中性粒细胞在脓毒症中的作用及研究进展

感染引发的脓毒症目前仍然是重症监护病房患者死亡的主要原因之一。除了抗感染治疗和对症支持疗法,目前仍缺乏特异性治疗手段。中性粒细胞是宿主防御病原体的效应阶段的主要参与者,在正常情况下对感染的控制起着至关重要的作用。在脓毒症发病过程中,中性粒细胞发挥双重作用。除了抗感染作用外,中性粒细胞的失调和过度活化可能导致严重炎症或组织损伤,是脓毒症不良预后的潜在机制。本文综述了中性粒细胞在脓毒症各病理过程中的功能状态的研究进展,以期探讨中性粒细胞参与脓毒症各病理过程的机制,为今后以中性粒细胞为靶点进行脓毒症的治疗提供线索。     

蛋白质泛素化修饰及其在脓毒症中的研究进展

蛋白质在机体生命活动中扮演关键角色,其降解途径中,泛素-蛋白酶体途径(UPS)通过泛素化修饰调控蛋白降解,同时通过共价修饰底物蛋白参与细胞生理活动。去泛素化酶(DUBs)对蛋白质泛素化具有平衡作用,通过移除泛素化修饰来维持泛素化修饰的动态平衡,它们在脓毒症中发挥着关键作用,通过调控炎症因子的表达,影响机体的炎症反应。脓毒症是导致患者重症监护的主要疾病,涉及复杂炎症反应。蛋白质泛素化修饰参与脓毒症信号转导,影响核因子-κB(NF-κB)信号通路和NOD样受体蛋白3炎症小体(NLRP3)活化。这些调控机制影响细胞内炎症因子的释放,进而影响机体炎症反应的强度和时机。本文探讨了近年来与脓毒症相关关键蛋白的泛素化及去泛素化机制,以期为脓毒症的治疗提供新的靶点和策略。     

脓毒症炎症反应与内皮细胞损伤研究进展

脓毒症被定义为机体对感染的异常反应最终引起危及生命的器官功障碍综合征.血管内皮细胞在多种炎症细胞和因子的作用下经历活化一损伤过程是脓毒症发展恶化的中心环节.了解炎症反应与血管内皮损伤关系对理解脓毒症发生发展及其治疗具有重要意义.     

白花前胡甲素通过铁蛋白抑制中性粒细胞炎症反应及其在脓毒症中的作用

目的 探究白花前胡甲素(praeruptorin A, PA)是否通过抑制铁蛋白的表达减轻炎症反应,从而改善脓毒症引起的炎症性损伤。 方法 C57BL/6小鼠腹腔注射脂多糖(lipopolysaccharide,LPS)构建脓毒症模型;PA干预6和12 h后,ELISA检测血清中炎症因子IL-6和TNF-α的表达变化;72 h取肾脏组织进行HE染色,观察炎性细胞浸润和组织损伤情况。将人中性粒细胞分为对照组、LPS组、铁蛋白组和LPS＋铁蛋白组,干预12 h,qRT-PCR检测炎症因子IL-6和TNF-α的mRNA水平表达变化。为观察PA对炎症因子及铁蛋白表达的影响,将人中性粒细胞分为对照组、LPS组、LPS＋PA(2/3/4 μmol/L)组,12 h后qRT-PCR检测IL-1β、IL-6、TNF-α和铁蛋白的mRNA表达水平;ELISA法检测上清液中IL-1β、IL-6和TNF-α的分泌水平;Western blot检测铁蛋白表达水平。 结果 脓毒症过程中伴随炎性细胞大量募集、组织损伤及炎症因子IL-6和TNF-α的显著升高( P<0.01),PA可显著抑制小鼠血清中炎症因子的分泌( P<0.01)并改善组织损伤。在人中性粒细胞模型中,铁蛋白显著上调了炎症因子IL-6和TNF-α的mRNA表达水平( P<0.01);LPS单独刺激显著上调了IL-1β、IL-6、TNF-α和铁蛋白的mRNA及蛋白质表达水平( P<0.01),而PA(3/4 μmol/L)与LPS共刺激后显著降低了这些炎症因子及铁蛋白的mRNA及蛋白质表达水平( P<0.01)。分子对接证明PA和铁蛋白存在相互作用位点。 结论 PA能够显著改善脓毒症中的炎症因子释放和组织损伤,其机制可能是通过调控铁蛋白的表达抑制脓毒症中的炎症反应。     

足糖萼蛋白对恶性肿瘤预后的影响及其作用机制

足糖萼蛋白(podocalyxin-like protein,PODXL)是一种细胞表面的跨膜蛋白,其表达与多种恶性肿瘤的预后不良相关,并可以作为上述肿瘤预后的独立预测因子。PODXL的表达在转化生长因子(transforming growth factor,TGF)-β诱导肿瘤细胞EMT的过程中也显著增加。PODXL可以促进多种癌细胞侵袭和迁移,但其在肿瘤发生中的作用机制还不清楚,了解PODXL在肿瘤发生和发展中的作用便于全面分析PODXL在肿瘤中的作用及机制。     

外泌体在脓毒症诊疗作用中的研究进展

脓毒症是一种具有高死亡率的严重感染,严重威胁人们的生命安全。一种特异性生物标志物检测手段用于早期鉴别脓毒症亟待开发。外泌体是机体内多种细胞分泌的囊泡,其内包含多种蛋白质、脂质和核酸等信息分子,在细胞间通讯起重要作用,可调节多种病理生理过程。脓毒症期间多个器官组织释放多种外泌体,并对多个器官产生关键影响。大量研究表明,外泌体和脓毒症的发展密切相关,特别是外泌体应用于脓毒症的诊断及临床治疗中初现效果。本文简要阐述外泌体的特性、外泌体在血浆及脓毒症中的作用、外泌体临床诊断及治疗潜能以及存在的问题和应用前景。     

内毒素中和蛋白及其在脓毒症防治中的作用

来源于体内诱导的实质细胞、中性粒细胞以及天然组织细胞的几种重要的内毒素中和蛋白(ENP)及其衍生肽可特异地结合或中和细菌内毒素(LPS),从而显示出它们对革兰氏阴性细菌感染和脓毒症防治具有潜在的作用.本文就近年来有关ENP中主要成员的生物学特性及其LPS拮抗效应作一简要介绍.     

固有免疫中信号转导和转录激活因子在脓毒症中的作用

固有免疫是生物体长期种系进化过程中形成的一系列防御机制.其可对侵入的病原体迅速产生应答,发挥非特异抗感染免疫作用.在固有免疫中,白细胞的募集和激活是很有必要的,可被各种化学介质调控,这其中就包括细胞因子.研究表明,信号转导和转录激活因子(STAT)蛋白在脓毒症期间大鼠的固有免疫中起着重要作用,并且不同的细胞因子活化的STAT不同.STAT1、STAT3、STAT4和STAT6可以分别介导IFN-γ、IL-10、IL-12和IL-13信号.细胞因子信号转导抑制因子(SOCS)是对细胞因子应答而迅速被诱导的蛋白质家族,可以通过JAK/STAT信号途径减弱细胞因子的信号传导,由此将为治疗脓毒血症提供了理论依据.     

脓毒症中免疫负调控途径的研究进展

传统观念认为脓毒症(sepsis)是一种失控的、持久性全身炎症反应.目前,人们渐渐认识到,在脓毒症的发病过程中机体并非处于一成不变的免疫激活状态,负向调控机制在脓毒症的发生与发展中也发挥着重要作用.在脓毒症的初始阶段,以大量的促炎介质释放为主要特征,但随着病程的进展,机体可能经历了一个免疫负调控阶段,表现为淋巴细胞增殖能力下降,并呈现以辅助性T细胞(helper T-cell,Th)2为主的免疫反应和大量淋巴细胞凋亡等,从而使机体对病原体的易感性增加.     

细胞因子风暴在脓毒症中的研究进展

脓毒症(sepsis)病情进展快、死亡率高,是现阶段重症医学领域面临的最常见、最棘手的危急重症之一。随着对脓毒症的不断深入研究,学术界证实细胞因子风暴是脓毒症患者宿主免疫反应失调紊乱继而导致多器官功能衰竭的最重要因素。文章对脓毒症中相关细胞因子及其损伤机制、细胞因子风暴的治疗策略等方面的最新研究进展进行综述,旨在为脓毒症中细胞因子风暴的临床防治及研究提供借鉴与参考。     

带糖萼层的大分子跨动脉壁传质模型研究

目的 通过研究复杂血管内的糖萼层、高血压等因素对大分子跨血管壁传输的影响,为进一步认识动脉粥样硬化的成因提供了理论依据。方法 考虑动脉壁的生理结构：内皮、内膜、内膜弹性层、中膜和糖萼层,建立了动脉壁中大分子跨壁传质的5层多孔介质模型。假设动脉为一段轴对称长直圆管,血浆为牛顿流体,用解析法得到稳态流动下的动脉壁内血浆渗流速度和大分子浓度分布。结果 糖萼层的厚度对血浆渗流速度的影响几乎可以忽略。糖萼层的厚度越大,对大分子传质的阻碍作用越明显。糖萼层的存在降低了高血压对大分子传质的影响。结论 糖萼层对大分子跨壁传质有很大的阻碍作用,即使在高血压情况下,内膜层大分子浓度的增幅也非常小。因此,糖萼层的存在能有效降低因高血压引起的大分子跨血管过度传输。     

血管内皮糖萼在炎症中的作用

血管内皮糖萼是血管内皮细胞腔侧面的多糖蛋白复合物层.在生理状态下,其主要功能是调节血管内皮通透性及血细胞与内皮细胞间相互作用,介导血流剪切力诱导一氧化氮的释放等.炎症条件下,多种炎症介质导致血管内皮糖萼脱落,削弱了其血管保护功能;同时血管内皮糖萼的组分硫酸乙酰肝素可调控炎症发展,包括作为L-选择素的配体调节白细胞的滚动,形成趋化因子浓度梯度调节白细胞在血管腔侧面的移行及其与内皮细胞的紧密黏附,调控趋化因子由组织向血管腔的转运等.动脉粥样硬化作为一种炎症性疾病,其多种危险因子与血管内皮糖萼联系密切.综述了血管内皮糖萼在炎症和动脉粥样硬化中的作用.     

胆碱能抗炎通路的机制及其在脓毒症的应用

胆碱能抗炎通路是近年来发现的对全身性炎症反应有调节作用的通路,可通过迷走神经抑制促炎细胞因子的合成从而抑制机体炎症反应.核因子-κB和Janus激酶/信号转导与转录激活子是该通路细胞内信号转导中最重要的两条信号通路.脓毒症以全身炎症反应为特点,是危重症患者的常见死因.根据胆碱能抗炎通路作用迅速有效的特点,推测其可应用于...     

Modulation of inflammatory response in sepsis by proteasome inhibition

The Ubiquitin-proteasome system has recently been shown to be involved in the regulation of cytokine expression. We tested the hypothesis of whether the in vivo administration of proteasome inhibitor MG-132 can modulate cytokine response and mortality in sepsis. Sepsis was induced in mice by caecal ligation and puncture (CLP). Animals were divided into four groups: control, CLP, CLP and 1 microg MG-132/g of b.w. intraperitoneally, and CLP and 10 microg MG-132/g of b.w. Plasma levels of interleukin (IL)-1, tumour necrosis factor-alpha (TNF-alpha, IL-6 and IL-10 were determined by ELISA 6 h after the induction of sepsis. CLP induced significant increase in plasma levels of all measured cytokines. MG-132 treatment resulted in lower increase in IL-1, TNF-alpha and IL-10 levels. IL-6 was not significantly affected. A mortality study revealed prolonged survival in MG-132 treated mice. We conclude that MG-132 treatment decreases inflammatory response and prolongs survival in the CLP model of sepsis.     

Recurrent late-onset sepsis in the neonatal intensive care unit: incidence,clinical characteristics and risk factors

We aimed to characterize the incidence, clinical features, risk factors and outcomes of recurrent late-onset sepsis (LOS) in the neonatal intensive care unit (NICU). All neonates with LOS from the NICU of a tertiary-level teaching hospital in northern Taiwan between 2004 and 2011 were enrolled for analyses. A case-control study was performed to determine risk factors for recurrence. Of 713 neonates with LOS, 150 (21.0%) experienced recurrence and 48 (6.7%) had >1 recurrences; c. two-thirds of recurrent LOS occurred in infants with birth weight (BW) ≦ 1500 g or gestational age (GA) ≦ 30 weeks. The recurrent LOS episodes were significantly more severe and had a higher sepsis-attributable mortality rate than the first episodes. The overall in-hospital mortality rate was 30.7% for neonates with recurrent LOS and 7.8% for those with single LOS (odds ratio (OR), 5.22; 95% CI, 3.28–8.30). When both BW and GA were controlled, neonates with recurrent LOS had a significantly prolonged hospitalization compared with the controls (median 109 vs. 84 days, p <0.001). After multivariate logistic regression, longer duration of total parenteral nutrition (TPN; OR, 1.30; 95% CI, 1.10–1.52 for every 10-day increment), presence of congenital anomalies (OR, 2.64; 95% CI, 1.10–6.35) and neurological co-morbidities (OR, 4.14; 95% CI, 1.14–15.10) were identified as the independent risk factors for LOS recurrence. We concluded that c. one-fifth of neonates with LOS had recurrence, which significantly resulted in prolonged hospitalization and increased mortality. Longer TPN administration, presence of congenital anomalies and neurological co-morbidities are independently associated with recurrent LOS.     

Significance of serum procalcitonin in sepsis

Context:

Rapid treatment of sepsis is of crucial importance for survival of patients. Specific and rapid markers of bacterial infection have been sought for early diagnosis of sepsis. One such measurement, Procalcitonin (PCT), has recently become of interest as a possible marker of the systemic inflammatory response to infection.

Aims:

This study was done to find out the common sources of sepsis and to evaluate the diagnostic value of PCT, its predictive value and its relation with Sepsis-related Organ Failure Assessment (SOFA) scores and mortality in various stages of sepsis.

Settings and Design:

The prospective study was conducted at our tertiary care center from October 2006 to December 2008. A total of 100 patients were included in the study. The study sample included all patients aged above 18 years presenting consecutively to our center during the study period with acute sepsis. They were divided into three groups: sepsis, severe sepsis and septic shockbased on standardized criteria.

Materials and Methods:

PCT and various other relevant factors were measured in all study subjects. These parameters were compared among the three study groups. The statistical analyses were done using Student “t” test and two-way analysis of variance (ANOVA).

Results:

Respiratory tract infection was the most common source of sepsis. PCT proved to be an excellent indicator of sepsis with sensitivity of 94%. There was a significant association between serum PCT and SOFA scores (P < 0.05). Serum PCT levels did not predict mortality in the present study.

Conclusions:

PCT is among the most promising sepsis markers, capable of complementing clinical signs and routine lab parameters suggestive of severe infection.     

Toll-like receptor signaling in neonatal sepsis and inflammation: a matter of orchestration and conditioning

Altered neonatal Toll-like receptor (TLR) function is hypothesized to contribute to the heightened susceptibility to infection and perpetuated inflammation in term and preterm neonates, clinically evident in neonatal sepsis and increased rates of inflammatory disorders. Current data indicate that basal TLR expression in term neonates equals adult expression patterns, while expression in preterm infants seems to increase, depending on gestational age. Regarding TLR signaling, some studies suggest TLR incompetence in neonates associated with impaired pro-inflammatory responses, others describe neonatal TLR function well developed and allude to its hyper-inflammation tendency. We discuss the competing positions and considerable limitations of research approaches and conclude that neonatal innate immunity is not generally less able to respond to TLR stimulation. Moreover, we describe pre-conditioning factors other than immaturity having a comparable impact. In the long term, better understanding of the complex interplay of pre- and postnatal conditions and maturation-dependent neonatal TLR function may provide new therapeutic approaches.     

Effect of severe sepsis on platelet count and their indices

Background

Sepsis is a major disease affecting almost all organs and systems.

Objectives

To examine platelet count and indices (mean platelet volume (MPV) and platelet distribution width (PDW)) in severe sepsis.

Methods

Patients with criteria for sepsis at a first examination by an Infectious Diseases specialist were selected. Consecutive patients who were admitted to the out-patient clinic and who were not diagnosed with any infectious disease were selected as the control group.

Results

A total of 145 patients with sepsis and 143 patients as a control group were included in the study. MPV and PDW were significantly differentbetween sepsis patients and control group (P<0.05). Platelet count in sepsis patients was lower than control group but the difference was not significant. PDW was the unique significantly different parameter between survivors and non-survivors (p=0.001).

Conclusion

Platelet indices are important laboratory findings in the diagnosis of sepsis and severe sepsis. Severe sepsis patients who have greater than 18 % PDW levels have a higher risk of death. Therefore, PDW, which is part of an inexpensive, easily accessible and routinely performed test for almost all patients admitted to health facilities may be used for predicting mortality.