病理生理英文课件2.ppt

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1、Apoptosis and DiseaseDepartmentofPathophysiology邝晓聪邝晓聪Section 1 General Conception Apoptosis is programmed cell death,in which the cell goes through a highly regulated process of dyingDefinition of ApoptosisBy the time I was born,more of me had died than survived.It was no wonder I cannot remember;d

2、uring that time I went through brain after brain for nine months,finally contriving the one model that could be human,equipped for language.Inhumans,asmanyas1011cellsdieineachadulteachdayandarereplacedbyothercells.The mass of cells we lose each year is close to our entire bodyweight!LelandLelandHart

3、wellHartwell，Paul NursePaul Nurse，TimothyTimothyHuntHuntCaenorhabditis elegans 10911091960960131ApoptosisDifferencesinapoptosisandnecrosisApoptosis轻轻的我走了，正如我轻轻的来；轻轻的我走了，正如我轻轻的来；我轻轻的招手，作别西天的云彩。我轻轻的招手，作别西天的云彩。悄悄的我走了，正如我悄悄的来；悄悄的我走了，正如我悄悄的来；我挥一挥衣袖，不带走一片云彩。我挥一挥衣袖，不带走一片云彩。Necrosis大江东去，浪淘尽，千古风流人物。大江东去，浪淘尽，

4、千古风流人物。故垒西边，人道是、三国周郎赤壁。故垒西边，人道是、三国周郎赤壁。乱石穿空，惊涛拍岸，卷起千堆雪。乱石穿空，惊涛拍岸，卷起千堆雪。江山如画，一时多少豪杰。江山如画，一时多少豪杰。Physiological Significance of Apoptosis1.Insure normal growth and development resorption of tadpole tail,formation of fingers and toes of fetus,formation of synapses 2.Maintain internal homeostasis&exert d

5、efensive function to destroy the cells which represent a threat to the integrity of the organism,such as virus infected,mutated,auto-immune or aged cellsSection 2Morphology and Biochemical Changes in Apoptosis 1.Morphological changesEarly stage:plasma dehydration,membrane blebbing,cell condensationL

6、ater stage：chromatin margination，apoptotic body formationThree stages:ApoptosisApoptosisCell Membrane AlterationsCell Nuclei in Normal Cell Chromatin Margination in Apoptotic Cell Apoptotic Bodies Observed Under the Scanning MicroscopyPhagosomeInductionofapoptosisintumorsbyInductionofapoptosisintumo

7、rsbycytolyticcytolyticimmuneeffectorsimmuneeffectors2.Biochemical Changes(1)Intracellular Ca2+i elevation Activate Ca2+-dependent enzymes,such as endogenous endonuclease,calpain,etc (2)DNA fragmentation Activated endonuclease cleaves DNA and forms 180-200 bp fragmentsBiochemical Changes(cont.)(3)Act

8、ivation of caspase A class of proteases specifically cleaves aspartic acid peptide bond and with enriched cysteine in the catalytic activity center(4)Synthesis of bio-macromolecules Including activators and inhibitors of apoptosis Mode for the Function of Endogenous EndonucleaseH1180-200 bpZnZn2+CaC

9、a2+MgMg2+EndonucleaseDNA ladder DNA fragmentationSection 3Apoptotic Pathways1.Signals for Cell Apoptosis Withdrawal of inhibitorysignals NGF,Bcl-2,etcORReceipt of stimulatory signals:TNF,Fas,Bax,Lymphotoxin,etcPhysiologic baculovirus P35 growth factors cowpox virus CrmA extracellular matrixMedicamen

10、t estrogen carcinogenic androgen phenobarbital neutral amino acid PMAVirus hexachlorocyclohexane adenovirus E1B cysteine protease inhibitors Inhibitory Factors for ApoptosisStimulatory Factors for Apoptosis Physiologic Pathologic Family of TNF virus infection FasL、TNF P53、PTEN transforming growth fa

11、ctors cytotoxin carcinoma gene free radical Neurotransmitters Therapeutic factors glutamate,dopamine chemotherapy GF withdraw ultraviolet radiation ECM lesion herbal medicineApoptotic PathwaysDeath receptor-mediated apoptotic pathwayMitochondria-mediated apoptotic pathwayNuclear-mediated apoptotic p

12、athwayApoptotic inducers+death receptor(FasL,TNF,etc)(death domain)Recruit procaspase 8 via death domainDimerization of procaspase-8Auto-activation of caspase-8Activate caspases-3,-6 and-7Target proteinsApoptosis1.Receptor-Mediated Apoptotic PathwayDeath factor binds to death-receptorThe binding ind

13、uces trimerization of the receptorsDeath Receptor-Mediated Cell ApoptosisDeath receptor-mediated cell apoptosisActivation of apoptotic cascadeActivate caspases 3,6,7ApoptosisFas-associatedDeathDomainDeath-inducingsignalingcomplexFADD/MORT-1(DED)FASFAS-LProcaspase 8DD downstream caspasesAPOPTOSISFLAS

14、H“DISC”FLIPLigand/Death ReceptorCaspase Cascade Signaling Pathway ICE(caspase8)RobertFrostSome say the world will end in fire,Some say in ice.From what Ive tasted of desireI hold with those who favor fire.But if it had to perish twice,I think I know enough of hateTo say that for destruction iceIs al

15、so great And would sufficeTNF Mediated Apoptotic PathwayThe Jak/Stat Mediated Apoptotic Pathway2.Mitochondria-Mediated Apoptosis PathwayApoptotic inducers (irradiation,anti-carcinogenic drugs,hypoxia,ischemia)Attack mitochondria PTP Cyt.C+Apaf1 Recruit procaspase-9 AIF Activation of caspase-9 Endonu

16、clease Activation of caspase-3,-6,-7 DNA fragmentation Proteolysis of cytoskeleton proteinapoptosis MtmCyt C+Apaf-1 procaspase9caspase9procaspase3caspase3AIFcytoskeletal protein proteolysisPTPCaCa2+ischemiahypoxia ROSactivate endonucleaseDNA fragmentationMechanisms of Apoptosis Mitochondria Lesion H

17、ypothesisAPOPTOSIS3.Nuclear-Mediated ApoptosisApoptotic inducers(irradiation,nuclear toxin)Nuclearp53 over expression(wild type)Pro-apoptosisThe p53 Signaling PathwayUltraviolet(UV)radiation-DesquamateSection 4Apoptosis and DiseasesBalance of Cell Growth and DeathGrowthNecrosis and apoptosisNormal T

18、he Consequences of DysregulationDevelopmentElimination of damaged cells:Viral infectionDNA damage Inhibition:malignanciesautoimmune diseaseExcess:Neurodegenerative diseaseIschemia/reperfusion injuryFulminant liver failureTumor,autoimmune disease,virus infectionInsufficiency in Cell Apoptosis (1)Tumo

19、r Pathogenesis for tumor:stimulated cell proliferation inhibited cell apoptosis Cell survival cell death in diseased tissue Etiologically,cell apoptosis is actually one of the natural anti-carcinogenic mechanismsEDUCATIONALREVIEWRecentInsightsIntoAngiogenesis,Apoptosis,Invasion,andMetastasisinColore

20、ctalCarcinomaWilliamM.Boedefeld,II,MD,KirbyI.Bland,MDandMartinJ.Heslin,MDAnnals of Surgical Oncology10:839-851(2003 (2)Autoimmune Diseases The lesion caused by attack of auto-antibody or sensitized T cell to auto-antigen Normally,T cells against auto-antigen are eliminated by apoptosis during the de

21、velopment When the negative selection was deregulated(thymus diseases),The T cells survive and abnormally proliferate,then attack self tissue,lead to autoimmune diseases Mechanism of Autoimmune Disorders Disrupted apoptosis of self-reactive cellPoint mutation of FasLInsertion mutation of FasStructur

22、al abnormity of FasLDecreased expression of Fas protein Escape the negative selection of self-reactive T cellsAutoimmune DisordersRheumatoid arthritisIt is caused by decreased apoptosis and increased proliferation of arthral cell Increased IL-1 and TGF-1 and decreased Fas expression,which inhibit ap

23、optosis;Increased Bcl-2、Bcl-XL,which increased the threshold of apoptosis;Increased sFas,which inhibits Fas/FasL apoptotic pathway;Resistance of T-cells to apoptosisNormalApoptosisAIDS,Neurodegenerative diseases,aberrant myocardial ischemic-reperfusion Excess in Apoptosis（1）Acquired Immune Deficienc

24、y Syndrome AIDS HIV infectionincreased Fas gene expressiongp120glycoprotein expression+receptor in CD4 lymphocyteinfusion of infected CD4 cell leads to syncytin formation produce tat protein(enhance Fas expression)secret TNF CD+4T-lymphocyte apoptosis AIDSAIDS(cont.)Activation-induced cell death(AIC

25、D)Normal activated CD 4 HIV-infected activated CD4 proliferation apoptosis enough LGF not enough LGF target cell effecter cell effecter induces target cell go to apoptosis(2)Cardiovascular diseases Cell death induced by ischemia-reperfusion Apoptosis Necrosis Early stage Later stage Peripheral regio

26、n of infarct Center of infarct Mild ischemia Severe ischemia Chronic Acute Possible mechanism(myocardial cell apoptosis induced by ischemia-reperfusion):(1)oxidative stress(SOD reduce apoptosis);(2)calcium overload;(3)p53 gene activation;(4)death receptor Fas,TNF over expressedCardiovascular disease

27、s(cont.)Cardiovascular diseases(cont.)Heart failure:Myocardial cell diminishes in pressure-overload-induced heart failure Possible mechanisms:Oxidative stress;cytokines;ischemia;hypoxia;pressure or volume overload,neural-endocrine system deregulation;Lead to myocardial cell apoptosisAlzheimer diseas

28、e，Parkinson disease，Huntington disease，multiple sclerosis Factors involved in neuronal apoptosis:amyloid peptide,calcium overload,oxidative stress and neuronal growth factor insufficiency,etc,Lead to neuronal cell apoptosis（3）Neurodegenerative diseasesCoexistence of Excessive and Insufficient Apopto

29、sisoxidative LDLplatelet activationAghypertension excess apoptosis insufficiency in in endothelium smooth muscle AtherosclerosisCoexistence of Excessive and Insufficient ApoptosisPrevention and Therapeutic Potential of Apoptosis To interfere signal transduction,signal molecules,receptors,2nd messengers,different proteins To properly regulate apoptosis-related enzymes and genesTo prevent decrease in mitochondria trans-membrane potential