SHOCK最新文献

Introduction: Trauma and hemorrhagic shock (T/HS) are associated with multiple organ injury. Antithrombin (AT) has anti-inflammatory and organ protective activity through its interaction with endothelial heparan sulfate containing a 3-O-sulfate modification. Our objective was to examine the effects of T/HS on 3-O-sulfated (3-OS) heparan sulfate expression and determine whether AT-heparan sulfate interactions are necessary for its anti-inflammatory properties.

Methods: Male Sprague Dawley rats underwent laparotomy, gut distension and fixed-pressure hemorrhagic shock (HS) and resuscitation. Liquid chromatography-coupled mass spectrometry analyses were performed to measure pulmonary and plasma heparan sulfate di/tetrasaccharides. Pulmonary mRNA levels were assessed by nCounter panel. Rats were treated with vehicle or surfen (1 mg/kg), a small molecule heparan sulfate antagonist, to block the interaction between AT and endothelial cells prior to T/HS and resuscitated with fresh frozen plasma (FFP), lactated Ringer's (LR), or AT-supplemented LR. Lung injury was assessed histologically for injury and fibrin deposition and immunostained for myeloperoxidase (MPO). Plasma was assessed for circulating inflammatory biomarkers.

Results: T/HS significantly reduced pulmonary expression of 6-O and 3-O sulfated heparan sulfate, which was associated with reduced pulmonary 6-O- and 3-O-sulfotransferase mRNA levels. Surfen increased fibrin deposition and inflammatory cell infiltration into pulmonary tissue in T/HS rats resuscitated with FFP but had no effect in LR resuscitated rats. Although T/HS and LR resuscitation worsened histologic lung injury compared to sham, regardless of surfen treatment, lung injury was notably improved in FFP resuscitated rodents pre-treated with vehicle but not surfen. Surfen abrogated the anti-inflammatory effects of FFP, indicated by notable increases in circulating levels of multiple pro-inflammatory mediators compared to rats pre-treated with vehicle. Finally, we observed significant increases in pulmonary fibrin and MPO staining in rats pre-treated with surfen followed by resuscitation with LR supplemented with AT compared to vehicle, which was associated with notable increases in lung injury scores.

Conclusions: T/HS causes pronounced reductions in pulmonary expression of 3-OS heparan sulfate, which is essential to AT's anti-thrombotic and anti-inflammatory activity. Blocking the interaction between AT and the endothelium attenuates the anti-thromboinflammatory and organ protective properties of FFP, suggesting that AT-endothelial anticoagulant function and anti-inflammatory signaling is important for organ protection during T/HS.

Introduction: The understanding of the interaction of closed-loop control of ventilation and oxygenation, specifically fraction of inspired oxygen (FiO2) and positive end-expiratory pressure (PEEP), and fluid resuscitation after burn injury and acute lung injury from smoke inhalation is limited. We compared the effectiveness of FiO2, PEEP, and ventilation adjusted automatically using adaptive support ventilation (ASV) and decision support fluid resuscitation based on urine output in a clinically relevant conscious ovine model of lung injury secondary to combined smoke inhalation and major burn injury.

Methods: Sheep were subjected to burn and smoke inhalation injury under deep anesthesia and analgesia. After injury, sheep were randomly allocated to two groups. 1) Closed-loop group: automated mechanical ventilation (ASV), oxygen FiO2 and PEEP (n = 9); and 2) Control group: mechanically ventilated with standard ASV mode (n = 8). FiO2, PEEP, and the percentage of the minute volume (%MV) were automatically adjusted in group 1, whereas PEEP was held at 5 cmH2O, and FiO2 and %MV were manually adjusted in group 2. Decision support fluid resuscitation was guided based on urine output. Cardiopulmonary hemodynamics were monitored for 48 h.

Results: There were no differences in body weight and the severity of smoke injury between the two groups. The Closed-loop group resulted in significantly higher PEEP, %MV, static lung compliance, and survival rate; the driving pressure was significantly lower compared to the Control group. In the Closed-loop group, the net fluid balance at 48 h was significantly greater than in the Control group.

Conclusion: Closed-loop ventilation and oxygenation with decision support fluid resuscitation improve lung mechanics and survival in sheep with combined burn and smoke inhalation. There were no negative interactions observed between automated PEEP control and fluid management.

Abstract: Severe acute pancreatitis (SAP) is a highly morbid acute digestive disorder linked to pyroptosis. N-acetyltransferase 10 (NAT10) facilitates the production of N4-acetylcytidine (ac4C) modifications in mRNA, thereby contributing to the progression of various diseases. However, the specific role of NAT10 in SAP remains to be elucidated. This study aimed to elucidate the mechanism through which NAT10 mediates pyroptosis in SAP. Sprague-Dawley rats and AR42J rat pancreatic exocrine cells were used to establish in vivo and in vitro models of SAP. The levels of ac4C and NAT10 expression were quantified using dot blot analysis and quantitative real-time PCR (qPCR). Assessment of cell viability, apoptosis, amylase content, and concentrations of lactate dehydrogenase (LDH), interleukin (IL)-1β, and IL-18 was conducted to evaluate the severity of SAP both in vivo and in vitro. Pyroptosis was assessed by measuring caspase-1 and gasdermin D (GSDMD)-N-terminal (GSDMD-N) expression. Further mechanistic insights were gained using methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), and dual-luciferase reporter assays. Our findings indicate that the levels of ac4C modification and NAT10 were elevated in both in vivo and in vitro SAP models. Knockdown of NAT10 inhibited cell death and reduced the levels of amylase, LDH, IL-1β, and IL-18 as well as the protein expression of caspase-1 and GSDMD-N, suggesting that NAT10 knockdown suppresses pyroptosis in SAP cell models. Mechanistically, NAT10 knockdown decreased the expression and stability of NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) mRNA by inhibiting ac4C modification of NLRP3. Moreover, NAT10 knockdown alleviated pancreatic tissue pathology, mitigated SAP severity, and suppressed pyroptosis in an SAP rat model. Collectively, these results demonstrate that NAT10 exacerbates pancreatic injury in SAP by promoting pyroptosis through ac4C modification of NLRP3, thereby enhancing its expression. These findings suggest a potential novel therapeutic target for SAP.

Objective: Recent studies have proposed that Krebs cycle metabolites may serve as potential biomarkers for prognosis in sepsis. However, whether these metabolites are associated with disease severity and can be applied to improve the effectiveness of current prognosis assessment in sepsis remains unclear and is explored in this study.

Methods: This prospective multicenter cohort study was conducted in medical intensive care units (ICUs). From December 2019 to September 2022, consecutive patients admitted to medical ICUs for sepsis were screened and recruited. Plasma samples were obtained for measurements of cytokines and Krebs cycle metabolites, including citrate/isocitrate, cis-aconitate, alpha-ketoglutarate, succinate, fumarate and malate.

Results: In total, 97 patients admitted for sepsis were enrolled in the study. The 28-day mortality rate was 17.5%, and non-survivors exhibited significantly increased plasma lactate levels and Sequential Organ Failure Assessment (SOFA) scores. Plasma levels of Krebs cycle metabolites were significantly correlated with both plasma lactate and interleukin-6 levels. Except for citrate/isocitrate, all Krebs cycle metabolites were significantly elevated in patients with acute kidney injury. Multivariate Cox proportional hazard models, adjusted for plasma lactate levels and SOFA scores, revealed that plasma levels of alpha-ketoglutarate (adjusted hazard ratio [HR]: 2.404, P = 0.002), fumarate (adjusted HR: 1.904, P = 0.001) and malate (adjusted HR: 1.327, P = 0.019) were associated with increased risk of 28-day mortality.

Conclusions: Study findings indicate that Krebs cycle metabolites, particularly alpha-ketoglutarate, fumarate, and malate, when applied with SOFA score, might enhance prognostic assessment in patients with sepsis.

Abstract: Background : The interrelation between the plasma proteome and plasma metabolome with sepsis presents a multifaceted dynamic that necessitates further research to elucidate the underlying causal mechanisms. Methods : Our investigation used public genome-wide association study data to explore the relationships among the plasma proteome, metabolome, and sepsis, considering different sepsis subgroup. Initially, two-sample Mendelian randomization established causal connections between the plasma proteome and metabolome with sepsis. Subsequently, multivariate and iterative Mendelian randomization analyses were performed to understand the complex interactions in plasma during sepsis. The validity of these findings was supported by thorough sensitivity analyses. Result : The study identified 25 plasma proteins that enhance risk and 34 that act as protective agents in sepsis. After P value adjustment (0.05/1306), ICAM5 emerged with a positive correlation to sepsis susceptibility ( P value = 2.14E-05, OR = 1.10, 95% CI = 1.05-1.15), with this significance preserved across three sepsis subgroup examined. Additionally, 29 plasma metabolites were recognized as risk factors, and 15 as protective factors for sepsis outcomes. After P value adjustment (0.05/997), elevated levels of 1,2,3-benzenetriol sulfate (2) was significantly associated with increased sepsis risk ( P value = 3.37E-05, OR = 1.18, 95% CI = 1.09-1.28). Further scrutiny revealed that this plasma metabolite notably augments the abundance of ICAM5 protein ( P value = 3.52E-04, OR = 1.11, 95% CI = 1.04-1.17), devoid of any detected heterogeneity, pleiotropy, or reverse causality. Mediated Mendelian randomization revealed ICAM5 mediated 11.9% of 1,2,3-benzenetriol sulfate (2)'s total effect on sepsis progression. Conclusion : This study details the causal link between the plasma proteome and metabolome with sepsis, highlighting the roles of ICAM5 and 1,2,3-benzenetriol sulfate (2) in sepsis progression, both independently and through crosstalk.

Abstract: The variant single nucleotide polymorphism rs8104571 has been associated with poor outcomes following traumatic brain injury (TBI) and is most prevalent in those of African ancestry. This single nucleotide polymorphism (SNP) resides within a gene coding for the TRPM4 protein, which complexes with SUR1 protein to create a transmembrane ion channel and is believed to contribute to cellular swelling and cell death in neurological tissue. Our study evaluates the relationship between circulating TRPM4 and SUR1, rs8104571 genotype, and clinical outcome in TBI patients. Trauma patients with moderate to severe TBI were included in this retrospective study. rs8104571 genotyping and admission plasma TRPM4 and SUR1 quantification were performed with real-time PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Adequate plasma for TRPM4 and SUR1 ELISA quantification was available for 289 patients, 54 of whom were African American (AA). Plasma TRPM4 concentration was increased in those with a variant rs8104571 allele compared with wild type when controlling for demographics and injury characteristics in the overall cohort ( P = 0.04) and within the AA subgroup ( P = 0.01). There was no significant association between plasma TRPM4 or SUR1 and clinical outcome (each P > 0.05). Plasma TRPM4 abundance increased with acute kidney injury severity ( P = 0.02). The association between increased plasma TRPM4 and variant rs810457 supports an underlying mechanism involving increased neuroinflammation with a subsequent increase in the leakage of TRPM4 from the central nervous system into circulation. Alternative sources of plasma TRPM4 including the kidney cannot be excluded and may play a significant role in the pathophysiology of trauma as well.

Abstract: Sepsis results from a dysregulated host immune response to infection and is responsible for ~11 million deaths each year. In the laboratory, many aspects of sepsis can be replicated using a cecal ligation and puncture model, which is considered the most clinically relevant rodent model of sepsis. In the present study, histological and biomarker multiplex analyses revealed that the cecal ligation and puncture model initiated a large-scale inflammatory response in mice by 24 h, with evidence of acute organ damage by 48-72 h. While many typical proinflammatory cytokine/chemokines were systemically elevated, a specific array including IL-10, eotaxin, MIP-1α, MIP-1β, MCP-1, and RANTES noticeably increased just prior to animals reaching the humane endpoint. Treatment of mice with 10 μg of a synthetic 68-amino acid peptide derived from an immunomodulatory molecule secreted by a parasitic worm of humans and livestock, F. hepatica , termed F. hepatica helminth defense molecule, potently suppressed the systemic inflammatory profile, protected mice against acute kidney injury, and improved survival between 48 and 72 h after procedure. These results suggest that the anti-inflammatory parasite-derived F. hepatica helminth defense molecule peptide has potential as a biotherapeutic treatment for sepsis.

Abstract: Sepsis is a life-threatening organ dysfunction that occurs due to a dysregulated host response to infection. Septic-associated liver injury (SALI) has been closely linked to the prognosis and mortality of sepsis. Recent investigations have delved into the gut-liver axis and its association with SALI, identifying its pivotal role in the gut microbiota. Bacterial translocation and the onset of SALI can occur due to an imbalance in the gut microbiota, impairing the function of the gut barrier. Moreover, their metabolites might exacerbate or initiate SALI by modulating immune responses. Nevertheless, interventions to restore the balance of the gut microbiota, such as the administration of probiotics, fecal microbiota transplantation, or dietary adjustments, may ameliorate SALI and enhance the prognosis and survival rates of septic patients. This review aimed to elucidate the function of the gut microbiota in the genesis and procession of SALI and its potential therapeutic value, offering a deeper understanding of the pathogenesis and therapeutic avenues for SALI.

Abstract: In natural disasters such as earthquakes and landslides, the main problem that wounded survivors are confronted with is crush syndrome (CS). The aim of this study was to explore more convenient and effective early treatment measures for it. In the present study, we investigated the protective effect of fasciotomy combined with different concentration of hypertonic saline flushing with CS rats. CS model was prepared by compressing the buttocks and both lowering limbs of rats with 7.5 kg dumbbell for 4 h. The rats were divided into 10 groups, which were normal control group, model group, incision without flushing group, 0.45%, 0.9%, 3%, 5%, 7% saline group, 3%-0.45% and 7%-0.45% saline alternating flushing group, respectively. Six hours after the treatment, the blood was sampled for measurement of the potassium, calcium, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, creatinine, urea, myoglobin, and lactic acid content. The blood flow of the compressed tissue and kidneys, the pathological changes of the kidneys, and the survival rate of 3%-0.45% saline alternating flushing group were also observed. The experimental results showed that fasciotomy alone for treatment cannot improve the presentation of CS of rats. Instead, hypertonic saline flushing significantly improved the glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, creatinine, urea indices, blood flow of muscles, and kidneys. It also enormously decreased the blood K+, myoglobin, lactic acid concentration, and slight increased the blood Ca 2+ . Among them, alternating flushing with 3%-0.45% saline had the best therapeutic effect on CS. Finally, it can be found that 3%-0.45% saline treatment regimen dramatically raised the survival rate of CS rats. All in all, this study suggests that fasciotomy combined with hypertonic saline flushing is a good therapeutic approach for CS.

Abstract: Introduction: The prehospital environment is fraught with operational constraints, making it difficult to assess the need for resources such as lifesaving interventions (LSI) for adults with traumatic injuries. While invasive methods such as lactate have been found to be highly predictive for estimating injury severity and resource requirements, noninvasive methods, to include continuous vital signs ( VS ), have the potential to provide prognostic information that can be quickly acquired, interpreted, and incorporated into decision making. In this work, we hypothesized that an analysis of continuous VS would have predictive capacity comparable to lactate and other laboratory tests for the prediction of injury severity, need for LSIs and intensive care unit admission. Methods: In this preplanned secondary analysis of 300 prospectively enrolled patients, venous blood samples were collected in the prehospital environment aboard a helicopter and analyzed with a portable lab device. Patients were transported to the primary adult resource center for trauma in the state of Maryland. Continuous VS were simultaneously collected. Descriptive statistics were used to describe the cohort and predictive models were constructed using a regularized gradient boosting framework with 10-fold cross-validation with additional analyses using Shapley additive explanations (SHAP). Results: Complete VS and laboratory data from 166 patients were available for analysis. The continuous VS models had better performance for prediction of receiving LSIs and intensive care unit length of stay compared to single (initial) VS measurements. The continuous VS models had comparable performance to models using only laboratory tests in predicting discharge within 24 h (continuous VS model: area under the receiver operating curve [AUROC] 0.71; 95% CI, 0.68-0.75 vs. lactate model: AUROC, 0.65; 95% CI, 0.68; 95% CI, 0.66-0.71). The model using all laboratory data yielded the highest sensitivity and sensitivity (AUROC, 0.77; 95% CI, 0.74-0.81). Discussion: The results from this study suggest that continuous VS obtained from autonomous monitors in an aeromedical environment may be helpful for predicting LSIs and the critical care requirements for traumatically injured adults. The collection and use of noninvasively obtained physiological data during the early stages of prehospital care may be useful for in developing user-friendly early warning systems for identifying potentially unstable trauma patients.