SHOCK最新文献

Aim: To elucidate whether the application of the mitochondrial division inhibitor Mdivi-1 can protect organ function and prolong the treatment window for traumatic hemorrhagic shock.

Methods: Before definitive haemostasis treatment, Mdivi-1 (0.25 mg/kg, 0.5 mg/kg and 1 mg/kg) was administered to uncontrolled haemorrhagic shock (UHS) model rats. Lactate Ringer's solution plus hydroxyethyl starch (130/0.4) was used as a control. The effects of Mdivi-1 on blood loss, fluid demand, survival time, vital organ function, myocardial mitochondrial structure, and mitochondrial function of the heart, liver, kidney and intestine, and oxidative stress at 1 hour after hypotensive resuscitation (50-60 mmHg) were investigated. In addition, we investigated the effect of varying doses of Mdivi-1 on the maintenance time of hypotensive resuscitation without definitive haemostasis and the beneficial effect of Mdivi-1 after prolonging the duration of hypotensive resuscitation to 2 hours.

Results: Compared to conventional resuscitative fluid, Mdivi-1 significantly reduced blood loss and fluid demand, improved important organ functions during hypotensive resuscitation, improved animal survival and reduced the incidence of early death. Mdivi-1 significantly alleviated oxidative stress injury, reduced mitochondrial damage and restored myocardial mitochondrial structure and mitochondrial function of the heart, liver, kidney and intestine. In addition, Mdivi-1 increased the maintenance time of hypotensive resuscitation and improved rat survival after the duration of hypotensive resuscitation was prolonged to 2 h.

Conclusions: Mdivi-1 significantly prolonged the treatment window for traumatic hemorrhagic shock to 2 hours in UHS model rats. The underlying mechanism may be that Mdivi-1 inhibits excessive mitochondrial fission and oxidative stress and improves the structure and function of mitochondria.

Abstract: Septic cardiomyopathy is linked to a dysregulation in mitochondrial integrity and elevated mortality rates, for which an efficacious treatment remains elusive. PDS, a panaxadiol saponin extracted from ginseng stem and leaf. This study identified the protective effects of PDS and DEX in LPS-induced cardiomyopathy and explored the mechanism of them treating LPS-induced cardiomyopathy from the perspectives of mitochondrial quality control. DEX and PDS enhance antioxidant defense by degrading Keap1 to activate Nrf2, activate mitochondrial occurrence protein PGC-1α and fusion protein OPA1, Mfn1, Mfn2 expression, inhibit phosphorylation of mitochondrial fission protein Drp1, aiming to maintain normal structure and function of mitochondrial, thereby preserving oxidative phosphorylation capacity. In summary, our findings highlighted that the protective efficacy of PDS and DEX in maintaining mitochondrial in LPS-induced cardiomyopathy, and mechanism improving mitochondrial quality control at least in part by promoting Nrf2 activation.

Abstract: Severe burn injuries induce acute and chronic susceptibility to infections, which is largely attributed to a hyper-pro-inflammatory response followed by a chronic anti-inflammatory response. Concurrent inhalation injury (B + I) causes airway inflammation. Pulmonary macrophages and neutrophils are "hyperactive" with increased reactive oxygen (ROS) and nitrogen species (RONS) activity, but are unable to clear infection, causing airway damage upon activation. Nuclear Factor-Erythroid-2-Related Factor (NRF2) is a critical immunomodulatory component that induces compensatory anti-inflammatory pathways when activated. On the other hand, inhibition of Mammalian Target of Rapamycin (mTOR) reduces pro-inflammatory responses. The therapeutic use of these targets is limited, as known modulators of these pathways are insoluble in saline and require long-term administration. A biocompatible NRF2 agonist (CDDO) and rapamycin (RAPA) poly (lactic-co-glycolic acid) (PLGA) microparticles (MP) were created, which we hypothesized would reduce the acute hyper-inflammatory response in our murine model of B + I injury. BI-injured mice that received CDDO-MP or both CDDO-MP and RAPA-MP (Combo-MP) an hour after injury displayed significant changes in the activation patterns of pulmonary and systemic immune genes and their associated immune pathways 48 h after injury. For example, mice treated with Combo-MP showed a significant reduction in inflammatory gene expression compared to untreated or CDDO-MP-treated mice. We also hypothesized that Combo-MP therapy would acutely decrease bacterial susceptibility after injury. BI-injured mice that received Combo-MP an hour after injury, inoculated 48 h later with Pseudomonas aeruginosa (PAO1), and sacrificed 48 h after infection, displayed significantly decreased bacterial counts in the lungs and liver versus untreated B + I mice. This reduction in infection was accompanied by significantly altered lung and plasma cytokine profiles and immune reprogramming of pulmonary and splenic cells. Our findings strongly suggest that multimodal MP-based therapy holds considerable promise for reprogramming the immune response after burn injuries, particularly by mitigating the hyper-inflammatory phase, and preventing subsequent susceptibility to infection.

Introduction: Gut ischemia and reperfusion (I/R) injury promotes the release of damage-associated molecular patterns (DAMPs) such as extracellular cold-inducible RNA-binding protein (eCIRP). Gut I/R often leads to acute lung injury (ALI), a major contributor to mortality. Milk fat globule-epidermal growth factor-factor VIII-derived oligopeptide-3 (MOP3) is a novel peptide that attenuates sepsis by opsonizing eCIRP and facilitating its phagocytic clearance. We hypothesized that MOP3 reduces inflammation, mitigates gut and lung injury, and improves survival in gut I/R injury.

Methods: Phagocytosis of FITC-labeled eCIRP by intestinal epithelial cells was determined by confocal microscopy, and the cell supernatant was evaluated for cytokine expression by ELISA. Adult C57BL/6 mice underwent 60 min of gut ischemia via superior mesenteric artery occlusion followed by reperfusion. Mice were treated with MOP3 or vehicle via retro-orbital injection at the time of reperfusion. At 4 h post-I/R, blood, gut, and lungs were harvested for further assay. In additional mice, 36 h survival was assessed. Plasma levels of injury and inflammatory markers were measured with colorimetry and ELISA, respectively. Tissue mRNA expression was measured with qPCR. Myeloperoxidase (MPO), TUNEL, histologic injury, and ZO-1 immunohistochemistry assessments were performed.

Results: MOP3 significantly increased eCIRP phagocytosis by intestinal epithelial cells (p < 0.01) and decreased IL-6 release (p < 0.001). Gut I/R caused elevated plasma eCIRP levels. MOP3 treatment significantly reduced plasma levels of IL-1β (p < 0.01), IL-6 (p < 0.05), and lactate dehydrogenase (p < 0.05) along with a significant decrease in gut (p < 0.05) and lung (p < 0.001) injury scores as well as gut cell death (p < 0.05). Moreover, MOP3 reduced pulmonary levels of chemokines and the granulocyte activation marker MPO after gut I/R. Mechanistically, ZO-1 expression in the gut was decreased following gut I/R injury, while MOP3 significantly reversed the decrease in ZO-1 mRNA expression (p < 0.001). Finally, mice treated with MOP3 exhibited a significant decrease in mortality (p < 0.05).

Conclusions: Treatment with MOP3 effectively mitigates organ injury induced by gut I/R. This beneficial effect is attributed to the facilitation of eCIRP clearance, directing the potential of MOP3 as an innovative therapeutic approach for this critical and often fatal condition.

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 hours. 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. 6 hours after the treatment, the blood was sampled for measurement of the potassium, calcium, AST, ALT, Cr, 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 AST, ALT, Cr, Urea indices, blood flow of muscles and kidneys. It also enormously decreased the blood K+, myoglobin, lactic acid concentration and slight increased the blood Ca2+. 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.

Background: Acute kidney injury (AKI) is a common, fatal complication of acute cholangitis (AC). The link between AC and AKI is poorly understood.

Aims: To delineate the incidence trends, clinical outcomes and healthcare utilization of inpatients with AKI following AC and to explore the risk factors for AKI following AC.

Methods: This population-based retrospective study used the National Inpatient Sample database from 2010 to 2018 to compare the demographics, complications, in-hospital mortality and healthcare utilization between AC patients with and without AKI. Predictors of AKI and the prognostic impact of AKI on in-hospital outcomes were defined using multivariate logistic regression.

Results: The overall incidence of AKI was 24.06% among AC patients. Its trend generally increased annually. AKI was associated with more complications, greater invasive therapy requirements, longer hospital stays, costlier total hospital charges, and higher in-hospital mortality. The risk factors for AKI following AC were advanced age, black race, multiple comorbidities, large hospitals, teaching hospitals, urban hospitals, hospitals in the southern and western USA, choledocholithiasis/cholelithiasis, surgery, percutaneous transhepatic biliary drainage, deficiency anemia, congestive heart failure, coagulopathy, diabetes, hypertension, chronic liver disease, obesity, chronic kidney disease excluding end-stage renal disease, weight loss, acute pancreatitis, and severe sepsis. Female sex, private insurance, elective admission, and endoscopic retrograde cholangiopancreatography were protective factors against AKI in AC patients.

Conclusion: AKI often follows AC and is strongly associated with poor prognosis and increased healthcare utilization. Healthcare professionals should make more efforts to identify patients with AC at risk of AKI and start management promptly to limit adverse outcomes.

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: This study aimed to investigate the protective effect of pentoxifylline (PTX) on vascular endothelial dysfunction in uraemia. The human aortic endothelial cells (HAECs) required for the experiments were all obtained from the National Collection of Authenticated Cell Cultures (Salisbury, UK). The permeability of HAECs was assessed. Each group had six samples. Compared with the healthy volunteer group, HAEC proliferation in the 20% uraemia group was significantly inhibited after 72 h (p < 0.001), co-localisation of nucleotide-binding domain, leucine-rich repeat-containing receptor family pyrin domain-containing 3 (NLRP3) and apoptosis-associated speck-like (ASC) protein induced by uremic serum was enhanced (p < 0.01) and high mobility group box 1 (HMGB1) release was increased (0.594 ± 0.057, p = 0.03). The co-immunoprecipitation of NLRP3, ASC and HMGB1 induced by uremic toxin was also enhanced (p < 0.01), and PTX inhibited this phenomenon. The expression of NLRP3 (0.810 ± 0.032, p = 0.02) and caspase-1 (0.580 ± 0.041, p = 0.03) was increased, whereas the expression of ZO-1 (0.255 ± 0.038, p = 0.03) and VE-cadherin (0.0546 ± 0.053, p = 0.02) was decreased in the uraemia group; compared with the healthy volunteer group, treated with PTX (NLRP3, 0.298 ± 0.042, p = 0.03; caspase-1, 0.310 ± 0.021, p = 0.03; ZO-1, 0.412 ± 0.028, p = 0.02; VE-cadherin, 0.150 ± 0.034, p = 0.02) and MCC950 (NLRP3, 0.432 ± 0.022, p = 0.03; caspase-1, 0.067 ± 0.031, p > 0.05; ZO-1, 0.457 ± 0.026, p = 0.03; VE-cadherin, 0.286 ± 0.017, p = 0.03) lessened this trend. Pentoxifylline promoted the HAEC permeability mediated by uremic toxins (1.507 ± 0.012, p = 0.02). In conclusion, PTX enhances the release of HMGB1, which is dependent on NLRP3 activation, and consequently exerts positive effects on interconnecting proteins, ultimately leading to an improvement in vascular permeability.

Introduction: Hematopoiesis proceeds in a tiered pattern of differentiation, beginning with hematopoietic stem cells (HSC) and culminating in erythroid, myeloid, and lymphoid lineages. Pathologically altered lineage commitment can result in inadequate leukocyte production or dysfunctional cell lines. Drivers of emergency hematopoiesis after burn injury are inadequately defined. Burn injury induces a myeloid predominance associated with infection that worsens outcomes. This study aims to further profile bone marrow HSCs following burn injury in a murine model.

Methods: C57BL/6 mice received burn or sham injury with ~12% total body surface area (TBSA) scald burn on the dorsal surface with subsequent sacrifice at 1, 2, 3, 7 and 10 days post-injury. Bone marrow (BM) from hindlimbs were analyzed for HSC populations via flow cytometry and analyzed using FlowJo Software (version 10.6). Event counts and frequencies were analyzed with multiple unpaired t-tests and linear mixed-effect regression. RT-PCR performed on isolated lineage negative BM cell RNA targeted PU.1, GATA-1, and GATA-3 with subsequent analysis conducted with QuantStudio 3 software. Statistical analysis and representation were performed on GraphPad software (Prism).

Results: Flow cytometry revealed significantly elevated proportions of Long-Term HSCs at 3 days post-injury (p < .05) and Short-Term HSCs at days 2, 3, and 10 (all p < .05) in burn-injured mice. There was a sustained, but not significant, increase in proportions in the multi-potent progenitor (MPP) 2 and 3 subpopulations in the burn cohort compared to sham controls. The common myeloid progenitor (CMP) proportion was significantly higher on days 3 and 10 (both p < .01), while the granulocyte-macrophage progenitor (GMP) proportion increased on days 1, 2, and 10 (p < .05, p < .01, p < .01). Although the megakaryocyte-erythrocyte progenitor (MEP) proportion appeared consistently lower in the burn cohort, this did not reach significance. mRNA analysis resulted in a downregulation of PU.1 on day 1 (p = 0.0002) with an upregulation by day 7 (p < 0.01). GATA-1 downregulation occurred by day 7 (p < 0.05), and GATA3 showed downregulation on days 3 and 7 (p < 0.05).

Discussion: Full-thickness burn results in an emergency hematopoiesis via proportional increase of Long Term-HSC and Short Term-HSC/MPP1 subpopulations beginning in the early post-injury period. Subsequent lineage commitment displays a myeloid predominance with a shift toward myeloid progenitors with mRNA analysis corroborating this finding with associated upregulation of PU.1 and downregulation of GATA-1 and GATA-3. Further studies are needed to understand how burn-induced emergency hematopoiesis may predispose to infection by pathologic lineage selection.