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Sepsis, defined as life-threatening organ failure caused by a dysregulated host response to severe infection, is a major cause of death among intensive care unit patients. Therapies targeting on immunomodulatory is a new research field in sepsis treatment. B- and T-lymphocyte attenuator (BTLA) is an inhibitory costimulatory factor molecule of B and T lymphocytes. Studies have shown that elevated expression of BTLA in lymphocytes can reduce mortality in sepsis, but its regulatory compounds and the underlying mechanism remains to be elucidated. Here, we show that treatment with CP-673451 significantly decreases mortality of septic mouse. CP-673451 is a PDGFR kinase inhibitor which can promote the expression of BTLA, inhibit the release of chemokines such as CXCL13, and reduce first the chemotaxis of B cells to the peripheral blood and vital organs. CP-673451 also inhibits both the release of cytokines and chemokines such as IL-1β, IL-6, IL-10, TNF-α, CCL1, CCL2 and CCL7 and reduces both the chemotactic ability of T cells. This suggests that CP-673451 may prevent septic death by inhibiting lymphocyte chemotaxis and alleviating "cytokine storm". In conclusion, our study provides a new therapeutic target and an effective compound for sepsis treatment.

Clove is a kind of food spice, which can be used as food flavoring additive. In this work, we looked at clove's impact and underlying mechanism on cognitive impairment in infected mice. By using the open field test, Morris water maze, ELISA technique, kit method, and qPCR method, the biochemical and molecular biological indices of mice were identified. Clove component composition was established using HPLC. The findings demonstrated that clove might enhance mouse survival rates in comparison to the model group and could also lengthen driving distances, standing and combing periods, target quadrant duration, and crossing periods. In the hippocampus of infected mice, clove can lower levels of TNF-α, IL-6, IL-1β, and MDA while increasing SOD and CAT activity. In the hippocampus of infected animals, clove additionally increased the mRNA expression of SIRT1 and FOXO1 and decreased the mRNA expression of NF-B and p53. Animal studies revealed that clove's impact was comparable to dexamethasone in that it might help septic mice with cognitive impairment. The analysis revealed that rutin, isoquercitrin, ferulic acid, dihydroquercetin, and quercitrin were all present in clove. It is clear that clove can help septic mice with cognitive impairment by triggering SIRT1 through its active components.

PurposeCXC chemokines are mediators which mediate immune cells migration to sites of inflammation and injury. Chemokine C-X-C motif ligand 16 (CXCL16) plays an important role in the occurrence and development of sepsis through leukocyte chemotaxis, leukocyte adhesion and endotoxin clearance. In this study, we selected a set of tagging single nucleotide polymorphisms (tag SNPs) in the CXCL16 gene and investigated their clinical relevance to the development of sepsis and multiple organ dysfunction syndrome (MODS) in patients with major trauma in three independent Chinese Han populations.MethodsA total of 1,620 major trauma patients were enrolled in this study. Among these patients, 920 came from Chongqing in western China, 350 came from Zhejiang Province in eastern China, and 350 came from Guizhou Province in southwestern China. The improved multiplex ligation detection reaction (iMLDR) method was employed in the genotyping and genetic association analyses to determine the associations between CXCL16 haplotypes and sepsis morbidity rate and higher MOD scores in three cohorts.ResultsOnly CXCL16 T123V181 haplotype was associated with an increased risk for sepsis morbidity and higher MOD scores in the three cohorts (OR = 1.89,P= 0.001 for the Chongqing cohort; OR = 1.76,P= 0.004 for the Zhejiang cohort; OR = 1.55,P= 0.012 for the Guizhou cohort). The effect of T123V181 haplotype on the chemotaxis, migration and endotoxin clearance of immune cells were further observed. Protein modeling analysis showed that T123 and V181 might alter the structure of the CXCL16 active center. Thus it enhanced the chemotaxis and adhesion ability of immunocytes.ConclusionWe demonstrate the mechanism of CXCL16 T123V181 haplotype which regulates the sepsis morbidity rate and thus provide a new biomarker for early diagnosis of sepsis and MODS.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT01713205 (https://www.clinicaltrials.gov/ct2/results?cond=&term=+NCT01713205&cntry=&state=&city=&dist=).

Background HLA-DR is a common and significant biomarker in sepsis. However, as a biomarker of post-traumatic sepsis, there are few studies. This meta-analysis was conducted to evaluate the value of HLA-DR in the diagnosis of severe traumatic sepsis. Methods We developed a strategy for literature retrieval from the PubMed, MEDLINE, Web of Science,EMBASE, and Cochrane Library databases. All studies published until June 1, 2021, were retrieved. All studies that were included considered HLA-DR in the diagnosis of adult post-traumatic sepsis, and each study calculated the sensitivities and specificities. Results The study included 8 articles involving 639 trauma patients. combined sensitivity was 0.81 (95% CI, 0.75–0.86), the combined specificity was 0.67 (95% CI, 0.62–0.71), the positive likelihood ratio was 2.29 (95% CI, 1.73–3.04), and the negative likelihood ratio was 0.32 (95% CI, 0.23–0.44). The area under the summary receiver operating characteristic curve was 0.84(95% CI, 0.80–0.87), and the Q index was 0.76. The combined diagnostic odds ratio was 9.11 (95% CI, 5.37–15.45). Conclusions The results of this meta-analysis showed that HLA-DR could be considered as a useful biomarker for the early diagnosis of severe traumatic sepsis. Its sensitivity and diagnostic abilities are excellent. However, its specificity is inadequate. Therefore, it should be combined with other clinical indicators to assess post-traumatic sepsis, and cannot be used in the diagnosis of a disease alone.

Background: Early-onset neonatal sepsis is a great managerial challenge worldwide. Studying the risk factors of early-onset neonatal sepsis is one of the most significant ways of reducing the incidence of sepsis and the associated health burden.Methods: A literature search strategy was constructed, including PubMed, EMBASE, Web of Science, and the Cochrane Library. All publications until April 30, 2021 were retrieved; the key words were “neonatal sepsis” and “risk factors.” Moreover, the references of the retrieved articles were screened to identify related eligible studies. Data abstraction was performed in accordance with PRISMA guidelines. The Newcastle-Ottawa Scale and Agency for Healthcare Research and Quality scale scores were used to evaluate the quality of the included studies, and the fixed-effects model was used to combine the results. Risk factors related to the occurrence of early-onset neonatal sepsis, the pooled OR, and the 95% CI upper and lower limits were obtained to represent the correlation strength between risk factors and early-onset neonatal sepsis occurrence; the pooled I2 value was used to determine the heterogeneity of the combined results.Results: We included 21 articles with 44 non-repetitive risk factors, 91985 neonates, and 6627 cases of neonatal sepsis. We identified seven independent risk factors of early-onset neonatal sepsis, including at least three per vaginal examinations during labor and delivery, chorioamnionitis, premature rupture of membranes > 18 h, male fetus, gestational age < 37 weeks, neonatal resuscitation, and central venous catheterization, with the following ORs and 95% CIs: 7.18 (3.51-14.69), 6.56 (3.19-13.49), 2.74 (1.44-5.21), 3.03 (1.94-4.73), 4.08 (2.76-6.03), 2.6 (2.03-3.34), and 3.06 (1.64-5.73), respectively.Conclusions: Our results suggest that frequent per vaginal examination during labor and delivery, chorioamnionitis, premature rupture of membranes (> 18 h), male fetus, gestational age (< 37 weeks), neonatal resuscitation, and central vascular catheterization are independent risk factors of early-onset neonatal sepsis. These findings support the use of empirical antibiotic therapy in neonates with these risk factors.

BackgroudVanin-1 plays a pivotal role in oxidative stress and the inflammatory response. However, its relationship with traumatic sepsis remains unknown. The aim of our study was to evaluate whether plasma vanin-1 expression can be used to predict traumatic sepsis in an early time.MethodsIn this three-stage prospective cohort study, severe trauma patients admitted to two hospitals from January 2015 to October 2018 were enrolled. Clinical data during hospitalization and APACHE II score were collected. Plasma vanin-1 levels were measured by enzyme linked immunosorbent assay. The associations among variables and traumatic sepsis were identified by logistic regression model. The receiver-operating characteristic curve was analyzed to evaluate the diagnostic efficiency of the selected factors.ResultsA total of 426 trauma patients (22 patients in the discovery cohort, 283 patients in the internal test cohort, and 121 patients in the external validation cohort) and 16 healthy volunteers were enrolled. The plasma vanin-1 level of trauma patients was significantly higher than that of healthy volunteers (P P P = 1.62⊆10− 12). As a predictive biomarker, vanin-1 obtained a better area under the curve (AUC) (0.82, 95% CI = 0.77–0.87) than C-reaction protein (CRP) (0.62, 95% CI = 0.56–0.68, P P P = 6.70⊆10− 3). In addition, the clinical relevance between plasma vanin-1 and traumatic sepsis was validated in the external validation cohort (OR = 4.26, 95% CI = 2.22–8.17, P = 1.28⊆10− 5). The AUC of vanin-1 was 0.83 (95% CI = 0.75–0.89), which was better than that of CRP, PCT, and APACHE II.ConclusionsOur study demonstrated that plasma vanin-1 increased among trauma patients and was independently associated with the risk of sepsis. Vanin-1 might be a potential biomarker for the early prediction of traumatic sepsis.Trial registrationClinicaltrials.gov Identifier NCT01713205. Registered 24 October 2012.

Background: CXC chemokine famliy genes play an important role in inflammatory and immune diseases. CXCL16 affects the occurrence and development of inflammation through leukocyte chemotaxis, leukocyte adhesion and endotoxin clearance. In this study, we selected a set of tag SNPs in the CXCL16 gene and investigated their clinical relevance to the development of sepsis and multiple organ dysfunction syndrome (MODS) in patients with major trauma in three independent Chinese Han populations.Methods: A total of 1,620 major trauma patients were enrolled in this study. Among these patients, 920 came from Chongqing in western China, 350 came from Zhejiang Province in eastern China, and 350 came from Guizhou Province in southern China. The improved multiplex ligation detection reaction (iMLDR) method was employed in the genotyping and genetic association analyses to determine the associations between CXCL16 haplotypes and sepsis morbidity rate and higher MOD scores in three cohorts.Results: The CXCL16 T123V181 haplotype was determined to be associated with increased risk for sepsis morbidity and higher MOD scores in the three cohorts. In vitro chemotactic experiments demonstrated that the T123V181 protein enhanced the chemotaxis of immunocytes. The adhesion ability of THP-1 cells expressing T123V181 to immunocytes was also stronger than those of cells with the other three haplotypes. T123 and V181 altered the structure of the CXCL16 active center, which resulted in changes in protein function and changes in the adhesion and chemotaxis of CXCL16-expressing immunocytes. These structural changes might be responsible for the increased incidence of sepsis and the higher MODS scores.Conclusions: We demonstrate that genetic variations in the CXCL16 gene regulate the sepsis morbidity rate, and we explore a paradigm for the prewarning diagnosis of sepsis tailored to the genetic information of individual patients.Trial registration: ClinicalTrials.gov, NCT01713205.

Background The transplantation of bone marrow mesenchymal stem cells (BMSCs) is a promising therapeutic strategy for wound healing. However, the poor migration capacity and low survival rate of transplanted BMSCs in wounds weaken their potential application. Objective To identify the optimal protocol for BMSCs preconditioned with H2O2 and improve the therapeutic efficacy using H2O2-preconditioned BMSCs in wound healing. Methods Mouse BMSCs were exposed to various concentrations of H2O2, and the key cellular functional properties were assessed to determine the optimal precondition with H2O2. The H2O2-preconditioned BMSCs were transplanted into mice with full-thickness excisional wounds to evaluate their healing capacity and tissue engraftment. Results Treatment BMSCs with 50 μM H2O2 for 12 h could significantly enhance their proliferation, migration, and survival by maximizing the upregulation of cyclin D1, SDF-1, and its receptors CXCR4/7 expressions, and activating the PI3K/Akt/mTOR pathway, but inhibiting the expression of p16 and GSK-3β. Meanwhile, oxidative stress-induced BMSC apoptosis was also significantly attenuated by the same protocol pretreatment with a decreased ratio of Bax/Bcl-2 and cleaved caspase-9/3 expression. Moreover, after the identification of the optimal protocol of H2O2 precondition in vitro, the migration and tissue engraftment of transfused BMSCs with H2O2 preconditioning were dramatically increased into the wound site as compared to the un-preconditioned BMSCs. The increased microvessel density and the speedy closure of the wounds were observed after the transfusion of H2O2-preconditioned BMSCs. Conclusions The findings suggested that 50 μM H2O2 pretreated for 12 h is the optimal precondition for the transplantation of BMSCs, which gives a considerable insight that this protocol may be served as a promising candidate for improving the therapeutic potential of BMSCs for wound healing.

BackgroundSepsis is a life-threatening condition associated with an exacerbated production of cytokines that can promote a hyperactive response to infection or induce immunoparalysis. The trauma victim’s inherent state of hyperinflammation frequently camouflages septic events, delaying the initiation of targeted therapy. Thus, this study aimed to establish the profiles of cytokines in trauma patients to characterize the nature of the immune responses to sepsis, which might enable early prediction and individualized treatments to be developed and targeted.MethodsA 15-plex human cytokine magnetic bead assay system was used to measure analytes in citrated plasma samples. Analysis of these cytokine kinetics was performed on 40 patients with severe blunt trauma admitted to our trauma center between March 2016 and February 2017 with Injury Severity Score (ISS) more than 20 with regard to sepsis (Sepsis-3) over a 14-day time course.ResultsIn total, six cytokines changed in trauma patients between the different timepoints at day 1, 3, 5, 7, and 14. Additionally, IL-6, IL-10, IL-15, MDC, GRO, sCD40L, G-CSF, and FGF-2 significantly distinguished between sepsis and nonsepsis at day 3 and afterward with an area under the curve of up to 0.90 when the eight biomarkers (P < 0.001) were combined. Event-related analysis demonstrated 1.5- to 4-fold serum level changes for these cytokines within 72 hours before clinically apparent sepsis. ConclusionCytokine profiles demonstrate high discriminatory ability to timely identify evolving traumatic sepsis. These abrupt changes allow sepsis detection up to 72 hours before clinically overt deterioration. Measurement of these cytokines might enable future studies to better predict, diagnose, and characterize traumatic sepsis, as well as confer the potential for physicians to timely initiate treatment with reduced mortality and costs.

Background: CXC chemokine famliy genes play an important role in inflammatory and immune diseases. CXCL16 affects the occurrence and development of inflammation through leukocyte chemotaxis, leukocyte adhesion and endotoxin clearance. We selected a set of tagSNPs in CXCL16 gene and investigated their clinical relevance in relation to the development of sepsis and MODS in patients with major trauma in three independent Chinese Han populations.Methods: A total of 1,620 major trauma patients were enrolled in this study. Among which, 920 patients came from Chongqing in western China, 350 patients came from Zhejiang province in eastern China and 350 patients came from Guizhou province in southern China. Improved multiplex ligation detection reaction (iMLDR) was used in the genotyping and genetic association study was used to analyze the association between CXCL16 haplotypes and sepsis morbidity rate and higher MOD Scores in three cohorts. Results: CXCL16 T123V181 haplotype was associated with an increased risk for sepsis morbidity rate and higher MOD Scores in three cohorts. In vitro chemotactic experiment showed that T123V181 protein enhanced the chemotaxis of immunocytes. The adhesion ability of THP-1 cells which expressing T123V181 to immunocytes was also stronger than that of the other three haplotypes. T123 and V181 altered the structure of CXCL16 active center, which led to the change of protein function and the change of adhesion and chemotaxis of CXCL16 expressing immunocytes. The structural change might be the cause of the increased incidence of sepsis and higher score of MODS.Conclusions: We demonstrate that CXCL16 genetic variation regulates sepsis morbidity rate and explore a paradigm for the prewarning diagnosis of sepsis tailored by individual genetic information.Trial registration： ClinicalTrials.gov , NCT01713205. Registered 18 October 2012, retrospectively registered.

Sepsis arises from an aberrant and excessive host response to infection. Long noncoding RNAs (lncRNAs) are involved in multiple cellular functions, including inflammation and immunity. However, to date there has been no systematic attempt to identify lncRNAs whose expression is changed after the induction of the innate immune response. In this study, we profiled global lncRNA and mRNA expression changes in peripheral blood mononuclear cells (PBMCs) treated with lipopolysaccharide (LPS) using a microarray platform. Of the 40 914 lncRNAs screened, 596 were significantly upregulated and 250 were significantly downregulated (corrected P

Background Previous study revealed that rs2232618 polymorphism (Phe436Leu) within LBP gene is a functional variant and associated with susceptibility of sepsis in traumatic patients. Our aim was to confirm the reported association by enlarging the population sample size and perform a meta-analysis to find additional evidence. Methods Traumatic patients from Southwest (n = 1296) and Southeast (n = 445) of China were enrolled in our study. After genotyping, the relationship between rs2232618 and the risk of sepsis was analyzed. Furthermore, we proceeded with a comprehensive literature search and meta-analysis to determine whether the rs2232618 polymorphism conferred susceptibility to sepsis. Results Significance correlation was observed between rs2232618 and risk of sepsis in Southwest patients (P = 0.002 for the dominant model, P = 0.006 for the recessive model). The association was confirmed in Southeast cohort (P = 0.005 for the dominant model) and overall combined cohorts (P = 4.5 × 10−4, P = 0.041 for the dominant and recessive model). Multiple logistical regression analyses suggested that rs2232618 polymorphism was related to higher risk of sepsis (OR = 1.77, 95% CI = 1.26–2.48, P = 0.001 in Southwest patients; OR = 2.11, 95% CI = 1.24–3.58, P = 0.006 in Southeast cohort; OR = 1.54, 95% CI = 1.34–2.08, P = 0.006 in overall cohort). Furthermore, meta-analysis of four studies (including the present study) confirmed that rs2232618 within LBP increased the risk of sepsis (OR = 1.75, P

Summary Suppressor of cytokine signalling (SOCS) proteins are crucial negative regulators in many signalling pathways and are implicated in the pathogenesis of infectious diseases. The purpose of this study was to uncover possible associations of common polymorphisms within SOCS genes with infectious outcomes after traumatic injury. A total of 1087 trauma patients (Chongqing cohort 806 and Yunnan cohort 281) were recruited and followed-up for the development of infectious outcomes, such as sepsis and multiple organ dysfunction syndrome (MODS). Twelve selected single nucleotide polymorphisms (SNPs) were screened by pyrosequencing to determine their genotypes and associations with infectious complications. Among the 12 selected SNPs, only the cytokine-inducible Src homology (SH2) domain protein (CISH) promoter rs414171 polymorphism was found consistently to be associated statistically with the incidence of sepsis and MOD score in the two cohorts, despite analysing the SNPs independently or in combination. Further, patients with a T allele had significantly lower CISH expression and lower production of tumour necrosis factor (TNF)-α, but higher production of interleukin (IL)-10. Luciferase assay confirmed that the A→T variant in the rs414171 polymorphism inhibited the transcriptional activities of the CISH gene significantly. The CISH rs414171 polymorphism is associated significantly with susceptibility to sepsis and MODS in traumatic patients, which might prove to be a novel biomarker for indicating risk of infectious outcomes in critically injured patients.

Background Peroxisome proliferator-activated receptor gamma (PPARγ) is a major regulator in sepsis. Our previous study identified the enhancer polymorphism rs10865710C/G to be associated with susceptibility to sepsis in trauma patients. We performed two-stage cohort studies integrating biological experiments of potential functional variants that modify susceptibility to traumatic sepsis. Methods Improved multiplex ligation detection reaction (iMLDR) was used to genotype rs10865710 in 797 Han Chinese trauma patients in Chongqing. Clinical relevance was validated in 334 patients in Guizhou. The potential function of rs10865710 in transcriptional regulation was explored through a dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). Expression of PPARγ was assessed by expression quantitative trait locus (e-QTL) and western blot analyses. Results The association results confirmed rs10865710 to be significantly strongly associated with sepsis risk in trauma patients of the Chongqing and Guizhou cohorts (OR = 1.41 (1.11–1.79), P = 0.004 and OR = 1.45 (1.01–2.09), P = 0.046, both for allele-dose effect, respectively). A meta-analysis of both cohorts and a previous study indicated strong evidence for this association (OR = 1.41 (1.17–1.71), P = 0.0004 for the dominant model, OR = 1.78 (1.34–2.36), P P P = 0.0005) and CREB2 binding. Expression analysis also indicatevd rs10865710 genotypes to be associated with levels of PPARγ expression (P = 9.2 × 10−5 for dominant effect and P = 0.005 for recessive effect). Conclusions Our study provides evidence that the enhancer-region polymorphism rs10865710 might influence transcription factor binding and regulate PPARγ expression, thus conferring susceptibility to traumatic sepsis. Trial registration ClinicalTrials.gov, NCT01713205. Registered 18 October 2012, retrospectively registered.

Background Patients suffering from major trauma often experience complications such as sepsis. The early recognition of patients at high risk of sepsis after trauma is critical for precision therapy. We aimed to derive and validate a novel predictive score for sepsis risk using electronic medical record (EMR) data following trauma. Materials and methods Clinical and laboratory variables of 684 trauma patients within 24 h after admission were collected, including 411 patients in the training cohort and 273 in the validation cohort. The least absolute shrinkage and selection operator (LASSO) technique was adopted to identify variables contributing to the early prediction of traumatic sepsis. Then, we constructed a traumatic sepsis score (TSS) using a logistic regression model based on the variables selected in the LASSO analysis. Moreover, we evaluated the discrimination and calibration of the TSS using the area under the curve (AUC) and the Hosmer-Lemeshow (H-L) goodness-of-fit test. Results Based on the LASSO, seven variables (injury severity score, Glasgow Coma Scale, temperature, heart rate, albumin, international normalized ratio, and C-reaction protein) were selected for construction of the TSS. Our results indicated that the incidence of sepsis after trauma increased with an increasing TSS (Ptrend = 7.44 × 10−21 for the training cohort and Ptrend = 1.16 × 10−13 for the validation cohort). The areas under the receiver operating characteristic (ROC) curve of TSS were 0.799 (0.757–0.837) and 0.790 (0.736–0.836) for the training and validation datasets, respectively. The discriminatory power of our model was superior to that of a single variable and the sequential organ failure assessment (SOFA) score (P 0.05). Conclusions We developed and validated a novel TSS with good discriminatory power and calibration for the prediction of sepsis risk in trauma patients based on the EMR data. Electronic supplementary material The online version of this article (10.1186/s13017-019-0231-8) contains supplementary material, which is available to authorized users.

Additional file 2: Table S1. Overall characteristics of patients with major trauma.

Table S2. Characteristics of the genetic variants investigated for associations with the risk of sepsis. (DOCX 70 kb)

Search strategy. Venice criteria. The list of included articles. (DOCX 70 kb)

Background Organ regeneration in mammals is hypothesized to require a functional pool of stem or progenitor cells, but the role of these cells in lung regeneration is unknown. Methods Based on the fact that postnatal regeneration of alveolar tissue has been attributed to alveolar epithelial cells, we established a hemorrhagic shock and Lipopolysaccharide (LPS) lung injury model. Using this model, we analyzed the cellular kinetics of lung alveolar epithelial cells. Results The results showed that alveolar epithelium type 2 cells (AEC2s) are damage resistant during acute lung injury, they might be the main cells involved in lung injury and repair. Then we observed the relationship between the expression of HGF, c-Met following ALI in rat lung and proliferation of AEC2s. The proliferation of AEC2s was inhibited when isolated primary AEC2s were co-cultured with c-Met inhibitor SU11274. Furthermore, the numbers of AEC2s was significantly decreased when ALI rats were administrated with SU11274 in vivo. It provided further evidence that the HGF/c-Met signaling plays a vital role in ALI-induced AEC2s proliferation. Conclusions AEC2s are damage resistant during acute lung injury and the HGF/c-Met signaling pathway is of vital importance in the proliferation of AEC2s after ALI.