SHOCK最新文献

Severe burn injury induces prolonged immune dysfunction, but the underlying molecular mechanisms remain poorly defined. We hypothesized that burn injury causes epigenetic and transcriptional training of innate immune cells. Splenic F4/80⁺ macrophages were isolated from mice at 2, 9, and 14 days after 20% total body surface area contact burn. Targeted transcriptomics and chromatin profiling revealed a biphasic response: early transcriptional silencing of inflammatory genes (e.g., Stat3 , Traf6 , and Nfkb1 ), followed by increased accessibility and expression of anti-inflammatory loci ( Il-10 and Socs3 ). Metabolic genes showed persistent suppression of mitochondrial and oxidative phosphorylation programs. Canonical pathway analysis indicated early interleukin-10 signaling activation and long-term repression of classical macrophage activation. Chromatin remodeling included nucleosome repositioning events, supporting dynamic, and locus-specific regulation. These findings challenge the notion that burn-induced immune suppression is solely due to systemic inflammation and instead suggest durable, epigenetically programmed alterations in macrophage function.

Objective: Diagnosis of infection in patients with sepsis takes days via culture, and appropriate treatment of pathogens is delayed awaiting results. We hypothesize that we can use RNA sequencing from patients with sepsis to identify novel targets for faster nucleic acid-based tests.

Methods: Cohort study of sepsis patients admitted to the intensive care unit with RNA sequencing was done after obtaining the consent. RNA sequencing data that did not map to the human genome were then aligned to resistance genes and pathogen genomes and used to design novel polymerase chain reaction (PCR) tests. These tests were correlated with blood culture diagnosis and clinical outcomes.

Results: Forty-six patients were enrolled, and samples from 87 time points were collected. These samples resulted in 8.6 billion RNA sequencing reads to identify pathogen RNA. PCR target discovery focused on positive blood cultures (n = 40 total) due to Escherichia coli (five samples), Staphylococcus aureus (six samples), and Pseudomonas aeruginosa (three samples) as well as identification of resistance genes. From RNA sequencing reads, 40 targets were defined and tested by quantitative PCR. In a cohort of patients (9 of 46) with available samples, some of the proposed PCRs identified all cases of positive blood cultures ( P. aeruginosa and S. aureus ); E. coli had no positive blood cultures in this cohort.

Conclusions: RNA sequencing from patients with sepsis can identify RNA from pathogens causing the infection. This is used to design PCR primers that identify patients with positive blood cultures. Translation of these primers to clinical microbiology machines will allow the diagnosis faster than blood culture.

Nearly half of the burn patients in the United States are under the influence of alcohol at the time of injury, and alcohol intoxication is associated with poor clinical outcomes. Ethanol has been shown to worsen burn-induced intestinal dysfunction and inflammation, facilitating bacterial translocation from the intestine to the mesenteric lymph nodes and systemic circulation. Regenerating islet-derived protein 3-gamma (REG3G), an antimicrobial peptide crucial for maintaining intestinal homeostasis, protects mice from ethanol-induced bacterial translocation. In this study, we utilized a murine model to determine whether REG3G protects against the combined effects of acute ethanol exposure and burn injury. Mice with intestinal epithelial cell-specific overexpression of REG3G (Reg3g-Tg) were evaluated for gut barrier function, intestinal and hepatic inflammatory cytokines, and antimicrobial peptide expression after ethanol and burn injury. Additionally, we performed 16S rRNA gene sequencing of fecal microbiota. Our results demonstrate that ethanol exposure before burn injury downregulates the antimicrobial peptide REG3G in the ileum, when compared to burn alone. Intestine-specific overexpression of REG3G reversed several gastrointestinal effects of the combined injury, reducing intestinal inflammation and preventing bacterial translocation to the lymph nodes. Moreover, Reg3g-Tg mice exhibited reduced liver inflammation after combined injury, suggesting that improving intestinal function can also influence extra-intestinal organs. These findings highlight the therapeutic potential of REG3G in mitigating the effects of burn injury and alcohol intoxication.

Lipopolysaccharide, interleukin-1β, and tumor necrosis factor-α induce glomerular microvascular endothelial cell permeability and production of IL-6 and IL-8, suggesting that glomerular endothelial activation may contribute to sepsis-related acute kidney injury.

Background: Sepsis is characterized by systemic inflammation and microcirculatory dysfunction, contributing to multiorgan failure. In the gastrointestinal tract, impaired microcirculation and mitochondrial dysfunction promote barrier failure and bacterial translocation. While dobutamine is commonly used to augment cardiac output in septic shock, its direct effects on intestinal microcirculation and mitochondrial respiration remain unclear. The microcirculatory impact of adjunctive low-dose vasopressin is similarly uncertain.

Methods: Twenty-four hours after colon ascendens stent peritonitis or sham surgery, 88 male Wistar rats were randomized to receive vehicle, vasopressin, dobutamine, or their combination under septic or sham conditions. Colonic and hepatic microcirculatory oxygenation (µHbO 2 ) and microvascular blood flow (µFlow) were measured for 90 minutes using tissue-reflectance spectrophotometry and laser Doppler flowmetry. Mitochondrial respiration was assessed in colon and liver homogenates of septic animals by high-resolution respirometry. Microcirculatory data were analyzed using mixed-effects models with Tukey's and Dunnett's post hoc tests. Mitochondrial data were analyzed using the Kruskal-Wallis test. A two-sided P < 0.05 was considered statistically significant.

Results: In septic rats, dobutamine significantly improved colonic microvascular oxygenation (∆µHbO 2 10.2% ± 13.4% vs. -2.3% ± 4.4% in controls and vs. baseline, P < 0.05) and microvascular blood flow (∆µFlow 30 ± 20 arbitrary units vs. baseline, P < 0.05). Combined dobutamine and vasopressin increased microvascular blood flow (∆µFlow 28 ± 27 arbitrary units vs. baseline, P < 0.05) but did not improve tissue oxygenation. Hepatic microcirculation and mitochondrial respiration remained largely unaltered.

Conclusions: Dobutamine improves colonic microcirculation in sepsis, whereas concomitant vasopressin attenuates its oxygenation effects.

Objective: To identify risk factors for cardiac rupture (CR) in patients with acute myocardial infarction (AMI) and develop a validated prognostic model.

Methods: This study included 89 consecutive AMI patients with CR and 451 randomly selected controls without CR from a pool of 4,559 patients (2013-2024). Risk factors were identified using least absolute shrinkage and selection operator regression alongside univariate and multivariate logistic regression. A nomogram prediction model was built and evaluated using the receiver operating characteristic curve, calibration plots, the Hosmer-Lemeshow test, and decision curve analysis.

Results: Among 540 participants (74.3% male, 25.7% female), CR occurred in 89 (16.5%) cases. Univariate analysis identified 24 associated factors. Least absolute shrinkage and selection operator regression refined these to six key predictors for the final model: older age, male sex, higher Killip classification, lower use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers medications, higher CK-MB levels, and lower ejection fraction. The nomogram demonstrated strong predictive performance, with an area under the curve of 0.874 in the training set and 0.820 in the validation set. Calibration curves showed excellent agreement between predictions and observations, and the Hosmer-Lemeshow test indicated good fit ( P > 0.05).

Conclusion: Advanced age, higher Killip class, and elevated creatine kinase MB are risk factors for CR, while angiotensin-converting enzyme inhibitors/angiotensin receptor blockers therapy and higher ejection fraction are protective. The developed nomogram provides a reliable tool for individualized risk prediction.

Background: Septic shock (SS) is deadly. Sepsis-immune response transitions from an endotoxin-sensitive, hyper-inflammatory phase to an endotoxin-tolerant hypo-inflammatory phase. In mice, we implicated sirtuin 2 (SIRT2) for prolonged hypo-inflammation using leukocyte adhesion, the earliest in vivo inflammatory response to cytokine, chemokine, and metabolite stimuli. The role of SIRT2 in human sepsis remains unknown. We hypothesized that (1) peripheral blood mononuclear cells (PBMCs) adhesion response can be used as a physiological biomarker of hypo-inflammation, and (2) SIRT2 regulates the functions of PBMCs and macrophages during the hypo-inflammatory phase of human sepsis.

Methods: We stimulated control and SS whole blood and PBMCs ± lipopolysaccharide (LPS) and investigated plasma cytokines, PBMC cell adhesion to intercellular adhesion molecule-1-coated plates, adhesion molecule CD18 activation, SIRT2 expression, and cytokine response. In adhesion-/endotoxin-tolerant PBMCs and THP-1 cells treated ± SIRT2 inhibitor AK-7, we analyzed cell adhesion, CD18 activation, and transmigration ± LPS. In monocyte-derived macrophages from SS versus controls ± AK-7, we analyzed phagocytosis.

Results: We found the following: (1) Muted plasma tumor necrosis factor and interleukin-1β-response to LPS in SS versus control (endotoxin tolerance); (2) endotoxin-tolerant SS-PBMCs exhibit high SIRT2 expression, and muted adhesion (adhesion tolerance), CD18 activation, and transmigration with LPS; and (3) SIRT2 inhibitor AK-7 reverses endotoxin and adhesion tolerance in SS-PBMCs via CD18 activation, reverses the defective transmigration of endotoxin-tolerant PBMCs, and improves phagocytosis in monocyte-derived macrophages from SS patients.

Conclusions: PBMC adhesion, a physiological biomarker, can be used to detect hypoinflammation. Defective PBMC and macrophage function in SS patients occur via high SIRT2 expression. SIRT2 inhibition is a potential therapeutic strategy for treating sepsis-associated hypo-inflammation.

Hemorrhagic shock induces immune dysfunction via mesenteric lymph return, leading to systemic inflammatory response and multiple organ dysfunction. Dendritic cells (DCs) play a pivotal role in immune response following hemorrhagic shock. Therefore, identifying regulatory targets within DCs is essential for understanding hemorrhagic shock-induced immune dysfunction. Endoplasmic reticulum (ER) autophagy (ER-phagy), a selective form of autophagy, is critical for DC function. Here, we investigated the role of tumor necrosis factor-α-induced protein-8-like 2 (TIPE2), a protein known to regulate autophagy, in modulating DC ER-phagy after hemorrhagic shock. We analyzed the function and ER-phagy in splenic DCs from wild-type (WT) mice following hemorrhagic shock in vivo and DCs stimulated with posthemorrhagic shock mesenteric lymph (PHSML) in vitro . Our results showed an increased number of autophagosomes containing ER structures, with significantly enhanced colocalization between ER and autophagosomes in DCs during hemorrhagic shock. The proliferation of CD4 + T cells co-cultured with DCs was weakened, and the expression of surface molecules on the DCs was significantly increased after stimulation with PHSML. Subsequently, WT, TIPE2 -/- , and TIPE2 +/+ mice were used to further analyze the correlation between TIPE2 and ER-phagy in the context of hemorrhagic shock. The results demonstrated that under hemorrhagic shock conditions, TIPE2 -/- mice exhibited a significantly reduced microtubule-associated protein 1 light chain 3 (LC3)-II/I ratio and elevated SEC61 translocon subunit β (SEC61B) expression in the spleen tissue compared with WT mice, suggesting a diminished level of ER-phagy. Conversely, TIPE2 +/+ mice showed the opposite changes. Following stimulation with PHSML, the findings revealed a marked increase in the colocalization between ER and autophagosomes and a significant inhibition of DC function compared to the control group. Additionally, the deletion of TIPE2 weakened ER-phagy and decreased the inhibitory effect on DC function. In contrast, the overexpression of TIPE2 further enhanced ER-phagy and intensified the inhibition of DC function. In addition, TIPE2 is involved in the regulation of the nonclassical ER-phagy receptor tripartite motif 13 expression. These results suggest that ER-phagy is enhanced in DCs after hemorrhagic shock and that TIPE2 may regulate ER-phagy and DC function via tripartite motif 13. This research provides a theoretical basis for future clinical therapeutic strategies targeting the regulation of ER-phagy to improve the function of DCs.

Background: Traumatic injury is a leading cause of death, in large part driven by coagulopathy associated hemorrhage and thrombotic complications. Identification of biological pathways and therapeutic targets has been limited. We performed a proteomic analysis using plasma isolated from trauma patients and assessed proteome relation to clot formation and stability.

Methods: Platelet-poor plasma was isolated from trauma patients upon emergency department arrival. Coagulation was characterized using rheology, turbidity, and confocal microscopy. Proteomics were measured using liquid chromatography-mass spectrometry and compared between: (1) healthy donors vs. trauma patients, (2) non-severe vs. severe injury, (3) survived vs. deceased patients, (4) penetrating vs. blunt injuries, (5) traumatic brain injury (TBI) vs. No-TBI and (6) presence vs absence of physiological shock. Spearman correlations were calculated between coagulation tests, clinical vitals, and proteomics data. Gene Ontology and STRING analysis identified enrichment of biological processes and interconnectedness of mortality-related proteins.

Results: Hemostatic processes were enriched in healthy donors, severe injury patients, surviving patients, No-TBI patients and patients not exhibiting shock. PAI-3 was in higher abundance in those who survived their injuries compared to those who died. PAI-3 was correlated with faster clotting time, thrombin generation, and decreased D-dimer. Proteins higher in deceased patients compared to those who survived, such as PTGDS, related to immune activity, correlated with weaker clots and increased D-dimer.

Conclusions: This exploratory analysis of plasma proteomics in trauma patients identified potential markers related to coagulation and immune activity, which may contribute to coagulopathy associated mortality after injury and serve as therapeutic targets.