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.     

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.     

眼镜蛇毒因子抑制脓毒症大鼠的炎症反应

目的观察补体抑制剂眼镜蛇毒因子（CVF）对脓毒症大鼠血清细胞因子释放的影响及对肺组织的保护作用。方法144只清洁雄性SD大鼠（体重250～300g）随机分为A、B、C3组,每组48只。A组假手术组,B组（脓毒症组）采用盲肠结扎穿孔术（CLP）复制脓毒症大鼠模型,C组（CVF组）在盲肠结扎穿孔术前24h按50μg/kg注射CVF,A和B组给予等量生理盐水。于术后6个时间点分别采用放射免疫分析法和酶联免疫吸附法检测血清TNF-α、IL-6和IL-10水平,肺组织MPO含量及病理学改变。结果B组大鼠脓毒症反应最强,A组表现轻微;B组TNF-α及IL-6水平均明显高于A组（P〈0.05,P〈0.01）;B组除2h点外,肺组织MPO水平显著高于A组（P〈0.05,P〈0.01）;B组肺组织损伤最严重;C组经CVF干预后脓毒症反应及肺组织损伤较B组明显减轻,TNF-α、IL-6及MPO水平均较B组明显下降（P〈0.05,P〈0.01）。结论补体抑制剂CVF可减轻脓毒症大鼠的炎症反应,具有肺保护作用。     

干细胞移植治疗脓毒症的研究进展

脓毒症是以全身炎症反应综合征为表现的一组临床综合征,现有的治疗方法不能取得满意的疗效,死亡率仍然居高不下.研究证实,骨髓间充质干细胞(MSCs)具有再生修复功能和强大的免疫调节以及抗炎功能.借此干细胞移植能从整体上调节宿主免疫和炎症反应,同时还能修复受损的组织和器官,有望成为脓毒症救治的新希望.     

脓毒症中骨髓来源的抑制细胞的研究进展

骨髓来源的抑制细胞是由一群同时表达表面分子GR-1和CD11b的非成熟骨髓细胞组成,对天然免疫和获得性免疫具有显著抑制作用。尽管骨髓来源的抑制细胞最早出现在肿瘤研究中,然而已有大量研究显示它与创伤、炎症、自身免疫性疾病以及脓毒症有密切关系。本文就目前骨髓来源的抑制细胞在脓毒症中作用的研究进展及其用于脓毒症治疗的前景进行论述。     

衰老引发的糖萼损伤与血管功能障碍

血管内皮糖萼(endothelial glycocalyx, EG)是位于血管内表面的一层多糖蛋白复合结构,其损伤与动脉粥样硬化、中风、脓毒症、糖尿病、肾脏疾病、高血压、肺水肿等诸多疾病存在关联。基于此,糖萼的健康程度已被列为评估血管健康的重要指标。研究表明,衰老会伴随糖萼发生退行性改变,体现在其厚度变薄、合成及降解相关酶基因水平的失调等方面。作为血管的天然保护性屏障,衰老引发的糖萼损伤与血管舒缩功能受损、通透性增大、炎症及免疫反应失调、凝血/抗凝功能失衡等存在关联。从“结构决定功能”角度出发,开展衰老过程中糖萼厚度、成分、微观结构、力学特性等变化规律及其与血管功能障碍的相关性研究,对于预防、诊断、治疗动脉粥样硬化等年龄相关性心血管疾病具有重要意义。     

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.     

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.     

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...     

Translocation of gut flora and its role in sepsis

Bacterial translocation is the invasion of indigenous intestinal bacteria through the gut mucosa to normally sterile tissues and the internal organs. Sometimes instead of bacteria, inflammatory compounds are responsible for clinical symptoms as in systemic inflammatory response syndrome (SIRS). The difference between sepsis and SIRS is that pathogenic bacteria are isolated from patients with sepsis but not with those of SIRS. Bacterial translocation occurs more frequently in patients with intestinal obstruction and in immunocompromised patients and is the cause of subsequent sepsis. Factors that can trigger bacterial translocation from the gut are host immune deficiencies and immunosuppression, disturbances in normal ecological balance of gut, mucosal barrier permeability, obstructive jaundice, stress, etc. Bacterial translocation occurs through the transcellular and the paracellular pathways and can be measured both directly by culture of mesenteric lymph nodes and indirectly by using labeled bacteria, peripheral blood culture, detection of microbial DNA or endotoxin and urinary excretion of non-metabolisable sugars. Bacterial translocation may be a normal phenomenon occurring on frequent basis in healthy individuals without any deleterious consequences. But when the immune system is challenged extensively, it breaks down and results in septic complications at different sites away from the main focus. The factors released from the gut and carried in the mesenteric lymphatics but not in the portal blood are enough to cause multi-organ failure. Thus, bacterial translocation may be a promoter of sepsis but not the initiator. This paper reviews literature on the translocation of gut flora and its role in causing sepsis.     

Expression of CD11c and EMR2 on neutrophils: potential diagnostic biomarkers for sepsis and systemic inflammation

There is a need for cellular biomarkers to differentiate patients with sepsis from those with the non‐infectious systemic inflammatory response syndrome (SIRS). In this double‐blind study we determined whether the expression of known (CD11a/b/c, CD62L) and putative adhesion molecules [CD64, CD97 and epidermal growth factor (EGF)‐like molecule containing mucin‐like hormone receptor (EMR2)] on blood neutrophils could serve as useful biomarkers of infection and of non‐infectious SIRS in critically ill patients. We studied 103 patients with SIRS, 83 of whom had sepsis, and 50 healthy normal subjects, using flow cytometry to characterize neutrophils phenotypically in whole blood samples. Patients with SIRS had an increased prevalence of neutrophils expressing CD11c, CD64 and EMR2 in comparison with healthy subjects (P < 0·001), but normal expression of CD11a, CD11b, CD62L and CD97. An increase in the percentage of neutrophils bearing CD11c was associated with sepsis, EMR2 with SIRS and CD64 with sepsis and SIRS. Neutrophils expressing CD11c had the highest sensitivity (81%) and specificity (80%) for the detection of sepsis, and there was an association between the percentage of neutrophils expressing EMR2 and the extent of organ failure (P < 0·05). Contrary to other reports, we did not observe an abnormal expression of CD11b or CD62L on neutrophils from patients with SIRS, and suggest that this discrepancy is due to differences in cell processing protocols. We propose that blood neutrophils expressing CD11c and EMR2 be considered as potential biomarkers for sepsis and SIRS, respectively.     

Plasma PTX3, MCP1 and Ang2 are early biomarkers to evaluate the severity of sepsis and septic shock

Sepsis is associated with significant mortality. Early diagnosis and prognosis of patients with sepsis is still a difficult clinical challenge. In this study, the ability of plasma PTX3 (pentraxin 3), MCP1 (monocyte chemoattractant protein 1) and Ang (angiopoietin)1/2 was investigated to evaluate the severity of sepsis. Blood samples were obtained from 43 patients with sepsis. A total of 33 post‐surgery patients with infections and 25 healthy individuals served as controls. The results showed that plasma PTX3, MCP1 and Ang2 significantly increased in patients on the first day of septic shock onset, while sepsis patients had significantly higher Ang2 level, compared with controls. Furthermore, PTX3, MCP1 and Ang2 had high AUROC values in patients with septic shock on the first day of sepsis onset. The findings suggest that PTX3, MCP1 and Ang2 maybe early predictors to evaluate the severity of sepsis and septic shock with the latest Sepsis 3.0 definitions.     

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.