CXCL4:NLRP3-mediated pyroptosis product that regulates cardiac fibrosis.

Severe myocarditis is often accompanied by cardiac fibrosis, but the underlying mechanism has not been fully elucidated. NOD-like receptor protein 3 (NLRP3) inflammation is involved in the development of myocarditis and is closely related to the form of cell death. Inhibiting pyroptosis mediated by NLRP3 inflammasome can reduce cardiac fibrosis, although its exact mechanism remains unknown. In this study, we induced Viral myocarditis (VMC) via infection of CVB3 to explore the relationship between pyroptosis and fibrosis. Our results showed that intraperitoneal injection of an NLRP3 inhibitor MCC950 or use of NLRP3-/- mice inhibited cardiac pyroptosis mediated by NLRP3 inflammasome in VMC. CXCL4 is a chemokine that has been reported to have pro-inflammatory and pro-fibrotic functions. In VMC, we further found that pyroptosis of Mouse myocardial fibroblasts (MCF) promoted the secretion of CXCL4 by activating Wnt/ß-Catenin signaling. Subsequently, the transcriptome sequencing data showed that CXCL4 could promote cardiac fibrosis by activating PI3K/AKT pathway. In summary, infection of CVB3 induced host oxidative stress to further activate the NLRP3 inflammasome and ultimately lead to heart pyroptosis, in which MCF secreted CXCL4 by activating Wnt/ß-Catenin signaling and CXCL4 participated in cardiac fibrosis by activating PI3K/AKT pathway. 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.

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.

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.

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.

LBP rs2232618 polymorphism contributes to risk of sepsis after trauma.

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 < 0.001 for the dominant model; OR = 6.08, P = 0.003 for the recessive model; OR = 2.72, P < 0.001 for the allelic model). Conclusions: The results from our replication study and meta-analysis provided firm evidence that rs2232618T allele significantly increased the risk of sepsis.

Association between smoking and the risk of acute mountain sickness: a meta-analysis of observational studies.

BACKGROUND: People rapidly ascending to high altitudes (>2500 m) may suffer from acute mountain sickness (AMS). The association between smoking and AMS risk remains unclear. Therefore, we performed a meta-analysis to evaluate the association between smoking and AMS risk. METHODS: The association between smoking and AMS risk was determined according to predefined criteria established by our team. Meta-analysis was conducted according to the PRISMA guidelines. We included all relevant studies listed in the PubMed and Embase databases as of September 2015 in this meta-analysis and performed systemic searches using the terms "smoking", "acute mountain sickness" and "risk factor". The included studies were required to provide clear explanations regarding their definitions of smoking, the final altitudes reached by their participants and the diagnostic criteria used to diagnose AMS. Odds ratios (ORs) were used to evaluate the association between smoking and AMS risk across the studies, and the Q statistic was used to test OR heterogeneity, which was considered significant when P < 0.05. We also computed 95% confidence intervals (CIs). Data extracted from the articles were analyzed with Review Manager 5.3 (Cochrane Collaboration, Oxford, UK). RESULTS: We used seven case-control studies including 694 smoking patients and 1986 non-smoking controls to analyze the association between smoking and AMS risk. We observed a significant association between AMS and smoking (OR = 0.71, 95% CI 0.52-0.96, P = 0.03). CONCLUSIONS: We determined that smoking may protect against AMS development. However, we do not advise smoking to prevent AMS. More studies are necessary to confirm the role of smoking in AMS risk.

Association between endothelial nitric oxide synthase (ENOS) G894T polymorphism and high altitude (HA) adaptation: a meta-analysis.

OBJECTIVE: Highland natives adapt well to the hypoxic environment at high altitude (HA). Several genes have been reported to be linked to HA adaptation. Previous studies showed that the endothelial ni- tric oxide synthase (ENOS) G894T polymorphism contributed to the physiology and pathophysiology of hu- mans at HA by regulating the production of NO. In this meta-analysis, we evaluate the association between the ENOS G894T polymorphism and HA adaptation through analyzing the published data. METHODS: We searched all relevant literature about the ENOS G894T polymorphism and HA adaptation in PubMed, Med- line, and Embase before Step 2015. A random-effects model was applied (Revman 5.0), and study quality was assessed in duplicate. Six studies with 634 HA native cases and 621 low-altitude controls were included in this meta-analysis. RESULTS: From the results, we observed that the wild-type allele G was significantly overrepresented in the HA groups (OR = 1.85; 95% Cl, 1.47-2.33; P < 0.0001). In addition, the GG genotype was significantly associated with HA adaptation (OR = 1.99; 95% Cl, 1.54-2.57; P < 0.0001). CONCLUSION: Our results showed that in 894 G allele carriers, the GG genotype might be a beneficial factor for HA adaptation through enhancing the level of NO. However, more studies were needed to confirm our findings due to the limited sample size.