CELL DEATH
细胞的衰老与细胞死亡-衰老死亡的细胞是什么细胞
机体衰老与细胞衰老之间有着密切的联系，机体
衰老以细胞总体的衰老为基础 。
Cell Senescence and Cell Death
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第十六章
细胞衰老与细胞死亡
(二)机体内各类细胞的寿命不同
根据细胞寿命情况将细胞分为三类： 细胞寿命接近于动物的整体寿命，如神经元、脂 肪细胞、肌细胞等。 缓慢更新的细胞，其寿命比机体的寿命短，如肝 细胞、胃壁细胞等。
Cell Senescence and Cell DБайду номын сангаасath
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细胞衰老与细胞死亡
酶：活性中心被氧化，总的效应是酶失活；但β-半
乳糖苷酶（senescence-associated β- galactosidase ， SA-βgal）活性增强。
脂类：不饱和脂肪酸被氧化，膜的流动性降低。
人正常体细胞一般分裂次数平均为50次. （二）体外细胞 体外培养细胞可传代30～50次,停止分裂增殖后细胞多停 留于G0或G1期,此时细胞表现为:
形态变化大;DNA复制能力降低
蛋白质合成能力
第十六章
细胞衰老与细胞死亡
(一)细胞衰老与机体的衰老既有区别又有联系
机体衰老：指绝大多数生物性成熟以后，机体形 态结构和生理功能逐渐退化或老化的过程，是一
快速更新且寿命较短的细胞，如皮肤的表皮细胞、
红细胞和白细胞等。
Cell Senescence and Cell Death
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第十六章
细胞衰老与细胞死亡
(三)细胞在体外培养条件下的寿命
•离体细胞同在体细胞一样，也有一定的寿命 •细胞的寿命不是指培养天数的多少，而是指群体倍增次数。 •其寿命长短取决于培养细胞的平均代数，所取培养组织的年
autophagic cell death名词解释
autophagic cell death名词解释嘿，朋友！今天咱来聊聊“autophagic cell death”这个听起来有点神秘的家伙。
你知道吗，细胞就像是一个个小小的城市，里面有着各种各样的“设施”和“工作”。
而“autophagic cell death”呢，就像是这个城市里的一场特殊的“拆迁行动”。
在细胞的世界里，autophagy （自噬）就像是细胞的自我清洁和修复机制。
它会把一些损坏的或者不需要的“零件”收集起来，准备处理掉。
而当这个自噬的过程过度或者失控的时候，就可能导致细胞的死亡，这就是“autophagic cell death”啦。
想象一下，如果细胞是一个工厂，里面的机器和工人都在有条不紊地工作。
自噬就像是工人们把一些老旧的、损坏的机器零件挑选出来。
可要是挑得太多太狠，整个工厂的运作就会出问题，甚至工厂会倒闭，这就跟“autophagic cell death”差不多。
比如说，在某些疾病的发生过程中，细胞的自噬可能会异常活跃。
这就好比工厂里突然来了个特别严格的质检员，把太多还能用的零件也给扔了，结果影响了整个生产流程，导致工厂没办法正常运转，细胞也就走向死亡啦。
再打个比方，细胞好比是一个大家庭，自噬就是家里的大扫除。
正常的大扫除能让家里整洁有序，但要是把家里有用的东西也都当垃圾扔了，那这个家不就乱套了吗？这就是“autophagic cell death”的情况。
研究“autophagic cell death”对于理解很多生理和病理过程都非常重要。
比如说癌症，有些癌细胞可能会利用自噬来逃避治疗，导致治疗效果不佳。
这难道不可怕吗？所以啊，搞清楚“autophagic cell death”的机制，就像是掌握了细胞世界的一把神秘钥匙，可以帮助我们更好地治疗疾病，保护我们的健康。
这难道不值得我们去深入探索吗？总之，“autophagic cell death”是细胞世界里一个复杂而又关键的现象，我们对它的了解还只是冰山一角，还有更多的奥秘等待着我们去揭开呢！。
细胞死亡(cell death)
第五节 细胞损伤的原因和机制 原因： 1、缺氧：全身性缺氧、局部性缺氧 2、物理因子：X线、高温、低温、电流 3、化学因子： 4、生物因子：细菌、病毒、真菌、寄生虫等。 5、免疫反应： 机理：各种因素影响了细胞基本生命活动和功 能有关的细胞内的功能中心及有关的细胞器。
第二章 损伤的修复 （ repair） 1、概念：损伤造成机体部分细胞和组织丧失后， 机体对所形成缺损进行修补恢复的过程，称为 修复（repair）。修复后可完全或部分恢复原组 织的结构和功能。 2、修复的过程： 损伤 →引发炎症→通过炎症处理坏死组织→局 部周围健康细胞（实质、间质）→分裂增生及 再生→完成修复
又称纤维性修复。
一、组织的再生能力：按其强弱分为三类。 1、不稳定细胞：(labile cells )此类细胞总在不断地
增殖，以代替衰亡或破坏的细胞。 如：某些被覆上皮，淋巴造血细胞。 2、稳定细胞：(stable cells)这类细胞在生理情况下， 细胞增殖现象不明显，细胞的增殖周
期似乎处于静止期（G0），受到组织
第一节 再生 （regeneration） 概述：
1、概念：组织和细胞丧失后形成的组织缺损、由损伤
局部周围的同种细胞增生来修复的过程。
2、再生的类型：
①生理性再生： ②病理性再生：是指病理状态下细胞、组织缺损后所发
生的再生，分为两种：
•完全再生：修复后完全恢复了原组织的结构及功能 •不完全再生：由纤维组织增生（肉芽组织）来代替，
凋亡பைடு நூலகம்apoptosis)
坏死 • 概念：是以酶溶性变化为特点的活体内局部组织细
胞的死亡称为坏死。
坏死细胞质膜崩解、结构自溶、急性炎症反应
• 渐进性坏死： 多数情况下坏死是由可逆性损伤发展而来，在坏死 未发生前病因去除是可复性的,坏死后则为不可复的。
细胞死亡的检测方法和相关指标
细胞死亡的检测方法和相关指标English Answer：Cell Death Detection Methods and Associated Markers.Cell death is a fundamental biological process that occurs in organisms throughout their lifespan. It plays a crucial role in maintaining homeostasis, eliminating damaged or unwanted cells, and facilitating tissue development and remodeling. Various methods are employed to detect and characterize cell death, each with its advantages and limitations.Methods for Cell Death Detection:1. Morphological Assessment:Microscopy: Examination of cells under a microscopecan reveal morphological changes associated with cell death, such as nuclear fragmentation, chromatin condensation, cellshrinkage, and blebbing.Flow Cytometry: Cells stained with fluorescent dyes that bind to degraded DNA or proteins can be quantified using flow cytometry.2. Biochemical Assays:DNA Fragmentation Assays: Detection of fragmented DNA fragments released into the cell supernatant by activated nucleases.Caspase Activity Assays: Measurement of caspase activity, a family of proteases involved in apoptosis execution.Cytochrome c Release Assays: Assessment of the translocation of cytochrome c from mitochondria into the cytosol, an event associated with mitochondrial outer membrane permeabilization (MOMP).3. Fluorescent Reporters:Annexin V Staining: A fluorescent dye that binds to phosphatidylserine, a lipid that flips to the outer leaflet of the plasma membrane during apoptosis.Propidium Iodide Staining: A fluorescent dye that enters cells with compromised plasma membrane integrity, indicating necrosis.4. Genetic Reporters:Caspase CLEAVAGE: Genetically engineered reporter constructs that express fluorescent proteins under the control of caspase recognition sites.MOMP Reporters: Constructs that monitor mitochondrial outer membrane permeabilization by releasing fluorescent dyes into the cytosol.Associated Cell Death Markers:Specific markers are associated with different types ofcell death, providing insights into the underlying mechanisms involved:1. Apoptosis:Cleaved caspase-3。
医学细胞生物学细胞死亡
凋亡：细胞核的特点是染色质凝聚成球状或半月状。 早期磷脂酰丝氨酸（Phosphatidylserine, PS）从细胞 膜内侧翻转至外侧、细胞皱缩、凋亡小体形成等，并 伴随胱冬肽酶尤其是胱冬肽酶3的活化。 凋亡样程序性细胞死亡：细胞核的特点是染色质凝聚 程度较低，比凋亡细胞的染色体疏松一些，可以或没 有凋亡细胞其它方面的形态学的变化。 坏死样程序性细胞死亡：一般无染色质的凝聚或者只 有疏松的点状分布。 坏死 ：细胞核依序呈现核固缩、核碎裂、核溶解。
10
比较内容
促成因素
ቤተ መጻሕፍቲ ባይዱ
细胞凋亡
外来因素触发细胞内部死亡机制
细胞坏死
缺O2、高热、理化性创伤 等严重损伤细胞 肿胀变大 核膜可能破裂，核组分散出
细胞体积 胞核变化
固缩变小 核染色质固缩，集聚至核膜周边并呈 月牙形斑块 细胞器一般完整，胞浆浓缩，内质网 扩张，可形成凋亡小体 特异性梯状(ladder)电泳 一般无 有 需要
细胞的生命活动
细胞死亡
概述
细胞死亡（cell death）是细胞生命活动的正常组成部 分。 引起细胞死亡的因素不外乎内因和外因两种。内因通 常是指由于衰老所导致的自然死亡，而外因则指外界 环境的各种因子超过了细胞所承受的强度及阈值，对 细胞造成的损害。
细胞死亡的分类
细胞死亡按机制可分为程序性细胞死亡（programmed cell death，PCD）和非程序性细胞死亡。 程序性细胞死亡主要由细胞内部基因调控的一类死亡 方式，如细胞凋亡（apoptosis）、自噬性细胞死亡 （autophagic cell death）、坏死性细胞死亡 （necroptosis）等 ，非程序性细胞死亡一般指细胞坏
细胞死亡(cell death)
膜破裂，染色质碎片分散在的细胞浆中。 ③核溶解（ karyolysis）：由非特异性DNA酶和蛋白酶激 活分解核DNA和核蛋白所致，DNA失去碱性染料的亲和 力→色变淡，只能看到核的轮廓，继而染色质中残余蛋白 质被溶蛋白酶溶解→死亡细胞核在1-2天内将会完全消失。
间质的改变： 实质细胞坏死一段时间内，间质常无改变。
间质→基质崩解，胶原纤维肿胀→崩解断裂或液化。
最后坏死区表现为坏死的细胞和崩解的间质融合成
一片模糊的颗粒壮、无结构的红染物质。
上述形成学改变要在组织细胞死亡相当时间（2-10 小时）才出现，坏死早期，用肉眼乃至在电镜下也
不能确定组织、细胞坏死是与否，将这种失去生活 能力（坏死）的组织称为失活组织。是不可复的易 于细菌寄生感染，应切除。
好发器官：心、肝、肾、脾等
凝固性坏死的特殊类型： 干酪样坏死（caseous necrosis）原因：主要见于结核菌 引起的坏死→结核病特征性病变 病理变化： 肉眼：坏死组织含较多脂质（来自崩解的粒细胞和结核菌） 故呈黄色或白+微黄；腊质可阻抑溶解体酶的溶蛋白作用， 使坏死组织呈固体状，如奶酪，故称为干酪样坏死。 镜下：坏死组织彻底崩解，组织结构消失，坏死物为无定 形的颗粒状物质。是坏死更为彻底的凝固性坏死
（钙皂形成：脂肪酸+营养不良性钙化）
(3）、纤维素样坏死（fibrinoid necrosis) 又称纤维素样变性（fibrinoid degeneration）
a、部位：结缔组织及小血管壁 b、形态变化：病变处组织结构逐渐消失，变为一 堆境界不甚 清晰的细丝状、颗粒状、小条或小块状无结构物质，呈强嗜酸 性红染，状似纤维素（纤维蛋白），有时呈纤维素染色。
cell death
3 cell deathIt is now recognised that cell death can take place in two distinct ways. Apoptosis is mainly the result of a physiological process by which cells are eliminated when they are no longer required by the body. Necrosis, on the other hand, is invariably a pathological consequence of cell damage.ApoptosisApoptosis (literally ‘falling off’as of leaves in autumn) is characterised by shrinkage and compaction of the dyingcell. It rapidly breaks upp to form ‘apoptotic bodies’ which are phagocytosed by neighbouring cells. Cells tend to be affected singly rather than in contiguous groups and appear as inconspicuous round or oval eosinophilic structures with dense chromatin inclusions. Electron microscopy shows that apoptotic bodies are bounded by intact plasma membrane and crowded with organelles. There is no inflammatory reaction. It has been shown that, unlike necrosis, apoptosis requires continuing synthesis of RNA and protein and a suppply of ATP, features suggesting that the process is one of active self destruction.Occurrence. Apoptosis is an essential component of normal cell turnover and it corresponds exactly to the rate of cell division in maintaining many organs at a constant size. It is also responsible forprogrammed destruction of cells (e.g. in the interdigital clefts) during embryonic development, and for endocrine-dependent involution of tissues (e.g. during the mestrual cycel).In pathological states it occurs as a consequence of special froms of cell injury, notably that due to damage by UV or ionising radiation or following attack by cytotoxic T-cells. Thus the shrunken eosinophilic Councilman bedies seen in the liver in viral hepatitis are apoptotic hepatocytes injured by the reaction of cytotoxic T lymphocytes to cell surface antigens modified by intracellular virus.Apoptosis is also the usual mechanism by which cell numbers are reduced in various forms of pathological atrophy.NecrosisIn contrast to apoptosis, necrosis usually affects groups of contiguous cells. Unless the cells are killed very rapidly, their death is preceded by osmotic swelling and depletion of ATP, and characterised by rupture of internal and plasma membranes and eventual disappearance of chromatin. There is frequently an associated inflammatory reaction.Causes of necrosis(a)Marked impairment of blook supply, usually due to obstruction of anend-artery (that is, one without adequate collaterals) is a common and important cause of necrosis, the necrotic area being known as aninfarct.(b)Toxins derived from bacteria, plants and animals such as snakesand scorpions, produce toxic organic compounds which even in very small quantities can cause cell damage amounting to necrosis. Some toxins have identifiable enzyme activity; for example, the causal organism of gas gangrene, Clostridium welchii, forms a lecithinase which digests the lipid of cell membranes. Kiphtheria toxin inhibits protein synthesis indirectly through production of ADP-ribosome, which blocks ribosomal transpeptidase. Certain bacterial toxins, including those mentioned above, exert their effects not only locally, but are distributed via the blood-stream and other routes and so injure the cells of organs remote from the infection. The necrosis accompanying bacterial infection may be partly due to interference with the circulation brought about by toxic injury to the vascular endothelium with inflammation and sometimes thrombosis.(c) Immunological injury can result from the reaction of antibody and complement, or of T lymphocytes, with antigenic constituents of cell surfaces. The reaction of antibody and complement with non-cellular antigen can also cause injury to adjacent tissues. These effects are classed as hypersensitivity reactions.(b)Infection of cells notably by viruses, which are obligateintracellular parasites. This is the cause of necrosis in vivo of theanterior horn cells of the spinal cord in poliomyelitis.(c)Chemical poisons. Many chemicals in high concentrationcause necrosis by non-selective denaturation of the cellular proteins(e.g. strong acids, strong alkalis, carbolic acid, vercuric chloride).Others, such as cyanide and fluoroacetate, have much more specific effects and in low concentrations quickly cause cell death by interfering with oxidative production of energy. The action of some poisons is indirect and less specific. Thus carbon tetrachloride is toxic to liver cells because it is metabolised by the microsomal enzyme P450 to produce free radicals which lead to peroxidation of mRNA and of unsaturated fatty acids in cell membranes.(d)Physical agents. Cells are very sensitive to heat and,depending on the type of cell, they die after variable periods of exposure to a temperature of 45 centigrade. Cold is much less injurious and, proviede certain precautions are taken, cell suspensions and even small animals can be frozen without being killed. Necrosis after frostbite is due to damage to capillaries, resulting in thrombosis which may even extend to the arteries.Mechanical trauma such as crushing may cause direct disruption of cells. Certain disorders of the nervous system are sometimes accompanied by necrotic lesions in the limbs; these ‘trophic’ lesions were previously attributed to an illdefined effect of denervation ontissue nutrition but are now thought to result from mechanical trauma which occurs unnoticed because of sensory loss.The recognition of necrosisIt is not possible to determine exactly when a particular cell becomes necrotic –i.e. when the disintegration of tis vital functions has reached an irreversible stage. Many of the changes by which necrosis is recognised occur after cell death and are due to the secondary release of lytic enzymes normally sequestrated within the cell, e.g. in the lysosomes; this process of autolysis is described below.In organised tissues such as liver or kidney, necrosis is usually recognised by secondary changes seen on histological examination. In preparations stained with haematoxylin and eosin, the nuclei may gradually lose their characteristic staining with haematoxylin so that the whole cell stains uniformly with eosin, although the nuclear outline may persist; this change, the result of hydrolysis of chromatin within the cell after its death, is called karyolysis. Sometimes the chromatin of necrotic cells,especially those with already dense chromatin such as polymorphonuclear leucocytes, forms dense haematoxylinophilic masses (pyknosis) and these may break up (karyorrhexis) to form granules inside the nuclear membrane or throughout the cytoplasm. In many necroticlesions the outlines of swollen nicrotic cells can be recognised but the cytoplasm is abnormally homogeneous or granular and frequently takes up more eosin than normal. In other tissues, e.g. the central nervous system, necrotic cells absorb water and then disintegrate, leaving no indication of the architecture of the original tissue; the lipids derived from myelin etc. persist in the debris of the necrotic tissue. The activities of certain enzymes, e.g. succinic acid dehydrogenase, diminish rapidly after cell death and appropriate tests provide sueful indicators of recent tissue necrosis.Electron microscopy of cells which have undergone necrosis shows severe disorganisation of structure. Gaps are seen in the various membranes and abnormal polymorphic inclusions, presumably derived from membranes, lie in the ground substance. Fragmentation and vacuolation of endoplasmic reticulum and mitochondrial membranes precede the disappearance of these stuructures. Curious lamellar structures with concentric whorling form from the cell membrane, especially where there have been microxilli. Ribosomes and Golgi apparatus are unrecognisable from an early stage. There is loss of density of the nucleoplasm and large chromatin granules accumulate just inside the nuclear membrane before it disappears.Necrosis can often be recognised macroscopically when large groups of cells die. The necrotic area may become swollen, firm, dull and lustreless, and is yellowish unless it contains much blood. This appearace is often found in infarcts of kidney, spleen and myocardium. Histologically, the outlines of the dead cells are usually visible and the firmness of the tissue may be due to the action of tissue thromboplastins on fibrinogen which together with other plasma proteins has been shown to diffuse through the damaged membranes of necrotic cells. This type of necrosis is appropriately described as coagulative necrosis. By contrast, necrotic brain tissue, which has a large fluid component, becomes ‘softened’and ultimately turns into a turbid fluid (colliquative necrosis) with profound loss of the previous histological architectrue.Certain necrotic lesions develop a firm cheese-like appearance to the naked eye and microscopy shows amorphous granular eosinophilic material lacking in cell outlines; a varying amount of finely divided fat is present and there may be minute granules of chromatin. Because of its gross appearance this lesion is cescribed as ‘caseation’. It is very common in tuverculosis but essentially similar changes are occasionally seen in infarcts, necrotic tumours and in inspissated collections of pus.Necrotic lesions affecting skin or mucosal surfaces are frequently infected by organisms which cause putrefaction, i.e. the production of foul-smelling gas and brown, green or black discolouration of the tissue due to alteration of haemoglobin. Necrosis with putrefaction is called gangrene. It may be primarily due to vascular occlusion, e.g. in the limbs or bowel where the necrotic tissue is exposed to putrefactive bacteria, but it may also result from infection with certain bacterea, namely the clostridia which cause gas gangreneor fusiform bacilli which result in noma. AutolysisThe structural disintegration of cells as a result of digestion by their own enzymes if largely responsible ofr the softening of necrotic tissues and the associated loss of histological structure. In the intact cell, the enzymes concerned are restricted to specific organelles, such as the lysosomes, and do not have general access to the cytoplasm. After cell death, the lysosomal acid hydrolases are activated by the low pH which prevails in necrotic cells due to acid production from anaerobic glycolysis and the action of phosphatases and proteolytic enzymes. The small molecules produced by hydrolysis of macromolecules lead to osmotic swelling of the necrotic cells and their organelles provided that the membranes are sufficiently intact.It should be noted that when many polymorphonuclear leucocytes are present in necrotic tissue the enzymes from their abundant lysosomes may contribute to the hydrolysis of other cells. This is an important factor in the liquefaction of pus and in the softening seen in infected organs at autopsy.If tissue is killed by heating, e.g. to 55 cenigrade, or by immersion in fixative such as ofrmalin, the enzymes and other proteins are denatured and the histological features of necrosis attributable to autolysis do not develop. By contrast, if a piece of tissue is deprived of its blood supply by removal from the living body and kept at 37 cetigrade, the development of autolysis can be observed, with marked osmotic swelling of membrane-bounded structures.Two points of practical importance in the recognition of necrosis deserve emphasis. First, morphological signs of necrosis are not apparent until autolysis has developed in the necrotic tissue, and this takes 12-24 hours. Second, following death of the individual (sommatic death), all cells of the body will in time die due to lack of blood supply and postmortem autolysis will gradually take place. This is particularly marked in the parenchymal cells of the liver and kidney tubules and when seen at autopsy it may be mistaken for true necrosis, i.e. cell deathoccurring while the individual was still alive. This problem is of great importance in electron microscopy which shows fine structural evidence of necrosis and of post-mortem autolysis within a very short time.Somatic deathThough not strictly related to cell necrosis, the interesting subjuct of somatic death (death of the individual) deserves some consideration. For many years, somatic death was defined as complete and persistent cessation of respiration and circulation. For legal purposes persistence of the state was arbitrarily taken as five or more minutes, by which time irreversible anoxic damage would have developed in the neurons of the vital centres. However, it is now possible to restore the circulatory and respiratory functions of heart and lungs in many cases of somatic death as defined above, and integrated function both of cells and of organs (excluding those of the central nervous system) can then continue for prolonged periods with the adi of special equipment. This fact is of great importance in obtaining organs for transplantation from cadaveric donors and a legal redefinition of somatic death in terms of extensive and irreversible brain damage is now necessary.Effects of necrosisBy definition, necrotic cells are functionless. The effect of cell necrosis on the general wellbeing of the body accordingly depends on the functional importance of the tissue involved, the extent of the necrosis, the functional reserve of the tissue, and on the capacity of surviving cells to proliferate and replace those which have become necrotic. For example, splenectom is compatible with good health in man (although it increases the risk of certain infections) and extensive splenic necrosis is apparently of little importance. By contrast, extensive necrosis of renal tubular epithelium results in the serious clinical condition of renal failure which is likely to be fatal unless the patient is kept alive (e.g. by haemodialysis) until there is regeneration of tubules by proliferation of surviving cells. Necrosis of a relatively small number of motor nerve cells may produce severe paralysis which persists because nerve cells cannot proliferate to replace those lost. Since myocardial cells have not only a contractile but also a conducting function, quite small necrotic lesions may result in striking alterations in the electrical activity of the heart.The break down of necrotic cells results in escape of their contents. Enzymes such as aminotransferases released into the plasma from necrotic liver or myocaidial cells form the basis of clinical tests ofr necrosis in these tissues. It should be emphasised,however, that abnormal enzyme release occurs from cells with damage short of necrosis (e.g. in muscular dystrophy). In poisoning by alloxan, which kills the B(beta) cells of the pancreatic islets, discharge of stored insulin from the necrotic cells results in hypoglycaemia which may be fatal: those animals which survive develop diabetes from lack of insulin.Reactions to necrosisNuetrophil polymorphs frequently accumulate in small numbers around necrotic cells. Occasionally infarcts and caseous lesions are invaded by lafge numbers of these cells and this leads to softening as already described. Such softening is a notable feature in a small proportion of myocardial infarcts (which usually show coagulative necrosis) and may lead to rupture of the heart; it is also common in tuberculosis of the lumbar vertebrae where the caseous material liquifies and tracks soen beneath the psoas fascia to form a ‘cold abscess’ in the groin.Individual cells killed by toxins rapidly undergo autolysis and are absorbed, especially when the circulation is maintained. They may be quickly replaced by proliforation of adjacent surviving cells. When a large mass of tissue undergoes necrosis, e.g. in an infarct, the necrotic material may be gradually replaced by growth of capillaries and fibroblasts from the surrounding viable tissue sothat a fibrous scar results. If this process is incomplete the necrotic mass becomes enclosed a fibrous capsule, may persist for a long time, and may become calcified. Areas of necrotic softening in the brain are usually invaded by macrophages and eventually become cyst-like spaces containing clear liquid and surrounded by proliferated astroglia.Old caseous lesions and necrotic fat have a marked affinity ofr calcium and frequently become lheavily calcified.。
第10章+细胞凋亡
Two orthologous regulators, CED-9 and Bcl-2, suppress apoptosis in the presence of trophic factors (D. L. Vaux and S. J. Korsemeyer, 1999, Cell 96:245) (ced: cell death abnormal) 10
Incomplete differentiation in two toes (syndactyly) due to lack of apoptosis
In adult tissues, cell death exactly balances cell division
12
Disease & Apoptosis
第十章 细胞凋亡
1
Outline
Cell death Cell apoptosis Cytochrome c and apoptosis
2
1、Cell death
Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, or may result from such factors as disease, localized injury, or the death of the organism of which the cells are part. Kinds of cell death include：
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Necrosis Apoptosis Mechanism ATP depletion Gene activation Membrane Endonuclease injury Free radicals Tissue Inflammation No inflammation reaction Phagocytosis of apoptotic bodies
Three pattern of nuclear changes
Karyolysis (DNase activity) Pyknosis (DNA condensation) Karyorrhexis (fragmentation of pyknotic nucleus)
Morphologic appearance of necrosis
Wound healing
• Healing by first intention • Healing by second intention
• Healing under scab
• Fig 4-18
• Fig 4-19
Systemic factors influencing wound healing: • Nutrition • Metabolic status • Circulatory status • Hormones
Caseous necrosis
A subtype of coagulation necrosis White and cheesy Tuberculosis Completely obliterated tissue architecture
Gangrene
A subtype of coagulation necrosis Dry gangrene Wet gangrene Gas gangrene
MORPHOLOGICAL FEATURES OF APOPTOSIS
• Cell shrinkage • Chromatin condensation and fragmentation. • Formation of cytoplasmic blebs and apoptotic bodies. • Phagocytosis of apoptotic bodies by adjacent healthy cells or macrophages. • Lack of inflammation.
TYPES OF CELL DEATH • necrosis
Coagulation necrosis
Caseous necrosis
Gangrene
Liquefaction necrosis( fat necrosis) Fibrinoid necrosis
• Apoptosis
Coagulation necrosis Denatures of both structural and enzymatic proteins by injury or the subsequent increasing intracellular acidosis.
• Fig 1-19
• Apoptosis-associated genes bcl-2, c-myc, p53
• Fig 1-20
Fates of necrosis
• Absorption • Discharge: Erosion Ulcer Sinus Fistula Cavitation • Organization • Encapsulation • Calcification
Chapter Three Repair
Section A
Regeneration: Completely regeneration Fibrous repair
Regeneration capacity • Labile cells • Stable cells • Permanent cells
• Pathologic atrophy in parenchymal organs after duct obstruction. • Cell death by cytotoxic T cells. • Cell injury in certain viral diseases. • Cell death produced by a variety of injurious stimuli given in low doses (e.g. mild throsis
Bacterial or fungal infections Central nervous system Amebiasis
Fat necrosis
Traumatic Activated pancreatic lipases
Fibrinoid degeneration Deeply eosinophilic • Collagen diseases • Necrotic vasculitis • Malignant hypertension
Local factors influencing wound healing: • Infection • Mechanical factors • Foreign bodies • Size, location and types of wound
Liquefactive necrosis
Necrosis Stimuli Hypoxia Toxins Histology Cell swelling Coagulation N Disruption of organelles DNA Random breakdown Diffuse
Apoptosis Physical Pathological Single cell Chromatin condensation Apoptotic bodies Internucleosomal
• Increased eosinophilia: Loss of RNA in the cytoplasm Increased binding of eosin to denatured cytoplasmic protein • More glassy homogeneous appearance Loss of glycogen particles • Vacuolated and moth-eaten cytoplasm • Calcification of necrotic cells
NECROSIS
The sum of the morphologic changes that follow cell death in living tissue and organ:
• Denaturation of proteins. • Enzymatic digestion of organelles and cytosol.
APOPTOSIS (Programmed cell death)
• Programmed destruction of cells during embryogenesis. • Hormone dependent involution of tissues in the adult. • Cell deletion in proliferating cell populations (intestinal crypt epithelium), tumors, and lymphoid organs.
Bacterial or fungal infections Central nervous system Amebiasis
Fat necrosis
Traumatic Activated pancreatic lipases
• Fig 1-18
Biochemical features of apoptosis
1.PROTEIN CLEAVAGE: Caspases (cysteine protease) Nuclear scaffold Cytoskeletal protein 2.PROTEIN CROSS-LINKING: Transglutaminase Cytoplasmic proteinshrunken shalls apoptotic bodies Biochemical features of apoptosis
Factors influencing regeneration
1. Cell-cell interaction Conditioned medium Contact inhibition 2. Extracellular matrix Laminin: Epithelia Fibroblasts Fibronectin : Epithelia Fibroblasts 3. Growth factors
3. DNA breakdown: 50-300 kb pieces Ca2+, Mg2+ dependent endonucleases DNA oligonucleosomes DNA ladders (also seen in necrosis) 4. PHAGOCYTIC RECOGNITION Receptors on macrophages for the surface components (phosphatidylserine, thrombospondin) on apoptotic bodies.
AUTOLYSIS • Enzymatic digestion by lysosomal enzymes of the dead cells themselves. HETEROLYSIS • Digestion by lysosomal enzymes of immigrant leukocytes.
GROWTH FACTORS EGF, TGF-A, PDGF, aFGF, bFGF, IGF-1, IGF-2, VEGF, HGF, MG-CSF, M-CSF, G-CSF, ERYTHROPOITIN, ILs, TNF, IFN, NGF.