高迁移率族蛋白B1与相关病理妊娠的研究进展

高迁移率族蛋白B1（HMGBI）是一种传统的DNA结合蛋白,是强大的致炎细胞因子,存在于多种真核细胞的细胞核中,HMGB1可由单核／巨噬细胞等固有免疫细胞在致炎细胞因子刺激下主动分泌,也可由坏死细胞被动释放,该分子除了参与核小体的构建、稳定、调节基因的转录外,还可刺激炎性细胞活化并向炎症部位聚集,促进炎性细胞因子分泌造成组织损伤。HMGB1参与妊娠,若其表达异常,将引发妊娠期高血压疾病、流产、胎膜早破等妊娠相关疾病。     

The cytokine activity of HMGB1--extracellular escape of the nuclear protein

High mobility group box 1 (HMGB1), a mobile chromatin protein, passively leaks from necrotic cells and signals neighboring cells that tissue damage has occurred. Resting, non-activated inflammatory cells such as monocytes or macrophages contain HMGB1 in the nuclear compartment. When activated by lipopolysaccharide or inflammatory cytokines, they actively translocate the nuclear HMGB1 into the cytoplasm; HMGB1 is then exocytosed. At least one receptor for extracellular HMGB1 has been identified. HMGB1 acts as a mediator of systematic inflammation; it causes different cells to divide, migrate or elicit an immune response. Here, we give an abridged review of the cytokine activity of HMGB1, including its secretion mechanism, the putative signal transduction pathways, and its role in several inflammatory diseases. Finally, we cite a few examples in which therapeutic administration of HMGB1 antagonists rescued mice from lethal sepsis, arthritis and liver damage. The new findings of HMGB1 as a cytokine provide a better understanding of inflammatory diseases, establishing a clinically relevant therapeutic target that is significantly more efficient than other known cytokines.     

高迁移率族蛋白1和风湿免疫性疾病

目的:高迁移率族蛋白1(HMGB1)是细胞核内典型的非组蛋白。受到炎症刺激的单核巨嗜细胞能主动释放HMGB1至细胞外。核外HMGB1是多种急慢性系统性炎症的重要的炎症介质。文中详细介绍了核外HMGB1在关节炎、肌炎、红斑狼疮、干燥综合症等风湿性疾病中的表达情况。HMGB1在风湿免疫性疾病中主要呈核外表达,在单核细胞中表达尤其明显,在炎症细胞渗出明显的部位,有分泌型HMGB1在细胞外基质沉积。同时,在这些部位TNFα和IL-1等细胞因子的表达也升高,提示HMGB1和这些炎症因子之间形成一个炎症环,激发免疫反应并维持慢性炎症过程。HMGB1在风湿性疾病中的研究有助于人们更好地理解这些慢性免疫性炎症,从而找到以其为靶向的有效治疗手段。     

脓毒症时高迁移率族蛋白B1干预策略的研究进展

高迁移率族蛋白B1(HMGB1)作为新的潜在"晚期"炎性介质参与脓毒症的发病过程,在揭示HMGB1作用的分子机制、HMGB1表达、释放规律及药物抑制方面已经取得了一定进展,给临床医师提供了对脓毒症和失控炎性反应实施早期干预的可能。同时,检测血清HMGB1水平也可能成为预测和判断脓毒症患者病情的一种新手段。     

高迁移率族蛋白B1信号转导通路的研究进展

高迁移率族蛋白B1(HMGB1)是一种DNA结合蛋白,在细胞外具有细胞因子功能,可以启动免疫反应,引起细胞炎性效应。HMGB1的识别及跨膜信号转导需要一系列分子的参与,其受体主要是晚期糖基化终产物、Toll样受体等,这一转导过程也是导致脓毒血症等急慢性炎性反应的重要机制。研究HMGB1信号转导通路中的信号传递分子和信号转导调控机制可以为临床治疗寻找"新靶点"。     

HMGB1调控IL-17分泌与中性粒细胞性哮喘的研究进展

哮喘是一种慢性炎症性疾病,根据不同炎症细胞类型分为Th2型和非Th2型。非Th2型哮喘的特征是类固醇激素抵抗,以中性粒细胞性哮喘为主。高迁移率族蛋白1(HMGB1)是一种属于警报素家族的染色质结合蛋白,作为促炎介质参与急性和慢性免疫疾病的发生发展,是非Th2型哮喘生物标志物。本文综述HMGB1调控IL-17分泌与中性粒细胞性哮喘的关系。     

血清高迁移率族蛋白B1与糖尿病肾病病人肾功能、炎症因子及氧化应激指标的相关性研究

目的探讨血清高迁移率族蛋白B1(HMGB1)与糖尿病肾病(DN)病人肾功能、炎症因子及氧化应激指标的相关性。方法117例DN病人根据24 h尿白蛋白定量(24hUPQ)分为微量白蛋白尿组(n=55例)和大量白蛋白尿组(n=62例),同期选择50例单纯2型糖尿病病人作为对照组。检测各组肾功能指标[血清肌酐(SCr)、尿素氮(BUN)、肾小球滤过率(GFR)、胱抑素C(Cys-C)]、炎症因子[血清核因子κB(NF-κB)、肿瘤坏死因子-α(TNF-α)、细胞间黏附分子-1(ICAM-1)、白细胞介素-6(IL-6)]及氧化应激指标[丙二醛(MDA)、晚期氧化蛋白产物(AOPP)、超氧化物歧化醇(SOD) 总抗氧化能力(T-AOC)], 并分析血清HMGB1与肾功能、炎症因子及氧化应激指标的相关性。结果大量白蛋白尿组和微量白蛋白尿组病人血清HMGB1表达水平均高于单纯2型糖尿病组,差异有统计学意义(P < 0.05),而大量白蛋白尿组病人血清HMGB1表达水平高于微量白蛋白尿组,差异有统计学意义(P < 0.05);各组病人SCr、BUN、GFR、Cys-C等肾功能指标比较差异均有统计学意义(P < 0.01),单纯2型糖尿病组、微量白蛋白尿组、大量白蛋白尿组病人SCr、BUN、Cys-C依次逐渐升高,而GFR依次逐渐降低(P < 0.01);各组病人血清NF-κB、TNF-α、ICAM-1、IL-6等炎症因子表达水平比较差异均有统计学意义(P < 0.01),单纯2型糖尿病组、微量白蛋白尿组、大量白蛋白尿组病人血清NF-κB、TNF-α、ICAM-1、IL-6水平依次逐渐升高(P < 0.01);各组病人血清MDA、T-AOC、SOD、AOPP等氧化应激指标比较差异均有统计学意义(P < 0.01),单纯2型糖尿病组、微量白蛋白尿组、大量白蛋白尿组病人血清MDA、AOPP水平依次逐渐升高,而血清T-AOC、SOD水平依次逐渐降低(P < 0.01);血清HMGB1与肾功能、炎症因子及氧化应激指标呈明显的相关性关系(P < 0.05)。结论DN病人血清HMGB1表达水平随病情严重程度加重而明显升高,与肾功能损伤、炎症及氧化应激反应严重程度存在一定相关性。     

他汀类药物对心房颤动的影响

近年来研究发现心房颤动(房颤)与炎症、氧化应激关系密切。他汀类药物除降脂作用外,还可通过抑制炎性反应、抗氧化应激、改善内皮功能、抗血小板聚集及抑制神经激素激活等作用机制使形成房颤的病理基础减少。他汀类药物的"多效性"被越来越多的证据证明具有降低房颤发生率的作用。该文对最近几年国内外这方面的研究进展予以综述。     

晚期糖基化终产物受体在心房颤动患者血清中的表达及意义

目的探讨心房颤动（AF）患者血清高迁移率族蛋白1（HMGB1）、晚期糖基化终产物内源性分泌受体（es-RAGE）及晚期糖基化终产物C端短截受体（cRAGE）水平的变化。方法本研究收集我院连续入院的75例AF患者,另外纳入32例年龄和性别与AF组相匹配的健康查体者作为对照组。采用ELISA法检测两组人群血清HMGB1、cRAGE及esRAGE水平。结果阵发性AF组及持续性AF组HMGB1水平高于对照组（均P〈0.05）;持续性AF组HMGB1水平高于阵发性AF组（P〈0.05）。阵发性AF组及持续性AF组cRAGE水平高于对照组（均P〈0.05）;持续性AF组cRAGE水平高于阵发性AF组（P〈0.05）。阵发性AF组及持续性AF组esRAGE水平低于对照组（均P〈0.05）;持续性AF组esRAGE水平低于阵发性AF组（P〈0.05）。结论本研究显示持续性和阵发性AF患者血清HMGB1和cRAGE水平显著升高,而esRAGE水平显著降低,提示cRAGE和esRAGE可能成为AF的两种新型生物标记物,且可能与HMGB1共同参与了AF发生的病理生理过程。     

高迁移率族蛋白B1在神经系统疾病中的研究进展

高迁移率族蛋白B1是一种在哺乳动物中广泛表达的非组蛋白染色体结合蛋白,并通过晚期糖基化终产物受体和TOLL样受体参与炎症反应过程,而大多数神经系统疾病的发病机制与自身免疫或免疫炎性损伤相关.本文就高迁移率族蛋白B1在神经系统疾病中的研究进展进行综述.     

激活素A与绒毛膜羊膜炎关系研究进展

激活素A是重要的炎性介质。近年研究表明胎膜早破并发绒毛膜羊膜炎时,羊膜、绒毛膜及母体单核巨噬细胞系统在细菌等代谢产物刺激下,可导致激活素A等多种炎性细胞因子的释放,从而启动内源性炎性反应,激活素A作为前炎性因子通过细胞因子网络参与母体炎性反应和免疫防御过程调节,在急性期反应阶段同时具有抗炎和促炎活性。激活素A在血清、羊水中的异常表达对早期预测羊膜腔感染有一定价值。     

高迁移率族蛋白1在高容量血液滤过防治MODS中的变化及意义

目的：通过观察高迁移率族蛋白1（HMGB1）在多脏器功能障碍综合征（MODS）发生过程中的变化趋势，探讨MODS发生机制及高容量血液滤过（HVHF）防治MODS的理论依据。方法：采用失血性休克复苏十内毒素血症复合因素建立猪MODS模型，将19只健康雄性家猪随机分成MODS组和HVHF组，HVHF组动物内毒素注射后予血液滤过，血滤采用F50聚矾膜滤器，超滤量3L／h。Western blot法检测血浆HMGB1蛋白含量变化，并通过与各自基础值的比较，了解HMGB1蛋白相对变化趋势。结果：HVHF组2例发生MODS，占20％（2／10），显著低于MODS组88．9％（8／9）（P〈0．01），主要器官功能明显改善。HMGB1蛋白水平于内毒素注射后1h无明显升高，至24h两组均显著升高，后呈缓慢下降趋势。HVHF组，HMGB1蛋白相对于基础值水平升高幅度明显低于MODS组。结论：HMGB1蛋白等炎症介质的过度表达是MODS发生的本质原因之一；HVHF能够降低血循环中HMGB1等炎症介质的峰值浓度，有效遏制过度的炎症反应，防止MODS发生。     

Probucol attenuates atrial autonomic remodeling in a canine model of atrial fibrillation produced by prolonged atrial pacing

Background We hypothesize that increased atrial oxidative stress and inflammation may play an important role in atrial nerve sprouting and heterogeneous sympathetic hyperinnervation during atrial fibrillation （AF）. To test the hypothesis, we examined whether the antioxidant and anti-inflammatory treatment with probucol attenuates atrial autonomic remodeling in a canine model of AF produced by prolonged rapid right atrial pacing.
Methods Twenty-one dogs were divided into a sham-operated group, a control group and a probucol group. Dogs in the control group and probucol group underwent right atrial pacing at 400 beats per minute for 6 weeks, and those in the probucol group received probucol 1 week before rapid atrial pacing until pacing stopped. After 6-week rapid atrial pacing, general properties including left atrial structure and function, atrial hemodynamics and the inducibility and duration of AF were measured in all the groups. Atrial oxidative stress markers and serum C-reactive protein （CRP） concentration were estimated. The degree of nerve sprouting and sympathetic innervation at the right atrial anterior wall （RAAW） and the left atrial anterior wall （LAAW） were quantified by immunohistochemistry, atrial norepinephrine contents were also detected. Atrial beta-nerve growth factor （beta-NGF） mRNA and protein expression at the RAAW and LAAW were assessed by real-time quantitative RT-PCR and Western blotting respectively.
Results Atrial tachypacing induced significant nerve sprouting and heterogeneous sympathetic hyperinnervation, and the magnitude of nerve sprouting and hyperinnervation was higher in the RAAW than in the LAAW. Atrial beta-NGF mRNA and protein levels were significantly increased at the RAAW and LAAW, and the upregulation of beta-NGF expression was greater at the RAAW than at the LAAW in the control group. The beta-NGF protein level was positively correlated with the density of sympathetic nerves in all groups. Probucol decreased the increase of CRP concentration and attenuated atrial oxidative stress caused by atrial tachypacing. In addition, probucol could effectively inhibit atrial beta-NGF upregulation, significantly attenuate atrial nerve sprouting and heterogeneous sympathetic hyperinnervation, and dramatically reduce the inducibility and duration of AF.
Conclusions The atrial over-expression of beta-NGF possibly caused by increased oxidative stress and inflammation may be the main mechanism underlying atrial autonomic remodeling during AF. Probucol attenuates atrial autonomic remodeling possibly by its antioxidant and anti-inflammatory actions.     

血必净注射液对烫伤大鼠肾组织高迁移率族蛋白B1和急性肾损伤的干预效果

目的探讨烫伤大鼠肾组织高迁移率族蛋白B1(HMGB1)表达的变化规律,并观察血必净注射液(简称血必净)对烫伤大鼠肾脏HMGB1及急性肾损伤的可能干预效果。方法采用大鼠30%总体表面积Ⅲ度烫伤模型,78只动物随机分为假伤组(n=18)、烫伤组(n=30)和血必净组(n=30),分别于伤后8、24、72h活杀取材。采用逆转录聚合酶链反应检测肾组织HMGB1mRNA表达、蛋白免疫印迹及免疫组织化学法检测肾组织HMGB1蛋白表达;同时用全自动生化分析仪测定血清肌酐(Cr)水平,采用苏木素-伊红(HE)染色、光镜下观察肾组织病理改变。结果与假伤组比较,烫伤组肾组织HMGB1基因和蛋白表达于伤后8、24、72h显著增强(P<0.05,P<0.01),血清Cr水平于伤后24、72h显著增高(P<0.05,P<0.01)。给予血必净治疗后24、72h动物肾组织HMGB1基因和蛋白表达均显著抑制(P<0.05,P<0.01),血清Cr水平亦显著降低(P<0.05)。光镜下观察烫伤组肾组织大量炎细胞浸润,其中以24h最重,血必净组24、72h病理形态改变则明显减轻。结论HMGB1作为晚期炎症因子参与严重烫伤后肾脏炎症反应及组织损害的病理生理过程,血必净治疗可显著下调肾组织HMGB1合成与释放,并减轻烫伤所致急性肾损伤。     

高迁移率族蛋白B1在免疫应答中作用的研究进展

高迁移率族蛋白B1(HMGB1)是一种DNA结合蛋白,在细胞外有细胞因子功能,能启动免疫反应,引起细胞炎性效应。生理状态下,HMGB1有核结合蛋白的作用,释放进入细胞间隙后,则表现出晚期炎性因子作用。HMGB1的识别及跨膜信号转导需要一系列分子的参与,其受体主要是晚期糖基化终产物、Toll样受体等。HMGB1作为一个内源性分子,促进免疫反应和组织内稳态。     

Rheumatoid arthritis, cytokines and hypoxia. What is the link?

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder that affects approximately 1% of the population, in a female to male ratio of 3:1. The disease can occur at any age, but it is most common among those aged 40-70 years. Despite many years of study, the etiology of RA is still undefined. However, with increased understanding of the immune system the pathogenesis of RA has become clearer. A large bulk of data suggests that T lymphocytes and macrophages play a critical role in the initiation and perpetuation of synovial inflammation. Recently, the cytokine profile of T helper cells has been associated with the disease, the cytokine repertoire of inflamed synovia is categorized as that of T helper 1 response. Moreover, in RA elevated levels of pro-inflammatory or inflammatory cytokines such as Tumor Necrosis Factor - alpha (TNF-alpha) and Interleukin -1 beta (IL-1beta) have been detected. Hypoxia up-regulates TNF-alpha and IL-1beta; therefore, considerable research interest has been focused on the biological consequences of the hypoxic nature of the rheumatoid synovium. Hypoxia might underlie the functional polarization of the T cells and cytokine production, and thus may contribute to the progression and persistence of the disease. In this short review, we discuss our current knowledge of the link between cytokines and RA and the role of hypoxia in the pathogenesis of the disease.     

HMGB1在呼吸系统疾病中的研究进展

高迁移率族蛋白B1(HMGB1)是一种重要的晚期炎性介质,与脓毒症、免疫性疾病、恶性肿瘤等疾病相关。此外,HMGB1还参与多个呼吸系统疾病(如肺纤维化、急性肺损伤、慢性阻塞性肺疾病、肺炎等)的病理生理过程,在感染、炎症及免疫反应中发挥重要的作用。HMGB1浓度的高低可以反映机体炎症及组织损伤的严重程度,并且与疾病的预后密切相关。现主要对HMGB1与呼吸系统疾病的研究进展予以综述。     

高迁移率族蛋白B1在缺血/再灌注损伤中的研究进展

高迁移率族蛋白B1(HMGB1)是一类进化高度保守的DNA结合蛋白,广泛存在于真核细胞内。HMGB1可通过活化细胞的主动分泌或细胞坏死、损伤等被动释放至细胞外,通过与Toll样受体、晚期糖基化终末产物受体等结合,激活相应的信号转导通路,参与多种疾病的发生、发展。近年来研究显示,细胞外的HMGB1作为炎性介质在组织器官缺血损伤或缺血/再灌注损伤(IRI)中发挥重要作用,对HMGB1的干预治疗有可能成为防治IRI的新靶标。