NLRP3 inflammasome activation, with the C-terminal domain being essential for this pro-inflammatory activity, whereas deletion of the N-terminal mitochondrial targeting sequence did not abolish CMPK2-mediated NF-κB activation. Inhibition of NF-κB with BAY11-7082 reversed CMPK2-mediated inflammatory effects. Confocal microscopy revealed that LPS stimulation induced CMPK2 translocation from the cytoplasm to the nucleus, suggesting that LPS plays a dynamic role in inflammatory signalling. CONCLUSION: CMPK2 exacerbates SALI, at least in part, by promoting M1-skewed alveolar macrophage responses and enhancing NF-κB/NLRP3-associated inflammatory signalling. Mechanistically, CMPK2 associates with IKKα/β through its C-terminal domain, whereas the canonical N-terminal mitochondrial targeting sequence is not strictly required for its pro-inflammatory activity in this context. These findings highlight CMPK2 as a novel therapeutic target for alleviating SALI, offering potential for precision interventions to improve the clinical management of sepsis-related lung injury.

BACKGROUND: Sepsis remains a critical challenge in intensive care, necessitating reliable animal models that accurately mimic human pathophysiological responses. While cecal ligation and puncture (CLP) is widely considered the gold standard, its inherent variability often limits reproducibility. This study aimed to optimize a fecal intraperitoneal injection (FIP) murine model by evaluating the impact of fecal preparation (fresh vs. lyophilized) and dosage (0.5-1.0 g/kg) on model stability. We systematically compared the optimized FIP model with the conventional CLP method in male BALB/c mice to define their respective pathophysiological characteristics and suitability for therapeutic screening. RESULTS: Fresh fecal suspensions significantly enhanced model reproducibility compared to dried preparations, which exhibited inconsistent virulence. An optimized FIP dose of 0.7 g/kg induced a hyperacute sepsis phenotype, characterized by rapid systemic bacterial dissemination and severe acute organ damage within 24 h. Crucially, semi-quantitative histological scoring confirmed that FIP triggered a synchronized, hyperacute injury spike across the lung, kidney, liver, and heart, whereas the CLP model exhibited a more protracted, progressive exacerbation of organ dysfunction through 48 h. Hematological analysis further revealed that while both models induced systemic inflammation, the FIP model provided a much sharper and predictable onset of severe leukopenia and multi-organ failure. CONCLUSIONS: The optimized FIP model, characterized by its procedural simplicity, high controllability, and superior reproducibility, serves as a robust platform for investigating the early, fulminant pathophysiological mechanisms of unmitigated sepsis. Conversely, the CLP model remains the preferred choice for studies focusing on protracted infection and chronic organ dysfunction. These findings provide a methodological framework for selecting appropriate sepsis models based on specific research objectives in experimental medicine. CLINICAL TRIAL NUMBER: Not applicable.