Search

To explore the value of monocyte subsets and CD64 expression in the diagnosis and prognosis of sepsis.A prospective case-control study was designed. 30 septic patients and 30 non-septic patients who were admitted to the intensive care unit (ICU) of the PLA Army Characteristic Medical Center from March 2021 to March 2022 were enrolled. After 1, 3, and 5 days of ICU admission, peripheral blood samples were taken from patients. Flow cytometry was used to detect the proportion of monocyte subsets and the expression level of CD64 on the surface, and the difference of expression between patients in two group was analyzed. The risk variables for sepsis were analyzed using single-factor and multi-factor Logistic regression. The diagnostic efficacy of each risk factor for sepsis was determined using the receiver operator characteristic curve (ROC curve).One day after ICU admission, the proportions of monocytes and classic monocytes in white blood cells (WBC) of septic patients were significantly lower than those of non-septic patients [proportion of monocytes to WBC: (4.13±2.03)% vs. (6.53±3.90)%, proportion of classic monocytes to WBC: 1.97 (1.43, 2.83)% vs. 3.37 (1.71, 5.98)%, both P0.05]. The proportion of non-classical monocytes in monocytes was significantly higher in septic patients than that in non-septic patients [(11.42±9.19)% vs. (6.57±4.23)%, P0.05]. The levels of CD64 expression in monocytes, classic monocytes, intermediate monocytes and non-classic monocytes were significantly higher in sepsis patients than those in non-septic patients [mean fluorescence intensity (MFI): 13.10±6.01 vs. 9.84±2.83 for monocytes, 13.58±5.98 vs. 10.03±2.84 for classic monocytes, 13.48±6.35 vs. 10.22±2.99 for intermediate monocytes, 8.21±5.52 vs. 5.79±2.67 for non-classic monocytes, all P0.05]. Multivariate Logistic regression research showed that CD64 in typical monocytes [odds ratio (OR) = 1.299, 95% confidence interval (95%CI) was 1.027-1.471, P = 0.025] and the proportion of non-typical monocytes in monocytes (OR = 1.348, 95%CI was 1.034-1.758, P = 0.027) were the independent risk factors for sepsis. ROC curve showed that the area under the ROC curve (AUC) of CD64 expression of classical monocytes, the fraction of non-classical monocytes in monocytes, and procalcitonin (PCT) in the diagnosis of sepsis was 0.871. A correlation analysis revealed a negative relationship between the acute physiology and chronic health status evaluation II (APACHE II) on the first, third, and fifth days following ICU admission and the expression level of CD64 in patients' classic monocytes (r values were -0.264, -0.428 and -0.368, respectively, all P0.05).Combining the proportion of non-classical monocytes in monocytes, the level of plasma PCT, and the CD64 expression of classic monocytes in peripheral blood has good efficacy in identifying sepsis and assessing its severity.

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.

Neutrophil extracellular traps (NETs) are involved in the development of sepsis-induced acute respiratory distress syndrome (ARDS). Glycyrrhizin (GL), the main active ingredient of the traditional Chinese medicine Glycyrrhiza glabra, has anti-inflammatory, anti-viral, and immunomodulatory effects.The study aims to explore the efficacy and potential mechanism of GL on sepsis-induced ARDS in mice.Mice were randomly divided into 3 groups: Control, CLP, and GL + CLP. Mice sepsis ARDS model was induced by cecal ligation and puncture (CLP) followed by intraperitoneal GL treatment. Then, the 7-day survival rate of mice was recorded. The lung function of mice was determined by whole-body plethysmography. Lung pathology and scores were observed by hematoxylin-eosin staining. The wet/dry ratio (W/D) of the lung was measured by weighing method. The protein concentration in bronchoalveolar lavage fluid (BALF) was measured by the BCA method. NETs formation in lung tissue was detected by immunofluorescence. Furthermore, HMGB1、TLR9、MyD88 and IL6 expression in lung tissue were detected by western blot and by quantitative real-time PCR, respectively.The results showed that GL improved the survival rate, attenuated lung tissue injury and reduced the expression of inflammatory factors in mice with CLP-induced sepsis. Meanwhile, we confirmed that GL could inhibit TLR9 / MyD88 activation from reducing NETs formation by decreasing HMGB1 expression. The formation of NETs is regulated by HMGB1 / TLR9 / MyD88. In addition, GL improved lung function in mice with sepsis-induced ARDS. Lung function suggested that GL increased alveolar ventilation, alleviated ventilator fatigue and reduced airway resistance in mice with ARDS induced by sepsis.GL ameliorated sepsis-induced ARDS and reduced the NETs formation in lung tissues, which may be associated with the inhibition of the HMGB1 / TLR9 pathway.

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=).

miR-608 has been indicated to play an important role in the pathogenesis of various inflammation-related diseases, including sepsis and several types of cancers. However, there is little information about the underlying mechanism, especially in inflammatory cells. In this study, an hsa-miR-608-inhibition cell model was constructed in U937 cells using a lentivirus, and gene expression profiles were determined by a cDNA microarray. Altogether, 682 genes showed a difference greater than 1.2-fold, including 184 genes downregulated and 498 genes upregulated. Among these genes, one potential miR-608-target gene, ELANE, was further investigated. A positive relationship between the expression of miR-608 and that of ELANE was found both in vivo and in vitro. In addition, decreased expression of miR-608 resulted in overexpression of ELANE at both the mRNA and protein levels. Cotransfection of HEK293T cells with a miR-608 mimic inhibited reporter activity, and mutation of the miRNA seed sequences abolished the repression of reporter activity. These results suggest that miR-608 is an important posttranscriptional regulator of ELANE expression in human monocytes and may play an important role in the process of inflammation. miR-608 and neutrophil elastase may be novel targets for the diagnosis or treatment of sepsis.

Regeneration of pulmonary epithelial cells plays an important role in the recovery of acute lung injury (ALI), which is defined by pulmonary epithelial cell death. However, the mechanism of the regenerative capacity of alveolar epithelial cells is unknown. Using a lung injury mouse model induced by hemorrhagic shock and lipopolysaccharide, a protein mass spectrometry-based high-throughput screening and linage tracing technology to mark alveolar epithelial type 2 cells (AEC2s), we analyzed the mechanism of alveolar epithelial cells proliferation. We demonstrated that the expression of Hippo-yes-associated protein 1 (YAP1) key proteins were highly consistent with the regularity of the proliferation of alveolar epithelial type 2 cells after ALI. Furthermore, the results showed that YAP1+ cells in lung tissue after ALI were mainly Sftpc lineage-labeled AEC2s. An in vitro proliferation assay of AEC2s demonstrated that AEC2 proliferation was significantly inhibited by both YAP1 small interfering RNA and Hippo inhibitor. These findings revealed that YAP functioned as a key regulator to promote AEC2s proliferation, with the Hippo signaling pathway playing a pivotal role in this process.

Background Genetic backgrounds have been recognized as significant determinants of susceptibility to sepsis. CXC chemokines play a significant role in innate immunity against infectious diseases. Genetic polymorphisms of CXC chemokine genes have been widely studied in inflammatory and infectious diseases but not in sepsis. Thus, we aimed to investigate the clinical relevance of CXC chemokine gene polymorphisms and susceptibility to sepsis in a traumatically injured population. Methods Thirteen tag single nucleotide polymorphisms were selected from CXC chemokine genes using a multimarker tagging algorithm in the Tagger software. Three independent cohorts of injured patients (n = 1700) were prospectively recruited. Selected single nucleotide polymorphisms were genotyped using an improved multiplex ligation detection reaction method. Cytokine production in lipopolysaccharide-stimulated whole blood was measured using an enzyme-linked immunosorbent assay. Results Among the 13 tag single nucleotide polymorphisms, four single nucleotide polymorphisms (rs1429638, rs266087, rs2297630, and rs2839693) were significantly associated with the susceptibility to sepsis, and three (rs3117604, rs1429638, and rs4074) were significantly associated with an increased multiple organ dysfunction score in the derivation cohort. However, only the clinical relevance of rs1429638 and rs266087 was confirmed in the validation cohorts. In addition, rs2297630 was significantly associated with interleukin 6 production. Conclusion The rs1429638 polymorphism in the CXCL1 gene and the rs2297630 polymorphism in the CXCL12 gene were associated with altered susceptibility to sepsis and might be used as important genetic markers to assess the risks of sepsis in trauma patients. Level of evidence Prognostic and epidemiologic study, level II.

Glucocorticoid (GC)-induced longitudinal bone growth retardation is a common and severe adverse effect in pediatric patients receiving GC immunosuppressive therapy. Molecular mechanisms underlying GC-induced growth inhibition are unclear. GC withdrawal following short-term high-dose use is common, including in the immediate post-transplant period. However, whether skeleton growth recovery is sufficient or whether growth-promoting therapy is required following GC withdrawal is unknown. The aim of this study was to investigate the effect of exogenous growth hormone (GH) on growth plate impairment in GC-induced longitudinal bone growth retardation. Here, apoptotic chondrocytes in the hypertrophic layer of growth plates increased whereas Indian Hedgehog (Ihh) and Parathyroid Hormone Related Peptide (PTHrP) protein levels in the growth plate decreased following GC exposure. The hypertrophic zone of the growth plate expanded following GC withdrawal. Subcutaneously injected GH penetrated the growth plate and modified its organization in rats following GC withdrawal. Ihh and PTHrP expression in GC-induced apoptotic chondrocytes decreased in vitro. GH promoted chondrocyte proliferation by activating Ihh/PTHrP signaling. Downregulating Ihh using specific siRNAs increased chondrocyte apoptosis and inhibited PTHrP, Sox9, and type II collagen (Col2a1) protein expression. GH inhibited apoptosis of Ihh-deficient growth plate chondrocytes by upregulating PTHrP, Sox9, and Col2a1 expression. Thus, reversal of the effect of GC on growth plate impairment following its withdrawal is insufficient, and exogenous GH provides growth plate chondral protection and improved longitudinal growth following GC withdrawal by acting on the Ihh/PTHrP pathway.

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.

To study the dynamic changes of cellular immune function in peripheral blood of trauma patients and its role in the evaluation of traumatic complications.A prospective cohort study design was conducted. Patients with blunt trauma admitted to Chongqing Emergency Medical Center from November 2019 to January 2020 were consecutively enrolled. The peripheral blood samples were collected at 1, 3, 5, 7, and 14 days after injury. The expressions of CD64, CD274, and CD279 on the surface of neutrophils, lymphocytes, and monocytes as well as CD3A total of 42 patients with trauma were finally enrolled, containing 8 severe trauma patients with ISS greater than 25 scores, 17 patients with ISS between 16 and 25 scores, and 17 patients with ISS less than 16 scores. The sepsis morbidity rates were 14.3% (n = 6) within 28 days after injury. CD64 index and CD4CD64 index and CD279 expression in neutrophils, lymphocytes, and monocytes are significantly related to the severity and prognosis of trauma. Dynamic monitoring the cellular immune function may be helpful for assessing the prognosis of trauma patients.

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.

miR-608 has been indicated to play an important role in the pathogenesis of various inflammation-related diseases, including sepsis and several types of cancers. However, there is little information about the underlying mechanism, especially in inflammatory cells. In this study, an hsa-miR-608-inhibition cell model was constructed in U937 cells using a lentivirus, and gene expression profiles were determined by a cDNA microarray. Altogether, 682 genes showed a difference greater than 1.2-fold, including 184 genes downregulated and 498 genes upregulated. Among these genes, one potential miR-608-target gene, ELANE, was further investigated. A positive relationship between the expression of miR-608 and that of ELANE was found both in vivo and in vitro. In addition, decreased expression of miR-608 resulted in overexpression of ELANE at both the mRNA and protein levels. Cotransfection of HEK293T cells with a miR-608 mimic inhibited reporter activity, and mutation of the miRNA seed sequences abolished the repression of reporter activity. These results suggest that miR-608 is an important posttranscriptional regulator of ELANE expression in human monocytes and may play an important role in the process of inflammation. miR-608 and neutrophil elastase may be novel targets for the diagnosis or treatment of sepsis.

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.