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Sepsis remains a significant cause of mortality and morbidity worldwide, with limited effective treatment options. The T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) has emerged as a potential therapeutic target in various immune-related disorders. This narrative review aims to explore the role of TIM-3 in sepsis and evaluate its potential as a promising target for immunotherapy. We discuss the dynamic expression patterns of TIM-3 during sepsis and its involvement in regulating immune responses. Furthermore, we examine the preclinical studies investigating the regulation of TIM-3 signaling pathways in septic models, highlighting the potential therapeutic benefits and challenges associated with targeting TIM-3. Overall, this review emphasizes the importance of TIM-3 in sepsis pathogenesis and underscores the promising prospects of TIM-3-based immunotherapy as a potential strategy to combat this life-threatening condition., 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 © 2024 Wang, Liu, Wu, Wang, Hu and Bo.)

Sepsis is a complex, multifactorial syndrome characterized by a dysregulated host response to infection, leading to severe organ dysfunction and high mortality rates among critically ill patients. Hypovitaminosis C and vitamin C deficiency are frequently observed in septic patients, prompting interest in the potential therapeutic role of ascorbic acid. Although intravenous administration of ascorbic acid has been investigated in multiple clinical trials for sepsis treatment, the specific immunomodulatory mechanisms underlying its effects remain elusive. This study aimed to investigate the protective effects of high-dose ascorbic acid on experimental sepsis. Results show that intravenous administration of high-dose ascorbic acid (250 mg/kg) attenuated sepsis-induced organ dysfunctions in a cecal ligation and puncture (CLP)-induced septic mouse model. Ascorbic acid improved splenic cell apoptosis and increased the number of CD3 + T cells in septic mice induced by CLP. Furthermore, ascorbic acid downregulated PD-L1 expression in livers, reduced PD-1 expression in spleens, and inhibited the phosphorylation of STAT1 at Y701 in multiple organs of CLP-induced septic mice. The in vitro experiments also revealed that 800 μM ascorbic acid suppressed STAT1 phosphorylation and inhibited lipopolysaccharide (LPS) and IFN-γ-induced PD-L1 expression in macrophages. These findings suggest that ascorbic acid prevents sepsis-associated organ dysfunction through the p-STAT1/PD-L1 signaling pathway. Our study provides new insights into the potential therapeutic use of ascorbic acid in sepsis., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Objective: Interpretable and real-time prediction of sepsis and risk factor analysis could enable timely treatment by clinicians and improve patient outcomes. To develop an interpretable machine-learning model for the prediction and risk factor analysis of sepsis and septic death., Methods: This is a retrospective observational cohort study based on the Medical Information Mart for Intensive Care (MIMIC-IV) dataset; 69,619 patients from the database were screened. The two outcomes include patients diagnosed with sepsis and the death of septic patients. Clinical variables from ICU admission to outcomes were analyzed: demographic data, vital signs, Glasgow Coma Scale scores, laboratory test results, and results for arterial blood gasses (ABGs). Model performance was compared using the area under the receiver operating characteristic curve (AUROC). Model interpretations were based on the Shapley additive explanations (SHAP), and the clustered analysis was based on the combination of K-means and dimensionality reduction algorithms of t-SNE and PCA., Results: For the analysis of sepsis and septic death, 47,185 and 2480 patients were enrolled, respectively. The XGBoost model achieved a predictive value of area under the curve (AUC): 0.745 [0.731-0.759] for sepsis prediction and 0.8 [0.77, 0.828] for septic death prediction. The real-time prediction model was trained to predict by day and visualize the individual or combined risk factor effects on the outcomes based on SHAP values. Clustered analysis separated the two phenotypes with distinct risk factors among patients with septic death., Conclusion: The proposed real-time, clustered prediction model for sepsis and septic death exhibited superior performance in predicting the outcomes and visualizing the risk factors in a real-time and interpretable manner to distinguish and mitigate patient risks, thus promising immense potential in effective clinical decision making and comprehensive understanding of complex diseases such as sepsis., 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 © 2023. Published by Elsevier B.V.)

Introduction: The T cell immunoglobulin and mucin domain 3 (Tim-3) mediated immunosuppressive pathway has been shown to play an essential role in the development of sepsis. However, the influence of Tim-3 blockade during sepsis and the possible effects on T cells' function remains largely unknown. Our study investigates the role of Tim-3 in cecal ligation and puncture (CLP)-induced sepsis in mice., Methods: Sepsis was induced in C57BL/6 male mice via CLP. The expression of Tim-3 in CD8 + T cells after CLP challenge was measured. A dose of 50 μg anti-Tim-3 antibodies was injected intraperitoneally 30 min after surgery. Postoperative survival, bacterial clearance in the blood and peritoneal lavage fluid, cytokine secretion in the blood, and lung and liver histology were evaluated. In addition, the apoptosis of immune cells in the spleen and thymus was examined, respectively., Results: Tim-3 expression was elevated in the splenic CD8 + T cells of septic mice. At the early stage of CLP-induced sepsis, blocking Tim-3 with anti-Tim-3 antibodies reduced the severity of sepsis. The anti-Tim-3 antibodies alleviated the morphology of lung and liver injuries in septic mice. The anti-Tim-3 antibodies also reduced the severity of the inflammatory responses and lymphocyte apoptosis in septic mice., Conclusions: Anti-Tim-3 antibodies might be a potential therapeutic strategy for sepsis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Sepsis is associated with multiple organ dysfunction, and the brain is particularly vulnerable. Sepsis-associated encephalopathy (SAE) increases the mortality of patients with sepsis; however, the pathogenesis of SAE remains unclear. Methane, the simplest aliphatic hydrocarbon, has been reported to have anti-inflammatory and organ-protective effects. This study aimed to investigate the effects of methane on the cognitive deficits in mice with experimental sepsis. We randomly divided C57BL/6 male mice into sham, cecal ligation and puncture (CLP), and CLP + methane-rich saline (MS) groups. Twenty-four hours after surgery, behavioral tests were conducted on surviving mice and the hippocampus were collected for biochemical analysis. We found that CLP resulted in cognitive deficits in septic mice. A physiological mechanistic investigation revealed that microglia in the hippocampus are largely activated, coupled with the production of inflammatory cytokines and reactive oxygen species (ROS). Notably, methane inhibited the activation of microglia in the hippocampus, reduced the severity of inflammation, diminished the generation of ROS, and ultimately alleviated behavioral impairment in septic mice. Together, these show that treatment with methane ameliorated cognitive deficits in septic mice, which is partly related to the anti-inflammatory and antioxidative effects in the hippocampus., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, of which the pathogenesis is complex and the mortality rate is high. However, current basic research is facing the dilemma of high heterogeneity and difficult translation to clinical practice. In-depth basic research is one of the most important ways to break through the "bottleneck" of clinical diagnosis and treatment of sepsis. The purpose of this review is to analyze the current progress and challenges in the field of basic research on sepsis, and look forward to the potential research directions in the future. Cell function, energy metabolism, microbiota, epigenetics and recovery period of sepsis may be the research priorities.

Background: B7 family members and ligands have been identified as critical checkpoints in orchestrating the immune response during sepsis. V-domain Ig suppressor of T cell activation (VISTA) is a new inhibitory immune checkpoint involved in restraining T cell response. Previous studies demonstrated that VISTA engagement on T cells and myeloid cells could transmit inhibitory signals, resulting in reduced activation and function. The current study was designed to determine the potential therapeutic effects of a high-affinity anti-VISTA antibody (clone MH5A) in a murine model of sepsis., Methods: Polymicrobial sepsis was induced in male C57BL/6 mice via cecal ligation and puncture. Expression profiles of VISTA on T lymphocytes and macrophage were examined at 24 and 72 h postsurgery. The effects of anti-VISTA mAb on the 7-day survival, lymphocyte apoptosis, cytokine expression, bacterial burden, and vital organ damage were determined. Furthermore, the effects of anti-VISTA mAb on CD3 + T cell apoptosis and macrophage activation were determined in vitro ., Results: VISTA was substantially expressed on T cells and macrophages in sham-operated mice; septic peritonitis did not induce significant changes in the expression profiles. Treatment with MH5A improved the survival of septic mice, accompanied by reduced lymphocyte apoptosis, decreased cytokine expression, and enhanced bacterial clearance. Engagement of VISTA receptor with MH5A mitigated CD3 + T cell apoptosis cultured from CLP mice and suppressed LPS-induced cytokine production by macrophage in vitro ., Conclusion: The present study identified VISTA as a novel immune checkpoint in the regulation of T cell and macrophage response during sepsis. Modulation of the VISTA pathway might offer a promising opportunity in the immunotherapy for sepsis., 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 © 2021 Tianzhu Tao et al.)

Background and Objective: Patients who survive sepsis in the intensive care unit (ICU) (sepsis survivors) have an increased risk of long-term mortality and ICU readmission. We aim to identify the risk factors for in-hospital mortality in sepsis survivors with later ICU readmission and visualize the quantitative relationship between the individual risk factors and mortality by applying machine learning (ML) algorithm., Methods: Data were obtained from the Medical Information Mart for Intensive Care III (MIMIC-III) database for sepsis and non-sepsis ICU survivors who were later readmitted to the ICU. The data on the first day of ICU readmission and the in-hospital mortality was combined for the ML algorithm modeling and the SHapley Additive exPlanations (SHAP) value of the correlation between the risk factors and the outcome., Results: Among the 2970 enrolled patients, in-hospital mortality during ICU readmission was significantly higher in sepsis survivors (n = 2228) than nonsepsis survivors (n = 742) (50.4% versus 30.7%, P<0.001). The ML algorithm identified 18 features that were associated with a risk of mortality in these groups; among these, BUN, age, weight, and minimum heart rate were shared by both groups, and the remaining mean systolic pressure, urine output, albumin, platelets, lactate, activated partial thromboplastin time (APTT), potassium, pCO2, pO2, respiration rate, Glasgow Coma Scale (GCS) score for eye-opening, anion gap, sex and temperature were specific to previous sepsis survivors. The ML algorithm also calculated the quantitative contribution and noteworthy threshold of each factor to the risk of mortality in sepsis survivors., Conclusion: 14 specific parameters with corresponding thresholds were found to be associated with the in-hospital mortality of sepsis survivors during the ICU readmission. The construction of advanced ML techniques could support the analysis and development of predictive models that can be used to support the decisions and treatment strategies made in a clinical setting in critical care patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2021. Published by Elsevier B.V.)

Objective: Immunosuppression plays a vital role in the pathophysiological mechanism of sepsis, and it is the main cause of death in patients with sepsis during the later phase. Sepsis induced immunosuppression is gradually recognized. Its underlying mechanisms involve immune cell apoptosis, autophagy, cell metabolism reprogramming, endotoxin tolerance, central nervous system regulation, and epigenetic regulation. New approaches that target the host immune response and reconstruct the immune balance are the keys to improve the prognosis of patients with sepsis. With the help of immune status monitor, novel immunomodulatory agents, such as thymosin α1, γ- interferon (IFN-γ), interleukin-7 (IL-7), granulocyte-macrophage colony stimulating factor (GM-CSF) and anti-programmed death receptor 1 (PD-1) antibody, are expected to become a new strategy for the treatment of sepsis in future.

Hemin, an inducer of heme oxygenase-1 (HO-1), can enhance the activation of HO-1. HO-1 exhibits a variety of activities, such as anti-inflammatory, antioxidative, and antiapoptotic functions. The objective of this study was to investigate the effects of hemin on sepsis-induced skeletal muscle wasting and to explore the mechanisms by which hemin exerts its effects. Cecal ligation and perforation (CLP) was performed to create a sepsis mouse model. Mice were randomly divided into four groups: control, CLP, CLP plus group, and CLP-hemin-ZnPP (a HO-1 inhibitor). The weight of the solei from the mice was measured, and histopathology was examined. Cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting were used to assess the expression levels of HO-1 and atrogin-1. Furthermore, we investigated the antioxidative effects of HO-1 by detecting malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. CLP led to dramatic skeletal muscle weakness and atrophy, but pretreatment with hemin protected mice against CLP-mediated muscle atrophy. Hemin also induced high HO-1 expression, which resulted in suppressed proinflammatory cytokine and reactive oxygen species (ROS) production. The expression of MuRF1 and atrogin-1, two ubiquitin ligases of the ubiquitin-proteasome system- (UPS-) mediated proteolysis, was also inhibited by increased HO-1 levels. Hemin-mediated increases in HO-1 expression exert protective effects on sepsis-induced skeletal muscle atrophy at least partly by inhibiting the expression of proinflammatory cytokines, UPS-mediated proteolysis, and ROS activation. Therefore, hemin might be a new treatment target against sepsis-induced skeletal muscle atrophy.

Sepsis is the leading cause of death in intensive care units worldwide. Autophagy has recently been shown to protect against sepsis-induced liver injury. Here, we investigated the roles of homeodomain-interacting protein kinase 2 (HIPK2) in the molecular mechanism of sepsis-induced liver injury. HIPK2 expression was reduced in sepsis-induced liver injury, and HIPK2 overexpression increased the survival rate and improved caecal ligation and puncture (CLP)-induced liver injury by reducing serum and liver aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) levels in mice with sepsis. HIPK2 overexpression significantly decreased CLP-induced release of inflammatory cytokines into the serum and attenuated oxidative stress-associated indicators in mice with CLP-induced liver injury, whereas HIPK2 knockdown produced the opposite results, suggesting that HIPK2 is a negative regulator of sepsis. Furthermore, HIPK2 overexpression inhibited lipopolysaccharide (LPS)-induced apoptosis of primary hepatocytes, increased the autophagic flux, and restored both autophagosome and autolysosome formation in the livers of CLP-induced mice by suppressing calpain signalling. Importantly, HIPK2 overexpression reduced the elevated cytosolic Ca 2+ concentration in LPS-treated primary hepatocytes by interacting with calpain 1 and calmodulin. Finally, several anti-inflammatory drugs, including resveratrol, aspirin, vitamin E and ursolic acid, significantly increased the levels of the HIPK2 mRNA and protein by modulating promoter activity and the 3'-UTR stability of the HIPK2 gene. In conclusion, HIPK2 overexpression may improve sepsis-induced liver injury by restoring autophagy and thus might be a promising target for the clinical treatment of sepsis.

Objective: During sepsis, circulating leukocytes are in a hyper inflammatory state, and with the progress of the inflammation, immune cells may become tolerated. Glycolysis and pentose phosphate pathway are up-regulated but oxidative phosphorylation is suppressed in hyper inflammatory cells, whereas during immune tolerance, glycolysis is often down-regulated. In this review, we will summarize the changes of cellular metabolic pathways in monocytes and macrophages during sepsis. We also review how the metabolism of glucose, amino acids, and fatty acids affect the function of monocytes and macrophages in sepsis. Current literature indicated that metabolism plays a significant role in regulating the functions of immune cells in sepsis, which might be a potential therapy for sepsis and deserved further research.

Background: As a common and life-threatening infectious syndrome, sepsis contributes significantly to morbidity and mortality in clinical settings. Vascular endothelial injury and hyperpermeability play an important role in the development of sepsis-induced organ dysfunction. Heat shock protein A12B (HSPA12B) is one of the HSP70 superfamily members and is mainly expressed in vascular endothelial cells. The present study was performed to investigate the role of HSPA12B in endothelial barrier dysfunction during sepsis., Methods: Human umbilical vein endothelial cells (HUVECs) were stimulated with 1 μg/mL of lipopolysaccharide (LPS) and harvested at 0, 3, 6, 9, 12, and 24 h. The messenger RNA and protein levels of HSPA12B were detected by Real Time-polymerase chain reaction and Western blot. Upregulation of HSPA12B was induced by transfection of pIRES2-EGFP plasmid carrying the HSPA12B complementary DNA. The in vitro effect of HSPA12B overexpression on endothelial permeability was manifested by the transendothelial electrical resistance value, expression of the adhesion molecules VE-cadherin, and the level of permeability-related kinase myosin light chain, SRC, and CDC42. Mice received cecal ligation and puncture surgery followed by nasal inhalation of nano-polymer-mediated siRNA. Lung endothelial permeability was assessed via intrajugular vein injection of Evans Blue 30 h after cecal ligation and puncture., Results: After LPS induction, the messenger RNA and protein level of HSPA12B in HUVECs increased and peaked at 12 h, whereas they returned to the baseline level at 24 h. Overexpression of HSPA12B can reduce the permeability of HUVEC stimulated by LPS in vitro, while increasing the expression of VE-Cadherin, myosin light chain, and CDC42. On the other hand, downregulating the expression of HSPA12B can significantly increase lung permeability in mice with sepsis-induced vascular injury., Conclusions: HSPA12B plays a protective role in vascular endothelial barrier dysfunction by preserving the endothelial permeability during sepsis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Salidroside (SDS) is the main effective component of Rhodiola rosea L with a variety of pharmacologic properties. The objective of this study was to investigate the efficacy of SDS in the treatment of experimental sepsis in mice and explore the possible underlying action mechanisms., Methods: Sepsis was induced in C57BL/6 male mice via cecal ligation and puncture (CLP). The animals were divided into three groups as follows: sham, CLP, and CLP plus SDS. SDS (50 mg/kg) was injected intraperitoneally 1 h after operation. Postoperative survival of the mice, bacterial clearance in blood and peritoneal lavage fluid, cytokine secretion in blood, and histology of lung were evaluated. In addition, apoptosis of immune cells in the spleen and thymus were examined, respectively., Results: SDS administration prolonged the survival of the septic mice, inhibited the proinflammatory responses, and enhanced bacterial clearance. It also alleviated the pathologic changes in the lung and inhibited the apoptosis of immune cells in the spleen and thymus after CLP challenge., Conclusions: SDS exerts a protective effect in CLP-induced sepsis by attenuating the proinflammatory responses, enhancing bacterial clearance, and preserving adaptive immunity. SDS may be a promising therapeutic strategy for the treatment of sepsis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Tumor necrosis factor related apoptosis inducing ligand (TRAIL) as a member of the TNF gene superfamily induces apoptosis primarily in tumor cells. TRAIL also plays an important role in the modulation of inflammatory responses, especially in the process of immune paralysis. The aim of the present study was to examine soluble TRAIL (sTRAIL) levels in septic patients in an attempt to explore the association between sTRAIL level and the risk of mortality., Methods: Plasma sTRAIL levels were detected by ELISA in 50 septic patients and 20 healthy volunteers. HLA-DR expression in monocytes was detected by flow cytometry. Selective biochemical parameters were recorded, and patients were monitored in a 28-day period for mortality., Results: The mean plasma sTRAIL level in septic patients was significantly lower than that in healthy controls (16.9±8.3 vs. 68.3±8.6 pg/ml, P<0.01), and was significantly higher in 28-day survivors than those in non-survivors (19.4±9.8 vs. 13.9±4.7 pg/ml, P<0.05). Univariate analysis indicated that plasma sTRAIL level was positively correlated with monocyte and lymphocyte counts and HLA-DR expression level (r = 0.5, P<0.01; r = 0.3, P<0.05; r = 0.43, P<0.01, respectively). STRAIL level was negatively correlated with APACHE II score, BUN and age (r = -0.48, P<0.01; r = -0.29, P<0.05; r = -0.45, P<0.01, respectively). Multiple linear regression analysis indicated that the predictor of plasma soluble TRAIL level was HLA-DR expression (P<0.01)., Conclusion: Low plasma sTRAIL levels were associated with immune paralysis and a high risk of mortality in patients with septic shock. sTRAIL may prove to be a potential biomarker of immune function and predict the survival of septic patients.

Liver plays a major role in hypermetabolism and produces acute phase proteins during systemic inflammatory response syndrome and it is of vital importance in host defense and bacteria clearance. Our previous studies indicated that programmed death-1 (PD-1) and its ligand programmed death ligand-1 (PD-L1) are crucial modulators of host immune responses during sepsis. Our current study was designed to investigate the role of PD-L1 in sepsis-induced liver injury by a mouse cecal ligation and puncture (CLP) model. Our results indicated that there was a significant increase of PD-L1 expression in liver after CLP challenge compared to sham-operated controls, in terms of levels of mRNA transcription and immunohistochemistry. Anti-PD-L1 antibody significantly alleviated the morphology of liver injury in CLP mice. Anti-PD-L1 antibody administration decreased ALT and AST release in CLP mice, decreased the levels of tumor necrosis factor (TNF)-α , interleukin (IL)-6, and IL-10 mRNA in liver after sepsis challenge. Thus, anti-PD-L1 antibody might have a therapeutic potential in attenuating liver injury in sepsis.

Introduction: The objective of this study was to identify and characterize the most highly cited clinical research articles published on sepsis., Methods: A comprehensive list of citation classics in sepsis was generated by searching the database of Web of Science-Expanded (1970 to present) using keywords 'sepsis' or 'septic shock'. The top 50 cited clinical research papers were retrieved by reading the abstract or full text if needed. Each eligible article was reviewed for basic information, including country of origin, article type, journals, authors, and funding sources., Results: A total of 2,151 articles were cited more than 100 times; the 50 top-cited clinical articles were published between 1974 and 2008. The number of citations ranged from 372 to 2,932, with a mean of 678 citations per article. These citation classics came from nine countries, of which 26 articles came from the United States. Rush University and the University of Pittsburgh lead the list of classics with six papers each. The 50 top-cited articles were published in 17 journals, with the New England Journal of Medicine and Journal of the American Medical Association topping the list. The top 50 articles consisted of 21 clinical trials and 29 observational studies., Conclusions: Our bibliometric analysis provides a historical perspective on the progress of clinical research on sepsis. Articles originating from the United States and published in high-impact journals are most likely to be cited in the field of sepsis research.

Introduction: Early identification of septic patients at high risk of dying remains a challenge. The prognostic role of brain natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) in septic patients remains controversial. The purpose of this systematic review and meta-analysis was to investigate the value of elevated BNP or NT-proBNP in predicting mortality in septic patients., Methods: PubMed, Embase and the Cochrane Central Register of Controlled Trials were searched (up to February 18, 2011). Studies were included if they had prospectively collected data on all-cause mortality in adult septic patients with either plasma BNP or NT-proBNP measurement. Studies that failed to construct a 2 × 2 table of results were excluded. Two authors independently determined the validity of included studies and extracted data., Results: 12 studies with a total of 1,865 patients were included. Elevated natriuretic peptides were significantly associated with increased risk of mortality (odds ratio (OR) 8.65, 95% confidence interval (CI) 4.94 to 15.13, P < 0.00001). The association was consistent for BNP (OR 10.44, 95% CI 4.99 to 21.58, P < 0.00001) and NT-proBNP (OR 6.62, 95% CI 2.68 to 16.34, P < 0.0001). The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were 79% (95% CI 75 to 83), 60% (95% CI 57 to 62), 2.27 (95% CI 1.83 to 2.81) and 0.32 (95% CI 0.22 to 0.46), respectively., Conclusions: Our results suggested that an elevated BNP or NT-proBNP level may prove to be a powerful predictor of mortality in septic patients. Future larger and more adequately powered prospective studies are warranted to clarify the assay standardization, the optimal cut-off, and the prognostic value of BNPs in conjunction with other biomarkers.

Background: An imbalance between overwhelming inflammation and lymphocyte apoptosis is the main cause of high mortality in patients with sepsis. Baicalin, the main active ingredient of the Scutellaria root, exerts anti-inflammatory, anti-apoptotic, and even antibacterial properties in inflammatory and infectious diseases. However, the therapeutic effect of baicalin on polymicrobial sepsis remains unknown., Methodology/principal Findings: Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in C57BL/6 mice. Mice were infused with baicalin intraperitoneally at 1 h, 6 h and 12 h after CLP. Survival rates were assessed over the subsequent 8 days. Bacterial burdens in blood and peritoneal cavity were calculated to assess the bacterial clearance. Neutrophil count in peritoneal lavage fluid was also calculated. Injuries to the lung and liver were detected by hematoxylin and eosin staining. Levels of cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-10 and IL-17, in blood and peritoneum were measured by enzyme-linked immunosorbent assay. Adaptive immune function was assessed by apoptosis of lymphocytes in the thymus and counts of different cell types in the spleen. Baicalin significantly enhanced bacterial clearance and improved survival of septic mice. The number of neutrophils in peritoneal lavage fluid was reduced by baicalin. Less neutrophil infiltration of the lung and liver in baicalin-treated mice was associated with attenuated injuries to these organs. Baicalin significantly reduced the levels of proinflammatory cytokines but increased the level of anti-inflammatory cytokine in blood and peritoneum. Apoptosis of CD3(+) T cell was inhibited in the thymus. The numbers of CD4(+), CD8(+) T lymphocytes and dendritic cells (DCs) were higher, while the number of CD4(+)CD25(+) regulatory T cells was lower in the baicalin group compared with the CLP group., Conclusions/significance: Baicalin improves survival of mice with polymicrobial sepsis, and this may be attributed to its antibacterial property as well as its anti-inflammatory and anti-apoptotic effects.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is one of the critical inhibitory regulators of early stages of T-cell activation and proliferation, which opposes the actions of CD28-mediated costimulation. Anti-CTLA-4 therapy has been effective clinically in enhancing immunity and improving survival in patients with metastatic cancer. Sepsis is a lethal condition that shares many of the same mechanisms of immune suppression with cancer. Given the similarities in immune defects in cancer and sepsis, we examined the ability of anti-CTLA-4 antibody to block apoptosis, reverse the immunosuppression of sepsis, and improve survival in the cecal ligation and puncture model. Mice underwent sham or cecal ligation and puncture, and spleens harvested at various time points after surgery. Expression of CTLA-4 on CD4, CD8, and regulatory T cells was quantitated. Anti-CTLA-4 was administrated 6 and 24 h after surgery. Spleens were harvested at 48 h after surgery, and apoptosis and cytokine production determined. Seven-day survival studies were also conducted. Expression of CTLA-4 on CD4, CD8, and regulatory T cells increased during sepsis. Anti-CTLA-4 therapy decreased sepsis-induced apoptosis but had little effect on proinflammatory or anti-inflammatory cytokines. There was a dose-dependent effect of anti-CTLA-4 on survival. At high dose, anti-CTLA-4 worsened survival, but at lower doses, survival was significantly improved. Survival in sepsis depends on the proper balance between the proinflammatory and anti-inflammatory/immunologic systems. Anti-CTLA-4-based immunotherapy offers promise in the treatment of sepsis, but care must be used in the timing and dose of administration of the drug to prevent adverse effects.

Introduction: To investigate the effects of G-CSF or GM-CSF therapy in non-neutropenic patients with sepsis., Methods: A systematic literature search of Medline, Embase and Cochrane Central Register of Controlled Trials was conducted using specific search terms. A manual review of references was also performed. Eligible studies were randomized control trials (RCTs) that compared granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) therapy with placebo for the treatment of sepsis in adults. Main outcome measures were all-cause mortality at 14 days and 28 days after initiation of G-CSF or GM-CSF therapy, in-hospital mortality, reversal rate from infection, and adverse events., Results: Twelve RCTs with 2,380 patients were identified. In regard to 14-day mortality, a total of 9 death events occurred among 71 patients (12.7%) in the treatment group compared with 13 events among 67 patients (19.4%) in the placebo groups. Meta-analysis showed there was no significant difference in 28-day mortality when G-CSF or GM-CSF were compared with placebo (relative risks (RR) = 0.93, 95% confidence interval (CI): 0.79 to 1.11, P = 0.44; P for heterogeneity = 0.31, I2 = 15%). Compared with placebo, G-CSF or GM-CSF therapy did not significantly reduce in-hospital mortality (RR = 0.97, 95% CI: 0.69 to 1.36, P = 0.86; P for heterogeneity = 0.80, I2 = 0%). However, G-CSF or GM-CSF therapy significantly increased the reversal rate from infection (RR = 1.34, 95% CI: 1.11 to 1.62, P = 0.002; P for heterogeneity = 0.47, I2 = 0%). No significant difference was observed in adverse events between groups (RR = 0.93, 95% CI: 0.70 to 1.23, P = 0.62; P for heterogeneity = 0.03, I2 = 58%). Sensitivity analysis by excluding one trial did not significantly change the results of adverse events (RR = 1.05, 95% CI: 0.84 to 1.32, P = 0.44; P for heterogeneity = 0.17, I2 = 36%)., Conclusions: There is no current evidence supporting the routine use of G-CSF or GM-CSF in patients with sepsis. Large prospective multicenter clinical trials investigating monocytic HLA-DR (mHLA-DR)-guided G-CSF or GM-CSF therapy in patients with sepsis-associated immunosuppression are warranted.

Introduction: Lymphocyte apoptosis and monocyte dysfunction play a pivotal role in sepsis-induced immunosuppression. Programmed death-1 (PD1) and its ligand programmed death ligand-1 (PD-L1) exert inhibitory function by regulating the balance among T cell activation, tolerance, and immunopathology. PD-1 deficiency or blockade has been shown to improve survival in murine sepsis. However, PD-L1 and PD-1 differ in their expression patterns and the role of PD-L1 in sepsis-induced immunosuppression is still unknown., Methods: Sepsis was induced in adult C57BL/6 male mice via cecal ligation and puncture (CLP). The expression of PD-1 and PD-L1 expression on peripheral T cells, B cells and monocytes were measured 24 hours after CLP or sham surgery. Additionally, the effects of anti-PD-L1 antibody on lymphocyte number, apoptosis of spleen and thymus, activities of caspase-8 and caspase-9, cytokine production, bacterial clearance, and survival were determined., Results: Expression of PD-1 on T cells, B cells and monocytes and PD-L1 on B cells and monocytes were up-regulated in septic animals compared to sham-operated controls. PD-L1 blockade significantly improved survival of CLP mice. Anti-PD-L1 antibody administration prevented sepsis-induced depletion of lymphocytes, increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production, decreased IL-10 production, and enhanced bacterial clearance., Conclusions: PD-L1 blockade exerts a protective effect on sepsis at least partly by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction. Anti-PD-L1 antibody administration may be a promising therapeutic strategy for sepsis-induced immunosuppression.

Sepsis is the leading cause of death in burn patients. Monocytes/macrophages rapidly exhibit impaired production of proinflammatory cytokines and an elevated generation of anti-inflammatory cytokines in septic patients with immunosuppression. However, the expression patterns of Tim4 and Nod-like receptor protein 3 (NALP3) inflammasome and their roles during immunosuppression in septic shock patients are not well understood. Tim4 and NALP3 inflammasome expression in monocytes were downregulated in immunosuppressive patients with sepsis compared with healthy volunteers. Meanwhile, NALP3 inflammasome expression was upregulated by Tim4 overexpression in murine bone marrow-derived macrophages (BMDMs) and J774A.1 macrophages. Tim4 overexpression improved the ability of BMDMs and J774A.1 macrophages to produce proinflammatory cytokines and increased the expression of cleaved-caspase-1 (p10) after LPS/ATP stimulation. In addition, overexpression of Tim4 enhanced phagocytosis of apoptotic polymorphonuclear neutrophils (PMNs) by BMDMs and J774A.1 macrophages, while depletion of NALP3 in Tim4 overexpressing BMDMs and J774A.1 macrophages decreased phagocytosis of apoptotic PMNs. In summary, the expression of Tim4 and NALP3 inflammasome in monocytes/macrophages was downregulated in septic shock patients, and diminished expression of Tim4 and NALP3 inflammasome in monocytes/macrophages might play a critical role in sepsis-elicited immunosuppression. [ABSTRACT FROM AUTHOR]