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Background: Heparin-binding protein (HBP) levels have been linked to organ failure and may represent an inflammatory biomarker of sepsis. We found disseminated intravascular coagulation (DIC) is associated with higher HBP levels in patients and in in vivo and in vitro models. This prospective, single-center observational study investigated the effects and underlying mechanisms of HBP on the coagulation cascade in sepsis., Methods: 538 patients with sepsis from June 2016 to December 2019 were enrolled. Mechanisms underlying HBP and the coagulation system were investigated in human umbilical vein endothelial cells (HUVEC) and C57 mice., Results: Increased HBP was associated with sepsis-induced DIC. The optimal cutoff value was 37.5 ng/mL (sensitivity: 56 %, specificity: 65 %). Antithrombin-III (AT-III) activity, plasmin-a2 plasmin inhibitor complex (PIC), procalcitonin (PCT), hemoglobin, and HBP ≥37.5 ng/mL were associated with of DIC occurrence. In HUVECs &C57 mice models, Western blotting, qPCR, and immunohistochemistry analysis showed that the binding between HBP and TGF-β receptor 2 (TGFBR2) caused elevation of plasminogen activator inhibitor-1 (PAI-1) levels. Furthermore, we found that mice stimulated with HBP had higher levels of fibrinogen and D-dimer in the blood. HBP treatment caused the accumulation of fibrinogen in mice lung tissue. Treatment with TGFBR2-small interfering RNAs inhibited the effects., Conclusion: Patients with sepsis having HBP ≥37.5 ng/mL at admission were more likely to develop DIC. HBP upregulates the expression of fibrinogen and PAI-1 via TGFBR2 and the TGF-β signalling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Intra-abdominal infections are frequently associated with acute respiratory distress syndrome, which significantly affects patient prognosis. However, little is known about the specific risk factors of acute respiratory distress syndrome in sepsis caused by intra-abdominal infections., Methods: This retrospective study included adult patients with intra-abdominal sepsis admitted to the intensive care unit of a tertiary teaching hospital in China between June 2017 and June 2022. Patients were categorized based on the presence or absence of acute respiratory distress syndrome. Data, including vital signs, laboratory values, and severity scores collected within 24 hours of sepsis diagnosis, as well as outcomes within 90 days, were analyzed. Multivariable logistic regression was used to identify independent risk factors associated with acute respiratory distress syndrome., Results: A total of 738 patients were included, of whom 218 (29.5%) developed acute respiratory distress syndrome. Patients with acute respiratory distress syndrome were younger, had a higher body mass index and disease severity scores, and exhibited higher proportions of septic shock and hospital-acquired intra-abdominal infections. The mortalities in the intensive care unit and at 28 and 90 days were higher in the acute respiratory distress syndrome group. In the multivariate logistic regression model, age under 65 years (odds ratio [95% confidence interval]: 1.571 [1.093-2.259]), elevated body mass index (2.070 [1.382-3.101] for overweight, 6.994 [3.207-15.255]) for obesity, septic shock (2.043 [1.400-2.980]), procalcitonin (1.009 [1.004-1.015]), hospital-acquired intra-abdominal infections (2.528[1.373-4.657]), and source of intra-abdominal infections (2.170 [1.140-4.128] for biliary tract infection, 0.443 [0.217-0.904] for gastroduodenal perforation) were independently associated with acute respiratory distress syndrome., Conclusion: In patients with intra-abdominal sepsis, age under 65 years, higher body mass index and procalcitonin, septic shock, hospital-acquired intra-abdominal infections, and biliary tract infection were risk factors for acute respiratory distress syndrome., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: Background: The dysregulated host responses play a crucial role in the pathophysiology process of sepsis-induced disseminated intravascular coagulation (DIC). The study aimed to characterize the dynamic alternation of immune-related biomarkers and their relationship with the progression of DIC during sepsis. Methods: A prospective, observational study was conducted in a tertiary care academic hospital. Six hundred forty patients with sepsis were classified into three groups according to the International Society on Thrombosis and Hemostasis (ISTH) score: 383 involved patients without DIC (ISTH = 0), 168 sepsis with nonovert DIC (ISTH = 1-4), and 89 sepsis with overt DIC (ISTH ≥5). Eighteen immune-related biomarkers and six routine coagulation variables were examined at D1, D3, and D7 upon enrollment. The association between the immune parameters and the DIC deterioration was assessed during sepsis. Results: The study showed a 40% coagulation disorder and a 14% incidence of overt DIC in patients with sepsis. The patients with overt DIC displayed pronounced immune disorders from D1 to D7 upon sepsis, which was characterized by the decreased percentage of monocyte HLA-DR (mHLA-DR), increased percentage of regulatory T cells, the levels of procalcitonin, neutrophil CD64 index, and systemic inflammatory cytokines relative to nonovert DIC or non-DIC patients. In multivariate analysis, the combination of anti-inflammatory cytokine IL-10 and mHLA-DR at D1 upon enrollment had a superior predictive value for predicting DIC deterioration in sepsis (area under the curve = 0.87, P < 0.0001). Conclusion: These data illustrate that immunosuppression can crosstalk with coagulation disorder during sepsis and present an additional evaluation tool to predict DIC deterioration., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

Background: Disseminated intravascular coagulation (DIC) occurs in 30-50% of septic patients and contributes to high mortality in the intensive care unit (ICU). However, there are few proven interventions for coagulation disorder management in sepsis. Experimental and clinical data have demonstrated that sepsis could benefit from unfractionated heparin (UFH) treatment. To date, there are no large multicenter trials to determine the safety and efficacy of UFH in septic patients with suspected DIC., Methods: A multicenter, double-blinded, placebo-controlled randomized trial is designed to recruit 600 patients who met sepsis 3.0 criteria and suspected DIC. Participants will be randomized (1:1) to receive UFH or saline via continuous intravenous administration for 7 days within 6 h of enrolment. The primary outcome is ICU mortality. The secondary outcome includes 28-day all-cause mortality, the improvement of Sequential Organ Failure Assessment scores, and the incidence of major hemorrhage. Investigators, participants, and statisticians will be blinded to the allocation., Discussion: The HepSIC trial is to evaluate the efficacy and safety of UFH on sepsis-related DIC across different areas of China. The small dosage of UFH administration would offer a new potential approach for treating sepsis-related coagulation disorders., Ethics and Dissemination: Ethical approval was granted by all the ethics committees of 20 participant centers. Results will be disseminated via peer-reviewed publications and presented at conferences., Trial Registration: ClinicalTrials.gov NCT02654561. Registered on 13 January 2016., (© 2023. The Author(s).)

Importance: Previous research has suggested that Xuebijing injection (XBJ), an herbal-based intravenous preparation, may reduce mortality among patients with sepsis., Objective: To determine the effect of XBJ vs placebo on 28-day mortality among patients with sepsis., Design, Setting, and Participants: The Efficacy of Xuebijing Injection in Patients With Sepsis (EXIT-SEP) trial was a multicenter, randomized double-blind, placebo-controlled trial conducted in intensive care units at 45 sites and included 1817 randomized patients with sepsis (sepsis 3.0) present for less than 48 hours. Patients aged 18 to 75 years with a Sequential Organ Failure Assessment score of 2 to 13 were enrolled. The study was conducted from October 2017 to June 2019. The final date of follow-up was July 26, 2019. Data analysis was performed from January 2020 to August 2022., Interventions: The patients were randomized to receive either intravenous infusion of XBJ (100 mL, n = 911) or volume-matched saline placebo (n = 906) every 12 hours for 5 days., Main Outcomes and Measures: The primary outcome was 28-day mortality., Results: Among the 1817 patients who were randomized (mean [SD] age, 56.5 [13.5] years; 1199 [66.0%] men), 1760 (96.9%) completed the trial. In these patients, the 28-day mortality rate was significantly different between the placebo group and the XBJ group (230 of 882 patients [26.1%] vs 165 of 878 patients [18.8%], respectively; P < .001). The absolute risk difference was 7.3 (95% CI, 3.4-11.2) percentage points. The incidence of adverse events was 222 of 878 patients (25.3%) in the placebo group and 200 of 872 patients (22.9%) in the XBJ group., Conclusions and Relevance: In this randomized clinical trial among patients with sepsis, the administration of XBJ reduced 28-day mortality compared with placebo., Trial Registration: ClinicalTrials.gov Identifier: NCT03238742.

Background: A blunt host defense response in older patients may contribute to different coagulation responses during sepsis. We aimed to investigate the differences in coagulation parameters between elderly and non-elderly patients with sepsis., Methods: Adult patients diagnosed with sepsis within 24 hours after admission to the intensive care unit between September 2018 and December 2020 were prospectively enrolled. Patients were categorized into the adult (18-64 years) and elderly (age ≥65 years) groups. Conventional coagulation parameters and inflammatory markers were measured on intensive care unit admission and on Days 3 and 7. Thromboelastography was performed on intensive care unit admission. The differences in the coagulation parameters between the 2 groups were evaluated. The adult and elderly patients were matched to adjust for baseline characteristics. Correlations between inflammatory markers and coagulation-related parameters were also analyzed., Results: Of the 567 patients, 303 (53.4%) were elderly. Compared with adult patients, elderly patients had lower prothrombin time elevation, lower fibrinogen, D-dimer, and fibrin/Fib degradation product levels, and lower proportion of disseminated intravascular coagulation on intensive care unit admission; and, they had lower dynamic platelet, lower fibrinogen, and D-dimer levels during the first week in the intensive care unit. Thromboelastography parameters were generally within the normal range, although elderly patients had lower R and K values and a higher alpha angle. Comparisons of coagulation parameters between the 2 groups revealed similar results in the matched cohort. The inflammatory markers correlated with prothrombin time, activated partial thromboplastin time, and antithrombin III., Conclusion: Elderly patients had milder coagulation activation, accompanied by a decreased inflammatory response during sepsis, compared to non-elderly patients., (Copyright © 2023. Published by Elsevier Inc.)

In 2021, the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM) jointly released the Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2020 with 93 recommendations. In the same year, the Japanese Society of Intensive Care Medicine (JSICM) and the Japanese Association for Acute Medicine (JAAM) also cooperated to publish the Japanese clinical practice guidelines for management of sepsis and septic shock 2020, covering 118 clinical issues in 22 areas. In this paper, 50 items in the contents of the two guidelines are compared in accordance with the order of international guidelines, including screening, initial resuscitation, mean arterial pressure, transfer to intensive care unit (ICU), diagnosis of infection, timing of antimicrobial administration, biomarkers for initiation of antimicrobial therapy, selection of antibiotic, antifungal therapy, antiviral therapy, infusion of antibiotic, pharmacokinetics and pharmacodynamics, source of infection control, antimicrobial de-escalation strategy, course of antimicrobial administration, biomarkers for discontinuation of antibiotic, fluid management, vasoactive agents, positive inotropic agents, monitoring and intravenous access, fluid balance, oxygenation targets, high-flow nasal cannula oxygen therapy, noninvasive ventilation, protective ventilation in acute respiratory distress syndrome (ARDS), low tidal volume in respiratory failure patients with non-ARDS, lung recruitment maneuvers, prone position ventilation, muscle relaxants, extracorporeal membrane oxygenation (ECMO), glucocorticoids, blood purification, red blood cell (RBC) transfusion, immunoglobulin, stress ulcer prevention, prevention of venous thromboembolism (VTE), renal replacement therapy, glycemic management, vitamin C, sodium bicarbonate therapy, nutrition, treatment goals, palliative care, peer support groups, transition of care, screening economic and social support, education for the knowledge about sepsis to the patients and their families, common decision-making, discharge planning, cognitive therapy and follow-up after discharge. It is convenient for everyone to understand some views in the field of sepsis and septic shock, and deepen their understanding.

Abstract: Objectives: We attempted to identify and validate the subphenotypes of sepsis-associated liver dysfunction (SALD) using routine clinical information. Design: This article is a retrospective observational cohort study. Setting: We used the Medical Information Mart for Intensive Care IV database and the eICU Collaborative Research Database. Patients: We included adult patients (age ≥18 years) who developed SALD within the first 48 hours of intensive care unit (ICU) admission. We excluded patients who died or were discharged from the ICU within the first 48 hours of admission. Patients with abnormal liver function before ICU admission were also excluded. Measurements and Main Results: Patients in the MIMIC-IV 1.0 database served as a derivation cohort. Patients in the eICU database were used as validation cohort. We identified four subphenotypes of SALD (subphenotype α, β, γ, δ) using K-means cluster analysis in 5234 patients in derivation cohort. The baseline characteristics and clinical outcomes were compared between the phenotypes using one-way analysis of variance/Kruskal-Wallis test and the χ 2 test. Moreover, we used line charts to illustrate the trend of liver function parameters over 14 days after ICU admission. Subphenotype α (n = 1,055) was the most severe cluster, characterized by shock with multiple organ dysfunction (MODS) group. Subphenotype β (n = 1,179) had the highest median bilirubin level and the highest proportion of patients with underlying liver disease and coexisting coagulopathy (increased bilirubin group). Subphenotype γ (n = 1,661) was the cluster with the highest mean age and had the highest proportion of patients with chronic kidney disease (aged group). Subphenotype δ (n = 1,683) had the lowest 28-day and in-hospital mortality (mild group). The characteristics of clusters in the validation cohort were similar to those in the derivation cohort. In addition, we were surprised to find that GGT levels in subphenotype δ were significantly higher than in other subphenotypes, showing a different pattern from bilirubin. Conclusions: We identified four subphenotypes of SALD that presented with different clinical features and outcomes. These results can provide a valuable reference for understanding the clinical characteristics and associated outcomes to improve the management of patients with SALD in the ICU., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by the Shock Society.)

Introduction: Levels of extracellular histones are highly increased in sepsis and may facilitate microcirculatory dysfunction. Unfractionated heparin (UFH) binds histones and neutralizes their cytotoxicity. We investigated the effect of UFH on microcirculatory dysfunction by interacting with extracellular histones in endotoxemic rats., Methods: Twenty-four Wistar rats were randomly divided into three groups: control, lipopolysaccharide (LPS) group, and LPS + UFH group. In the LPS and LPS + UFH groups, 10 mg/kg LPS was injected to induce endotoxemia, and 100 IU/kg/h UFH was administered intravenously in the LPS + UFH group. The rats underwent midline laparotomy, and then intestinal microcirculation was evaluated using an incident dark field microscope. Circulating histones and microstructures of the rat intestinal microvascular endothelium were also detected. Additionally, the antagonistic effect of UFH on histone-induced cytotoxicity was investigated in human intestinal microvascular endothelial cells., Results: UFH protected the microcirculation of the intestinal serosa and mucosa in endotoxemic rats, as evidenced by increased total vessel density, perfused vessel density, and proportion of perfused vessels of both the serosa and mucosa, and increased microcirculatory flow index of the mucosa in the LPS + UFH group. UFH treatment decreased the levels of circulating histones and alleviated intestinal microvascular endothelial injuries in endotoxemic rats. Furthermore, UFH inhibited histone cytotoxicity in vitro., Conclusions: UFH attenuated microcirculatory dysfunction in endotoxemic rats by antagonizing extracellular histones, thereby providing a potential therapeutic strategy for sepsis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Sepsis is frequently associated with hemostasis activation and thrombus formation, and systematic hemostatic changes are associated with a higher risk of mortality. The key events underlying hemostasis activation during sepsis are the strong activation of innate immune pathways and the excessive inflammatory response triggered by invading pathogens. Pyroptosis is a proinflammatory form of programmed cell death, that defends against pathogens during sepsis. However, excessive pyroptosis can lead to a dysregulation of host immune responses and organ dysfunction. Recently, pyroptosis has been demonstrated to play a prominent role in hemostasis activation in sepsis. Several studies have demonstrated that pyroptosis participates in the release and coagulation activity of tissue factors. In addition, pyroptosis activates leukocytes, endothelial cells, platelets, which cooperate with the coagulation cascade, leading to hemostasis activation in sepsis. This review article attempts to interpret the molecular and cellular mechanisms of the hemostatic imbalance induced by pyroptosis during sepsis and discusses potential therapeutic strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhu, Liang, Luo and Ma.)

Heparin-binding protein (HBP), as a granule protein secreted by polymorphonuclear neutrophils, participates in the pathophysiological process of sepsis. It has been reported that HBP is a biomarker of sepsis related to the severity of septic shock and organ dysfunction. HBP binds to vascular endothelial cells as a primary target site. However, it is still unclear whether HBP-binding protein receptors exist on the surface of endothelial cells. The effect of HBP on vascular permeability in sepsis and its mechanism needs to be explored. We conducted in vivo and in vitro studies and demonstrated that HBP binds to transforming growth factor-β receptor type 2 (TGF-β-R2) as a ligand. Glutathione S-transferase pull-down analysis revealed that HBP mainly interacts with the extracellular domain of TGF-β-R2. HBP induces acute lung injury and vascular leakage via activation of the TGF-β/SMAD2/3 signaling pathway. A permeability assay suggested that TGF-β-R2 is necessary for HBP-induced increased permeability. We also defined the role of HBP and its potential membrane receptor TGF-β-R2 in the blood-gas barrier in the pathogenesis of HBP-related acute lung injury., (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Coagulation disorders ranging from subtle changes in coagulation parameters to fatal disseminated intravascular coagulation (DIC) are common in septic patients. Coagulation activation is considered to be one of the most important factors contributing to multiple organ dysfunction syndrome (MODS) in sepsis. Anticoagulant therapy is, therefore, necessary to prevent MODS, but eligibility criteria remain controversial. Sepsis is a highly heterogeneous syndrome, which could explain the negative results of clinical studies on the treatment of sepsis. Recently, sepsis has been subdivided into several phenotypes with different therapeutic outcomes. At present, septic patients with dysfunctional coagulation expressed as increased D-dimer and fibrin/fibrinogen degradation products (FDPs) are considered to be candidates for anticoagulant therapy. In this review, we aimed to describe the features of different septic phenotypes. We also discuss factors that contribute to controversies in this area, and challenges in defining which septic phenotypes are good candidates for anticoagulant therapy., (© 2022. Japanese Society of Hematology.)

Background: Less is known about the risk factors for acute respiratory distress syndrome (ARDS) in sepsis patients diagnosed according to sepsis 3.0 criteria. Moreover, the risk factors for ARDS severity remain unclear., Methods: We retrospectively collected the characteristics of sepsis patients from the intensive care unit of the First Affiliated Hospital of China Medical University from January 2017 to September 2018. Logistic regression was used in determining the risk factors., Results: 529 patients with sepsis were enrolled and 179 developed ARDS. The most common infection sites were acute abdominal infection (n = 304) and pneumonia (n = 117). Multivariate analysis showed that patients with pancreatitis with local infection (odds ratio [OR], 3.601; 95% confidence interval [CI], 1.429-9.073, P = 0.007), pneumonia (OR 3.486; 95% CI 1.890-6.430, P < 0.001), septic shock (OR 2.163; 95% CI 1.429-3.275, P < 0.001), a higher sequential organ failure assessment (SOFA) score (OR 1.241; 95% CI 1.155-1.333, P < 0.001) and non-pulmonary SOFA score (OR 2.849; 95% CI 2.113-3.841, P < 0.001) were independent risk factors for ARDS. Moreover, pneumonia is associated with increased severity of ARDS (OR 2.512; 95% CI 1.039-6.067, P = 0.041)., Conclusions: We determined five risk factors for ARDS in sepsis patients. Moreover, pneumonia is significantly associated with an increased severity of ARDS., (© 2022. The Author(s).)

Background: The anticoagulant treatment and clinical efficacy of heparin in sepsis remains controversial. We conducted a meta-analysis to estimate the clinical efficacy of unfractionated heparin (UFH) in adult septic patients., Method: A systematic review of Medline, Cochrane Library, PubMed, Embase, WEIPU database, CNKI database, WANFANG database was performed from inception to January 2021. We included Randomized controlled trials (RCTs) and the main outcome was 28 d mortality. Data analysis was performed with Review Manager (RevMan) version 5.3 software. The meta-analysis included 2617 patients from 15 RCTs., Results: Comparing to control group, UFH could reduce 28 d mortality (RR: 0.82; 95% CI: 0.72 to 0.94) especially for patient with Acute Physiology and Chronic Health Evaluation II (APACHE II) > 15, (RR: 0.83; 95% CI: 0.72 to 0.96). In UFH group, the platelet (PLT) (MD: 9.18; 95% CI: 0.68 to 17.68) was higher, the activated partial thromboplastin time (APTT) was shorter (MD: -8.01; 95% CI: - 13.84 to - 2.18) and the prothrombin time (PT) results (P > 0.05) failed to reach statistical significance. UFH decreased multiple organ dysfunction syndrome (MODS) incidence (RR: 0.61; 95% CI: 0.45 to 0.84), length of stay (LOS) in ICU (MD: -4.94; 95% CI: - 6.89 to - 2.99) and ventilation time (MD: -3.01; 95% CI: - 4.0 to - 2.02). And UFH had no adverse impact on bleeding (RR: 1.10; 95% CI: 0.54 to 2.23)., Conclusion: This meta-analysis suggests that UFH may reduce 28 d mortality and improve the clinical efficacy in sepsis patients without bleeding adverse effect., (© 2022. The Author(s).)

Sepsis is a dysregulated host response to infection. T cell dysfunction results in the failure to eradicate pathogens and the increased susceptibility to nosocomial infections and mortality during sepsis. Although PD-1 has shown to be a promising target to interfere with T cells dysfunction, the role of other coinhibitory receptors in sepsis remains largely elusive. Here we demonstrated that the immune checkpoint molecule TIGIT on lymphocytes and the critical role of TIGIT in regulating T cell responses in sepsis. Fifty septic patients and seventeen healthy donors were prospectively enrolled. The expression patterns of TIGIT and other molecules on lymphocytes were quantitated by flow cytometry. Ex vivo functional assays were also conducted. Results show that TIGIT expression on T cells was significantly upregulated in sepsis and septic shock patients relative to healthy donors. Elevated frequencies of TIGIT + T cells correlated with aggravated inflammatory response and organ injuries. Of note, TIGIT expression on CD8 + T cells showed a competitive capability to predict ICU mortality in sepsis. TIGIT + T cells expressed higher levels of PD-1, lower levels of CD226, and released fewer cytokines. Strikingly, ex vivo blockade of TIGIT using anti-TIGIT antibody restored the frequencies of cytokine-producing T cells from septic patients. These data illustrate that TIGIT on T cells is being used not only as a clinical predictor of poor prognosis but also as a potential target of novel immunotherapeutic intervention during sepsis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cynaroside is the primary flavonoid component of honeysuckle which has been widely used as Chinese traditional medicine given its anti-inflammation properties. Overactive systemic inflammatory response and multi-organ injury are the leading causes of life-threatening sepsis. Regulation of macrophage polarization balance may act as a promising strategy for its treatment. In the present study, we aimed to investigate whether cynaroside exerted protective effects against sepsis and its potential mechanism. Building upon a sepsis mouse model, we observed cynaroside alleviated serum levels of inflammatory factors including IL-1β and TNF-α at 5 and 10 mg/kg. The pathological injury of heart, kidney and lung was remarkedly attenuated as the levels of blood urea nitrogen, creatinine, creatine kinase-MB and lactate dehydrogenase were reduced nearly 2.8-, 2.7-, 2.4-, and 2.5-fold as compared with the sepsis mice, respectively. We further demonstrated cynaroside suppressed the biomarker of pro-inflammatory macrophage M1 phenotype (iNOS+) and promotes the anti-inflammatory M2 polarization (CD206+) in the injury organs of septic mice. Mechanistic research verified cynaroside inhibited LPS-induced polarization of macrophage into M1 phenotype, which can be highly blocked by Nrf2 inhibitor. Expectedly, Nrf2 and its downstream (Heme oxygenase-1 (HO-1)) was upregulated in injury organs after treating with cynaroside, indicating the involvement of Nrf2 signaling. Taken together, the data claims cynaroside ameliorated systematic inflammation and multi-organ injury dependent on Nrf2/HO-1 pathway in septic mice., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To evaluate the clinical value of neutrophil/lymphocyte ratio (NLR) in early prediction of the incidence of sepsis-induced organ dysfunction and 28-day mortality., Methods: A retrospective study was conducted in 815 adult patients with sepsis admitted to the department of critical care medicine of the First Affiliated Hospital of China Medical University from January 2017 to December 2019. The clinical data including age, gender and complication were collected, and the peripheral blood routine indexes at 24, 48 and 72 hours after the diagnosis of sepsis were collected, and the NLR was calculated. The primary endpoint of the study was the incidences of sepsis related acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC) and acute liver failure (ALF); the secondary endpoint was the 28-day in-hospital mortality in septic patients with organ dysfunction. Univariate and multivariate Logistic regression were used to analyze the risk factors of organ dysfunction and 28-day mortality in patients with sepsis, the receiver operating characteristic curve (ROC curve) was drawn and the area under the ROC curve (AUC) was calculated to evaluate the predictive value of NLR for organ dysfunction and 28-day mortality in patients with sepsis., Results: A total of 714 patients with sepsis were enrolled for final statistical analysis. There was no significant difference in NLR at 24, 48 and 72 hours in patients with or without organ dysfunction (such as AKI, ARDS, DIC and ALF). Logistic regression analysis showed that there was no significant difference in NLR at 24 hours with 28-day in-hospital mortality [odds ratio (OR) = 1.006, 95% confidence interval (95%CI) was 0.994-1.019, P = 0.323]. However, NLR at 48 hours and 72 hours had a significant difference with 28-day mortality (48 hours: OR = 1.026, 95%CI was 1.013-1.040, P = 0.000; 72 hours: OR = 1.021, 95%CI was 1.005-1.037, P = 0.010), which suggested that NLR at 48 hours and 72 hours after diagnosis were independent risks factor for 28-day mortality in patients with sepsis. ROC curve showed that the AUC of NLR at 48 hours was 0.598, 95%CI was 0.540-0.658, P = 0.02; when the cut-off value was 10.1, the sensitivity and specificity for predicting 28-day mortality was 75.2% and 58.0%, respectively; the AUC of NLR at 72 hours was 0.595, 95%CI was 0.536-0.655, P = 0.03; when the cut-off value was 9.24, the sensitivity and specificity for predicting 28-day mortality was 75.3% and 59.9%, respectively., Conclusions: NLR cannot predict the occurrence of AKI, ARDS, DIC and ALF in sepsis in early stage. NLR has a certain clinical value in predicting 28-day mortality in patients with sepsis, but its predictive efficiency is low.

Background: Soluble CD40 ligand (sCD40L) exhibits proinflammatory and procoagulant effects. Recent data indicated that sCD40L plays a significant role in septic patients. The aim of the present study was to determine sCD40L changes in surgical patients without sepsis (SWS) and surgical sepsis patients (SS) during the first 3 days after intensive care unit (ICU) admission and to observe the association between sCD40L and mortality., Methods: Time changes in sCD40L levels were assessed for 3 days after ICU admission in 49 patients with SS and compared with those in 19 SWS patients. Serum sCD40L concentration was detected by ELISA. Survival at 28 days served as the endpoint., Results: SS had significantly higher sCD40L levels than SWS and control patients. We observed an association between sCD40L levels ≥1028.75 pg/mL at day 2 and 28-day mortality (odds ratio = 7.888; 95% confidence interval = 1.758 to 35.395; P = 0.007). We could not discover any significant differences in sex, presence of septic shock, site of infection, length of stay in the ICU, PaO 2 /FiO 2 ratio, incidence of AKI, ARDS, or type of surgery between nonsurvivors and survivors., Conclusions: Septic patients show persistently higher circulating sCD40L levels in the first 3 days after ICU admission, and serum sCD40L levels are associated with the mortality of patients with sepsis. Thus, serum sCD40L may be used as a reliable biomarker and therapeutic target in sepsis.

Objectives: We performed a national cross-sectional survey to determine the epidemiologic characteristics of patients with sepsis in ICU in China., Design: A cross-section survey study., Setting: Forty-four hospitals in mainland China from December 1, 2015, to January 31, 2016., Patients: All septic patients diagnosed according sepsis-1 criteria admitted to participating ICU., Interventions: None., Measurements and Main Results: We recorded demographic, physiologic, and microbiological data with follow-up for 90 days or death, if sooner. The frequency of sepsis and 90-day mortality rate were computed, and the relationship with gross domestic product determined. Multivariate logistic regression analysis was used to determine risk factors for 90-day mortality in patients with sepsis. Two-thousand three-hundred twenty-two patients with sepsis were included in the analysis, of whom 786 patients (33.9%) had hospital-acquired sepsis. The most common infection site was the lung (68.2%), followed by abdomen (26.6%) and bloodstream (7.8%). The frequency of sepsis in the ICU was 20.6 cases per 100 ICU admissions (95% CI, 15.8-25.4) with a 90-day mortality of 35.5%. The proportion of sepsis, severe sepsis, and septic shock were 3.10%, 43.6%, and 53.3% with a 90-day mortality of 2.78%, 17.69%, and 51.94%, respectively. Older age, low body weight, higher Sequential Organ Failure Assessment score, the number of systemic inflammatory response syndrome criteria, comorbid with heart failure, hematologic cancer, immunosuppression, higher level of lactate, infection site (pneumonia and bloodstream) were associated with 90-day mortality., Conclusions: Sepsis affects a fifth of patients admitted to ICUs in mainland China with a 90-day mortality rate of 35.5%. Our findings indicate that a large burden of sepsis, and we need to focus on sepsis as a quality improvement target in China given the high mortality. In addition, further studies are needed to delineate the epidemiology of sepsis outside the ICU.

Objective: To investigate the changes in coagulation of sepsis rats with protein-malnutrition or energy-malnutrition., Methods: 108 male Sprague-Dawley (SD) rats were divided into three groups by random number table, with 36 rats in each group. The rats in normal feeding group were given a free diet (27 g/d, containing 18% protein fodder), and the rats in protein-malnutrition group were given a low protein diet (27 g/d, containing 5% protein fodder). The rats in energy-malnutrition group were given a low energy diet (9 g/d, containing 18% protein fodder). After 4 weeks of continuous feeding, 8 rats from each group were sacrificed for malnutrition evaluation. The weights of body, thymus and spleen were measured. The percentages of spleen T lymphocyte subsets and M1 macrophage were determined by flow cytometry. Plasma interleukins (IL-6 and IL-10) levels were determined by enzyme-linked immunosorbent assay (ELISA). The remaining 28 rats in each group were collected for cecal ligation and puncture (CLP) to reproduce the sepsis model, 20 rats of which were used for Kaplan-Meier survival analysis, and the other 8 rats were sacrificed at 8 hours after CLP. The levels of plasma IL-6 and IL-10 were determined by ELISA, and the percentage of spleen M1 macrophages was determined by flow cytometry. The mRNA expressions of tissue factor (TF) and plasminogen activation inhibitor-1 (PAI-1) in liver tissue were determined by reverse transcription-polymerase chain reaction (RT-PCR). Pearson correlation method was used to analyze the correlation between the mRNA expressions of TF and PAI-1 and IL-6 in rats after CLP., Results: (1) After 4 weeks of feeding, the rats in the normal feeding group and protein-malnutrition group gained weight, while those in the energy-malnutrition group lost 25% of their initial body weight. The weights of body, thymus and spleen in the protein-malnutrition group and the energy-malnutrition group were significantly lower than those in the normal feeding group. Compared with the normal feeding group and the protein-malnutrition group, the percentages of spleen CD3 + T lymphocytes, CD4 + T lymphocytes, M1 macrophages and plasma IL-6 levels were significantly increased in the energy-malnutrition group [CD3 + T lymphocytes percentage: (52.1±3.7)% vs. (46.9±3.9)%, (44.5±2.2)%; CD4 + T lymphocyte percentages: (35.0±3.6)% vs. (26.3±2.2)%, (25.1±2.3)%; M1 macrophage percentages: (8.7±2.0)% vs. (3.2±1.3)%, (4.2±1.1)%; IL-6 (ng/L): 129.4±16.2 vs. 48.1±10.0, 53.0±8.3, all P < 0.05]. (2) Kaplan-Meier survival analysis at 7 days after CLP showed: all rats in the energy-malnutrition group died, and the 7-day cumulative survival rate was significantly lower than that in the normal feeding group and the protein-malnutrition group [0% (0/20) vs. 35% (7/20), 55% (11/20), both P < 0.05]. The mortality of the normal feeding group was 65%, which was consistent with moderate CLP mortality, indicating that the CLP model was successfully prepared. After CLP, the plasma IL-6 level in the protein-malnutrition group was significantly lower than that in the normal feeding group [IL-6 (ng/L): 154.6±34.7 vs. 233.4±41.2, P < 0.05]. Compared with the normal feeding group, the mRNA expressions of TF and PAI-1 in liver and plasma IL-6 levels in the energy-malnutrition group were significantly increased [TF mRNA (2 -ΔΔCT ): 4.5±2.2 vs. 1.1±0.7, PAI-1 mRNA (2 -ΔΔCT ): 3.3±1.8 vs. 1.3±0.9, IL-6 (ng/L): 382.7±118.2 vs. 233.4±41.2, all P < 0.05], the percentage of M1 macrophages in spleen was significantly lowered [(8.9±2.4)% vs. (15.2±5.4)%, P < 0.05]. There was no significant difference in plasma IL-10 level among all the groups. Correlation analysis showed that the mRNA expressions of TF and PAI-1 in the liver of rats after CLP were positively correlated with plasma IL-6 level (r 1 = 0.644, r 2 = 0.574, both P < 0.01)., Conclusions: Long-term sustained stress (starvation) leads to sustained chronic inflammatory state, and stimulated the release of related inflammatory factors and activation of the coagulation system after infection. And the inflammatory factors in sepsis rats without sustained stress protein malnutrition were significantly reduced.

Background: Unfractionated heparin (UFH) has been shown to ameliorate lung edema and lung vascular leakage in lipopolysaccharide-induced lung injury. Impaired tight junction (TJ) function is a sign of sepsis-induced acute respiratory distress syndrome (ARDS) and acute lung injury (ALI), which is closely related to the downregulated expression of TJ-specific proteins or the upregulated expression of inflammatory cytokines. Because UFH has been intensively studied in modulating inflammation, we hypothesize that UFH may play a positive role in treating sepsis-induced ARDS/ALI by protecting TJs., Material and Methods: Rat sepsis-induced lung injury was induced by cecal ligation and puncture and treated with UFH. Hematoxylin and eosin staining, lung wet/dry weight (W/D) ratio, and pulmonary microvascular leakage were evaluated to assess lung injury. Cytokines in bronchoalveolar lavage fluid were detected to determine lung inflammation. A transendothelial electrical resistance assay, a Transwell permeability assay, and transmission electron microscopy were used to study endothelial TJs in human lung microvascular endothelial cells. TJ protein expression was measured by western blotting or immunohistochemistry., Results: UFH treatment alleviated lung injury in vivo by reducing IL-6 in bronchoalveolar lavage fluid and protecting TJs in LMVECs. UFH also protected TJs against lipopolysaccharide-stimulated damage and functioned upstream by inhibiting the ERK1/2 MAPK pathway to attenuate endothelial hyperpermeability and downregulating the expression of TJ proteins such as claudin-5, occludin, and ZO-1., Conclusions: These findings suggested that UFH has therapeutic potential for sepsis-induced ARDS or ALI through protecting TJs in LMVECs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Abnormal platelet activation plays an important role in the development of sepsis. The effect of antiplatelet drugs on the outcome of patients with sepsis remains unclear. This meta-analysis aimed to determine the effect of antiplatelet drugs on the prognosis of patients with sepsis., Materials and Methods: PubMed, Cochrane Library, CBM, and Embase were searched for all related articles published from inception to April 2018. The primary end point was mortality. Adjusted data were used and statistically analysed., Results: Ten cohort studies were included. The total number of patients with sepsis was 689,897. Data showed that the use of antiplatelet drugs could effectively reduce the mortality of patients with sepsis (odds ratio (OR) = 0.82, 95% CI: 0.81-0.83, p < 0.05). Seven studies used aspirin for antiplatelet therapy, and subgroup analysis showed that aspirin effectively reduced ICU or hospital mortality in patients with sepsis (OR = 0.60, 95% CI: 0.53-0.68, p < 0.05). A subgroup analysis on the timing of anti-platelet drug administration showed that antiplatelet drugs can reduce mortality when administered either before (OR = 0.78, 95% CI: 0.77-0.80) or after sepsis (OR = 0.59, 95% CI: 0.52-0.67)., Conclusions: Antiplatelet drugs, particularly aspirin, could be used to effectively reduce mortality in patients with sepsis., (Copyright © 2018. Published by Elsevier Inc.)

: Recently, new criteria for sepsis-induced coagulopathy (SIC) were developed, including the sequential organ failure assessment (SOFA) criteria. The objective of this study was to evaluate the new SIC criteria in patients diagnosed with sepsis 3.0. Data from patients diagnosed with sepsis 3.0 after ICU admission were retrospectively obtained from July 2013 to June 2014. Relevant demographic, clinical, and laboratory parameters were noted. This study included 252 patients. The International Society on Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC), modified ISTH-DIC, and SIC scores were higher among nonsurvivors (P < 0.0001). The Acute Physiology and Chronic Health Evaluation II (P < 0.001), ISTH (P = 0.001), modified ISTH (P = 0.001), and SIC scores (P = 0.007) were independent predictors of ICU mortality. Using the receiver operating characteristic curve, SOFA had the greatest power for predicting ICU mortality; ISTH or modified ISTH score had greater predictive power than the SIC score. There were strong correlations between SIC score and ISTH (P < 0.0001), modified ISTH (P < 0.0001), the Acute Physiology and Chronic Health Evaluation II (P = 0.012), and SOFA (P < 0.0001) scores. More nonsurvivors were diagnosed with DIC using the ISTH and modified ISTH criteria (P < 0.001). In contrast, there was no significant difference in the proportion of patients with SIC between both groups (P = 0.055). ISTH score, modified ISTH score, and SIC score were independent risk factors for ICU mortality. Compared with the ISTH and modified ISTH scores, SIC score showed no advantage in diagnosing sepsis-associated coagulopathy or DIC. The application of these three criteria in patients with sepsis 3.0 needs further evaluation.

In sepsis-3, in contrast with sepsis-1, the definition "systemic inflammatory response" has been replaced with "dysregulated host response", and "systemic inflammatory response syndrome" (SIRS) has been replaced with "sequential organ failure assessment" (SOFA). Although the definition of sepsis has changed, the debate regarding its nature is ongoing. What are the fundamental processes controlling sepsis-induced inflammation, immunosuppression, or organ failure? In this review, we discuss the heterogeneity of sepsis-3 and address the central role of inflammation in the pathogenesis of sepsis. An unbalanced pro- and anti-inflammatory response, inflammatory resolution disorder, and persistent inflammation play important roles in the acute and/or chronic phases of sepsis. Moreover, powerful links exist between inflammation and other host responses (such as the neuroendocrine response, coagulation, and immunosuppression). We suggest that a comprehensive evaluation of the role of the inflammatory response will improve our understanding of the heterogeneity of sepsis.

Platelet activation plays an important role in the development of sepsis. During sepsis, platelet activation leads to endothelial cell injury and promotes neutrophil extracellular trap and microthrombus formation, exacerbating septic coagulation and inflammatory reactions. The resultant induction or aggravation of disseminated intravascular coagulation (DIC) leads to organ damage. Antiplatelet drugs can inhibit coagulation and inflammatory reactions in models of sepsis, reducing damage to organ function. Clinical studies suggest that aspirin may improve the prognosis of patients with sepsis. In conclusion, antiplatelet drugs are promising agents that can improve the prognosis of sepsis patients and are expected to become a new line of treatment. However, further clinical studies are required for validation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Despite progress in antibiotic treatment, mechanical ventilation, fluid resuscitation and blood glucose maintenance, sepsis remains a cause of high mortality in the intensive care unit to date, there are no proven treatment strategies for the routine management of septic patients. The extensive interaction between inflammation and coagulation contributes to the basic pathophysiology of sepsis. Thus, the agents that attenuate the activation of both inflammation and coagulation may improve the outcome in sepsis. Apart from the well-known anticoagulant effects of heparin, it also possesses various immunomodulatory properties and protects glycocalyx from shedding. Hence, heparin seems to be such an agent. Immunothrombosis plays an important role in early host defence against bacterial dissemination, thus the proper timing for anticoagulant therapy should be determined. We review the available experimental and clinical data supporting the use of heparin in sepsis. At this time the use of heparin in the treatment of sepsis is conflicting. Future trials of heparin therapy for sepsis should concentrate on the very severely ill patients, in whom benefit is most likely to be demonstrated., (© 2017 John Wiley & Sons Ltd.)

Objective: Neutrophil extracellular traps (NETs) are net-like structure composed of DNA and nuclear proteins, which are produced by activated neutrophils under the circumstances of a variety of pathogens or drugs. As part of defensive mechanism, NETs have been proved to restrict the spread of pathogens and release of antimicrobial molecules. NETs can not only strengthen the adhesion between neutrophils and platelets, promote platelet mediated procoagulant reaction, but also lead to endothelial cell damage and coagulopathy in sepsis. In addition, NETs also plays an important role in pathophysiological processes of venous thrombosis. Therefore, NETs may become the biomarkers of evaluating coagulation dysfunction and potential therapy target in sepsis.

Heparanase, a heparan sulfate (HS)-specific endoglycosidase, plays an important role in inflammation and mediates acute pulmonary and renal injuries during sepsis. To explore its role in septic intestinal injury, a non-anticoagulant heparanase inhibitor, N-desulfated/re- N-acetylated heparin (NAH), was administrated to a mouse sepsis model induced by cecal ligation and puncture (CLP). Immunohistochemical staining revealed massive shedding of HS from the intestinal mucosal surfaces after CLP, and effective inhibition of heparanase by NAH was confirmed by markedly reduced HS shedding. Following CLP, intestinal expression of heparanase was increased, whereas pretreatment with NAH reduced the sepsis-induced upregulation of heparanase expression. Meanwhile, CLP led to shedding of syndecan-1 and upregulated expression of proteases such as matrix metalloprotease-9 and urokinase-type plasminogen activator in the intestine, whereas NAH markedly suppressed syndecan-1 shedding and protease upregulation following CLP. In addition, pretreatment with NAH attenuated intestinal injury, inhibited neutrophil infiltration and suppressed the production of inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6) in the intestine during sepsis, and it also significantly reduced the elevation of inflammatory cytokines in the serum 24 hr after CLP. Our findings demonstrate that the activation of intestinal heparanase contributes to intestinal injury during early sepsis by facilitating the destruction of mucosal epithelial glycocalyx and promoting inflammatory responses.

Objective: To investigated the role of antithrombin III (AT-III) levels in the early diagnosis of disseminated intravascular coagulation (DIC) in patients with sepsis and the predictive effect of AT-III on the development of DIC., Methods: A retrospective study was conducted. Patients admitted to intensive care unit (ICU) of the First Affiliated Hospital of China Medical University from January to December in 2015 were enrolled. The patients were divided into sepsis group and non-sepsis group according to the diagnostic criteria of sepsis. In addition, sepsis patients were divided into 3 subgroups according to the international society on thrombosis and haemostasis (ISTH) scores on the first day: overt DIC (ISTH ≥ 5), non-overt DIC (ISTH 1-4) and none DIC group (ISTH = 0). Blood routine test, prothrombin time (PT), fibrinogen (Fib), D-dimer, fibrin degradation products (FDP), acute physiology and chronic health evaluation II (APACHE II) scores, sequential organ failure assessment (SOFA) scores and ISTH scores were recorded on the first ICU day. AT-III was recorded during 7 days. The differences were compared among these 3 groups. Correlations of AT-III with various parameters were calculated by using Pearson correlation analysis in sepsis group and overt DIC group. Receiver operating characteristic (ROC) curves for diagnosis of DIC with AT-III, AT-III+PT were drawn to evaluate the diagnostic efficiency. The AT-III levels of DIC patients were compared between early-onset DIC and late-onset DIC during their ICU stay. The change of AT-III levels with time and prognosis in patients with early-onset DIC was compared between groups., Results: Totally 445 patients were recruited, with 138 patients in sepsis group, and 307 in non-sepsis group. There were 20 patents diagnosed with overt DIC on the first ICU day, 115 patients non-overt DIC and 3 patients of none DIC. Twenty-five sepsis patients were diagnosed overt DIC during the ICU days. AT-III level in sepsis patients on the first ICU day were lower than that in non-sepsis patients [(55.29±13.92)% vs. (76.54±12.31)%, P < 0.01]. Patients with overt DIC had a lower AT-III level than non-overt DIC or none DIC patients [(43.85±13.00)% vs. (56.95±13.03)%, (68.00±16.52)%, both P < 0.05]. It was shown by Pearson correlation analysis that AT-III level of sepsis patients on the first ICU day was negatively correlated to ISTH score and PT (r value were -0.467, -0.654, both P < 0.01). AT-III level of overt DIC patient on the first ICU day was negatively correlated with PT (r = -0.675, P = 0.001). It was shown by ROC curve that area under ROC curve (AUC) of AT-III combined with PT for diagnosis overt DIC in sepsis patients was higher than that of AT-III or PT alone (0.843 vs. 0.763, 0.834), the sensitivity 90.0%, specificity 73.7%. The cut-off value for overt DIC diagnosis in sepsis patients of AT-III level alone was 48.5%, sensitivity was 78.0%, specificity was 70.0%. On the first ICU day, AT-III level was risen when ISTH score improved in patients with sepsis. There was similar change of AT-III level between patients with early-onset DIC and late-onset DIC. AT-III level increased with DIC improvement., Conclusions: AT-III level can be used for diagnosing sepsis-associated overt DIC independently or with a combination of PT. When ISTH score improved, AT-III level was risen in patients with sepsis associated DIC.

Objective: To investigate the effect of unfractionated heparin (UFH) on the expression of heme oxygenase-1 (HO-1) in intestinal mucosa of mice with sepsis., Methods: Thirty-six male C57BL/6J mice were randomly divided into sham group, cecal ligation and puncture (CLP) group and UHF group, n =12 in each group. Model of intestinal injury in sepsis was induced by CLP. In sham group, the mice were exposed without ligation of cecum. In UFH group, the mice were treated intravenously with 8 U of UFH via the tail vein half an hour before the operation and 12 hours after the surgery respectively. Six mice in each group were randomly chosen at 4 hours and 24 hours after operation to collect inferior vena venous blood samples and terminalileum tissues. The serum levels of interleukins (IL-1 β,IL-6),and tumor necrosis factor-α (TNF-α) were determined by enzyme linked immunosorbent assay (ELISA).The serum level of D-lactate was determined by colorimetry.Pathological changes of ileum tissue and Chiu score were observed after hematoxylin eosin (HE) staining. The HO-1 expression was detected immunohistochemically., Results: In sham group, no significant changes in the serum levels of IL-1 β,IL-6,TNF-α and D-lactate were observed. Twenty-four hours after the operation, the structure of intestinal mucosa was basically normal without obvious pathology change and no HO-1 positive cells were found. The serum levels of IL-1 β,IL-6,TNF-α,and D-lactate in CLP group were gradually increased, and they were significantly increased as compared with sham group [IL-1 β (ng/L):40.87±2.88 vs.22.60±2.05 at 4 hours,113.73±3.96 vs.22.07±2.74 at 24 hours;IL-6 (ng/L):63.89±3.26 vs.44.89±3.38 at 4 hours,176.56±5.45 vs.45.76±4.02 at 24 hours; TNF-α (ng/L):194.62± 14.13 vs.152.05±6.22 at 4 hours,599.62± 10.20 vs.155.90± 14.18 at 24 hours; D-lactate (mmol/L):0.24± 0.02 vs.0.19 ± 0.01 at 4 hours,0.33 ± 0.04 vs.0.20 ± 0.02 at 24 hours, all P ＜ 0.05].Twenty-four hours after the operation, edema and inflammation in ileal mucosa, intestinal villi structural damage were observed, the Chiu score was significantly higher than those in the sham group [4.5 (3.0-5.0) vs.0 (0-1.0),P ＜ 0.05],and a small amount of HO-1 positive cells were localized in the intestinal mucosa. Compared with CLP group, the serum levels of IL-1 β,IL-6,TNF-α,and D-lactate of UFH group were significantly decreased [IL-1 β (ng/L):31.53 ± 2.90 vs.40.87 ± 2.88 at 4 hours,61.13 ± 2.80 vs.113.73 ± 3.96 at 24 hours;IL-6 (ng/L):51.16 ± 5.68 vs.63.89 ± 3.26 at 4 hours,81.16 ± 4.54 vs.176.56 ± 5.45 at 24 hours; TNF-α (ng/L):171.76± 5.60 vs.194.62± 14.13 at 4 hours,328.48 ± 10.79 vs.599.62± 10.20 at 24 hours; D-lactate (mmol/L):0.21 ±0.01 vs.0.24±0.02 at 4 hours,0.24±0.02 vs.0.33±0.04 at 24 hours, all P ＜ 0.05]. Twenty-four hours after the operation, intestinal injury was ameliorated, the Chiu score was significantly lower [1.5 (1.0-5.0) vs.4.5 (3.0-5.0),P ＜ 0.05],and HO-1 positive cells in the intestinal mucosa was remarkably increased., Conclusion: UFH can enhance the expression of HO-1 in intestinal mucosa, reduce the release of inflammatory factors, ameliorate the intestinal inflammatory response, and thus play a protective role in intestinal tissue in mice with sepsis.

Intestinal injury is a key feature in sepsis. Heparanase, a heparin sulfate-specific glucuronidase, mediates the onset of organ injury during early sepsis. Heparin has the function to attenuate inflammation and injury induced by multiple factors; however, whether unfractionated heparin (UFH) can attenuate the intestinal injury induced by sepsis as well as the underlying mechanism is still unknown. In the present study, the function of UFH in intestinal injury induced by sepsis was explored. Results of our study showed that after CLP operation, the inflammatory response and expression of heparanase were increased and NF-κB and MAPK P38 signaling pathways were activated. However, pretreatment with UFH will inhibit the expression and activation of heparanase, and reverse the activation of NF-κB and MAPK P38 signaling pathways, thus attenuating inflammatory responses induced by sepsis. These results suggest that UFH may be a promising therapeutic drug for intestinal injury caused by sepsis.

Introduction: Information about sepsis in mainland China remains scarce and incomplete. The purpose of this study was to describe the epidemiology and outcome of severe sepsis and septic shock in mixed ICU in mainland China, as well as the independent predictors of mortality., Methods: We performed a 2-month prospective, observational cohort study in 22 closed multi-disciplinary intensive care units (ICUs). All admissions into those ICUs during the study period were screened and patients with severe sepsis or septic shock were included., Results: A total of 484 patients, 37.3 per 100 ICU admissions were diagnosed with severe sepsis (n = 365) or septic shock (n = 119) according to clinical criteria and included into this study. The most frequent sites of infection were the lung and abdomen. The overall ICU and hospital mortality rates were 28.7% (n = 139) and 33.5% (n = 162), respectively. In multivariate analyses, APACHE II score (odds ratio[OR], 1.068; 95% confidential interval[CI], 1.027-1.109), presence of ARDS (OR, 2.676; 95%CI, 1.691-4.235), bloodstream infection (OR, 2.520; 95%CI, 1.142-5.564) and comorbidity of cancer (OR, 2.246; 95%CI, 1.141-4.420) were significantly associated with mortality., Conclusions: Our results indicated that severe sepsis and septic shock were common complications in ICU patients and with high mortality in China, and can be of help to know more about severe sepsis and septic shock in China and to improve characterization and risk stratification in these patients.

Inflammatory responses can induce microvascular and endothelial dysfunction, which is associated with the development of sepsis. This study is aimed at examining the concentrations of plasma tissue factor (TF), von Willebrand factor (vWF), and tumor necrosis factor-α (TNF-α) in patients with sepsis and at determining how septic plasma (SP) regulates TF and vWF expression and p38 mitogen activated protein kinase (p38 MAPK)/nuclear factor-κB (NF-κB) pathways in human endothelial cells. The concentrations of plasma TF, vWF, and TNF-α in 22 septic patients and eight healthy controls (HCs) were examined by enzyme-linked immunosorbent assay, and their potential association with disease severity was analyzed. Human umbilical vein endothelial cells (HUVECs) were treated with SP from patients or normal plasma (NP) from the HCs, and the levels of TF and vWF were measured. The SP-induced ERK, p38 MAPK, and NF-κB activation was characterized by Western blot and immunofluorescent assays. The SP-induced HUVEC apoptosis was detected by flow cytometry. The concentrations of plasma TF, vWF, and TNF-α in the patients were significantly higher than that in the HCs and were positively correlated with the Acute Physiology and Chronic Health Evaluation II scores in the patients. Furthermore, treatment with SP, but not NP, induced TF and vWF production in HUVECs in a dose- and time-dependent manner, which was associated with sequential activation of the p38 MAPK and NF-κB pathways. Septic plasma induced HUVEC apoptosis, which was inhibited by activating the NF-κB pathway. The sepsis-related inflammatory factors promoted endothelial cell activation, dysfunction, and apoptosis through activation of the p38 MAPK pathway that was regulated by NF-κB signaling.

Objective: To systemically review the efficacy and safety of heparin for treatment of sepsis., Methods: Database search of IM/MEDLINE, Cochrane Library, SCIE, CBM, CNKI, VIP Data, WanFang Data (from January 2000 to June 2012) was conducted. The quality of included randomized controlled trials (RCTs) about heparin for treatment of sepsis was assessed, and relevant data were extracted according to the inclusion and exclusion criteria. Then meta analysis was performed using RevMan 5.1., Results: 17 trials with 1 167 participants were included. The results of meta-analysis showed: compared with the control group, heparin significantly decreased 28-day mortality in patients with sepsis [odds ratio (OR)=0.59, 95% confidence interval (95%CI) 0.45-0.77, P=0.0001]; heparin did not deteriorate coagulation disorders, but corrected sepsis-induced platelet (PLT) count reduction [mean difference (MD)=13.94, 95%CI 10.15 to 17.72, P<0.000 01], while it had no significant effect on the activated partial thromboplastin time (APTT) and prothrombin time (PT, APTT: MD=-3.18, 95%CI -6.88 to 0.53, P=0.09; PT: MD=-0.68, 95%CI -1.48 to 0.12, P=0.09). There was no significant difference between the two groups in the incidence of bleeding either. Acute physiology and chronic health evaluation II (APACHEII) score of heparin group was significantly lower than that of the control group (MD=-2.58, 95%CI -3.29 to -1.87, P<0.000 01), and the incidence of multiple organ dysfunction syndrome (MODS) was significantly lower than that of the control group (OR=0.32, 95%CI 0.17 to 0.61, P=0.000 6). In addition, heparin could shorten intensive care unit (ICU) stay (MD=-4.43, 95%CI -6.79 to -2.07, P=0.000 2), whereas it showed no significant effect on the total length of hospital stay., Conclusions: Heparin can ameliorate sepsis, and has high degree of safety and lower hospital expense. Due to limitation of the quality of included studies, larger sample and well-designed RCTs are needed to further support this conclusion.

Introduction: Excessive vascular permeability is a characteristic feature of ALI. We have previously demonstrated that UFH prevents LPS-induced disruption of endothelial barrier function in vitro. It was the objective of this study to determine whether UFH may attenuate endotoxin-induced lung vascular leak in mice and to further explore the possible underlying mechanisms., Methods: C57BL/6J mice were randomly divided into the control, LPS and LPS plus UFH groups. Sepsis was induced by intraperitoneal injection of LPS at a dose of 30 mg/kg. Mice in the LPS plus UFH group were intravenously received 8 units UFH (heparin sodium) diluted in 20 μl sterile saline at 0.5 h before the injection of LPS., Results: 1) UFH pretreatment attenuated LPS-induced histopathological changes in Lung at 6 h; 2) Pretreatment of mice with UFH ameliorated LPS-induced lung edema and lung vascular leak at 6 h; 3) UFH pretreatment dramatically inhibited RhoA and ROCK activation in the lung tissues of LPS-treated mice (3 and 6 h). 4) UFH pretreatment significantly down-regulated ROCK1 gene expression, but did not affect the increased expression of ROCK2 mRNA in the lung tissues of LPS-treated mice at 3 or 6 h., Conclusion: These data suggest that UFH may attenuate endotoxin-induced lung vascular leak by regulating RhoA/Rho kinase pathway., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Heparin, a potent blood anticoagulant, is known to possess anti-inflammatory activity. In this work, we investigated whether heparin can ameliorate acute lung injury and lethal response in lipopolysaccharide (LPS)-induced mouse model of sepsis. We found that heparin effectively rescued lethality, improved lung pathological changes, inhibited myeloperoxidase (MPO) activity, and reduced malondialdehyde (MDA) level, lung wet/dry weight ratio and Evans blue values in LPS-induced septic mice. In addition, heparin also inhibited the release of tumor necrosis factor (TNF)-α, interleukin-6 (IL-6) and IL-1β in serum and decreased the expression of p-p38, nuclear factor κB (NF-κB) and p-c-SRC kinase in lungs of septic mice. Our findings suggest that heparin is capable of suppressing the lethal response and acute lung injury associated with sepsis, and support the notion that heparin may be a potential therapeutic agent for the conditions associated with septic shock.

Background: Endothelial barrier dysfunction is central to the pathogenesis of sepsis-associated acute lung injury (ALI). Microtubule (MT) dynamics in vascular endothelium are crucial for the regulation of endothelial barrier function. Unfractionated heparin (UFH) possesses various biological activities, such as anti-inflammatory activity and endothelial barrier protection during sepsis.Methods: Here, we investigated the effects and underlying mechanisms of UFH on lipopolysaccharide (LPS)-induced endothelial barrier dysfunction. C57BL/6 J mice were randomized into vehicle, UFH, LPS and LPS + UFH groups. Intraperitoneal injection of 30 mg/kg LPS was used to induce sepsis. Mice in the LPS + UFH group received intravenous UFH 0.5 h prior to LPS injection. Human pulmonary microvascular endothelial cells (HPMECs) were cultured for analyzing the effects of UFH on LPS-induced and nocodazole-induced hyperpermeability, F-actin remodeling, and LPS-induced p38 MAPK activation.Results: UFH pretreatment significantly attenuated LPS-induced pulmonary histopathological changes, and increased the lung W/D ratio and Evans blue accumulation in vivo. Both in vivo and in vitro studies showed that UFH pretreatment blocked the LPS-induced increase in guanine nucleotide exchange factor (GEF-H1) expression and myosin phosphatase target subunit 1 (MYPT1) phosphorylation, and microtubule (MT) disassembly in LPS-induced ALI mouse model and human pulmonary microvascular endothelial cells (HPMECs). These results suggested that UFH ameliorated LPS-induced endothelial barrier dysfunction by inhibiting MT disassembly and GEF-H1 expression. In addition, UFH attenuated LPS-induced hyperpermeability of HPMECs and F-actin remodeling. In vitro, UFH pretreatment inhibited LPS-induced increase in monomeric tubulin expression and decrease in tubulin polymerization and acetylation. Meanwhile, UFH ameliorates nocodazole-induced MTs disassembly and endothelial barrier dysfunction.Additionally, UFH decreased p38 phosphorylation and activation, which was similar to the effect of the p38 MAPK inhibitor, SB203580.Conclusions: UFH exert its protective effects on pulmonary microvascular endothelial barrier dysfunction via microtubule stabilization and is associated with the p38 MAPK pathway. [ABSTRACT FROM AUTHOR]

• The novel molecular FGL2 has crucial roles in facilitating procoagulant, pro-inflammatory, and immune-regulatory responses. • The increased expression of FGL2 on macrophages or neutrophils is closely related to the amplified inflammatory responses. • The crucial role of FGL2 and its potential as a target for novel immune interventions in treating infectious diseases. Infectious diseases are complex inflammatory-immunologic host responses caused by various pathogens, such as viruses, bacteria, parasites, and fungi. In the process of infectious disease development, immune cells are activated, and a substantial number of inflammatory factors are released within the endothelium, which results in coagulation activation and the formation of intravascular thrombi. Furthermore, infection-induced hypercoagulability amplifies the inflammatory response and immune dysregulation. Emerging evidence suggests that fibrinogen-like protein 2 (FGL2) has a crucial role in facilitating procoagulant, pro-inflammatory, and immune-regulatory responses in various infectious diseases. This review illustrates the complex procoagulation and immunoregulatory roles of FGL2, suggesting it could be a target for novel immune interventions in intractable infectious diseases. [ABSTRACT FROM AUTHOR]

Rho kinase (ROCK) inhibition has been reported to improve various inflammatory diseases including endotoxemia. Mitochondrial dysfunction might be the key to the pathophysiology of sepsis-induced organ failure. Therefore, this study aimed to explore whether ROCK inhibition protects against the liver injury by regulating mitochondrial function in endotoxemia model mice. The mice were randomly divided into four groups ( N = 6–8 per group): control, LPS, LPS + Y-27632 (LPS + Y), and LPS + Mito-TEMPO (LPS + M). For induction of endotoxin-induced acute liver injury, the mice were intraperitoneally administered lipopolysaccharide (LPS, 20 mg/kg). The ROCK inhibitor Y-27632 (or mitochondrial antioxidant Mito-TEMPO) was intraperitoneally administered at 18 and 1 h before injection of LPS. The mice were euthanized 8 h after LPS administration. The liver and blood samples were taken and preserved for analysis. Results of this study showed that pretreatment with Y-27632 or Mito-TEMPO significantly attenuated the liver injury as compared to the LPS group. This was confirmed by decreased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and by reduced hepatocellular apoptosis and histologic damage. Pretreatment with Y-27632 or Mito-TEMPO markedly reduced the LPS-induced inflammatory response and oxidative stress the in liver. Furthermore, it showed similar protective effects on the hepatic mitochondrial function, including an increased activity of complexes I and IV and mitochondrial superoxide dismutase (MnSOD), and an upregulated expression of mtDNA-encoded genes. Taken together, these data demonstrate that Mito-TEMPO can potently inhibit the endotoxin-induced mitochondrial and hepatic abnormalities and indicate that mitochondrial dysfunction might play a key role in the endotoxemia-induced acute liver injury. Moreover, our study shows that ROCK inhibition protects against the endotoxemia-induced liver injury by improving the mitochondrial function. [ABSTRACT FROM AUTHOR]

Background This study was conducted to investigate whether Xuebijing injection can rectify the dysfunction of microcirculation in septic shock and assessed the microcirculatory parameters directly via orthogonal polarization spectral and software AVA 3.0. Material and methods Anesthetized and mechanically ventilated beagle dogs were modeled for septic shock via lipopolysaccharide (LPS) intravenous injection. They were divided randomly into four groups, control group accepted operation only for jejunostomy and cystostomy; LPS group accepted operation and LPS intravenous injection; saline group accepted operation, LPS intravenous injection, and saline resuscitation; XBJ group accepted operation, LPS intravenous injection, saline resuscitation, and Xuebijing injection infusion. The MAP was recorded via right femoral artery catheterization, at the same time, the blood gas analysis was taken via that pathway at the set time points. ScvO 2 was obtained via right jugular vein catheterization at the related time points. Microcirculatory parameters were recorded by orthogonal polarization spectral via the jejunum stoma, and the microcirculation image was analyzed via the software AVA 3.0 later. Results Xuebijing injection improved microcirculation of the jejunum villus in canine model of septic shock induced by endotoxin, especially for the proportion of perfused vessels. Conclusions Based on the adequate fluid resuscitation, Xuebijing injection plays a helpful role of improving microcirculation in septic shock. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Heparins, including unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH), are anticoagulants approved as a treatment for severe sepsis, which can also prevent apoptosis and inflammation. The aim of this study was to investigate whether UFH prevents vascular leakage induced by lipopolysaccharide (LPS) and to define the role of angiopoietin (Ang)/Tie2 signaling pathway since LPS is usually used to mimic the initiation of sepsis. Methods: Human pulmonary microvascular endothelial cells (HPMECs) were pretreated with UFH (0.1U/ml-10U/ml), 15min prior to stimulation with LPS (10μg/ml). Those samples not receiving LPS or UFH received an equal volume of Phosphate-buffered saline (PBS). Cells were cultured under various experimental conditions for 2h, 6h or 12h for analysis. Results: 1) Pretreatment with UFH significantly reduced HPMEC permeability compared with LPS-stimulated groups; 2) Pretreatment with UFH decreased the formation of stress fiber and intracellular gaps induced by LPS; 3) UFH significantly up-regulated gene expression of Tie2 and Ang-1 but down-regulated Ang-2 in HPMECs; 4) UFH prevented LPS-induced decrease in the level of ZO-1. Conclusion: This study demonstrates that UFH enhances endothelial barrier function and Ang/Tie2 axis probably represents one of the mechanisms by which UFH exerts its protective effect. [Copyright &y& Elsevier]

Abstract: Introduction: In the pathogenesis of sepsis, inflammation and coagulation play a pivotal role. In addition to the anticoagulant activity, unfractionated heparin (UFH) has important immunomodulatory properties. However, different studies have reported conflicting effects on sepsis in association with heparin. The objective of this study is to determine whether UFH is able to reduce endotoxin-induced inflammation and coagulation in mice or produce improved outcome. Methods: C57BL/6J mice were randomly divided into two groups. Experimental mice were given intravenous injection of 8 units/20g body weight UFH (heparin sodium) diluted in 20μl sterile saline while the control mice received vehicle sterile saline only. They were injected with LPS (30mg/kg, i.p.) 0.5h later. Blood was collected and Livers were harvested at 3 and 6h for analysis. In survival studies, a separate group of mice were treated with 8 units/20g UFH (n=20) or sterile saline (n=20) given intravenously at 1, 12, 24 and 36hours after LPS injection. Mice were monitored every 12hours for a maximum of 72hrs. Results: 1) Pretreatment of mice with UFH strongly reduced the levels of TNF-α, IL-1β and TAT in plasma at 3 and 6h; 2) Pretreatment of mice with UFH inhibited the expression of TNF-α, IL-1β and tissue factor genes in blood cells at 3h; 3) UFH pretreatment dramatically diminished LPS-induced neutrophil sequestration (at 3 and 6h) , thrombi formation and fibrin(ogen) deposition in the liver (at 6h). 4) The UFH-pretreated group exhibited significantly lower levels of ALT and CRE at 6h. 5) Treatment with UFH could prevent mortality associated with endotoxin challenge. Conclusion: These data suggest that UFH attenuates inflammation and coagulation and prevents lethality in endotoxemic mice. [Copyright &y& Elsevier]