The murine plasma protein response to polymicrobial intra-abdominal sepsis

Protein biomarkers in the peripheral blood could potentially be used as early indicators of sepsis and a means to stratify patients for clinical trials. Although individual molecular markers have been proposed for sepsis, none has clinical utility. The global changes in plasma proteins over the clinical course of sepsis have not been characterized using proteomic methods. We used cecal ligation and puncture to induce polymicrobial sepsis in mice and generated plasma protein profiles using 2‐D DIGE of plasma from septic mice and surgical controls. Replicate cohorts (n = 3) of 4–7 animals each were used to identify 62 gel features that changed significantly (Student's t‐test, p<0.05). We identified a suite of plasma proteins that describe uniquely the host plasma response to polymicrobial septic insult. Principal components analysis of protein abundance showed that ～90% of the variability between samples was due to sepsis. In addition to canonical acute phase proteins, we identified proteins that are associated with metabolic changes (e.g. α‐2 HS glycoprotein and zinc α‐2 glycoprotein) consistent with the pathophysiology of sepsis. The panel of sepsis‐associated molecular markers identified herein may prove useful in the diagnosis and categorization of sepsis.     

n-3 Polyunsaturated Fatty Acids Improve Inflammation via Inhibiting Sphingosine Kinase 1 in a Rat Model of Parenteral Nutrition and CLP-Induced Sepsis

The sphingosine kinase 1 (SphK1)/sphingosine‐1‐phosphate (S1P) pathway plays a key role in inflammation. Parenteral nutrition containing n‐3 polyunsaturated fatty acids (n‐3 PUFA) may regulate inflammatory reactions. The aim of this study is to determine whether n‐3 PUFA may improve inflammatory responses by neutralizing SphK1 signaling. Rat models of parenteral nutrition, cecal ligation and puncture (CLP)‐induced sepsis were generated. Male Sprague–Dawley rats were operated for CLP on day 2 after venous catheterization. The rats were randomized to receive normal saline (NS; n = 20), parenteral nutrition (PN; n = 20), or PN + fish oil (FO; n = 20) for 5 days. The daily intake of fish oil (1.25–2.82 g EPA and 1.44–3.09 g DHA per 100 ml) in the FO group was approximately 1.8 g/kg body weight/day. Rats in the control group (n = 10) were subjected to sham operation and received a chow diet. Spleen tissues were collected for SphK1 and S1P receptor expression analysis. Our data showed that n‐3 PUFA ameliorated the survival rate. SphK1 expression and its enzymatic activity were significantly upregulated in sepsis rats. Furthermore, mRNA and protein levels of S1PR3, but not S1PR1, were also facilitated after CLP. However, PN + FO dramatically decreased SphK1 mRNA level and its enzymatic activity. S1PR3 expression was also attenuated by FO addition. In conclusion, the anti‐inflammatory effect of n‐3 PUFA may be linked to the inhibition of the SphK1/S1P pathway in a rat model of parenteral nutrition and CLP‐induced sepsis.     

Toll样受体4与脓毒症相关性的研究进展

重症脓毒症(Sever sepsis)及脓毒性休克(Sepsis shock)是当前危重病患者的主要死亡原因。内毒素受体4(Toll-like receptor,TLR4)是革兰阴性菌细胞壁脂多糖的受体,TLR4及其信号通路基因多态性在脓毒症的发生发展过程中起着重要的作用。目前大部分针对单一炎症细胞因子的脓毒症治疗均宣告失败。由于TLR4的重要地位,靶向性针对TLR4及其信号通路的治疗充满希望。现就TLR4和信号通路基因多态性与脓毒症易感性及其调节剂之间的关系作一综述。     

Single-wall carbon nanohorns inhibited activation of microglia induced by lipopolysaccharide through blocking of Sirt3

Single-wall carbon nanohorns (SWNHs) have been demonstrated to accumulate in cytotoxic levels within organs of various animal models and cell types, which emerge as a wide range of promising biomedical imaging. Septic encephalopathy (SE) is an early sign of sepsis and associated with an increased rate of morbidity and mortality. Microglia activation plays an important role in neuroinflammation, which contributes to neuronal damage. Inhibition of microglia activation may have therapeutic benefits, which can alleviate the progression of neurodegeneration. Therefore, we investigated the functional changes of mice microglia cell lines pre-treated with or without lipopolysaccharide (LPS) induced by SWNHs. To address this question, the research about direct role of SWNHs on the growth, proliferation, and apoptosis of microglia cell lines in mice (N9 and BV2) pre-treated with or without LPS had been performed. Our results indicate that the particle diameter of SWNHs in water is between 342 to 712 nm. The images in scanning electron microscope showed that SWNHs on polystyrene surface are individual particles. LPS induced activation of mice microglia, promoted its growth and proliferation, and inhibited its apoptosis. SWNHs inhibited proliferation, delayed mitotic entry, and promoted apoptosis of mice microglia cells. The effects followed gradually increasing cultured time and concentrations of SWNHs, especially in cells pre-treated with LPS. SWNHs induced a significantly increase in G1 phase and inhibition of S phase of mice microglia cells in a dose-manner dependent of SWNHs, especially in cells pre-treated with LPS. The transmission electron microscope images showed that individual spherical SWNH particles smaller than 100 nm in diameters were localized inside lysosomes of mice microglia cells. SWNHs inhibited mitotic entry, growth and proliferation of mice microglia cells, and promoted its apoptosis, especially in cells pre-treated with LPS. SWNHs inhibited expression of Sirt3 and energy metabolism related with Sirt3 in mice microglia cells in a dose-dependent manner, especially in cells pre-treated with LPS. The role of SWNHs on mice microglia was implicating Sirt3 and energy metabolism associated with it.     

Modified binary PSO for feature selection using SVM applied to mortality prediction of septic patients

This paper proposes a modified binary particle swarm optimization (MBPSO) method for feature selection with the simultaneous optimization of SVM kernel parameter setting, applied to mortality prediction in septic patients. An enhanced version of binary particle swarm optimization, designed to cope with premature convergence of the BPSO algorithm is proposed. MBPSO control the swarm variability using the velocity and the similarity between best swarm solutions. This paper uses support vector machines in a wrapper approach, where the kernel parameters are optimized at the same time. The approach is applied to predict the outcome (survived or deceased) of patients with septic shock. Further, MBPSO is tested in several benchmark datasets and is compared with other PSO based algorithms and genetic algorithms (GA). The experimental results showed that the proposed approach can correctly select the discriminating input features and also achieve high classification accuracy, specially when compared to other PSO based algorithms. When compared to GA, MBPSO is similar in terms of accuracy, but the subset solutions have less selected features.     

Short term protective effect of digitoxin in sepsis-induced acute lung injury

Purpose: Digitoxin is a cardiac glycoside used in the treatment of heart failure. Inspired by its known anti-inflammatory effect, this study aims to investigate the effect of digoxin in a sepsis model and to bring to light its effect and underlying mechanism in acute lung injury (ALI). Method: 28 wistar albino rats were divided into 4 groups. Sepsis model is performed by the feces intraperitoneal-injection procedure (FIP). Results: TNF-a, CRP, IL-6, IL 1-Beta, lactic acid, and MDA values were significantly decreased in the FIP+digitoxin group compared to the FIP+Saline group. When the same groups were examined, histological improvements such as decrease in alveolar inflammation and decrease in septal thickening in the digitoxin group and thorax CT were found to be significantly higher in the Hounsfield unit digitoxin group compared to the Saline group. Conclusion: Digitoxin has shown biochemical improvement in sepsis with all known mechanisms of action, and healing effects in both computerized tomography and histology in the lung.     

血必净对严重脓毒症患者血管内皮细胞相关促炎因子和凝血因子的影响

目的 探讨血必净注射液对严重脓毒症患者血管内皮细胞相关促炎症因子和凝血因子的影响.方法 将52例严重脓毒症患者随机分为常规治疗组(A组)与血必净治疗组(B组).在相同的常规治疗基础上,B组给予血必净注射液100 ml加入0.9%氯化钠100 ml中静脉滴注,每天1次,持续7 d.A组则给予同等量的0.9%氯化钠作为对照.A、B两组患者治疗前及治疗后第3、7天分别抽血检测血清内血管内皮细胞(VEC)相关促炎症因子和凝血因子水平.促炎症因子包括血管细胞黏附分子(VCAM-1)和细胞间黏附分子(ICAM-1).凝血因子包括一氧化氮(NO)、抗凝血酶Ⅲ(AT-Ⅲ)、血栓调节蛋白(TM)、组织纤溶酶原激活物(TPA)、VWF因子(VWF)、纤溶酶原激活物抑制物(PAI-1);并统计两组患者的28 d病死率.结果 B组患者28 d的病死率为32.1%(9/28),低于A组的62.5%(15/24),差异有统计学意义(P<0.05).治疗第7天B组患者VEC诱导的促炎症因子VCAM-1和ICAM-1明显低于A组;VEC诱导的抗凝(NO、AT-Ⅲ、TM)和促纤溶物质(TPA)、促凝(VWF)和纤溶抑制因子(PAI-1)都明显高于A组(P<0.05).结论 血必净注射液能够改善严重脓毒症患者的病情,降低病死率,其机制可能与其稳定血管内皮细胞,改善严重炎症反应和凝血功能紊乱有关.     

血必净对鲍曼不动杆菌脓毒症大鼠中性粒细胞翻译控制肿瘤蛋白表达的影响

目的: 探讨血必净注射液对鲍曼不动杆菌脓毒症大鼠中性粒细胞翻译控制肿瘤蛋白(TCTP)表达的影响。方法: 雄性Wistar大鼠42只,随机分为对照组(n=6)、脓毒症组(n=18)和血必净组(n=18)。腹腔注射鲍曼不动杆菌悬液造模成功后,根据取血提取中性粒细胞的时间,脓毒症组和血必净组又随机各分为6、12 和 24 h 3个亚组,每亚组6只。Western-blotting方法检测中性粒细胞TCTP的表达,比较脓毒症和血必净各亚组TCTP的表达。结果: 脓毒症各亚组中性粒细胞TCTP表达量较对照组均增高(P<0.05);血必净组各亚组中性粒细胞TCTP表达量分别较脓毒症各对应亚组均降低(P<0.05)。结论: 血必净注射液治疗脓毒症可能与抑制中性粒细胞TCTP的表达有关。