1、Apoptosis and Disease,Department of Pathophysiology 邝晓聪,Section 1 General Conception,Apoptosis is programmed cell death, in which the cell goes through a highly regulated process of dying,Definition of Apoptosis,By the time I was born, more of me had died than survived. It was no wonder I cannot rem
2、ember; during that time I went through brain after brain for nine months, finally contriving the one model that could be human, equipped for language.,In humans, as many as 1011 cells die in each adult each day and are replaced by other cells.,The mass of cells we lose each year is close to our enti
3、re body weight!,Leland Hartwell，Paul Nurse，Timothy Hunt,Caenorhabditis elegans,1091,960,131,Apoptosis,Differences in apoptosis and necrosis,Apoptosis,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。 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。,Necrosis,大江东去，浪淘尽，千古风流人物。 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。 江山如画，一时多少豪杰。,Physiological
4、 Significance of Apoptosis,1. Insure normal growth and developmentresorption of tadpole tail, formation of fingers and toes of fetus, formation of synapses 2. Maintain internal homeostasis & exert defensive functionto destroy the cells which represent a threat to the integrity of the organism, such
5、as virus infected, mutated, auto-immune or aged cells,Section 2 Morphology and Biochemical Changes in Apoptosis,1. Morphological changes,Early stage: plasma dehydration, membrane blebbing, cell condensationLater stage： chromatin margination，apoptotic body formationThree stages:,Apoptosis,Apoptosis,C
6、ell Membrane Alterations,Cell Nuclei inNormal Cell,Chromatin Margination in Apoptotic Cell,Apoptotic Bodies Observed Under the Scanning Microscopy,Phagosome,Induction of apoptosis in tumors by cytolytic immune effectors,2. Biochemical Changes,(1) Intracellular Ca2+i elevationActivate Ca2+-dependent
7、enzymes, such as endogenous endonuclease, calpain, etc (2) DNA fragmentation Activated endonuclease cleaves DNA and forms 180-200 bp fragments,Biochemical Changes (cont.),(3) Activation of caspase A class of proteases specifically cleaves aspartic acid peptide bond and with enriched cysteine in the
8、catalytic activity center(4) Synthesis of bio-macromoleculesIncluding activators and inhibitors of apoptosis,Mode for the Function of Endogenous Endonuclease,H1,180-200 bp,Zn2+,Ca2+ Mg2+,Endonuclease,DNA ladder,DNA fragmentation,Section 3 Apoptotic Pathways,1. Signals for Cell Apoptosis,Withdrawal o
9、f inhibitory signalsNGF, Bcl-2, etcORReceipt of stimulatory signals:TNF, Fas, Bax, Lymphotoxin, etc,Inhibitory Factors for Apoptosis,Stimulatory Factors for Apoptosis,Apoptotic Pathways,Death receptor-mediated apoptotic pathwayMitochondria-mediated apoptotic pathwayNuclear-mediated apoptotic pathway
10、,Apoptotic 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 proteinsApoptosis,1. Receptor-Mediated Apoptotic Pathway,Death factorbinds to death-receptor,The bindi
11、ng induces trimerization of the receptors,Death Receptor-Mediated Cell Apoptosis,Death receptor-mediated cell apoptosis,Activation of apoptotic cascade,Activate caspases 3,6,7,Apoptosis,Fas-associated Death Domain Death-inducing signaling complex,FADD/MORT-1 (DED),FAS,FAS-L,Procaspase 8,DD,downstrea
12、m caspases,APOPTOSIS,“DISC”,FLIP,Ligand/Death Receptor,Caspase Cascade Signaling Pathway,ICE (caspase 8) Robert Frost,Some say the world will end in fire, Some say in ice. From what Ive tasted of desire I hold with those who favor fire. But if it had to perish twice, I think I know enough of hate To
13、 say that for destruction ice Is also great And would suffice,TNF Mediated Apoptotic Pathway,The Jak/Stat Mediated Apoptotic Pathway,2. Mitochondria-Mediated Apoptosis Pathway,Apoptotic inducers (irradiation,anti-carcinogenic drugs, hypoxia, ischemia)Attack mitochondriaPTP Cyt. C +Apaf1Recruit proca
14、spase-9 AIFActivation of caspase-9 EndonucleaseActivation of caspase-3,-6,-7 DNA fragmentation Proteolysis of cytoskeleton proteinapoptosis,Mtm,Cyt C + Apaf-1,procaspase9,caspase9,procaspase3,caspase3,AIF,cytoskeletal protein proteolysis,PTP,Ca2+ ischemia hypoxia ROS,activate endonuclease,DNA fragme
15、ntation,Mechanisms of ApoptosisMitochondria Lesion Hypothesis,APOPTOSIS,3. Nuclear-Mediated Apoptosis,Apoptotic inducers (irradiation, nuclear toxin)Nuclearp53 over expression (wild type)Pro-apoptosis,The p53 Signaling Pathway Ultraviolet (UV) radiation -Desquamate,Section 4Apoptosis and Diseases,Ba
16、lance of Cell Growth and Death,Growth,Necrosis and apoptosis,Normal,The Consequences of Dysregulation,Development Elimination of damaged cells: Viral infection DNA damage Inhibition: malignancies autoimmune disease Excess: Neurodegenerative disease Ischemia/reperfusion injury Fulminant liver failure
17、,Tumor, autoimmune disease, virus infection,Insufficiency in Cell Apoptosis,(1) TumorPathogenesis for tumor: stimulated cell proliferation inhibited cell apoptosisCell survival cell death in diseased tissueEtiologically, cell apoptosis is actually one of the natural anti-carcinogenic mechanisms,EDUC
18、ATIONAL REVIEW Recent Insights Into Angiogenesis, Apoptosis, Invasion, and Metastasis in Colorectal Carcinoma William M. Boedefeld, II, MD, Kirby I. Bland, MD and Martin J. Heslin, MD Annals of Surgical Oncology 10:839-851 (2003,(2) Autoimmune DiseasesThe lesion caused by attack of auto-antibody or
19、sensitized T cell to auto-antigenNormally, T cells against auto-antigen are eliminated by apoptosis during the developmentWhen the negative selection was deregulated (thymus diseases), The T cells survive and abnormally proliferate, then attack self tissue, lead to autoimmune diseases,Mechanism of A
20、utoimmune Disorders Disrupted apoptosis of self-reactive cell,Point mutation of FasL,Insertion mutation of Fas,Structural abnormity of FasL,Decreased expression of Fas protein,Escape the negative selection of self-reactive T cells,Autoimmune Disorders,Rheumatoid arthritis,It is caused by decreased a
21、poptosis and increased proliferation of arthral cell Increased IL-1 and TGF-1 and decreased Fas expression, which inhibit apoptosis; Increased Bcl-2、Bcl-XL, which increased the threshold of apoptosis; Increased sFas, which inhibits Fas/FasL apoptotic pathway; Resistance of T-cells to apoptosis,Norma
22、l,Apoptosis,AIDS, Neurodegenerative diseases, aberrant myocardial ischemic-reperfusion,Excess in Apoptosis,（1） Acquired Immune Deficiency SyndromeAIDS,HIV infectionincreased Fas gene expression gp120glycoprotein expression + receptor in CD4 lymphocyte infusion of infected CD4 cell leads to syncytin
23、formationproduce tat protein (enhance Fas expression) secret TNF CD+4T- lymphocyte apoptosis AIDS,AIDS (cont.),Activation-induced cell death (AICD) Normal activated CD 4 HIV-infected activated CD4proliferation apoptosis enough LGF not enough LGFtarget cell effecter celleffecter induces target cell g
24、o to apoptosis,(2) Cardiovascular diseases,Cell death induced by ischemia-reperfusion Apoptosis Necrosis Early stage Later stage Peripheral region of infarct Center of infarctMild ischemia Severe ischemiaChronic Acute,Possible mechanism (myocardial cell apoptosis induced by ischemia-reperfusion):(1)
25、 oxidative stress (SOD reduce apoptosis); (2) calcium overload; (3) p53 gene activation; (4) death receptor Fas, TNF over expressed,Cardiovascular diseases (cont.),Cardiovascular diseases (cont.),Heart failure:Myocardial cell diminishes in pressure- overload-induced heart failure Possible mechanisms
26、: Oxidative stress; cytokines; ischemia; hypoxia; pressure or volume overload, neural-endocrine system deregulation;Lead to myocardial cell apoptosis,Alzheimer disease，Parkinson disease，Huntington disease， multiple sclerosisFactors involved in neuronal apoptosis:amyloid peptide, calcium overload, ox
27、idative stress and neuronal growth factor insufficiency, etc,Lead to neuronal cell apoptosis,（3） Neurodegenerative diseases,Coexistence of Excessive and Insufficient Apoptosis,oxidative LDL platelet activation Ag hypertensionexcess apoptosis insufficiency in in endothelium smooth muscle Atherosclero
28、sis,Coexistence of Excessive and Insufficient Apoptosis,Prevention 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,
