CXCL4/CXCR3 axis regulates cardiac fibrosis by activating TGF-ß1/Smad2/3 signaling in mouse viral myocarditis.

BACKGROUND: Severe myocarditis is often accompanied by cardiac fibrosis, but the underlying mechanism has not been fully elucidated. CXCL4 is a chemokine that has been reported to have pro-inflammatory and profibrotic functions. The exact role of CXCL4 in cardiac fibrosis remains unclear. METHODS: Viral myocarditis (VMC) models were induced by intraperitoneal injection of Coxsackie B Type 3 (CVB3). In vivo, CVB3 (100 TCID50) and CVB3-AMG487 (CVB3: 100 TCID50; AMG487: 5 mg/kg) combination were administered in the VMC and VMC+AMG487 groups, respectively. Hematoxylin and eosin staining, severity score, Masson staining, and immunofluorescence staining were performed to measure myocardial morphology in VMC. Enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were performed to quantify inflammatory factors (IL-1ß, IL-6, TNF-α, and CXCL4). Aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine kinase-myocardial band (CK-MB) levels were analyzed by commercial kits. CXCL4, CXCR3B, α-SMA, TGF-ß1, Collagen I, and Collagen III were determined by Western blot and immunofluorescence staining. RESULTS: In vivo, CVB3-AMG487 reduced cardiac injury, α-SMA, Collagen I and Collagen III levels, and collagen deposition in VMC+AMG487 group. Additionally, compared with VMC group, VMC+AMG group decreased the levels of inflammatory factors (IL-1ß, IL-6, and TNF-α). In vitro, CXCL4/CXCR3B axis activation TGF-ß1/Smad2/3 pathway promote mice cardiac fibroblasts differentiation. CONCLUSION: CXCL4 acts as a profibrotic factor in TGF-ß1/Smad2/3 pathway-induced cardiac fibroblast activation and ECM synthesis, and eventually progresses to cardiac fibrosis. Therefore, our findings revealed the role of CXCL4 in VMC and unveiled its underlying mechanism. CXCL4 appears to be a potential target for the treatment of VMC.

sST2: A Bridge Between Sirt1/p53/p21 Signal-Induced Senescence and TGF-ß1/Smad2/3 Regulation of Cardiac Fibrosis in Mouse Viral Myocarditis.

Soluble interleukin 1 receptor-like 1 (sST2) is a novel predictor of poor outcomes, which is involved in inflammatory response and fibrosis of myocarditis. Cellular senescence is a state of irreversible cell cycle arrest. Studies have shown that senescence of myofibroblasts can limit or reduce cardiac fibrosis. However, the molecular mechanism of sST2 regulating cellular senescence is still unclear. Here, we investigate the role of sST2 on cellular senescence in cardiac fibrosis. Our results found that sST2 was upregulated in coxsackievirus group B type 3 (CVB3)-induced viral myocarditis (VMC), which correlated with the expression of senescence markers. In vitro, sST2 activated TGFß signaling through the phosphorylation of the SMAD complex to induce mouse cardiac fibroblast (MCF) activation and inhibit cellular senescence by the Sirt1/p53/p21 signaling pathway. In vivo, anti-ST2 mAb attenuated CVB3-induced cardiac fibrosis. Our findings elucidate a crucial mechanism underlying through which sST2 inhibits cellular senescence and regulates MCF activation, providing a potential treatment strategy for cardiac fibrosis.

VNN1 contributes to the acute kidney injury-chronic kidney disease transition by promoting cellular senescence via affecting RB1 expression.

The mechanisms underlying acute kidney injury (AKI) and chronic kidney disease (CKD) progression include interstitial inflammation, cellular senescence, and oxidative stress (OS). Although vanin-1 (VNN1) plays an important role in OS, its contribution to the AKI-CKD transition remains unknown. Here, we explored the roles and mechanisms of VNN1 in the progression of the AKI-CKD transition. We observed that VNN1 expression was upregulated after ischemia/reperfusion (I/R) injury and high VNN1 expression levels were associated with poor renal repair after I/R injury. In VNN1 knockout (KO) mice, recovery of serum creatinine and blood urea nitrogen levels after I/R injury was accelerated and renal fibrosis was inhibited after severe I/R injury. Furthermore, in VNN1 KO mice, senescence of renal tubular cells was inhibited after severe I/R injury, as assessed by P16 expression and SA-ß-Gal assays. However, our results also revealed that VNN1 KO renal tubular cells did not resist senescence when OS was blocked. To elucidate the mechanism underlying VNN1-mediated regulation of senescence during the AKI-CKD transition, retinoblastoma 1 (RB1) was identified as a potential target. Our results suggest that the reduced senescence in VNN1 KO renal tubular cells was caused by suppressed RB1 expression and phosphorylation. Collectively, our results unveil a novel molecular mechanism by which VNN1 promotes AKI-CKD transition via inducing senescence of renal tubular cells by activating RB1 expression and phosphorylation after severe renal injury. The present study proposes a new strategy for designing therapies wherein VNN1 can be targeted to obstruct the AKI-CKD transition.

Development and prospective validation of a novel risk score for predicting the risk of lower extremity deep vein thrombosis among multiple trauma patients.

INTRODUCTION: Trauma patients have an increased risk of deep vein thrombosis (DVT). Early identification of patients with a high risk of DVT after trauma is crucial for thromboembolism prophylaxis. We aimed to develop and prospectively validate a novel risk score based on a nomogram to predict lower extremity DVT among multiple trauma patients. MATERIALS AND METHODS: Clinical data were collected from 281 multiple trauma patients who were admitted to our trauma center within 24 h of admission from January 2016 to September 2019 to develop a novel DVT risk score. The DVT risk estimates were then calculated prospectively based on the score in a new study cohort from October 2019 to July 2020. The technique of least absolute shrinkage and selection operator (LASSO) was used to select variables for the early prediction of DVT in multiple trauma patients. The DVT risk assessment score (DRAS) was constructed by incorporating related features based on the LASSO analysis and nomogram prediction model. Further, the multiple trauma patients were divided into various risk groups according to the DRAS. The incidence of lower extremity DVT was compared between groups and the discrimination of the DRAS was assessed using the area under the curve (AUC). RESULTS: Based on the LASSO method, seven variables (age, injury severity score, body mass index, lower extremity fracture, D-dimer level, fibrin degradation products, and prothrombin time) were included in the DRAS. A total of 166 multiple trauma patients were enrolled in the prospective study. Increased risk of DVT after trauma was related to higher DRAS. The area under the receiver operating characteristic (ROC) curve for the DRAS was 0.890 (0.841-0.940) in the validation cohort. Moreover, the discriminatory capacity of the DRAS was superior to that of each variable independently and the TESS score (P < 0.05). CONCLUSIONS: We developed and prospectively validated the DRAS as a reliable tool for predicting the risk of lower extremity DVT among patients with multiple trauma. This may help guide trauma surgeons in making sound decisions in the administration of DVT prophylaxis.

Plasma Vanin-1 as a Novel Biomarker of Sepsis for Trauma Patients: A Prospective Multicenter Cohort Study.

INTRODUCTION: Vanin-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 could be used for the early prediction of traumatic sepsis. METHODS: In this three-stage prospective cohort study, severe trauma patients admitted from January 2015 to October 2018 at two hospitals were enrolled. Plasma vanin-1 levels were measured by enzyme-linked immunosorbent assay (ELISA). The associations among variables and traumatic sepsis were identified by logistic regression models and the receiver operating characteristic (ROC) curve was analyzed to evaluate the diagnostic efficiency. RESULTS: A total of 426 trauma patients (22 in the discovery cohort, 283 in the internal test cohort, and 121 in the external validation cohort) and 16 healthy volunteers were recruited. The plasma vanin-1 of trauma patients was significantly higher than that of healthy volunteers (P < 0.05). Patients with sepsis had higher plasma vanin-1 than patients without sepsis in the discovery trauma cohort (P < 0.05). In the internal test cohort, plasma vanin-1 at day 1 after trauma was significantly associated with the incidence of sepsis (OR = 3.92, 95% CI 2.68-5.72, P = 1.62 × 10-12). As a predictive biomarker, vanin-1 afforded 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 < 0.0001), procalcitonin (PCT) (0.66, 95% CI 0.60-0.71, P < 0.0001), and Acute Physiology and Chronic Health Evaluation II (APACHE II) (0.71, 95% CI 0.65-0.76, P = 6.70 × 10-3). The relevance was further validated in the external validation cohort (OR = 4.26, 95% CI 2.22-8.17, P = 1.28 × 10-5), with an AUC of 0.83 (95% CI 0.75-0.89). Vanin-1 could also improve the diagnostic efficiency of APACHE II (AUC = 0.85). CONCLUSIONS: Our 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 REGISTRATION: Clinicaltrials.gov Identifier, NCT01713205.

Polygenic Risk Score for Early Prediction of Sepsis Risk in the Polytrauma Screening Cohort.

BACKGROUND: Increasing genetic variants associated with sepsis have been identified by candidate-gene and genome-wide association studies, but single variants conferred minimal alterations in risk prediction. Our aim is to evaluate whether a weighted genetic risk score (wGRS) that aggregates information from multiple variants could improve risk discrimination of traumatic sepsis. METHODS: Sixty-four genetic variants potential relating to sepsis were genotyped in Chinese trauma cohort. Genetic variants with mean decrease accuracy (MDA) > 1.0 by random forest algorithms were selected to construct the multilocus wGRS. The area under the curve (AUC) and net reclassification improvement (NRI) were adopted to evaluate the discriminatory and reclassification ability of weighted genetic risk score (wGRS). RESULTS: Seventeen variants were extracted to construct the wGRS in 883 trauma patients. The wGRS was significantly associated with sepsis after trauma (OR = 2.19, 95% CI = 1.53-3.15, P = 2.01 × 10-5) after being adjusted by age, sex, and ISS. Patients with higher wGRS have an increasing incidence of traumatic sepsis (P trend = 6.81 × 10-8), higher SOFA (P trend = 5.00 × 10-3), and APACHE II score (P trend = 1.00 × 10-3). The AUC of the risk prediction model incorporating wGRS into the clinical variables was 0.768 (95% CI = 0.739-0.796), with an increase of 3.40% (P = 8.00 × 10-4) vs. clinical factor-only model. Furthermore, the NRI increased 25.18% (95% CI = 17.84-32.51%) (P = 6.00 × 10-5). CONCLUSION: Our finding indicated that genetic variants could enhance the predictive power of the risk model for sepsis and highlighted the application among trauma patients, suggesting that the sepsis risk assessment model will be a promising screening and prediction tool for the high-risk population.

Emergency trauma care during the outbreak of corona virus disease 2019 (COVID-19) in China.

BACKGROUND: A novel coronavirus pneumonia outbreak began in Wuhan, Hubei Province, in December 2019; the outbreak was caused by a novel coronavirus previously never observed in humans. China has imposed the strictest quarantine and closed management measures in history to control the spread of the disease. However, a high level of evidence to support the surgical management of potential trauma patients during the novel coronavirus outbreak is still lacking. To regulate the emergency treatment of trauma patients during the outbreak, we drafted this paper from a trauma surgeon perspective according to practical experience in Wuhan. MAIN BODY: The article illustrates the general principles for the triage and evaluation of trauma patients during the outbreak of COVID-19, indications for emergency surgery, and infection prevention and control for medical personnel, providing a practical algorithm for trauma care providers during the outbreak period. CONCLUSIONS: The measures of emergency trauma care that we have provided can protect the medical personnel involved in emergency care and ensure the timeliness of effective interventions during the outbreak of COVID-19.

Using polyethylene glycol to promote Nannochloropsis oceanica growth with 15 vol% CO2.

CO2 capture with microalgae has been put forward in response to global concern on greenhouse gas emission. However, the short residence time and slow diffusion of CO2 in water limits the growth of microalgae. In order to improve CO2 transfer from gas phase to liquid phase and utilization by algal cells, polyethylene glycol 200 (PEG 200) was used as CO2 absorbent to promote growth of Nannochloropsis oceanica with the bubbling of 15 vol% CO2. Total inorganic carbon (TIC) absorbed in culture medium remained constant at 5.6 mM when 15 vol% CO2 was bubbled continuously. PEG 200 in the medium provided additional CO2 absorption from 0.6 to 4.8 mM when PEG 200 concentration increased from 0.5 to 4 mM. The specific growth rate of N. oceanica reached the maximum (1.41 d-1) with 1 mM PEG 200 in culture medium, which was 21.5% higher than the specific growth rate without PEG 200. About 79% of the increase in biomass was attributed to the increased TIC with more CO2 dissolution in culture medium because of PEG 200, and about 21% was attributed to PEG 200 itself utilized as an organic carbon source. In conclusion, PEG 200 as a CO2 absorbent can effectively capture flue-gas CO2 for algal growth.

Fibroblast transdifferentiation promotes conversion of M1 macrophages and replenishment of cardiac resident macrophages following cardiac injury in mice.

Resident cardiac macrophages play important roles in homeostasis, maintenance of cardiac function, and tissue repair. After cardiac injury, monocytes infiltrate the tissue, undergo phenotypic and functional changes, and are involved in inflammatory injury and functional remodelling. However, the fate of cardiac infiltrating/polarized macrophages and the relationship between these cells and resident cardiac macrophage replenishment following injury remain unclear. Our results showed that angiotensin II induces cardiac fibroblast transdifferentiation into cardiac myofibroblasts (MFBs). In cocultures with MFBs and murine macrophages, the MFBs promoted macrophage polarization to M1 phenotype, followed by selective apoptosis, which was associated with TNF/TNFR1 axis and independent of NO production. Surprisingly, after 36 h of coculture, the surviving macrophages were converted to M2 phenotype and settled in heart, which was dependent on leptin produced by MFBs or polarized macrophages via the PI3K or Akt pathway. CCR2+ CD45.2+ cells adoptively transferred into CD45.1+ mice with viral myocarditis, differentiated into CD45.2+ CCR2+ CX3CR1+ M2 cells during the resolution of inflammation and settled within the heart. Our data highlight a novel mechanism related to the renewal or replenishment of cardiac resident macrophages following cardiac injury; and suggest that transdifferentiation of cardiac fibroblasts may promote the resolution of inflammation.

Calcinated MIL-100(Fe) as a CO2 adsorbent to promote biomass productivity of Arthrospira platensis cells.

In order to solve the problems of short residence time and low diffusion of CO2 gas in microalgal solution, calcinated metal-organic framework MIL-100(Fe) were first used as CO2 adsorbents to promote the growth of Arthrospira platensis cells by increasing carbon fixation. The adsorbent (MIL-100(Fe)-4 h) containing unsaturated metal sites, improved the conversion of CO2 to dissolved inorganic carbon by 52.3% and concentration of HCO3- by 20.0% in culture medium, as compared to the medium without CO2 adsorbent added. The increased HCO3- concentration facilitated carboxysome accumulation (increased to 21.7 times) to activate the photosynthetic Calvin cycle in Arthrospira cells. The increased cell growth rate promoted cell volume by 132% and knot length by 102%, while the fractal dimension of the cell surface decreased by 13.5%. The biomass productivity of Arthrospira cells cultivated with the CO2 adsorbent MIL-100(Fe)-4 h remarkably increased by 81.9%.

PGE2 ameliorated viral myocarditis development and promoted IL-10-producing regulatory B cell expansion via MAPKs/AKT-AP1 axis or AhR signaling.

B10 cells, a specific subset of regulatory B cells, are capable of regulating immune response and restricting inflammation and autoimmune disease progression by producing IL-10. B10 cells frequently change significantly during inflammation and autoimmunity. However, how B10 cell populations change in viral myocarditis (VMC) remains unclear. Therefore, this work was conducted to clarify the changes in B10 cells and their potential mechanisms. Our results showed that the B10 cell frequency significantly changed in the VMC model. Changes in prostaglandin E2 (PGE2) levels in VMC model hearts were consistent with B10 expansion. PGE2 induced B10 cell expansion via the MAPKs/AKT-AP1 axis or AhR signaling. Additionally, PGE2-pretreated B10 cells inhibited naïve CD4+ T cell differentiation into Th17 cells. In vivo, PGE2 treatment or adoptive B10 cell transfer significantly restricted VMC development. Our results provide sufficient evidence that PGE2-induced B10 cell expansion may become a promising therapeutic approach for VMC and acute inflammatory injury.

MiR-608 Exerts Anti-inflammatory Effects by Targeting ELANE in Monocytes.

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.

Dual faced HMGB1 plays multiple roles in cardiomyocyte senescence and cardiac inflammatory injury.

High mobility group box 1 (HMGB1) is constitutively expressed by many cells. In cells, HMGB1 is a transcription factor or transcription enhancer that is involved in nucleosome sliding, DNA repair, V(D)J recombination, telomere homeostasis, autophagy and viral sensing. HMGB1 can also be secreted or released by stressed cells and serves as an alarmin, cytokine or growth factor to activate the immune response. This protein facilitates CD4+ T cell differentiation and tissue repair through binding with its receptors, including toll-like receptors (TLRs) and the receptor for advanced glycation end-products (RAGE). Recent works have established that HMGB1 plays many vital functions in cardiac inflammatory injury, cardiac regeneration and remodelling. The present review addresses the novel role of HMGB1 in secretion and cardiomyocyte senescence and in the dual faced roles of HMGB1 in cardiac inflammatory injury, inflammatory resolution and cardiac regeneration and remodelling following cardiac injury.

Development and validation of a novel predictive score for sepsis risk among trauma patients.

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 < 0.001). Moreover, the TSS was well calibrated (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.

The Hippo-YAP pathway regulates the proliferation of alveolar epithelial progenitors after acute lung injury.

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.

The potential roles of long non-coding RNAs in lipopolysaccharide-induced human peripheral blood mononuclear cells as determined by microarray analysis.

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 < 0.05) in response to LPS. Of the 34 236 mRNAs screened, 802 were upregulated and 549 were downregulated. Functional annotation analysis indicated that lncRNA-associated differentially expressed mRNAs were primarily enriched in host immune and inflammatory responses. This study provides the first lncRNA and mRNA transcriptomic landscape of LPS-mediated changes in human PBMCs. These findings may provide potential insights into lncRNAs involved in the immunopathology of sepsis.

Host genetic variants in sepsis risk: a field synopsis and meta-analysis.

BACKGROUND: Published data revealed that host genetic variants have a substantial influence on sepsis susceptibility. However, the results have been inconsistent. We aimed to systematically review the published studies and quantitatively evaluate the effects of these variants on the risk of sepsis. METHODS: We searched the PubMed, EMBASE, Medline, Web of Knowledge, and HuGE databases to identify studies that investigated the associations between genetic variants and sepsis risk. Then, we conducted meta-analyses of the associations for genetic variants with at least three study populations and applied the Venice criteria to assess the association result credibility. RESULTS: A literature search identified 349 eligible articles that investigated 405 variants of 172 distinct genes. We performed 204 primary and 185 subgroup meta-analyses for 76 variants of 44 genes. The results showed that 29 variants of 23 genes were significantly associated with the risk of sepsis, including 8 variants of pattern recognition receptors (PRRs), 14 variants of cytokines, one variant of an immune-related gene and 6 variants of other genes. Furthermore, the cumulative epidemiological evidence of a significant association between each variant and the risk of sepsis was classified as strong or moderate for 18 variants. For the 329 variants with fewer than three study populations, 63 variants of 48 genes have been reported to be significantly associated with the risk of sepsis in a systematic review. CONCLUSION: We identified several genetic variants that could influence the susceptibility to sepsis by systematic review and meta-analysis. This study provides a comprehensive overview of the genetic architecture of variants involved in sepsis susceptibility and novel insight that may affect personalized targeted treatment in the future clinical management of sepsis.

Clinical relevance of single nucleotide polymorphisms in the CXCL1 and CXCL12 genes in patients with major trauma.

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.