SHOCK最新文献

Background: The uncontrolled inflammatory cascade triggered by hemorrhagic shock (HS) can exacerbate tissue damage and organ dysfunction. Neutrophils, as the most abundant type of leukocytes, are key mediators of the innate immune response in the early stages of injury. There is a lack of suitable treatments targeting neutrophils in HS.

Methods: We used machine learning algorithms to identify neutrophil-associated key genes in patients with HS and assessed the diagnostic efficacy of these genes. Weighted gene co-expression network analysis and consensus clustering analysis were performed based on the key genes to explore their role in HS. Finally, we predicted the binding of key genes to drug candidates using molecular docking and observed effects of drug candidates and expression of key genes in animals with HS.

Results: We screened for key genes with good diagnostic efficacy (ARG1, F2RL1, MPP1, RHOG, UPP1) that activate JAK-STAT3 signaling and apoptotic signaling, leading to poor prognosis. Pirinixic acid screened by CTD database has good affinity with key genes, and it can significantly restore the level of inflammatory factors and coagulation function in HS rats, protect the function of vital organs, and prolong the survival time. It was confirmed that pirinixic acid may improve neutrophil immunity disorders by acting on MPP1, RHOG and F2RL1, and thus protect against HS.

Conclusion: The protective effect of pirinixic acid against hemorrhagic shock-induced immune dysregulation is closely associated with the neutrophil genes MPP1, RHOG, and F2RL1.

Background: Circulatory disturbances in sepsis are heterogeneous but often present clinically as a mismatch between peripheral perfusion and tissue oxygenation. Peripheral perfusion index (PI) and central venous oxygen saturation (ScvO₂) have been independently validated as prognostic markers in sepsis; however, their combined utility has not been systematically explored.

Methods: This retrospective cohort study included patients admitted to three intensive care units (ICUs) between January 1, 2015, and December 31, 2021. A novel index, PISO = (PI - 1.1) × ScvO₂, was calculated every 6 hours during the first 72 hours following sepsis onset. Dynamic time warping and hierarchical agglomerative clustering were applied to the 72-hour PISO trajectories to identify sub-phenotypes, with internal validation and sensitivity analysis. Machine learning algorithms were used to predict the sub-phenotypes based on early clinical features. Survival outcomes were assessed using Kaplan-Meier analysis and log-rank tests, with particular focus on the association between 12-hour cumulative fluid balance and 28-day in-hospital survival.

Results: Among 12,975 patients, 5,205 (40.1%) developed sepsis. Of these, 720 patients with complete 6-hourly PI and ScvO₂ data were included. Three distinct PISO sub-phenotypes were identified. Phenotype 3, (n = 190, 33.0%), characterized by a persistently declining trajectory from a negative baseline, was associated with the poorest clinical outcomes. The random forest classifier demonstrated best performance and identified key early clinical features that differentiated each sub-phenotype. Kaplan-Meier analysis revealed that a 12-hour cumulative fluid balance of ≤0 mL was significantly associated with improved 28-day survival in Phenotype 1 (p = 0.038) and Phenotype 2 (p = 0.033).

Conclusions: A persistently negative and declining PISO index within the first 72 hours of sepsis onset identifies a potential-risk sub-phenotype associated with adverse outcomes. Additionally, a non-positive 12-hour cumulative fluid balance post-sepsis onset is associated with improved survival in select phenotypic subgroups.

Objective: This study aims to identify risk factors associated with septic cardiomyopathy (SCM) in patients diagnosed with septic shock and to assess differences in clinical outcomes between those with septic shock alone and those with concomitant SCM.

Methods: A retrospective observational study was conducted on 108 patients diagnosed with septic shock and admitted to Beijing Tongren Hospital, Capital Medical University, between December 2022 and July 2024. Patients were stratified into two groups based on the presence or absence of SCM: the non-SCM group (n = 90) and the SCM group (n = 18). Baseline characteristics, laboratory markers, cardiac function indices, and clinical outcomes were compared between the two groups. Multivariate logistic regression was employed to identify risk factors for SCM. Within the SCM group, outcomes were further analyzed according to survival status to assess the association between cardiac function recovery and mortality.

Results: The incidence of SCM among patients with septic shock was 16.67%. Compared with the non-SCM group, the SCM group showed a significantly higher prevalence of urinary tract infections and a history of diabetes mellitus (p < 0.05). Higher scores were observed for the Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment scales, along with increased levels of admission-day troponin I, interleukin-1 (IL-1), tumor necrosis factor-α, maximum lactic acid (LACmax), maximum brain natriuretic peptide, and peak troponin I (p < 0.05). In contrast, mean arterial pressure at admission, minimum left ventricular ejection fraction (LVEF), and end-point LVEF (LVEFend%) were significantly lower in this group (p < 0.05). Multivariate logistic regression identified elevated IL-1 levels (odds ratio [OR] = 1.14), higher APACHE II scores (OR = 1.13), and increased LACmax (OR = 1.47) as risk factors for SCM (p < 0.05). The presence of SCM was associated with significantly higher in-hospital mortality and increased healthcare costs (p < 0.05). Among patients with SCM, recovery of LVEF and cardiac output was correlated with improved survival outcomes.

Conclusion: Elevated IL-1 levels, increased peak lactic acid concentration, and higher APACHE II scores were associated with the development of SCM in patients with septic shock. SCM was further associated with increased mortality and greater healthcare resource utilization. Restoration of cardiac function, particularly improvements in LVEF and cardiac output, was correlated with improved prognosis and may serve as a valuable indicator of clinical outcomes.

Background: A life-threatening condition, sepsis is defined by dysregulated immune system responses and multi-organ dysfunction. There is still no drug or treatment that can completely and guarantee to cure this condition; available treatments mainly focus on controlling the infection with antibiotics, supporting organ function, and managing symptoms. Although artificial lymphoid tissues (ALTs) have potential for localized immunomodulation, their application is often limited by inadequate biological function and poor structural integrity. To address these issues, we developed a novel bioink that combines gelatin methacryloyl (GelMA) with M13 bacteriophage, a filamentous, non-lytic virus recognized for its immunomodulatory activity, self-assembling capacity, and biocompatibility. Male C57BL/6 mice (8-10 weeks, 22-25 g) were randomly assigned to six groups: sham + normal saline (NS), CLP + NS, CLP + M13, 3D-M13, 3D+M13, and 3D+M13 + CLP. The cecal ligation and puncture (CLP) procedure was applied to induce polymicrobial sepsis. Cell-laden, three-dimensional (3D) bioprinted GelMA scaffolds with or without M13 bacteriophage were surgically implanted on the spleen 35 days prior to sepsis induction. Subsequently, immune, histological, and biochemical parameters were assessed. Compared with GelMA-only scaffolds, M13-containing scaffolds demonstrated improved printability, mechanical stability, cellularity, and angiogenesis. Mice implanted with 3D+M13 scaffolds exhibited significantly reduced levels of pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), as well as higher levels of anti-inflammatory cytokines interleukin-10 (IL-10) and transforming growth factor beta (TGF-β). Additionally, the bacterial load was reduced, and organ injury in the liver, lungs, and kidneys was reduced. Circulating liver enzyme levels were also reduced, suggesting precautionary measures against sepsis-induced hepatic dysfunction. The integration of M13 bacteriophage into GelMA bioink is a distinctive approach that simultaneously enhances the stability of ALT and stimulates anti-inflammatory immune modulation. This dual structural-immunological effect defines a new paradigm for the development of multifunctional biomaterials in the fields of immune regulation and tissue engineering.

Acute kidney injury (AKI) remains a crucial condition associated with poor prognosis in critically ill patients. Renal oxygenation resulting from renal ischemia is a significant contributor to AKI, wherein urine oxygen partial pressure partially indicates renal medullary oxygenation. The partial pressure of oxygen in urine may serve as a potential biomarker for the prediction and prognosis of AKI. Advances in technology have rendered novel non-invasive and real-time method for urinary oxygen detection. This review examines the significance, detecting method and potential clinical utility of urinary oxygen partial pressure to predict AKI.

Reciprocal interactions between the central nervous system and immune are now recognized as critical components of the host response in sepsis. However, the precise mechanism by which the central nervous system modulates immune function remains largely elusive. The cerebrospinal fluid (CSF)-contacting nucleus (CSF-contacting nucleus) is a unique nucleus, with its neurons located in the brain parenchyma and processes extending into the CSF. Here, we demonstrate that the CSF-contacting nucleus plays a protective role in sepsis. We observed a significant Fos high expression within the CSF-contacting nucleus in response to sepsis with immunofluorescence assays. Ablation of the CSF-contacting nucleus exacerbated sepsis severity, result in levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNFα) elevated. Conversely, chemogenetic activation of the CSF-contacting nucleus resulted in a reduction in pro-inflammatory cytokine (IL-1β, IL-6, and TNFα) levels while simultaneously increasing the levels of IL-10. Inhibition of the CSF-contacting nucleus specifically elevated IL-6 levels. Notably, single-cell RNA sequencing was employed to identify key components within the CSF-contacting nucleus that regulate systemic inflammation in septic mice. Our findings indicate an upregulation of immune-related genes in the CSF-contacting nucleus during sepsis. Collectively, our study underscores a significant role of the CSF-contacting nucleus in neuro-immune interactions and suggests its potential as a novel therapeutic target for immune-mediated diseases.

Hemodynamic stabilization and preservation of organ perfusion are central elements in the management of septic shock. This is achieved by fluid resuscitation and by administration of vasoactive agents to secure a time window for definitive cause-directed therapy. Guided by the Surviving Sepsis Campaign, the optimization of vasoactive agent strategies, namely protective hemodynamic management, has become a central focus. Tracing key research over the past 25 years reveals a paradigm shift in vasopressor therapy, from empiricism to goal-directed strategy. This evolution has deepened our understanding of the benefit-risk profile of vasoactive agents and fostered a new conceptual framework regarding organ perfusion and protection. Under this framework, management strategies have advanced from the mere pursuit of hemodynamic parameters to care bundles that integrate the monitoring of organ perfusion, microcirculation, and oxygen metabolism. These advances have optimized agent selection, established safe dosing ranges, and ultimately promoted the widespread adoption of combined and multimodal therapy concepts. This review delineates this transformative journey, synthesizing evidence on the reappraisal of traditional agents and exploring "de-catecholaminization" strategies, thereby aiming to broaden the therapeutic landscape. The integration of artificial intelligence and genomic medicine is expected to further advance personalized management strategies for septic shock.

Background: LPS exposure results in prolonged immune dysfunction in human macrophages. Emerging evidence supports the hypothesis that epigenetic methylation of key pro-inflammatory genes contributes to this phenotype. Our data has shown that in response to LPS exposure extracellular vesicles (EVs) contain high amounts of DNMT mRNA cargo that is transferred to recipient cells with resultant methylation events and gene silencing at TNFα. It is unknown which DNMT isoform is responsible for these methylation events.

Methods: EVs containing DNMT mRNA were generated by exposing human macrophages to LPS. Using siRNAs targeting the individual isoforms of DNMT (1, 3A, and 3B) we generated EVs with selectively packaged DNMT mRNAs for each isoform. Recipient macrophages were treated with these EVs and methylation was assessed using bisulfate sequencing.

Results: siRNAs targeting DNMTs 1, 3A, and 3B achieved successful knockdown. Macrophages exposed to LPS only demonstrated significant increases in DNMT1 mRNA. siRNAs directed at DNMT1 successful knocked down mRNA expression. EVs generated from LPS exposure showed a 2-fold reduction in DNMT1 mRNA (p<0.001). In recipient cells exposed to these EVs, methylation of TNFα was reduced (58.3% vs. 31.3%). This reduction in methylation correlates with increased expression of TNFα mRNA following LPS exposure.

Conclusions: These data demonstrate that DNMT1 is the dominant mRNA isoform responsible for the methylation events and gene silencing seen in human macrophages following LPS exposure. Several pharmacologic therapies exist that selectively target DNMT1 function, which potentially can be utilized to limit the methylation events that occur at TNFα following LPS exposure.

Background: In vivo studies have reported cardiovascular benefits of lactate administration after cardiac arrest (CA). However, it remains unclear whether these improvements are due to direct or indirect myocardial effects of lactate. Therefore, we investigated the effects of lactate administration in an ex vivo CA model.

Methods: Isolated rat hearts were subjected to 20 min of non-shockable CA followed by 40 min of reperfusion. Four groups were analyzed: Control (n=9), reperfused with standard Krebs buffer; Lactate (n=9), reperfused with Krebs containing 20 mmol/L L-lactate; Lact5min (n=5), reperfused with Krebs for 5 min and then with Krebs containing 20 mmol/L L-lactate; LactHyper (n=6), reperfused with hypertonic (Na+ 163 mmol/L) Krebs containing 20 mmol/L L-lactate. Endpoints included rate-pressure product (RPP), left ventricular enddiastolic pressure (LVEDP), coronary flow (CF) and arrhythmia incidence. Troponin and creatine kinase (CK) release, mitochondrial calcium retention capacity (CRC) and mitochondrial respiration were assessed.

Results: RPP recovery at the end of reperfusion was 47±4% of baseline in Control versus 45±4%, 40±3%, and 42±3% in Lactate, Lact5min, and LactHyper (p=ns). LVEDP and CF were comparable across the groups. Ventricular arrhythmias occurred in 44%, 33%, 40%, and 50% of hearts, respectively (p=ns). Troponin and CK levels were similar (p=ns) between Controls and Lactate treated hearts. Mitochondrial functions, which were significantly impaired by CA, did not differ significantly between the two groups.

Conclusion: Lactate administration did not improve post-CA myocardial function and was not deleterious. These findings suggest that the in vivo benefits of lactate administration are unlikely due to direct myocardial effects.