Stress and Radiation-Induced Activation of Multiple Intracellular

Hematology 2009127Hemophagocytic lymphohistiocytosis (HLH) andrelated disordersAlexandra H. Filipovich11Immunodeficiency and Histiocytosis Program, Division of Hematology/Oncology, Cincinnati Children’sHospital Medical Center, Cincinnati, OHThe predominant clinical findings of hemophagocyticlymphohistiocytosis (HLH) are fevers (often hecticand persistent), cytopenias, hepatitis and splenom-egaly. Until recently, it was widely believed that symptomsof HLH due to genetic causes generally arose duringinfancy and early childhood. With the more widespreadavailability of genetic testing, it is apparent that the firstsignificant episode of HLH can occur throughout life, fromprenatal presentations through the seventh decade. Distinc-tions between primary (genetically determined) andsecondary (acquired) forms of HLH have become increas-ingly blurred together as new genetic causes are identified.Patients who develop HLH beyond early childhood or inthe context of Epstein-Barr virus (EBV) infection orautoimmune diseases are being found to share some of thesame genetic etiologies as infants with documented familialdisease.HLH results when critical regulatory pathways responsiblefor the natural termination of immune/inflammatoryresponses are disrupted or overwhelmed. In HLH, patho-logic genetic defects alter normal crosstalk between innateand adaptive immune responses in a manner that compro-mises homeostatic removal of cells that are superfluous ordangerous to the organism. The result is excessive andpersistent activation of antigen-presenting cells (histio-cytes) and T lymphocytes. The clinical findings associatedwith systemic inflammation such as prolonged high feversand hepatitis reflect this immunologic perturbation.Currently, HLH (FHL:OMIM 267700, 603553) includes theautosomal recessive genetic disorders as well as the“secondary” forms. In recent years, many more cases ofhemophagocytic disorders have been diagnosed, especiallyin the context of severe inflammatory reactions to viralexposure including, in addition to EBV, HIV and Avianinfluenza.Pathogenesis of HLH and Other HistiocyticDisordersHLH is characterized by multisystem inflammation—areactive process resulting from prolonged and excessiveactivation of antigen-presenting cells (macrophages,histiocytes) and CD8+ T cells, and excessive proliferationand ectopic migration of T cells. Normal functions ofhistiocytes, a major population of cells within the innateimmune system, include phagocytosis, antigen presentationand activation of the adaptive immune system throughcontact and cytokine signaling. Abnormalities in thefunction (but rarely the quantity) of NK cells have beenobserved in a proportion of patients with all forms of HLH.PRIMARY IMMUNODEFICIENCIES: THE FREQUENT ASSOCIATION WITH CYTOPENIAS___________________________________________Hemophagocytic lymphohistiocytosis (HLH), which has many genetic causes, is characterized by multi-system inflammation. HLH is a reactive process resulting from prolonged and excessive activation ofantigen presenting cells (macrophages, histiocytes) and CD8+ T cells. Hemophagocytosis, which ismediated through the CD163 heme-scavenging receptor, is a hallmark of activated macrophages/histiocytes and is the characteristic finding for which the disorder was named. The majority of geneticcauses identified to date affect the cytotoxic function of NK and T cells, crippling immunologic mecha-nisms that mediate natural immune contraction. The predominant clinical findings of HLH are fevers (oftenhectic and persistent), cytopenias, hepatitis and splenomegaly. Due to the life-threatening implications ofthe diagnosis of genetically determined HLH, antiinflammatory therapy, often consisting of steroids,etoposide or antithymocyte globulin (ATG), should be instituted promptly, followed by curative hemato-poietic cell transplantation. Secondary HLH, associated with autoimmune disorders or viral infections inteens and adults, also carries a significant mortality rate and should be managed in consultation withspecialists familiar with the diagnosis and treatment of such disorders.128American Society of HematologyNK and NKT cells play a major role in maintaining ahealthy threshold of immune responsiveness to noxiousexternal stimuli and are critical to prevention and control ofautoimmune conditions and severe reactions to viralinfections. NK cells form a frontline of defense againstintracellular pathogens, such as viruses, which infect non-lymphoid tissues early upon entry into the patient. NK cellsmodulate the initial responses of antigen-presenting cells toincoming pathogens (likely through cytokine signaling),thus attenuating the subsequent activation of antigen-specific T cells. NK cells likely also play a role in cullingactivated T cells and histiocytes in later stages of antigen-driven activation, contributing to the natural contraction ofthe immune response.Also critical to the contraction process of activated T-cellpopulations is the mechanism of activation-inducedapoptosis. Like NK cell cytotoxicity, this is driven bygranule-mediated cytotoxicity.Studies of cytokine levels in blood and tissues haveindicated persistently elevated circulating levels ofmultiple proinflammatory cytokines during symptomaticdisease. Recently, gene expression analysis of mononuclearcell samples from patients with several different genotypesof HLH have consistently demonstrated highly increasedexpression of interleukin (IL)1b, tumor necrosis factor(TNF)α, IL-6 and IL-8. Elevations in plasma levels ofinterferon-γ have been previously published in EBV-drivenHLH in Asian populations, as well as in a murine model ofHLH triggered by LCMV.1 It is currently believed that“hypercytokinemia” and possibly “hyperchemokinemia”generated by uncontrolled activation of histiocytes and Tcells underlies the progressive organ dysfunction thateventually leads to death in affected patients. Thesesymptoms and signs include fevers, hyperlipidemia,endothelial activation/coagulopathy, hepatitis triaditis,central nervous system (CNS) vasculitis and demyelination,inflammatory lung disease with acute respiratory distresssyndrome (ARDS) and marrow hyperplasia or aplasia.Hemophagocytosis, the characteristic finding for which thedisorder was named, is a hallmark of activated macroph-ages/histiocytes.Genetics of HLH and Other HemophagocyticDisordersTo date, autosomal recessive genetic defects associated withHLH (Table 1) are related to one another in the pathway ofgranule-mediated cytotoxicity. These genetic defectsinterrupt mechanisms responsible for triggered apoptosis(mediated by cytotoxic cells upon the target cell) oractivation-induced apoptosis (putative suicide of activatedT cells). The first gene reported in 1999 to be a cause ofHLH (FHL2) was perforin, PRF1, a soluble, pore-formingcytolytic protein synthesized in cytotoxic lymphocytes andsequestered, along with Granzyme serine proteases, insecretory cytotoxic granules.2 When cytotoxic cells contacttheir targets, an intracellular cytoskeletal scaffold (themicrotubule organizing center, or MTOC) is rotated to focuson the contact site where the cytotoxic immunologicsynapse forms. Cytotoxic granules are carried along theMTOC toward the immunologic synapse where theydegranulate, allowing perforin and Granzyme B to enter thecontact zone, permeabilize the target cell membrane andenable delivery of Granzyme B into the target cell. Onceinternalized, Granzyme B initiates both caspase-dependantand caspase-independent apoptotic pathways, thus killingthe target cell. No defects in Granzyme B have beenidentified in association with human HLH.A second gene responsible for HLH (FHL3) was reported in2003: MUNC 13-4.3 MUNC 13-4 was described as essentialfor cytolytic granule fusion with other structures related tothe cytoplasmic membrane in the process of degranulation.The gene defect responsible for FHL4 is Syntaxin 11,4which has been shown, as in MUNC 13-4 deficiency, toresult in defective degranulation. Syntaxin 11 is a memberof the SNARE protein family, which facilitates fusion inintracellular membrane trafficking events. It was recentlyshown to be expressed in NK cells and activated CTLs.5Although apparently far less common than defects in PRF1and MUNC 13-4, cases attributed to STX11 deficiency havea worldwide distribution. The genetic defect responsible forFHL1 linked to chromosome 9 in a study of two extendedPakistani families has not yet been discovered.Related hemophagocytic disorders occur with low fre-quency in five other genetic diseases that have been linkedwith defective cytotoxic function. Three distinct immuno-deficiencies that are typically associated withTable 1. Genetic causes of hemophagocyticlymphohistiocytosis (HLH).HLH related to defects in the perforin/granule-mediated pathway ofcytotoxicityFHL 2 – Perforin (PRF1) ARFHL 3 – MUNC 13-4 ARFHL4 – STX11 ARGriscelli s. type 2 – Rab27A ARChediak Higashi s. – LYST1 ARHermansky Pudlak s. type II - AP3B1 ARX-linked syndromes associated with HLHXLP1 – SH2D1A (SAP) XXLP2 – BIRC4 (XIAP) XAR indicates autosomal recessive; X, X-linked.

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文章编号：１６７１—２８９７（２０１０）０９—０９２—０３

ＰＰＡＲ一、／的神经保护作用研究进展・综述・

邓永兵１唐文渊２’（１重庆市急救医疗中心神经外科，重庆４０００１４；２重庆医科大学第一附属医院神经外科，重庆４０００１６）

关键词ＰＰＡＲ－ｒ；脑损伤；神经保护

中国图书资料分类号Ｒ７４１．０５文献标识码Ａ

过氧化物酶体增殖物激活受体（ｐｅｒｏｘｉｓｏｍｅｐｒｏｌｉｆｅｒａｔｏｒ－ａｃｔｉｖａｔｅｄｒｅｃｅｐｔｏｒｓ，ＰＰＡＲｓ）是配体活化的核转录因子，属Ⅱ犁

核受体超家族成员之一，有仅、Ｂ、Ｙ３种亚型。ＰＰＡＲ＾ｙ在１９９０

年由Ｉｓｓｅｍａｎ等首次发现存在于脂肪细胞的分化调控通路中，

故又称为脂激活转录冈子。该受体被其配体激活后町以和特

异的ＤＮＡ反应元件结合，调控多种基因的转录和表达，参与

体内多种牛理和病理过程，如ｌＩＩＬ糖调节、脂肪代谢…。研究表

明ＰＰＡＲ．、／的激活能促进神经细胞的分化和成熟，参与神经细

胞程序性夕匕亡，近年研究也发现ＰＰＡＲｙ的激活与神经细胞的

炎症和氧化应激有关１２１。本文就ＰＰＡＲ＾ｙ激活后的神经保护

作用作一综述。

一、中枢神经系统急慢性损伤及炎症反应

炎症反应对于组织修复，细胞再生起着重要作用，但失控

的炎症反应将会导致大餐细胞夕Ｅ亡。在中枢神经系统缺血、

创伤和慢性退行性疾病巾，炎症反应导致大嚣细胞凋亡，引起

继发性损伤，加重神经功能损害。

血脑屏障的内皮细胞是中枢神经系统炎症反应的蓖要调

控兀件。炎症反应时，由于粘附分子表达增加，促使白细胞聚

集于内皮细胞，导致血脑屏障破坏，白细胞渗入脑实质。渗入

的白细胞（嗜中性粒细胞和臣噬细胞）可激活小胶质细胞、星

形胶质细胞、少突胶质细胞，产牛大萤的炎症介质，如细胞因

子、趋化因了、前列腺素类物质、氧自由基等，这些物质将加重

神经细胞损伤ｐ１。

研究表明，短暂性脑缺血可使细胞因子表达增加，如肿瘤

坏死冈子．ｄ（ｔｕｍｏｒｎｅｃｒｏｓｉｓｆａｃｔｏｒ．ａｌｐｈａ，ＴＮＦ．ａ）、白细胞介素．

61科技视界Science & Technology Vision　生命与健康Life and health

󰀁▋引言NRF2是—种重要的转录因子，可调控细胞对外界刺激的应答[1]。在人体发生氧化应激反应的时候，会产生大量的活性氧和氧自由基，进而导致体内遗传物质和蛋白质等出现氧化损伤。在这种情况下，为了提高细胞对氧化应激的适应能力，细胞会活化NRF2下游的Ⅱ型解毒基因，并通过解毒酶等与有害物质结合，将有害物质排出。生理情况下，NRF2定位于胞浆并与Keap1的相互作用而泛素化，并通过26S途径被降解。因此，NRF2在胞浆内的稳态受Keap1的调控。然而，当Keap1在氧化应激或离子应激的情况下，其结构会改变，从而释放出NRF2。在此过程中，NRF2转位入核，并与抗氧化应答元件（ARE）结合，起到核转录因子的作用，调节—系列抗氧化和解毒相关基因的表达，起到了细胞保护的作用。然而，在肿瘤中，NRF2的功能是双向的[2]。研究表明，NRF2在多种恶性肿瘤中过表达，与肿瘤的劣质预后及对放、化疗耐受关系密切。肺癌是一种恶性肿瘤，严重危害人类健康。目前，临床上主要采用化学治疗与放射治疗相结合的方式进行治愈。放射治疗及某些化学治疗均可引起肿瘤组织中ROS的升高，从而产生毒性效应。新近研究表明，NRF2基因的高表达与肺癌的发生、发展、耐药性等密切相关。本项目旨在阐明NRF2对肺癌细胞增殖、分化及转移的调节机制，为肺癌的临床诊断与治疗提供新的思路。同时，传播相关科学知识。基金项目：福建省自然科学基金项目（2020D035）；厦门市医疗卫生科技计划项目（3502Z20224ZD1306）；福建省大学生创新创业训练（202012631010）。作者简介：江旭，本科，研究方向为医学检验技术。*通信作者：许雅苹，理学博士，副教授，硕士生导师，研究方向为呼吸疾病。NRF2信号通路对肺癌的作用机制研究进展综述 ◎江　旭1，2　许雅苹1，2*（1.厦门医学院机能与临床转化福建省高等学校重点实验室，福建　厦门　361023；2.厦门医学院呼吸疾病研究所，福建　厦门　361023）【摘　要】Nrf2是一种重要的转录调控因子，能够调节多个生物学功能，如抗氧化酶、解毒因子、抗凋亡及药物转运体等。在氧化胁迫下，miRNAs的表达被抑制，导致肿瘤细胞的功能紊乱。研究表明，Keap1为其负调控分子，而Nrf2则可活化ARE信号通路，进而调控其下游靶基因。Keap1-Nrf2/ARE信号途径与肿瘤关系密切，表现出“促癌”和“防癌”的双重功能。文章介绍了Nrf2的结构、功能、作用机理，进一步综述分析了Nrf2在肿瘤中的代谢及其肺癌的发生、发展和治疗方面的研究进展。【关键词】NRF2；肺癌；肿瘤

Pharmacy Information 药物资讯, 2017, 6(2), 31-35

Published Online May 2017 in Hans. /journal/pi https:///10.12677/pi.2017.62006

文章引用: 冯晓文, 何玲. 脑源性神经营养因子在阿尔茨海默症中作用研究进展[J]. 药物资讯, 2017, 6(2): 31-35. https:///10.12677/pi.2017.62006

Research Progress of Brain-Derived

Neurotrophic Factor in Alzheimer’s Disease

Xiaowen Feng, Ling He*

China Pharmaceutical University, Nanjing Jiangsu

Received: Apr. 23rd, 2017; accepted: May 13th, 2017; published: May 16th, 2017

Abstract Alzheimer’s disease (AD) is one of the most common causes of dementia in the elderly. It is cha-racterized by the accumulation of Aβ plaques and neurofibrillary tangles, which are accompanied by widespread neuronal and synaptic loss, causing progressive loss of memory and cognitive func-

tion. Brain-derived neurotrophic factor (BDNF) is the most widely distributed NTs in adult brain