微小RNA与脓毒症发病机制研究进展

脓毒症是因感染所致的机体炎症反应失调而引起危及生命的器官功能障碍[1-2].脓毒症严重时可并发多器官功能障碍综合征( multiple organ dys-function syndrome,MODS) ,是危重症患者主要死亡原因之一.脓毒症的发病率呈逐年上升趋势,病死率为22％ ～55％ [3-4].脓毒症发病机制复杂,是多种因素相互作用的结果,主要包括肠道细菌/内毒素移位、受体与信号转导、炎症平衡失调与免疫麻痹、凝血功能障碍等.多种细胞因子、炎症介质抑制剂在动物实验研究中取得一定进展,但其临床应用的疗效仍需进一步研究证实.研究报道,微小RNA( microRNA,miRNA)可通过调控脓毒症患者炎症反应参与多器官功能损害,在脓毒症发生、发展过程中发挥重要作用[5-7].了解miRNA 对脓毒症的精细调控机制,有助于诊断脓毒症及研制特效的靶向药物,改善患者预后.本研究对 miRNA 与脓毒症发病机制研究进展作一综述,现报道如下.     

促血管生成素（Ang）——一种新的脓毒症血清标志物北大核心CSCD

脓毒症（sepsis）是指由感染引起的全身炎症反应综合征,病情凶险,病死率高.目前,脓毒症的全球病死率高达30％～70％,脓毒症的高发病率与病死率逐渐成为威胁人民健康的全球性问题之一.最新美国国家卫生研究院资料显示,在美国ICU每年大约有70万至90万脓毒症患者入院,其中大约有20万患者死于脓毒症.目前脓毒症确切的发病机制尚未完全阐明,有大量的研究表明,细菌内毒素、失控的炎症反应、凝血功能紊乱、免疫功能紊乱、细胞凋亡、血管内皮细胞功能障碍、高代谢状态、基因多态性等因素与其发病机制均密切相关.     

转化生长因子TGF-β及TGF-β/smad信号通路与脓毒症的研究进展

脓毒症是感染导致炎症反应失控的紊乱状态,其病情发展迅速,病死率高.据报道,美国每年约有75万例重症脓毒症患者,其中2115万例死于脓毒症相关器官功能不全,已超过了急性心梗的病死率而成为良性疾病的主要死因[1].目前脓毒症尚缺乏确切的治疗手段,成为危重病医学面临的一大难题.TGF-β作为多功能细胞因子,它和其胞内TGF-β/smad信号传导通路参与脓毒症的发病并发挥重要免疫调节作用.现将TGF-β及其下游信号通路与脓毒症的关系,及可能参与脓毒症发病的受体机制等方面的国内外研究和前景,综述如下.     

参与脓毒症调控的信号通路的研究进展

脓毒症是外科重症监护病房（ICU）患者死亡的原因之一,其因高患病率、高死亡率、高费用,而且缺乏有效的针对性治疗策略,成为威胁人类健康的重要疾病之一。脓毒症的发生发展与促炎和抗炎反应失衡密切相关,但是具体调控机制尚不清楚。因此全面了解脓毒症患者炎症反应的发生机制,参与炎症反应细胞的各种重要的信号转导通路[核因子-κB通路、丝裂原激活的蛋白激酶（MAPK）通路、酪氨酸激酶-信号转导和转录激活子（JAK-STAT）通路、磷脂酰肌醇3激酶/丝苏氨酸蛋白激酶（PI3K/AKT）通路、糖原合成酶-3（GSK-3）通路、胆碱能抗炎通路（CAP）]和细胞因子的表达,对于找到有效特异性高的脓毒症预防和治疗措施具有重大的意义。本文就目前参与脓毒症反应的各种信号通路以及各信号通路之间交互作用进行综述。     

miR-181在动脉粥样硬化相关血管炎症和免疫调节中的研究进展

动脉粥样硬化(atherosclerosis,As)是病变从内膜开始的一种慢性炎症性疾病,主要累及全身大中动脉,是危害人类健康的主要疾病之一。近年来,研究发现微小核糖核酸(microRNAs,miRNAs)参与As的发生、发展。其中,miR-181家族通过调控血管炎症和免疫相关的信号通路在As发生、发展中起着重要作用,如调控下游NF-κB信号通路、内皮细胞激活相关靶点的表达和免疫细胞稳态等。该文就近年来miR-181在As相关炎症和免疫反应的研究进展作一综述。     

Toll样受体在慢性阻塞性肺疾病发病机制中的作用

慢性阻塞性肺疾病(COPD)是一种以气道炎症为主要标志的慢性呼吸系统疾病。而COPD气道炎症的启动、激发和炎性信号级联放大机制尚不甚明了。近年来研究表明模式识别受体(PRRs)在COPD慢性炎症的启动和维持过程中扮演着重要角色。其中,尤以Toll样受体(TLRs)与COPD发病关系最为密切。吸烟、有害气体、微生物及损伤相关分子模式(DAMPs)与TLRs相互作用,通过NF-κB信号转导通路完成跨膜信号转导,最终调节炎症基因的转录和翻译,产生大量炎症介质并趋化大量炎症细胞参与气道炎症反应的启动及维持。本文结合近年来国内外的最新相关研究成果,对TLRs及下游信号转导通路在COPD发病机制中的重要作用综述如下。     

提高对脓毒症免疫血栓发生机制和干预策略的认识

脓毒症是由于感染引起机体宿主反应失调, 最终导致多脏器功能障碍的临床综合征, 是当今重症监护病房(ICU)患者的主要死亡原因之一。据统计, 2017年全球脓毒症患者病死率已达到22.5%, 约占全球总死亡患者的五分之一[1]。脓毒症发病机制复杂, 主要涉及过度炎症反应、免疫功能紊乱、凝血功能障碍等, 多系统功能失调相互影响、相互促进, 通过网络状效应加剧脓毒症的恶性发展[2]。免疫应答与凝血系统相互作用失调时, 易导致多级血管中形成微小的免疫血栓(immunothrombosis), 是诱发弥散性血管内凝血(DIC)和多器官衰竭的主要原因。临床资料显示, 30%～50%的脓毒症患者会发生DIC, 其病死率高达28%～43%[3]。因此, 免疫血栓发病本质和干预途径问题日益受到关注与重视, 已成为脓毒症研究的重要领域之一。     

TOLL样受体在急性肺损伤发病机制中的研究进展

急性肺损伤 (ALI)是各种肺内外致病因素导致的以顽固性的低氧血症和呼吸窘迫为突出表现的全身炎症反应综合征。由于发病机制尚不完全明确 ,同时缺乏有效的治疗手段 ,因此 ,发病率和病死率仍居高不下。TOLL样受体 (Toll -likereceptors ,TLRs)是新近发现的天然免疫中细胞跨膜受体及病原模式识别受体 (PRRs)之一 ,在急性炎症反应调节中发挥着重要的作用。近几年来对TLRs与天然免疫之间的联系及其信号转导研究比较多 ,而在TLRs与ALI相互影响方面较少涉及。现就TLRs(主要是TLR2、TLR4 )在ALI发病机制中的研究进展简要综述如下。1…     

蛋白C通路在严重脓毒症炎症-凝血交叉对话中的作用及临床对策

脓毒症和脓毒性休克在国际范围内至今仍处于高发病率、高病死率状态.对其发病机理的进一步研究发现,重症患者炎症和凝血系统之间广泛的交叉对话导致病情恶性进展.目前研究的热点在于探讨机体应答反应的分子机制,发现蛋白C(PC)通路在其中发挥关键作用.重组人活化蛋白C(rhAPC)已获准用于严重脓毒症的临床治疗.本文就近年来有关蛋白C通路在脓毒症炎症-凝血交叉对话中的作用机制,以及rhAPC在严重脓毒症中应用的临床研究结果与争议做一综述.     

胆碱能抗炎通路与脓毒症发病机制的研究进展

脓毒症是由感染引起的全身炎症反应综合征,持续的炎症反应常导致多器官功能障碍、脓毒性休克,是现代危重病研究领域的热点及难点,患病率及病死率高,其发病机制复杂,迄今有效的治疗措施不多。研究发现,胆碱能抗炎通路主要通过迷走神经和烟碱型乙酰胆碱受体a7亚基（a7nAChR）及多个信号转导通路反馈地调控炎症反应,从而减轻机体炎症损害。因此,研究胆碱能抗炎通路与脓毒症发病机制的关系,有利于从本质上把握脓毒症,为临床治疗脓毒症提供新的策略,现将其研究进展综述如下。     

Role of Toll-like receptors in the development of sepsis

The outcome of sepsis and septic shock has not significantly improved in recent decades despite the development of numerous drugs and supportive care therapies. To reduce sepsis-related mortality, a better understanding of molecular mechanism(s) associated with the development of sepsis and sepsis-related organ injury is essential. There is increasing evidence that Toll-like receptors (TLRs) play a key role in the mediation of systemic responses to invading pathogens during sepsis. However, the role of TLRs in the development of sepsis and in sepsis-related organ injury remains debatable. In this review, we focus on the biological significance of TLRs during sepsis. Medline was searched for pertinent publications relating to TLRs, with emphasis on their clinical and pathophysiological importance in sepsis. In addition, a summary of the authors' own experimental data from this field was set in the context of current knowledge regarding TLRs. In both animal models and human sepsis, TLRs are highly expressed on monocytes/macrophages, and this TLR expression may not simply be a ligand-specific response in such an environment. The fact that TLR signaling enables TLRs to recognize harmful mediators induced by invading pathogens may be associated with a positive feedback loop for the inflammatory response among different cell populations. This mechanism(s) may contribute to the organ dysfunction and mortality that occurs in sepsis. A better understanding of TLR biology may unveil novel therapeutic approaches for sepsis.     

The Sepsis Six: helping patients to survive sepsis

Sepsis kills more people than lung cancer, and more people than bowel and breast cancer put together. The costs to the NHS are significant; it is estimated that in Europe, patients with severe sepsis cost healthcare funders around 7.6 billion euros per year (Daniels et al, 2007). Costs in the United States are estimated at $16 billion annually (Angus et al, 2001), and in the United Kingdom up to 46% of intensive care unit (ICU) bed days are used by patients with severe sepsis (Padkin et al, 2003), with each ICU bed costing around pounds sterling1700 per day. In 2002 an international campaign was launched: the Surviving Sepsis Campaign. The main aim of this campaign is to reduce mortality from sepsis by 25% by 2009. A lot of the early work has concentrated on improving sepsis care in intensive care units, but many patients on general wards develop sepsis, and the need to educate nurses throughout all areas of the hospital has been recognized. In September 2007 a new part of the campaign was launched called Survive Sepsis, which aims to deliver sepsis education to ward nurses and junior doctors. This article discusses how to recognize severe sepsis and explains how nurses can dramatically improve a patient's chance of survival by ensuring that six simple things (Sepsis Six) are done in the first hour.     

Epidemiologic features,risk factors,and outcome of sepsis in stroke patients treated on a neurologic intensive care unit

Purpose

Because of the immune-suppressive effect of cerebral damage, stroke patients are at high risk for infections. These might result in sepsis, which is the major contributor to intensive care unit (ICU) mortality. Although there are numerous studies on infections in stroke patients, the role of sepsis as a poststroke complication is unknown.

Methods

We retrospectively analyzed incidence of and risk factors for sepsis acquisition as well as outcome parameters of 238 patients with ischemic or hemorrhagic strokes consecutively admitted to the neurologic ICU in a tertiary university hospital between January 1, 2009, and December 31, 2010. Basic demographic and clinical data including microbiological parameters as well as factors describing stroke severity (eg, lesion volume and National Institute of Health stroke scale score) were recorded and included into the analysis. The diagnosis of sepsis was based on the criteria of the German Sepsis Society.

Results

We identified 30 patients (12.6%) with sepsis within the first 7 days from stroke onset. The lungs were the most frequent source of infection (93.3%), and gram-positive organisms were dominating the microbiologic spectrum (52.4%). Comorbidities (chronic obstructive pulmonary disease and immunosuppressive disorders) and Simplified Acute Physiology Score II but none of the factors describing stroke severity were independent predictors of sepsis acquisition. Sepsis was associated with a significantly worse prognosis, leading to a 2-fold increased mortality rate during in-hospital care (36.7% vs 18.8%) and after 3 months (56.5% vs 28.5%), but only in the subgroup of supratentorial hemorrhages, it was an independent predictor of in-hospital and 3-month mortality. Other factors significantly associated with death in a multivariate analysis were chronic obstructive pulmonary disease, malignancies (in-hospital mortality only), and Simplified Acute Physiology Score II (3-month mortality only) for ischemia and heart failure (in-hospital mortality only), National Institute of Health stroke scale score (in-hospital mortality only), and stroke volume for hemorrhages, respectively.

Conclusions

Sepsis seems to be a frequent complication of stroke patients requiring neurologic ICU treatment. Predictors of sepsis acquisition in our study were comorbidities and severity of deterioration of physiological status, but not stroke severity. A better understanding of risk factors is important for prevention and early recognition, whereas knowledge of outcome may help in prognosis prediction. Further studies are needed to clarify the optimal preventive treatment for these patients.     

-正方观点-全身性感染新定义：有助于ICU外的医护人员快速筛选出脓毒症患者

1992年共识会,定义脓毒症为当患者符合两个全身性发炎反应综合征（systemic inflammatory response syndrome,SIRS）且怀疑这些症状是因为感染所造成。2016年第三次国际脓毒症既脓毒症休克共识会,定义脓毒症为宿主对感染的失调反应导致危及生命的器官功能障碍,诊断脓毒症的临床条件为当患者在怀疑或确定感染的前提下,器官衰竭评估分数（sequential organ failure assessment,SOFA）急速增加超过2分。定义脓毒性休克为一部分脓毒症的患者,出现严重的循环障碍及细胞代谢异常,导致病死率显著增加,诊断标准为脓毒症患者,在充分补充血容量后,仍需要升压药物以维持平均动脉压≥65 mmHg（1 mmHg=0.133 kPa）且血清乳酸水平＞2 mmol/L。并提出快速器官衰竭评估（quick SOFA,qSOFA）即神志改变,收缩压≤100 mmHg,或呼吸频率≥ 22次/min,患者符合两个qSOFA条件时,即应怀疑脓毒症进入重症病房观察。作为一个医院管理者及脓毒症流行学者,新版定义为在ICU外的医护人员提供一个简洁的方法,快速筛选出脓毒症患者,进行积极治疗,增进照顾质量,新版定义除了专家意见外,运用流行病学的方法,以患者是否死亡或需要＞ 3 d ICU治疗作为结果指标,测试新定义的效度,新定义在预测死亡能力比SIRS高。在进行临床试验及流行病调查时,使用新版的脓毒症定义与我们最关心的终点——病死率有较好的相关,同时避免脓毒症与严重脓毒症定义不同所造成的混淆。     

目标性体温管理在脓毒症患者临床应用价值的研究进展

脓毒症是 ICU 患者的常见症之一,可以导致较高的病死率。一些动物实验及临床研究显示目标性体温管理对脓毒症各脏器功能具有保护作用,但是在脓毒症中体温管理的最佳时机、持续时间、干预措施、目标温度等仍存在较大争议,脓毒症患者能否从体温管理的临床上获益仍值得进一步研究,本文就近期脓毒症体温管理的研究进展作一综述。     

PD-1/PD-L1在脓毒症免疫抑制中的潜在作用

脓毒症是宿主对炎症反应失调引起的危及生命的器官功能障碍[1].免疫抑制在脓毒症发展过程中发挥重要作用,它是导致脓毒症患者二次感染及病死率居高不下的重要原因[2],其主要表现为免疫细胞活性降低、数量减少.程序性细胞死亡受体-l(programmed cell deathprotein 1,PD-1)/程序性细胞死亡配体-1(programmed cell death-ligand 1,PD-L1)通过负向调节免疫细胞,从而引起免疫抑制,对脓毒症患者免疫功能及预后产生重要影响.本文就脓毒症免疫抑制机制及PD-1/PD-L1在其中的潜在作用做一简要综述.     

血小板在脓毒症中的关键作用

脓毒症是危重症患者死亡的主要原因之一,由宿主对入侵病原体的有害反应引起的。脓毒症主要涉及炎症反应和凝血激活两个关键的机制,近年来研究发现血小板不仅在止血和伤口愈合方面发挥着作用,也在固有性免疫和适应性免疫方面发挥着重要的作用,同时,还是局部和全身炎症反应的促进者、组织器官损伤的参与者,血小板的这些功能使其在脓毒症的发生发展中发挥了关键的作用。     

脓毒症氧化应激与抗氧化治疗研究进展

脓毒症(sepsis)是感染引起的全身炎性反应综合征,是急危重患者的严重并发症之一。氧化应激是机体活性氧簇和活性氮簇产生过多或清除能力下降,导致潜在性损伤的病理过程。氧化应激在脓毒症发生、发展中发挥重要作用,早期进行抗氧化干预可能有益于脓毒症防治。丙酮酸乙酯(ethyl pyruvate,EP)是一种稳定的丙酮酸酯类衍生物,它对于发生急性损伤的器官具有显著的保护作用。本文就脓毒症氧化应激与丙酮酸乙酯抗氧化治疗的最新进展作一综述。