SHOCK SYNOPSIS APRIL 2024

ROLE OF MICROGLIA IN SEPSIS-ASSOCIATED ENCEPHALOPATHY PATHOGENESIS: AN UPDATE Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis characterized by cognitive dysfunction and high mortality rates. Yu et al. review how microglia, the main macrophage in the CNS, play a crucial role in SAE by inducing neuroinflammation, brain tissue injury, and neuronal dysregulation through various pathways. As part of the review, they discuss how targeting microglia could be a potential therapeutic strategy for ameliorating SAE by addressing neuroinflammation and other underlying mechanisms. HEMORRHAGIC SHOCK ASSESSED BY TISSUE MICROCIRCULATORY MONITORING: A NARRATIVE REVIEW Hemorrhagic shock (HS) is a common complication of traumatic injury, and early identification is crucial for reducing the risk of death. Current methods rely on macrocirculation indicators like blood pressure and heart rate, which can be influenced by compensatory mechanisms. Microcirculation indicators have shown promise in monitoring HS, as they can detect changes in tissue perfusion before macrocirculation changes occur and can improve tissue perfusion after macrocirculation stabilization. This review by Yao et al. discusses the use of microcirculation metrics in monitoring hemorrhagic shock, highlighting their potential benefits and limitations compared to traditional macrocirculation indicators. ACETATE RINGER’S SOLUTION VERSUS NORMAL SALINE SOLUTION IN SEPSIS: A RANDOMIZED, CONTROLLED TRIAL Fluid therapy is crucial in managing sepsis and acute kidney injury related to sepsis. A single-center, prospective, open-label, parallel-controlled trial by Zhang et al. assessed the effect of Ringer’s acetate solution (RAS), normal saline solution (NSS), and combination RAS+NSS on kidney function and mortality in patients with sepsis and septic shock. No difference in major adverse kidney events within 28 days (MAKE28) and secondary outcomes was observed among patients treated with either RAS or NSS; however, uncontrolled fluid choice before admission may have narrowed the difference between groups. EVALUATION OF COMPONENTS OF THE EXTRACELLULAR PURINERGIC SIGNALING SYSTEM IN HUMAN SEPSIS Extracellular purines have potent immunomodulatory effects, binding to, and activating receptors on the surface of leukocytes. Lováski et al. conducted a comprehensive assessment of the extracellular purinergic signalling system in peripheral blood mononuclear cells (PBMCs) and neutrophils of septic patients. Several differences in the regulation of the purinergic systems in PMBCs were demonstrated in septic patients compared to healthy individuals, including lower ATP levels possibly due to increased CD39 expression, and decreased signalling through P2X4 and P2X7 receptors. THE RISKS OF FIRST ONSET PRIMARY HYPERTENSION DIAGNOSIS IN THERMAL-INJURED PATIENTS Although hypertension (HTN) is known to increase the risk of developing various comorbidities, the impact of burn-induced HTN on patient outcomes remains unclear. Efejuku et al. compared burn patients with HTN diagnosed at least 1 day after burn to those without HTN using propensity score matching to account for differences in demographics, injury characteristics, and biomarkers. New-onset HTN after burn was positively associated with several in-hospital morbidities and mortality, which differed based on sex, age, and burn size. NEW PREDICTIVE BIOMARKERS FOR SCREENING COVID-19 PATIENTS WITH RHABDOMYOLYSIS IN COMBINATION WITH CYSTATIN C Rhabdomyolysis (RM) is a rare and life-threatening complication of COVID-19. A study by Yu et al. evaluated the effectiveness of serum cystatin C (CysC) and new composite measures, LDH*CysC and AST*CysC, in identifying high-risk COVID-19 patients with poor prognosis. Using various grouping models, the findings confirmed that CysC could predict the prognosis of COVID-19 patients. LDH*CysC and AST*CysC outperformed CysC in predicting RM, skeletal muscle impairment, and death. DIFFERENTIAL SIGNALING EFFECTS OF ESCHERICHIA COLI AND STAPHYLOCOCCUS AUREUS IN HUMAN WHOLE BLOOD INDICATE DISTINCT REGULATION OF THE NRF2 PATHWAY Escherichia coli and Staphylococcus aureus are the two most common bacterial species implicated in sepsis. Pourquoi et al. compared the transcriptomic signatures of heat-killed E. coli or S. aureus. Compared to controls, exposure to E. coli and S. aureus resulted in significant inflammatory dysregulation and some commonality in the activation of pro- and anti-inflammatory pathways by each pathogen. These insights reveal the complexity of host-pathogen interactions, which may be important for targeting unique pathways to improve outcomes in sepsis. ASSESSING THE CAUSAL RELATIONSHIP BETWEEN SEPSIS AND AUTOIMMUNE: A MENDELIAN RANDOMIZATION STUDY Numerous epidemiological studies have identified a potential relationship between sepsis and several autoimmune disorders. To investigate this potential causality, Wang et al. applied two-sample Mendelian randomization (MR) using Genome-wide association studies (GWAS) data from a European cohort. Their MR analysis largely failed to confirm a connection between the majority of autoimmune diseases and the risk of developing sepsis, with a notable exception for primary sclerosing cholangitis and the development of sepsis. SIMPLIFIED IMMUNE-DYSREGULATION INDEX: A NOVEL MARKER PREDICTS 28-DAY MORTALITY OF INTENSIVE CARE PATIENTS WITH SEPSIS Many biomarkers investigated to determine inflammatory responses in response to sepsis cannot be easily and timely obtained in clinical practice. A retrospective cohort study by Liu et al. assessed the efficacy of the IL-6 level and lymphocyte count (IL-6/LY#) ratio as a simple indicator for 28-day mortality in sepsis patients. Results showed that IL-6/LY# measured on the first day of ICU admission can be used to predict 28-day mortality among septic patients, with a decreasing trend suggesting a lower mortality rate. THE RELATIONSHIP BETWEEN CIRCULATING IMMUNE CELL PHENOTYPES AND SEPSIS: A MENDELIAN RANDOMIZATION STUDY Circulatory immune cells are known to play a role in the development of sepsis. Liu et al. applied a two-sample Mendelian randomization (MR) analysis of Genome-wide association studies (GWAS) data to investigate relationships and establish causality among various immunophenotypes, sepsis, and 28-day mortality. Using Inverse Variance Weighing (IVW), the analysis indicated that several immune profiles are positively associated with the risk of sepsis and mortality, with only one immunophenotype confirming a protective (negative) relationship. These findings offer new insights into the intricate relationship between immune cells and sepsis. IDENTIFICATION OF POTENTIALLY MODIFIABLE FACTORS TO IMPROVE RECOGNITION AND OUTCOME OF NECROTIZING SOFT-TISSUE INFECTIONS Necrotizing Soft-Tissue Infections (NSTI) are serious conditions, with survivors often experiencing long-term decreases in quality of life. Suijker et al. conducted a retrospective multicentre cohort study of patients admitted for acute treatment of NSTI to identify early modifiable factors associated with misdiagnosis, morbidity, and mortality. The study found that NSTI were frequently misdiagnosed, particularly in patients with more severe comorbid conditions, emphasizing the need for better recognition of NSTI, effective treatment of sepsis, and skin-sparing debridement to improve patient outcomes. C-TYPE LECTIN-2D RECEPTOR CONTRIBUTES TO HISTONE-INDUCED VASCULAR BARRIER DYSFUNCTION DURING BURN INJURY Severe burns lead to tissue destruction and cell death, releasing nuclear histones and other molecules into the circulation, contributing to multi-organ dysfunction. Using a murine model of thermal injury, Yang et al. show that histones cause endothelial barrier dysfunction, and treatment with a histone antibody reduces plasma leakage. Their data showed that C-type lectin domain family 2 member D (Clec2d), a receptor on endothelial cells, may play a role in histone-induced vascular injury, as its inhibition also attenuated burn-induced plasma leakage, suggesting a potential therapeutic target for managing burn-induced microvascular barrier dysfunction. LIRAGLUTIDE ALLEVIATES ACUTE LUNG INJURY AND MORTALITY IN PNEUMONIA-INDUCED SEPSIS THROUGH REGULATING SURFACTANT PROTEIN EXPRESSION AND SECRETION Glucagon-like peptide 1 (GLP-1) analogs, commonly used to treat type 2 diabetes, regulate insulin secretion, energy homeostasis, inflammation, and immune cell function. Using a pneumonia induced sepsis mouse model, Guo et al. show that GLP-1 agonist, liraglutide, improved survival, reduced bacterial loads, and decreased lung injury in septic mice. It also decreased inflammatory cells and cytokines in the lungs, while increasing pulmonary surfactant proteins and phospholipid secretion. These findings suggest that liraglutide has potential as a treatment for pneumonia-induced sepsis by enhancing host defense mechanisms and maintaining alveolar respiratory function. MIR-155 PROMOTES ACUTE ORGAN INJURY IN LPS-INDUCED ENDOTOXEMIC MICE BY ENHANCING CCL-2 EXPRESSION IN MACROPHAGES During sepsis, macrophages release chemokines like chemokine ligand 2 (CCL-2), which attract more immune cells to the infection site. Using an LPS-induced endotoxemia murine model, Wang et al. found that a molecule called microRNA (miR)-155 increases CCL-2 expression in macrophages, leading to more immune cell recruitment and worsened organ injury in sepsis. Specifically, they show that miR-155 targets serum/glucocorticoid regulated kinase family member 3 (SGK3), a protein that regulates CCL-2, suggesting it as a potential therapeutic target for sepsis treatment. KNOCKDOWN OF CIRC_0114428 ALLEVIATES LPS-INDUCED HK2 CELL APOPTOSIS AND INFLAMMATION INJURY VIA TARGETING MIR-215-5P/TRAF6/NF-ΚB AXIS IN SEPTIC ACUTE KIDNEY INJURY Circular RNAs (circRNAs) have been implicated in sepsis-induced acute kidney injury (AKI). Li et al. show that HK2 kidney cells treated with lipopolysaccharide (LPS), a sepsis-inducing agent, showed increased circ_0114428 expression. Their data show knockdown of circ_0114428 reversed the effects of LPS treatment, reducing cell proliferation, apoptosis, and inflammatory response. The study also found that circ_0114428 regulates the NF-κB signaling pathway by sponging miR-215-5p and targeting TRAF6, suggesting a potential therapeutic target for sepsis-induced AKI. A NOVEL OLIGONUCLEOTIDE MRNA MIMIC ATTENUATES HEMORRHAGE-INDUCED ACUTE LUNG INJURY Hemorrhagic shock (HS) often leads to acute lung injury (ALI) due to an inflammatory response, with extracellular cold-inducible RNA-binding protein (eCIRP) playing a key role. A12, an oligonucleotide poly(A)mRNA mimic, has been found to inhibit eCIRP binding to its receptor, toll-like receptor 4 (TLR4), reducing inflammation and tissue injury in mouse models. Here, Hu et al. treated mice with A12 in a mouse HS model significantly decreased markers of injury and inflammation in both blood and lung tissues, suggesting a potential therapeutic strategy for managing HS-induced ALI. YIQIFUMAI INJECTION AMELIORATED SEPSIS-INDUCED CARDIOMYOPATHY BY INHIBITION OF FERROPTOSIS VIA XCT/GPX4 AXIS Sepsis-induced cardiomyopathy (SIC) is a major cause of mortality in sepsis patients, and effective treatments are currently lacking. YiQiFuMai injection (YQFM), a traditional Chinese medicine, has shown promise in treating cardiovascular diseases, including SIC. Here, Guo et al. investigated the therapeutic effects of YQFM on a SIC rat model and found that it alleviated myocardial injury by reducing iron concentrations, lipid peroxidation, and activating the xCT/GPX4 axis, which is involved in ferroptosis. YQFM's effects were confirmed in vitro using a GPX4 inhibitor, suggesting a potential mechanism for its cardioprotective effects in SIC.

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