单核细胞趋化蛋白-1与慢性肝病及并其发症的相关性

持续的肝脏炎症是慢性肝脏疾病进展的一个重要因素,趋化因子通过调节肝细胞、库普弗细胞、肝星状细胞、内皮细胞和循环免疫细胞的活动和迁移,在肝脏炎症的发生和发展中起着重要作用。单核细胞趋化蛋白-1(monocyte chemoattractant protein-1,MCP-1)属于CC趋化因子家族,在机体发生炎症反应和组织损伤时发挥激活、招募、迁移单核-巨噬细胞、中性粒细胞和淋巴细胞的功能。MCP-1对慢性乙型肝炎、慢性丙型肝炎、非酒精性脂肪性肝病、自身免疫性肝病、肝纤维化和肝硬化自发性细菌性腹膜炎等的发生、发展及预后有重要影响。本文对近几年MCP-1与慢性肝病及并发症相关性的进展进行综述。     

脂质运载蛋白2在肝脏疾病发生发展中的作用

脂质运载蛋白2(LCN2)最初是从感染猴空泡病毒40的小鼠肾细胞培养物中纯化得到的一种分泌糖蛋白,在炎症期间对细胞稳态控制以及应对细胞应激或损伤的反应中发挥着关键作用,被认为是风湿病、癌症、肝脏疾病和炎症性疾病的一种潜在的生物标志物。已有研究表明,LCN2在肝实质细胞和非实质细胞中表达并分泌入血,与急性肝损伤、肝硬化、病毒性肝炎、酒精性肝病、非酒精性脂肪性肝病以及肝细胞癌等的发生发展密切相关。本文总结了LCN2与肝脏疾病发病机制相关的动物实验和临床研究,以期为肝脏疾病的防治提供新思路和治疗靶点。     

HMGB1在心肌缺血再灌注损伤中作用的研究进展

高迁移率族蛋白1(HMGB1)是一种核蛋白,几乎存在于所有细胞的细胞核中,可调节染色质结构、DNA复制和基因转录等.它对细胞正常发育起到至关重要的作用.当HMGB1作为一种损伤相关分子模式从细胞内向外释放时,在介导炎症反应中扮演重要角色.心肌缺血再灌注损伤是一种多种细胞及细胞因子参与的病理生理过程,涉及的信号分子及通路...     

危险信号分子与原发性肝癌的研究进展

危险信号分子,是一大类细胞结构蛋白,病理情况下释放到细胞外,通过启动和介导炎症反应,传递着细胞损伤的危险信号.以HMGB1、HSPs和S100为代表的危险信号分子,在肝脏慢性炎症和肿瘤形成的微环境中持续存在,在原发性肝癌形成和进展过程中发挥着重要的作用.危险信号分子可以成为新的预测和监测原发性肝癌发生、转移和复发的标志...     

高迁移率族蛋白B1在脑出血炎症损伤和修复中的作用研究进展

综述脑出血后高迁移率族蛋白B1(HMGB1)在脑出血急性期炎症损伤和恢复期促进神经血管再生的作用。提示HMGB1可以由活化的免疫细胞主动分泌或者通过损伤及坏死细胞被动释放至细胞外,并作为损伤相关分子的模式(DAMP)启动和维持下游炎症反应,从而发挥其化学趋化因子和促炎性因子的作用,而炎症反应是脑出血继发性损伤的主要机制之一。脑出血急性期,HMGB1作为一种早期的促炎细胞因子触发炎症反应促进病情的进展。然而,脑出血恢复期,HMGB1可以介导有益神经血管修复作用,细胞外HMGB1蛋白特殊的双重生物学特性可能与半胱氨酸残基的氧化还原状态有关。     

自噬相关蛋白Beclin 1在肝脏缺血再灌注损伤模型中的作用

手术切除是原发性肝癌的最佳治疗方法,手术治疗往往面临肝脏储备功能衰退、残肝缺血再灌注损伤等弊端,这些因素明显增加了肝癌手术治疗或肝移植的难度和风险.自噬是肝脏缺血再灌注后细胞程序性死亡方式之一,其在缺血再灌注伤损中的作用是近年来研究的热点.在模拟肝脏缺血再灌注损伤的实验研究时,常检测到自噬相关蛋白Beclin 1的变化,并以此代表自噬活动变化.目前已发现多种预处理方法可降低肝脏缺血再灌注损伤模型中Beclin 1蛋白的含量并且减轻肝损伤.现就Beclin 1在肝脏缺血再灌注损伤模型中的研究进展作一综述.     

Kupffer细胞与肝缺血再灌注损伤

Kupffer细胞作为肝脏固有巨噬细胞在炎症反应及肝脏缺血再灌注损伤中发挥重要作用.Kupffer细胞激活后将诱发TNF-α、前列腺素、一氧化氮及氧自由基等各种炎症细胞因子的大量形成,除导致自身功能形态发生改变外,还直接影响邻近的肝细胞、血管内皮细胞以及位于血窦腔内的中性粒细胞等多种细胞,进而启动热缺血或冷缺血后肝脏的缺血再灌注损害.现就Kupffer细胞在肝脏缺血再灌注损伤中的作用机制及对其治疗靶点研究进展作一综述.     

肝X受体激动剂对大鼠肝脏再灌注损伤的保护作用及其机制

肝脏缺血再灌注损伤(reperfusion injury,RI)是肝脏缺血再灌注后肝脏功能障碍和结构损伤加重的现象.炎症反应是肝脏缺血再灌注损伤的重要机制之一[1].近年研究结果表明,肝X受体(live X receptor,LXR)除调节细胞内胆固醇平衡外,还可发挥抗炎效应[2].尽管LXR的抗炎作用业已明确,但其是否在RI后抑制肝脏炎症反应进而减轻损伤,目前仍鲜见报道.我们拟通过LXR化学激动剂T0901317诱导肝内LXR激活,观察其对肝脏RI后炎症反应及损伤情况的影响,研究其对肝脏RI损伤的保护机制,为治疗肝脏RI损伤提供新的作用靶点.     

砷致肝细胞的炎症反应及凋亡

砷致肝脏损伤的机制尚未完全清楚.研究发现,砷可通过诱发活性氧自由基,促发脂质过氧化,刺激释放与肝损伤有关的各种促炎症因子在肝组织表达,并可通过激发caspase途径引起细胞凋亡,导致肝脏损伤.     

中性粒细胞与肝损伤

本文综述了中性粒细胞在肝脏炎症中介导组织损伤的机制。中性粒细胞既参与宿主本身的防御反应，又因对某些致炎因素的过度反应而加重组织损伤。机体暴露于促炎症介质中会使中性粒细胞活化并聚集到肝脏脉管系统，实质细胞受损发出趋化信号激活中性粒细胞游走、脱颗粒释放蛋白酶和活性氧簇攻击靶细胞，引起细胞内氧化应激和线粒体机能障碍。此外有多种中性粒细胞源性的蛋白酶参与了中性粒细胞的游走和细胞毒性，同时通过对促炎症介质的加工而促进了炎症反应。另外，坏死细胞释放介质如高迁移率组信号-1也会进一步促进中性粒细胞介导的组织损伤。     

高迁移率族蛋白B1在慢性乙型肝炎患者肝组织中的表达及意义

目的了解高迁移率族蛋白B1（HMGB1）在慢性乙型肝炎（CHB）患者肝组织中的表达及其与肝组织损伤程度的关系。方法经血清学证实为慢性乙型肝炎患者46例。对穿刺的肝组织采用常规HE染色、Masson三色特染及Gordon—Sweet银染法观察肝组织炎症与纤维化程度,用免疫组化方法判断HMGB1在肝组织中的表达。结果正常肝组织HMGB1不表达或在细胞核内微弱表达,HMGB1随肝脏炎症及纤维化加重而表达逐渐增强（P〈0．005）。结论HMGB1与肝组织的炎症及纤维化程度密切相关,可作为慢性乙型肝炎患者炎症及纤维化发展以及治疗随访、预后判断的敏感指标。     

Anti-HMGB1 antibody reduces weight gain in mice fed a high-fat diet

Insulin resistance in obesity is believed to be propagated by adipose tissue and liver inflammation. HMGB1 is a multifunctional protein that is pro-inflammatory when released from cells. It has been previously demonstrated that anti-HMGB1 antibody reduces atherosclerotic lesion pro-inflammatory cells and progression of atherosclerosis in a mouse model. To test the potential beneficial role of blocking HMGB1 in adipose tissue and liver inflammation in mice fed an obesogenic diet, we administered anti-HMGB1 antibody to C57Bl/6 mice fed a high (60%)-fat diet. The mice were treated with weekly injections of an anti-HMGB1 antibody or anti-KLH antibody (isotype control) for 16 weeks. Mice that received the anti-HMGB1 antibody gained less weight than the control-treated animals. Anti-HMGB1 treatment also reduced hepatic expression of TNF-alpha and MCP-1, molecules that promote inflammation. However, adipose tissue inflammation, as measured by gene expression analyses and immunohistochemistry, did not differ between the two groups. There also were no differences in glucose or insulin tolerance between the two groups. When feeding mice a high-fat diet, these data suggest that HMGB1 may have a crucial role in weight gain and liver inflammation.     

HMGB1 cytoplasmic translocation in patients with acute liver failure

Background  

High-mobility group box 1 (HMGB1) is a late mediator of lethal systemic inflammation. Acute liver failure (ALF) has been shown to trigger systemic inflammation in clinical and animal studies. To evaluate the possibility of HMGB1 cytoplasmic translocation in ALF, we determined whether HMGB1 is released in hepatocytes and end organ in patients with liver failure/injury.     

Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1)

Sustained proinflammatory responses in rheumatoid arthritis, atherosclerosis, and diabetic retinopathy, as well as in cancer, are often associated with increased angiogenesis that contributes to tissue disruption and disease progression. High mobility group B1 (HMGB1) has been recognized as a proinflammatory cytokine and more recently, as a proangiogenic factor. HMGB1 can either be passively released from necrotic cells or actively secreted in response to angiogenic and inflammatory signals. HMGB1 itself may signal through the receptor for advanced glycation end products (RAGE), and via toll-like receptors, TLR2 and TLR4. Activation of these receptors results in the activation of NFκB, which induces the upregulation of leukocyte adhesion molecules and the production of proinflammatory cytokines and angiogenic factors in both hematopoietic and endothelial cells, thereby promoting inflammation. Interestingly, HMGB1 seems to be involved in a positive feedback mechanism, that may help to sustain inflammation and angiogenesis in several pathological conditions, thereby contributing to disease progression. Endothelial cells express HMGB1, as well as the receptors RAGE, TLR2, and TLR4, and in diverse pathologies HMGB1 and its receptors are overexpressed. Furthermore, HMGB1-induced signaling can activate NFκB, which can subsequently induce the expression of HMGB1 receptors. Thus, HMGB1 can mediate amplification of inflammation and angiogenesis through increased secretion of HMGB1 and increased expression of the receptors it can interact with. In this review, we discuss signaling cascades that HMGB1 can induce via TLRs and RAGE, as well as its contribution to pathologies involving endothelial cells.     

HMGB1 is a promising therapeutic target for acute liver failure

Introduction: Although acute liver failure (ALF) is a rare disease, it continues to have high mortality and morbidity rates due to its many causes. High mobility group box 1 (HMGB1), originally reported as a ubiquitous non-histone chromosomal protein, is a multi-functional protein with varying functions depending on its location, such as in the nucleus, cytoplasm and extracellular space. The role of extracellular HMGB1 as an inflammatory mediator has been well studied, and the elevation of serum HMGB1 has been reported in several diseases that are closely associated with ALF.

Areas covered: In this review, we focus on the relationship between causes of acute liver failure, such as viral infection, drug-induced liver injury, ischemia/reperfusion injury, and acute-on-chronic liver failure, and the role of HMGB1. Furthermore, we also consolidate and summarize the current reports of HMGB1-targeting therapies in hepatic injury models.

Expert commentary: HMGB1 could be a novel therapeutic candidate for ALF, and the clinical testing of HMGB1-targeting therapies for ALF patients is expected.     

HMGB1在肝癌及癌旁肝组织中的表达及意义

目的了解高迁移率族蛋白B1（HMGB1）在肝炎、肝癌癌旁组织、肝癌组织中的表达,及其与肝组织损伤程度、肝癌发生发展的关系。方法慢性乙型肝炎（CHB）患者46例,肝癌癌旁组织标本20例,肝癌组织标本20例（配对组织）,采用常规HE染色法观察肝组织炎症与纤维化程度,用免疫组化方法判断HMGB1在肝组织中的表达。结果（1）正常肝、CHB、癌旁组织、肝癌组织中的HMGB1的表达差异有统计学意义（H=7．29,P=0．027）;（2）肝组织炎症不同分级与HMGB1的表达有等级相关关系（0=0．318,P=0．031）,肝组织纤维化不同程度与HMGB1的表达有等级相关关系（rs=0．296,P=0．042）;（3）肝癌组织中HMGBI的表达与肝癌Edmondson分级间无等级相关关系（rs=0．206,P〉0．05）。结论HMGB1有可能作为反映肝脏炎症和纤维化的间接指标,与肝癌的发生发展密切相关。     

高迁移率族蛋白B1与糖尿病及其并发症

高迁移率族蛋白B1( HMGB1)是近来发现的一种重要的晚期炎性反应介质,可由激活的免疫细胞、坏死细胞释放到胞外,并与受体结合,通过激活核因子-KB(NF-KB)的表达及增加其活性,诱导大量炎性反应介质的释放.研究表明,炎性反应与糖尿病有关,HMGB1可导致糖尿病患者持续的炎性反应,参与糖尿病及其慢性并发症的发生、发展...     

高迁移率族蛋白B1与炎症反应

早期主要将高迁移率族蛋白B1(high mobility group box1,HMGB1)作为非组蛋白DNA结合蛋白进行广泛研究.近年来发现HMGB1这一传统的DNA结合蛋白具有强大的致炎细胞因子活性.HMGB1可由活化的单核细胞、巨噬细胞、成熟树突细胞和活化的自然杀伤细胞等主动分泌,也可由坏死细胞被动释放,从而触发机体的免疫炎症反应.HMGB1本身也具有细胞毒性,全身给予HMGB1可以剂量依赖方式致小鼠死亡;巨噬细胞、中性粒细胞等暴露于HMGB1时可诱导致炎细胞因子肿瘤坏死因子和白介素1β等产生增多.HMGB1拮抗剂治疗对脓毒症和内毒素血症的致死性有显著的拮抗作用,潜在拓宽了临床危重感染患者的治疗时间窗.此外,HMGB1还参与轴突生长,且与肿瘤发生和预后相关.     

脂多糖诱导原代培养肝实质细胞与库普弗细胞表达和释放高迁移率族蛋白B1

目的观察LPS诱导HMGB1在肝实质细胞（HC）与库普弗细胞（KC）的表达和细胞外释放。方法培养瓶中分别培养原代HE和KC,24h后收获对照组和500μg/L LPS诱导组两种细胞,反复冻融,用半定量RT-PCR和Western blot法检测HMGB1 mRNA水平和HMGB1表达水平;接种原代HC和KC于24孔板中,继续培养6、12、24h和48h,Western blot法检测各时间点对照组和LPS诱导组培养液中HMGB1含量。结果LPS诱导24h后,与相应对照组比较,HC和KC中HMGB1 mRNA表达水平明显增强（t值分别为31.32和45.90,P值均〈0.05）,HMGB1表达水平也明显增强（t值分别为46.19和38.44,P值均〈0.05）;在6、12、24h和48h,对照组两种细胞及诱导组HC培养上清液中仅检测到少量HMGB1,延长培养时间,培养上清液中HMGB1含量无明显变化（F=1.61,P〉0.05）;与对照组比较,诱导组KC培养液中的HMGB1含量在6h无显著增加（t=1.48,P〉0.05）,但随培养时间延长,其含量明显增高（F=42.74,P〈0.05）,且在12、24h和48h均明显高于对照组（t值分别为21.95,32.39和44.16,P值均〈0.05）。结论LPS可诱导HC和KC中HMGB1表达增强,HC不主动释放HMGB1,而KC能主动释放HMGB1到细胞外。     

M2-like Kupffer cells in fibrotic liver may protect against acute insult

AIM To investigate the mechanism of hepatoprotection conferred by liver fibrosis through evaluating the activation phenotype of kupffer cells.METHODS Control and fibrotic mice were challenged with a lethal dose of D-Gal N/lipopolysaccharide(LPS),and hepatic damage was assessed by histology,serum alanine transferase(ALT)levels,and hepatic expression of HMGB1,a potent pro-inflammatory mediator.The localization of F4/80(a surrogate marker of KCs),HMGB1,and type I collagen(Col-1)was determined by immunofluorescence staining.The phenotype of KCs was characterized by real-time PCR.KCs isolated from control or fibrotic mice were challenged with LPS or HMGB1 peptide,and HMGB1 translocation was analyzed.RESULTS Liver fibrosis protected mice against D-Gal N/LPS challenge,as shown by improved hepatic histology and reduced elevation of ALT compared with the normal mice treated in the same way.This hepatoprotection was also accompanied by inhibition of HMGB1 expression in the liver.Co-localization of F4/80,HMGB1,and Col-1 was found in fibrotic livers,indicating the close relationship between KCs,HMGB1 and liver fibrosis.KCs isolated from fibrotic mice predominantly exhibited an M2-like phenotype.In vitro experiments showed that HMGB1 was localized in the nucleus of the majority of M2-like KCs and that the translocation of HMGB1 was inhibited following stimulation with LPS or HMGB1 peptide,while both LPS and HMGB1 peptide elicited translocation of intranuclear HMGB1 in KCs isolated from the control mice.CONCLUSION M2-like Kupffer cells in fibrotic liver may exert a protective effect against acute insult by inhibiting the translocation of HMGB1.