HP
Uploaded byHelder Jorge Semedo Pires
PPT, PDF706 views

4.pathology apoptosis2016

1. Programmed cell death (PCD) refers to regulated cell death processes that eliminate cells when they are no longer useful or potentially harmful. 2. Apoptosis is a form of PCD characterized by nuclear fragmentation, chromatin condensation, cell shrinkage and blebbing, and formation of apoptotic bodies that are quickly phagocytosed, avoiding inflammation. It relies on caspase activation through the mitochondrial or death receptor pathways. 3. Alternative cell death pathways include necroptosis, pyroptosis and autophagy. Necroptosis resembles necrosis morphologically but is caspase-independent and regulated. Pyroptosis involves caspase-1 and occurs during microbial infection, triggering inflammation. Autophagy

Embed presentation

Downloaded 25 times
Pathology ---Cell Injury, Death And Adaptation Xi’an Jiaotong University 2017.1.2017.1.
XI’AN JIAOTONG UNIVERSITY Page 2 Programmed Cell Death (PCD) Refers to processes that are lethal to individual cells and are regulated by pre-existing signaling pathways. PCD is part of the balance between the life and death of cells and determines that a cell dies when it is no longer useful or when its survival may be harmful to the larger organism.
XI’AN JIAOTONG UNIVERSITY Page 3 Apoptosis A pathway of cell death that is induced by a tightly regulated suicide program in which cells destined to die, activate intrinsic enzymes that degrade the cells’own nuclear DNA and nuclear and cytoplasmic proteins Apoptosis is a form of PCD that relies exclusively on the caspase cascade Originally, PCD was synonymous with apoptosis. However, mutant mice lacking the key elements of the apoptotic machinery develop almost normally. This observation indicated that alternatives to apoptosis exist. Thus, a number of mechanisms of PCD have been identified
XI’AN JIAOTONG UNIVERSITY Page 4 Morphologic changes Cell shrinkage Recall that in other forms of cell injury, an early feature is cell swelling, not shrinkage Chromatin condensation and fragmentation. The most characteristic feature of apoptosis Formation of cytoplasmic blebs and apoptotic bodies.
XI’AN JIAOTONG UNIVERSITY Page 5 Phagocytosis of apoptotic cells or cell bodies, usually by macrophages. Histologically, apoptotic cell appears as a round or oval mass of intensely eosiniphilic cytoplasm (H&E staining) with or without fragments of dense nuclear chromatin. Because these pieces are quickly formed and phagocytosed, without eliciting inflammation, even substantial apoptosis may be more difficult to detect histologically.
XI’AN JIAOTONG UNIVERSITY Page 6 Sequence of ultrastructural changes in apoptosis of glandular epithelial cells. The earliest change is segregation of the chromatin in sharply circumscribed masses that abut nuclear envelop (1). Convolution of the nuclear and cell outlines precedes fragmentation of the nucleus and budding of the cell as a whole to produce membrane-bound apoptotic bodies of varying size and structure(2), which are phagocytosed by adjacent epithelial cells(3) and macrophages(4) and degraded within lysosomes(5). Finally, the bodies are reduced to unrecognizable residues(6). An occasional apoptotic body escapes phagocytosis and is shed into the gland lumen(7) where it undergoes degenerative changes similar to those occurring in necrosis(8)
XI’AN JIAOTONG UNIVERSITY Page 7 Early apoptosis of acinar cell in rat pancreas after duct ligation. Note granular fibrillar core remnant of nucleolus adjacent condensed chromatin(arrow) adjacent cells appear normal(x6200) Apoptotic HeLa cell after addition of actinomycin D to cultured medium(SEM x9000)
XI’AN JIAOTONG UNIVERSITY Page 8 Early apoptotosis of rat prostatic epithelial cell after castration.Note irregular cell outline, basal position of cell in epithelium, segregated chromatin in nuclear fragments and whorling of endoplasmic reticulum(x8200) Intact extracellular condensed apoptotic bodies, some containing characteristic nuclear fragments, derived from transplanted EMT6 sarcoma cell after mild hyperthermic treatment(x10,000)
XI’AN JIAOTONG UNIVERSITY Page 9 Crowded condensed intraepithelial apoptotic bodies derived from pancreas acinar cell after subcutaneous cerulein injection(x8,300). Well preserved large apoptotic body with characteristic nuclear fragment phagocytosed by a tubular epithelial cell in rat kidney after ureteric ligation(x4500)
XI’AN JIAOTONG UNIVERSITY Page 10 Partly degraded apoptotic bodies, one with nuclear fragments(arrow), in intraepithelial macrophage in rat pancreas after duct ligation(x7500) Well-preserved hepatocyte-derived apoptotic body with condensed cytoplasm, crowded organelles, and characreistic nuclear fragment phagocytosed by Kupffer cell in rat liver after portal vein branch ligation
XI’AN JIAOTONG UNIVERSITY Page 11 Multiple partly degraded apoptotic bodies in intraepithelial macrophage in rat pancreas after duct ligation(x6700) Residual bodies in cytoplasm of intraepithelial macrophage in rat pancreas after duct ligation(x7500)
XI’AN JIAOTONG UNIVERSITY Page 12 Luminal apoptotic bodies in lactating mouse breast after weaning(A),intact apoptotic bodies with characteristic nuclear fragment. (B), Partly degraded apoptotic body with nuclear fragment showing decreased density and loss of membrane integrity. (C) , Degraded apoptotic body showing membrane loss and dispersal of nuclear fragments(arrows) and organelles.(x3000, 3900, 5200)
XI’AN JIAOTONG UNIVERSITY Page 13 Apoptotic cells and bodies in rat liver after portal vein branch ligation. Note apoptotic hepatocyte with characteristic crescentic chromatin clumps in nucleus(1), budding cells(2), and typic apoptotic body with basophilic chromatin dot(3). Also note numerous small inconspicuous phagocytosed apoptotic bodies without nuclear fragments in the backgroud Clusters of apoptotic bodies in rat parotid after duct ligation. Some small clusters may represent bodies derived from a single cell(short arrow). Larger clusters are likely to be phagocytosed apoptotic bodies within intraepithelial macrophages(long arrow)
XI’AN JIAOTONG UNIVERSITY Page 14 Aoptosis of epithelial cells(arrow) in ductules of normal human breast Apoptotic bodies in intraepithelial macrophages in late secretory human endometrium
XI’AN JIAOTONG UNIVERSITY Page 15 Cause of apoptosis Apoptosis in physiologic situations Death by apoptosis is a normal phenomenon that serves to eliminate cells that are no longer needed, and to maintain a steady number of various cell populations in tissue The destruction of cells during embryogenesis Fetal development involves the sequential appearance and regression of many evolutionary relics.
XI’AN JIAOTONG UNIVERSITY Page 16 Involution of hormone-dependent tissue upon hormone withdrawal menstrual cycle, lactating breast after weaning Cell loss in proliferating cell populations turnover of intestinal crypt epithelia, bone marrow lymphocytes, Elimination of potentially harmful self-reactive lymphocytes either before or after they have completed their maturation Death of host cells that have served their useful purpose neutrophils, lymphocytes at the end of response Cell death induced by cytotoxic T lymphocytes.
XI’AN JIAOTONG UNIVERSITY Page 17 Apoptosis in pathologic situations Apoptosis eliminates cells that are injured beyond repair without eliciting a host reaction, thus limiting collateral tissue damage. DNA damage radiation, cytotoxic anticancer drugs, hypoxia, either directly or via free radicals Accumulation of misfolded proteins excessive amount of these proteins in ER leads to a condition called ER stress, which culminates in apoptotic cell death, which may cause several degenerative disease of CNS
XI’AN JIAOTONG UNIVERSITY Page 18 Cell death in certain infections Directly such as adenovirus –cytolysis,indirectly cell mediated immune response ； Conversly, HPV infection Pathologic atrophy in parenchymal organs after duct obstruction, such as in pancreas, paroit gland, and kidney
XI’AN JIAOTONG UNIVERSITY Page 19 Mechanism of Apoptosis Apoptosis results from the activation of enzymes called caspase. Two distinct pathways converge on caspase activation: the mitochondrial pathway and the death receptor pathway
XI’AN JIAOTONG UNIVERSITY Page 20 The two pathways of apoptosis differ in their induction and regulation, and both culminate in the activation of "executioner" caspases. The induction of apoptosis is dependent on a balance between pro- and anti-apoptotic signals and intracellular proteins. The figure shows the pathways that induce apoptotic cell death, and the anti-apoptotic proteins that inhibit mitochondrial leakiness and cytochrome c-dependent caspase activation and thus function as regulators of mitochondrial apoptosis.
XI’AN JIAOTONG UNIVERSITY Page 21 Necroptosis A hybrid form of cell death that shares aspects of both necrosis and apoptosis （ programmed necrosis) Morphologically, and to some extent biochemically, it resembles necrosis, both characterized by loss of ATP, swelling of the cell and organelles, generation of ROS, release of lysosomal enzymes and ultimately rupture of the plasma membrane as discussed early
XI’AN JIAOTONG UNIVERSITY Page 22 Mechanistically, it is triggered by genetically programmed signal transduction events that culminate in cell death. In this respect it resembles programmed cell death---the hallmark of apoptosis. In sharp contrast to apoptosis, the genetic program that drives necroptosis does not result in caspase activation (caspase independent programmed cell death)
XI’AN JIAOTONG UNIVERSITY Page 23 TNF-induced formation of apoptotic and necroptotic signaling complexes. nature immunology 2011,12(12):1143
XI’AN JIAOTONG UNIVERSITY Page 24 Necroptosis is induced by various stimuli. Different necroptotic stimuli are recognized or sensed by specific receptors or sensors on the cell surface or inside cells
XI’AN JIAOTONG UNIVERSITY Page 25 Pyroptosis Bearing some biochemical similarities with apoptosis and releasing fever producing cytokine IL-1 Initially described in immune cells during antimicrobial response, is a caspase-1 or caspase-11- dependent regulated type of cell death that plays a central role in inflammation and immunity
XI’AN JIAOTONG UNIVERSITY Page 26 Anoikis Activated by Loss of Cell Attachments Anoikis (Greek: “homelessness”) is a variety of apoptosis that occurs in epithelial cells and is caused by loss of cell adhesion or inappropriate cell adhesion Correct binding of a cell to the ECM helps to determine whether that cell is in its appointed location
XI’AN JIAOTONG UNIVERSITY Page 27 Mechanisms of anoikis. A. Normal. Under normal circumstances, epithelial cells are bound to their native ECM by transmembrane molecules, including α- and β-integrins. These molecules activate survival signals and block both intrinsic and extrinsic apoptotic signaling pathways. B. Loss of attachment. When the cell’s integrins are not bound, or not bound by the appropriate ECM moieties, their survival signals are eliminated. Then, activation of apoptosis by death receptor signaling is no longer blocked, and apoptosis may proceed.
XI’AN JIAOTONG UNIVERSITY Page 28 Entosis Is a Cell-Eat-Cell Form of Cell Death Entosis is a type of cellular cannibalism in which cells that are not professional phagocytes engulf nearby living cells. Aggressor cells may engulf cells of either the same or other lineages. For example, hepatocytes may ingest and destroy autoreactive T lymphocytes, thus inhibiting experimental autoimmune liver disease. More often, Entosis is seen in tumors
XI’AN JIAOTONG UNIVERSITY Page 29 SUMMARY: Morphologic Alterations in Injured Cells Reversible cell injury: Cell swelling, fatty change, plasma membrane blebbing and loss of microvilli, mitochondrial swelling, dilation of ER, eosinophilia (due to decreased cytoplasmic RNA).
XI’AN JIAOTONG UNIVERSITY Page 30 Irreversible cell injury Necrosis: increased eosinophilia; nuclear shrinkage, fragmentation, and dissolution; breakdown of plasma membrane and organellar membranes; leakage and enzymatic digestion of cellular contents(tissue pattern/ inflammation). Apoptosis: nuclear chromatin condensation; formation of apoptotic bodies (fragments of nuclei and cytoplasm)
XI’AN JIAOTONG UNIVERSITY Page 31 Key concepts on apoptosis ● Regulated mechanism of cell death that serves to eliminate unwanted and irreparably damaged cells, with the least possible host reaction ● Characterized by enzymatic degradation of proteins and DNA, initiated by caspases; and by recognition and removal of dead cells by phagocytes
XI’AN JIAOTONG UNIVERSITY Page 32 ● Initiated by two major pathways: Mitochondrial (intrinsic) pathway is triggered by loss of survival signals, DNA damage and accumulation of misfolded proteins (ER stress); associated with leakage of pro-apoptotic proteins from mitochondrial membrane into the cytoplasm, where they trigger caspase activation; inhibited by anti-apoptotic members of the Bcl family, which are induced by survival signals including growth factors. Death receptor (extrinsic) pathway is responsible for elimination of self-reactive lymphocytes and damage by cytotoxic T lymphocytes; is initiated by engagement of death receptors (members of the TNF receptor family) by ligands on adjacent cells.
XI’AN JIAOTONG UNIVERSITY Page 33 Key concepts on necroptosis and pyroptosis ● Necroptosis resembles necrosis morphologically and apoptosis mechanistically as a form of programmed cell death ● Necroptosis is triggered by ligation of TNFR1, and viral proteins of RNA and DNA viruses ● Necroptosis is caspase-independent but dependent on signalling by the RIP1 and RIP3 complex (receptor-interacting protein 1/3, RIP1/3)
XI’AN JIAOTONG UNIVERSITY Page 34 ● RIP1-RIP3 signally reduces mitochondria ATP generation, cause production of ROS, and permeabilize lysosomal membranes, thereby causing cellular swelling and membrane damage as occurs in necrosis. ● Release of cellular contents evokes an inflammatory reaction as in necrosis ● Pyroptosis occurs in cells infected by microbes. It involves activation of caspase-1 which cleaves the precursor form of IL- 1 to generate biologically active IL-1. Caspase-1 along with closely related caspase-11 also cause death of the infected cell.
XI’AN JIAOTONG UNIVERSITY Page 35 Autophagy A process in which a cell eat its own content, based on both the cargoes involved and how they arrive at Lysosomes, Autophagic degradation is generally divided into three categories ● Chaperone-mediated autophage (direct translocation across the lysosomal membrane by chaperone proteins) ● Microautophagy (inward invagination of lysosomal membrane for delivery) ● Macroautophagy ( the major form of autophagy involving the sequestration and transportation of protein of cytosol in a double membrane bound autophagic vacuole
XI’AN JIAOTONG UNIVERSITY Page 36 Types of autophagy. A. Macroautophagy. Cytoplasmic organelles are partially sequestered by an open membrane, the phagophore. Upon closure by fusion, the phagophore becomes an autophagosome, which then delivers its contents to a lysosome. Lysosomal enzymes degrade the contents to small molecules for reutilization. B. Microautophagy. Cytosolic cargoes are engulfed by invagination of the lysosomal membrane.The contents are then degraded by lysosomal enzymes. C. Chaperone-mediated autophagy. Proteins conjugated to chaperones (e.g., Hsc70) are recognized by lysosomal receptor proteins (LAMP-2A) and translocated to the lysosomal interior, where they are received by a second chaperone and then degraded. The original, extralysosomal chaperone survives to work further.
XI’AN JIAOTONG UNIVERSITY Page 37 Autophagy. Cellular stresses, such as nutrient deprivation, activate autophagy genes (Atg genes), which initiate the formation of membrane- bound vesicles in which cellular organelles are sequestered. These vesicles fuse with lysosomes, in which the organelles are digested, and the products are used to provide nutrients for the cell. The same process can trigger apoptosis, by mechanisms that are not well defined.
XI’AN JIAOTONG UNIVERSITY Page 38
XI’AN JIAOTONG UNIVERSITY Cellular Injury Microbiologic Immunologic GeneticPhysical Chemical Hypoxia Nutrition Aging Causes of Cell InjuryCauses of Cell Injury
XI’AN JIAOTONG UNIVERSITY Page 40 Oxygen deprivation ----Hypoxia Cause of Hypoxia: Reduced blood flow—ischemia Inadequate oxygenation—cardiorespiratory failure Decreased oxygen-carrying capacity of the blood---anemia or CO poisoning or severe blood loss Hypoxia → ATP synthesis↓ (affects oxidative phosphorylation and ATP synthesis) → membrane damage → cell injury.
XI’AN JIAOTONG UNIVERSITY Page 41 Physical agents  Mechanical trauma; Extremes of temperatures Abrasion(scratch) represents the tearing away of epidermal cells by fraction or crushing, such a defect may or may not penetrate the corium Multiple Laceration of liver caused by laterial compression of thorax. There were no external wounds of fracture. Death resulted from hemoperitoneum contusion Solar Dermatitis
XI’AN JIAOTONG UNIVERSITY Page 42 Mechanisms by which ionizing radiation at low and high doses causes cell death Radiation
XI’AN JIAOTONG UNIVERSITY Page 43 p53-mediated apoptosis. p53 is recruited to areas of DNA damage following external irradiation. Activated p53 activates p21WAF/CIP1, which halts cell cycle progression at the G1/S and G2/M transition points. If DNA damage is irreparable, p53 activates transcription of NOXA and PUMA, which alter the balance of proapoptotic and antiapoptotic Bcl-2 family proteins at the mitochondrial membrane in favor of apoptosis. The MPTP is opened leading to apoptosis.
XI’AN JIAOTONG UNIVERSITY Page 44 Chemical agents  Any chemical substance can cause injury, even normal substances such as glucose or salt.  Poisons can cause severe damage at the cellular level by altering membrane permeability, osmotic homeostasis, or the integrity of an enzyme and result in the death of the whole organism.  eg.: air pollutants, insecticides, carbon monoxide, strong acids or alkali, and social “stimuli” such as alcohol, and other poisons such as arsenic, cyanide, melamine, even therapeutic drugs.
XI’AN JIAOTONG UNIVERSITY Page 45 Infectious agents Virus, Rickettsiae, Bacteria, Fungi, Parasites. Immunologic reactions May be lifesaving or lethal. Immune system defends against biologic agents; may lead to cell injury. e.g., hypersensitivity: anaphylaxis (asthma), autoimmune diseases (systemic lupus erythematosus, SLE), etc.
XI’AN JIAOTONG UNIVERSITY Page 46 Nutritional imbalances Protein-calorie insufficiency; Specific vitamin deficiency; The excesses of nutrition: e.g. obesity markedly increases the risk for type 2 diabetes, AS and many disorders.
XI’AN JIAOTONG UNIVERSITY Page 47 Genetic abnormalities Chromosome abnormality -Down syndrome Single base pair mutation– sickle cell anemia Mutations may cause alteration of functional proteins, influencing metabolism Somatic mutations involved in activation of proto-oncogene and deletion of tumor suppressor gene may lead to cellular malignant transformation.
XI’AN JIAOTONG UNIVERSITY Page 48 Mechanisms of cell injury ● The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity. ● The consequences of cell injury depend on the type, status and adaptability of the injured cell. ● Cell injury results from different biochemical mechanisms acting on several essential cellular components
XI’AN JIAOTONG UNIVERSITY Page 49 The principal biochemical mechanisms and sites of damage in cell injury. (1) ATP generation, largely via mitochondrial aerobic respiration; (2) Cell membrane integrity, critical to cellular ionic and osmotic homeostasis ;(3) Protein synthesis (4) The integrity of the genetic apparatus
XI’AN JIAOTONG UNIVERSITY Page 50 Mitochondria damage Mitochondria are critical players in cell injury and cell death by all pathways. Three major consequences of mitochondria damage ● Mitochondria damage often results in the formation of a high- conductance channel in the mitochondria membrane, called mitochondrial permeability transition pore ● Abnormal oxidative phosphorylation also leads to the formation of reactive oxygen species, ● The mitochondria sequester between their outer and inner membranes several proteins that are capable of activating apoptotic pathway.
XI’AN JIAOTONG UNIVERSITY Page 51 Role of mitochondria in cell injury and death. Mitochondria are affected by a variety of injurious stimuli and their abnormalities lead to necrosis or apoptosis.
XI’AN JIAOTONG UNIVERSITY Page 52 Influx of Sources and consequences of increased cytosolic calcium in cell injury. ● The accumulation of Ca2+ in mitochondria results in opening of the mitochondria permeability transition pore ●increased cytosolic Ca2+ activates a number of enzymes with potentially deleterious effects on cells ●increased intracellular Ca2+ levels also result in the induction of apoptosis by direct activation of caspases and by increasing mitochondrial permeability.
XI’AN JIAOTONG UNIVERSITY Page 53 The generation, removal, and role of reactive oxygen species (ROS) in cell injury. The production of ROS is increased by many injurious stimuli. These free radicals are removed by spontaneous decay and by specialized enzymatic systems. Excessive production or inadequate removal leads to accumulation of free radicals in cells, which may damage lipids (by peroxidation), proteins, and deoxyribonucleic acid (DNA), resulting in cell injury.
XI’AN JIAOTONG UNIVERSITY Page 54 Defects in membrane permeability Mechanisms of membrane damage in cell injury. Decreased O2 and increased cytosolic Ca2+ typically are seen in ischemia but may accompany other forms of cell injury. Reactive oxygen species, which often are produced on reperfusion of ischemic tissues, also cause membrane damage
XI’AN JIAOTONG UNIVERSITY Page 55 Damage to DNA and proteins Cells have mechanisms that repair damage to DNA, but if DNA damage is too severe to be corrected(e.g., after exposure to DNA damaging drugs, radiation, or oxidative stress), the cell initiates a suicide program that results in death by apoptosis
XI’AN JIAOTONG UNIVERSITY Page 56 Aging Biological aging can be defined as a constellation of deleterious functional and structural changes that are inevitable consequences of longevity. Importantly, aging must be distinguished from disease. Although the aging process may increase vulnerability to many diseases, it is independent of the pathogenesis of any specific illness. Biological longevity is generally interpreted as the extension of life well beyond the period of reproduction and childrearing
XI’AN JIAOTONG UNIVERSITY Page 57 Life span of animals in their natural environment compared with that in a protected habitat. Note that both curves reach the same maximal life span. Decrease in human physiologic capacities as a function of age.
XI’AN JIAOTONG UNIVERSITY Page 58 Cellular aging the result of a progressive decline in the life span and functional capacity of cells. The Hallmarks of Aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication
XI’AN JIAOTONG UNIVERSITY Page 59 1960 Leonard Hayflik’s work by counting the number of times that population of cells had doubled . When the cells enter into senescence , they could remain viable but nonproliferating for as long as a year
XI’AN JIAOTONG UNIVERSITY Page 60 Barbara McClintock 1983 Nobel Prize Telomeres detected by FISH(left),( right) karyotype seen in left compared with that of cells have been deprived of TRF2
XI’AN JIAOTONG UNIVERSITY Page 61 Role of large T antigen in circumventing senescence Inactivation of both pRB and p53 is needed to ensure that these cells do not senesce in culture. This can be archived through the expression of the SV40 large T antigen in the target cells
XI’AN JIAOTONG UNIVERSITY Page 62 Hutchinson-Guilford progeria. A 10-year-old girl shows the typical features of premature aging associated with progeria.
XI’AN JIAOTONG UNIVERSITY Page 63 Interventions that Might Extend Human Health span The nine hallmarks of aging are shown together with those therapeutic strategies for which there is proof of principle in mice

More Related Content

PPT
Molecular mechanism of cancer metastasis
byGopi krishna Giri
 
PPTX
Pathology of Healing & repair
byMuhammadasif909
 
PDF
Apoptosis
byAshish Jawarkar
 
PPT
Apoptosis
byjinx11
 
PPTX
Apoptosis
byImran Ahmad
 
PPT
A Brief Introduction to Mannose-Binding Lectin (MBL) and its Clinical Signifi...
byKatie B
 
PPT
Apoptosis
byAbhishek Yadav
 
PPTX
AMYLOIDOSIS
byzubiya4
 
Molecular mechanism of cancer metastasis
byGopi krishna Giri
 
Pathology of Healing & repair
byMuhammadasif909
 
Apoptosis
byAshish Jawarkar
 
Apoptosis
byjinx11
 
Apoptosis
byImran Ahmad
 
A Brief Introduction to Mannose-Binding Lectin (MBL) and its Clinical Signifi...
byKatie B
 
Apoptosis
byAbhishek Yadav
 
AMYLOIDOSIS
byzubiya4
 

What's hot

PPTX
Prion diseases
bykasinghshekhawat
 
PPTX
Pigments
bySADDA_HAQ
 
PPTX
Hallmarks of cancer
byMohammed Fathy
 
PPTX
Apoptosis
bySumana Choudhury
 
PPTX
Metastatic cascade and Epithelial Mesenchymal Transition
byShruti Dogra
 
PPTX
Apoptosis
byJilsha Cecil
 
PPTX
Amyloidosis presentation
byHarshit Saxena
 
PPTX
Mast cells in health and disease
byPannaga Kumar
 
PPTX
Apoptosis
byAshwini Somayaji
 
PPTX
Heat shock proteins presentation
byPooja Chaudhary
 
PDF
Human growth factorS
byGovtRoyapettahHospit
 
PPTX
Notch signaling pathway
byAhmedMajid19
 
PPT
Apoptosis
byDhanalakshmi Srinivasan Medical College
 
PPTX
Tensins 123
bySpoorthy Gurajala
 
DOC
INTRACELLULAR ACCUMULATIONS
byDAWN V TOMY
 
PPTX
Cell death
byAnnwyne Houldsworth MSc, PhD, PGCME, FHEA, FIBMS
 
PPTX
Apoptosis in health and diseases
bymeenuev
 
PPTX
Immunoglobulin or antibody and their types
bySoniaBajaj10
 
PDF
Cell Injury and Cell Death
byImhotep Virtual Medical School
 
PPTX
Role of micro rna in oncogenesis
byKasturba Medical College
 
Prion diseases
bykasinghshekhawat
 
Pigments
bySADDA_HAQ
 
Hallmarks of cancer
byMohammed Fathy
 
Apoptosis
bySumana Choudhury
 
Metastatic cascade and Epithelial Mesenchymal Transition
byShruti Dogra
 
Apoptosis
byJilsha Cecil
 
Amyloidosis presentation
byHarshit Saxena
 
Mast cells in health and disease
byPannaga Kumar
 
Apoptosis
byAshwini Somayaji
 
Heat shock proteins presentation
byPooja Chaudhary
 
Human growth factorS
byGovtRoyapettahHospit
 
Notch signaling pathway
byAhmedMajid19
 
Apoptosis
byDhanalakshmi Srinivasan Medical College
 
Tensins 123
bySpoorthy Gurajala
 
INTRACELLULAR ACCUMULATIONS
byDAWN V TOMY
 
Cell death
byAnnwyne Houldsworth MSc, PhD, PGCME, FHEA, FIBMS
 
Apoptosis in health and diseases
bymeenuev
 
Immunoglobulin or antibody and their types
bySoniaBajaj10
 
Cell Injury and Cell Death
byImhotep Virtual Medical School
 
Role of micro rna in oncogenesis
byKasturba Medical College
 

Viewers also liked

PPT
Apoptosis (presentation)
byLeo Vang
 
PPTX
Seminar- recent advances in apoptosis
byEkta Jajodia
 
ODP
Cell injury, adaptation, and death fix
byKenneth Juatas
 
PPT
Cell Injury And Cell Death (2006)(1)
byaxix
 
PPT
Apoptosis
byUSmile Ï Ṩṃïlệ
 
PPTX
Necrosis,gangrene and apoptosis
byDr Neha Mahajan
 
PPT
APOPTOSIS
byAMORMIO34346
 
PPT
Cell injury, adaptation, and death fix
byRaniagaye Mansibang
 
PDF
Two principal pathways of apoptosis signal transduction. (Dissertation Thesis)
byAbeba Demelash
 
PPTX
Panchakarma Equipments from Poornimas
bypoornimaspanchakarmaequipments
 
PDF
GRANDHILL PHASE II RESIDENTIAL PLOTS FOR SALE OFF OLD MADRAS ROAD, BANGALORE
byBangalore Prj
 
PPTX
Estructura del computador
byGabrielCastillo04
 
PPTX
Partes del computador
byNoreisy Paredes
 
PDF
Acta de constitución del proyecto
byEdwin Ardila
 
PPTX
Greyston Wall of Gratitude
byKaren Tumelty
 
PPTX
The summer of beautiful white horse
byrisidin
 
PPTX
Mm unit 3point1
byRai University
 
PPT
Mm unit 4point3
byRai University
 
Apoptosis (presentation)
byLeo Vang
 
Seminar- recent advances in apoptosis
byEkta Jajodia
 
Cell injury, adaptation, and death fix
byKenneth Juatas
 
Cell Injury And Cell Death (2006)(1)
byaxix
 
Apoptosis
byUSmile Ï Ṩṃïlệ
 
Necrosis,gangrene and apoptosis
byDr Neha Mahajan
 
APOPTOSIS
byAMORMIO34346
 
Cell injury, adaptation, and death fix
byRaniagaye Mansibang
 
Two principal pathways of apoptosis signal transduction. (Dissertation Thesis)
byAbeba Demelash
 
Panchakarma Equipments from Poornimas
bypoornimaspanchakarmaequipments
 
GRANDHILL PHASE II RESIDENTIAL PLOTS FOR SALE OFF OLD MADRAS ROAD, BANGALORE
byBangalore Prj
 
Estructura del computador
byGabrielCastillo04
 
Partes del computador
byNoreisy Paredes
 
Acta de constitución del proyecto
byEdwin Ardila
 
Greyston Wall of Gratitude
byKaren Tumelty
 
The summer of beautiful white horse
byrisidin
 
Mm unit 3point1
byRai University
 
Mm unit 4point3
byRai University
 

Similar to 4.pathology apoptosis2016

PPTX
Apoptosis..pptx
byssuser12303b
 
PPTX
apopwqgdcbhuredgbcfyhhvhcctosis (1).pptx
bySarithaRani4
 
DOCX
Previous year question on apoptosis based on neet pg, usmle, plab and fmge or...
byAbhishek Gupta
 
PPTX
APOPTOSIS.pptx
byGowthun
 
PPTX
5. cell injury...APOPTOSIS ppt.programmed cell death
byarpitaacharia1
 
PPTX
CELL DEATH presentation in oral pathology
byAhteshamSami1
 
PPTX
1. CELL DEATH 17-5-2023 oral pathology.pptx
byAhteshamSami1
 
PPTX
Cell injury apoptosis lect 08jan 2020
byDrAbdulAzizShaikh
 
PDF
apoptosis lecture-powerpoint slides (1) (1).pdf
bySrimathideviJ
 
PDF
The cellular basis of disease cell injury apoptosis and necrosis
bySudershan8
 
PDF
Apoptosis basics + microphotographs
byashish223
 
PPT
Apoptosis. and mechanism of cell death ppt
byvarsha uma
 
PPTX
Cell death
byAmani Riyadh
 
PDF
Apoptosis.pdf
bychimerasally
 
PPTX
APOPTOSIS-PARAMEDICAL LECTUR for teaching everdayE.pptx
byPankhuri Gupta
 
PPTX
Apoptosis
byAj Cocjin
 
PPTX
cell Death- Apoptosis, Necrosis, Autophagy .pptx
bydeveshvarichaudhary
 
PPTX
Cell etiology : Cell death and Apoptosis.pptx
bypritisah4069
 
PPTX
apoptosis.............................pptx
byHarishankarSharma27
 
PPTX
Apoptosis - An Introduction
byMallikharjuna Palle B
 
Apoptosis..pptx
byssuser12303b
 
apopwqgdcbhuredgbcfyhhvhcctosis (1).pptx
bySarithaRani4
 
Previous year question on apoptosis based on neet pg, usmle, plab and fmge or...
byAbhishek Gupta
 
APOPTOSIS.pptx
byGowthun
 
5. cell injury...APOPTOSIS ppt.programmed cell death
byarpitaacharia1
 
CELL DEATH presentation in oral pathology
byAhteshamSami1
 
1. CELL DEATH 17-5-2023 oral pathology.pptx
byAhteshamSami1
 
Cell injury apoptosis lect 08jan 2020
byDrAbdulAzizShaikh
 
apoptosis lecture-powerpoint slides (1) (1).pdf
bySrimathideviJ
 
The cellular basis of disease cell injury apoptosis and necrosis
bySudershan8
 
Apoptosis basics + microphotographs
byashish223
 
Apoptosis. and mechanism of cell death ppt
byvarsha uma
 
Cell death
byAmani Riyadh
 
Apoptosis.pdf
bychimerasally
 
APOPTOSIS-PARAMEDICAL LECTUR for teaching everdayE.pptx
byPankhuri Gupta
 
Apoptosis
byAj Cocjin
 
cell Death- Apoptosis, Necrosis, Autophagy .pptx
bydeveshvarichaudhary
 
Cell etiology : Cell death and Apoptosis.pptx
bypritisah4069
 
apoptosis.............................pptx
byHarishankarSharma27
 
Apoptosis - An Introduction
byMallikharjuna Palle B
 

More from Helder Jorge Semedo Pires

PPT
G.2014-immuno~ (10a.humoral immunity'bcell'-jyh)
byHelder Jorge Semedo Pires
 
PPT
G.2014-immuno~ (10b.humoral immunity'bcell'-jyh)2016-11-10
byHelder Jorge Semedo Pires
 
PPT
G.2014-immuno~ (7.innate immunity-wjy)
byHelder Jorge Semedo Pires
 
PPT
2.g.2014-patho~ (2.adaptation-wyl)
byHelder Jorge Semedo Pires
 
PPT
G.2014-immuno~ (14.imm.tolerance & autoimm. diseases-ls)2
byHelder Jorge Semedo Pires
 
PPT
G.2014-immuno~ (15.immunodeficiency diseases-xm)
byHelder Jorge Semedo Pires
 
PPT
1.g.2014-patho~ (1.introduction-wyl)
byHelder Jorge Semedo Pires
 
PPT
G.2014-immuno~ (9.apc-jyh)
byHelder Jorge Semedo Pires
 
PPT
G.2014-immuno~ (2.antigen-lyj)
byHelder Jorge Semedo Pires
 
PPT
G.2014-immuno~ (8.adaptive immunity'tcell'-jyh)
byHelder Jorge Semedo Pires
 
PPT
G.2014-immuno~ (13.hypersensitivity-ls)
byHelder Jorge Semedo Pires
 
PPT
1.general introduction to medical parasitology
byHelder Jorge Semedo Pires
 
PPT
2.a.lumbricoides and hookworms
byHelder Jorge Semedo Pires
 
PPTX
G.2014 pathophysio~ (1'.introduction-lr)
byHelder Jorge Semedo Pires
 
PPT
G.2014-immuno~ (3.antibody-lyj)
byHelder Jorge Semedo Pires
 
PPT
G.2014-immuno~ (18.immunologic application-xm)
byHelder Jorge Semedo Pires
 
G.2014-immuno~ (10a.humoral immunity'bcell'-jyh)
byHelder Jorge Semedo Pires
 
G.2014-immuno~ (10b.humoral immunity'bcell'-jyh)2016-11-10
byHelder Jorge Semedo Pires
 
G.2014-immuno~ (7.innate immunity-wjy)
byHelder Jorge Semedo Pires
 
2.g.2014-patho~ (2.adaptation-wyl)
byHelder Jorge Semedo Pires
 
G.2014-immuno~ (14.imm.tolerance & autoimm. diseases-ls)2
byHelder Jorge Semedo Pires
 
G.2014-immuno~ (15.immunodeficiency diseases-xm)
byHelder Jorge Semedo Pires
 
1.g.2014-patho~ (1.introduction-wyl)
byHelder Jorge Semedo Pires
 
G.2014-immuno~ (9.apc-jyh)
byHelder Jorge Semedo Pires
 
G.2014-immuno~ (2.antigen-lyj)
byHelder Jorge Semedo Pires
 
G.2014-immuno~ (8.adaptive immunity'tcell'-jyh)
byHelder Jorge Semedo Pires
 
G.2014-immuno~ (13.hypersensitivity-ls)
byHelder Jorge Semedo Pires
 
1.general introduction to medical parasitology
byHelder Jorge Semedo Pires
 
2.a.lumbricoides and hookworms
byHelder Jorge Semedo Pires
 
G.2014 pathophysio~ (1'.introduction-lr)
byHelder Jorge Semedo Pires
 
G.2014-immuno~ (3.antibody-lyj)
byHelder Jorge Semedo Pires
 
G.2014-immuno~ (18.immunologic application-xm)
byHelder Jorge Semedo Pires
 

Recently uploaded

PPTX
YSPH VMOC Special Report - Measles - The Americas 1-25-2026
byYale School of Public Health - The Virtual Medical Operations Center (VMOC)
 
PPTX
West Hatch High School - GCSE Media Studies
byWestHatch
 
PDF
West Hatch High School - GCSE Media Specification
byWestHatch
 
PPTX
Grade 9 and 10 learner Fuse and Switch.pptx
byCarlJohnCabayao
 
PPTX
HABIT. Cognitive process. I Semester Shilpa Hotakar pptx
bySHILPA HOTAKAR
 
PPTX
Toba Tek Singh - Visualising Partition through Manto's Lens
bymiraljoshi48
 
PPTX
West Hatch High School - GCSE Art Presentation
byWestHatch
 
PPTX
MENTAL STATUS EXAMINATION Part-1.Shilpa hotakar.pptx
bySHILPA HOTAKAR
 
PPTX
literary theory and criticism by Vivek p
byvivekrathodborda
 
PDF
Darwinism: Theory of Natural Selection and Origin of Species
byIPGDCWA,NAMPALLY
 
PPTX
Drug Distribution in Pharmacology: Mechanisms, Barriers, Factors & Volume of ...
byamrin3379
 
PPTX
28 January 2026 Rebecca Frankum Are high-stakes exams and assessments still r...
byEduSkills OECD
 
PPTX
West Hatch High School -- GCSE Geography
byWestHatch
 
PDF
Information about Presentation strategies
bymansivaja18126
 
PDF
Bishan_Singh_Presentation - Toba tek Singh
bygopalsinhchauhan9313
 
PPTX
West Hatch High School - GCSE Spanish Presentation
byWestHatch
 
PPTX
COMMUNICATION ITS PROCESS ELEMENTS & BARRIER .pptx
byPoojaSen20
 
PPTX
'Colonial Mentality and Social Identity in Karma by Khushwant Singh'
byKrishnarajsinh Parmar
 
PPTX
Master of Punjabi Short Story "kartar singh duggal
bybhautikbharwad4
 
PPTX
Drugs modulating serotonergic system.pptx
byNorman Arockiaraj G
 
YSPH VMOC Special Report - Measles - The Americas 1-25-2026
byYale School of Public Health - The Virtual Medical Operations Center (VMOC)
 
West Hatch High School - GCSE Media Studies
byWestHatch
 
West Hatch High School - GCSE Media Specification
byWestHatch
 
Grade 9 and 10 learner Fuse and Switch.pptx
byCarlJohnCabayao
 
HABIT. Cognitive process. I Semester Shilpa Hotakar pptx
bySHILPA HOTAKAR
 
Toba Tek Singh - Visualising Partition through Manto's Lens
bymiraljoshi48
 
West Hatch High School - GCSE Art Presentation
byWestHatch
 
MENTAL STATUS EXAMINATION Part-1.Shilpa hotakar.pptx
bySHILPA HOTAKAR
 
literary theory and criticism by Vivek p
byvivekrathodborda
 
Darwinism: Theory of Natural Selection and Origin of Species
byIPGDCWA,NAMPALLY
 
Drug Distribution in Pharmacology: Mechanisms, Barriers, Factors & Volume of ...
byamrin3379
 
28 January 2026 Rebecca Frankum Are high-stakes exams and assessments still r...
byEduSkills OECD
 
West Hatch High School -- GCSE Geography
byWestHatch
 
Information about Presentation strategies
bymansivaja18126
 
Bishan_Singh_Presentation - Toba tek Singh
bygopalsinhchauhan9313
 
West Hatch High School - GCSE Spanish Presentation
byWestHatch
 
COMMUNICATION ITS PROCESS ELEMENTS & BARRIER .pptx
byPoojaSen20
 
'Colonial Mentality and Social Identity in Karma by Khushwant Singh'
byKrishnarajsinh Parmar
 
Master of Punjabi Short Story "kartar singh duggal
bybhautikbharwad4
 
Drugs modulating serotonergic system.pptx
byNorman Arockiaraj G
 

4.pathology apoptosis2016

  • 1.
    Pathology ---Cell Injury, DeathAnd Adaptation Xi’an Jiaotong University 2017.1.2017.1.
  • 2.
    XI’AN JIAOTONG UNIVERSITY Page 2 ProgrammedCell Death (PCD) Refers to processes that are lethal to individual cells and are regulated by pre-existing signaling pathways. PCD is part of the balance between the life and death of cells and determines that a cell dies when it is no longer useful or when its survival may be harmful to the larger organism.
  • 3.
    XI’AN JIAOTONG UNIVERSITY Page 3 Apoptosis Apathway of cell death that is induced by a tightly regulated suicide program in which cells destined to die, activate intrinsic enzymes that degrade the cells’own nuclear DNA and nuclear and cytoplasmic proteins Apoptosis is a form of PCD that relies exclusively on the caspase cascade Originally, PCD was synonymous with apoptosis. However, mutant mice lacking the key elements of the apoptotic machinery develop almost normally. This observation indicated that alternatives to apoptosis exist. Thus, a number of mechanisms of PCD have been identified
  • 4.
    XI’AN JIAOTONG UNIVERSITY Page 4 Morphologicchanges Cell shrinkage Recall that in other forms of cell injury, an early feature is cell swelling, not shrinkage Chromatin condensation and fragmentation. The most characteristic feature of apoptosis Formation of cytoplasmic blebs and apoptotic bodies.
  • 5.
    XI’AN JIAOTONG UNIVERSITY Page 5 Phagocytosisof apoptotic cells or cell bodies, usually by macrophages. Histologically, apoptotic cell appears as a round or oval mass of intensely eosiniphilic cytoplasm (H&E staining) with or without fragments of dense nuclear chromatin. Because these pieces are quickly formed and phagocytosed, without eliciting inflammation, even substantial apoptosis may be more difficult to detect histologically.
  • 6.
    XI’AN JIAOTONG UNIVERSITY Page 6 Sequenceof ultrastructural changes in apoptosis of glandular epithelial cells. The earliest change is segregation of the chromatin in sharply circumscribed masses that abut nuclear envelop (1). Convolution of the nuclear and cell outlines precedes fragmentation of the nucleus and budding of the cell as a whole to produce membrane-bound apoptotic bodies of varying size and structure(2), which are phagocytosed by adjacent epithelial cells(3) and macrophages(4) and degraded within lysosomes(5). Finally, the bodies are reduced to unrecognizable residues(6). An occasional apoptotic body escapes phagocytosis and is shed into the gland lumen(7) where it undergoes degenerative changes similar to those occurring in necrosis(8)
  • 7.
    XI’AN JIAOTONG UNIVERSITY Page 7 Earlyapoptosis of acinar cell in rat pancreas after duct ligation. Note granular fibrillar core remnant of nucleolus adjacent condensed chromatin(arrow) adjacent cells appear normal(x6200) Apoptotic HeLa cell after addition of actinomycin D to cultured medium(SEM x9000)
  • 8.
    XI’AN JIAOTONG UNIVERSITY Page 8 Earlyapoptotosis of rat prostatic epithelial cell after castration.Note irregular cell outline, basal position of cell in epithelium, segregated chromatin in nuclear fragments and whorling of endoplasmic reticulum(x8200) Intact extracellular condensed apoptotic bodies, some containing characteristic nuclear fragments, derived from transplanted EMT6 sarcoma cell after mild hyperthermic treatment(x10,000)
  • 9.
    XI’AN JIAOTONG UNIVERSITY Page 9 Crowdedcondensed intraepithelial apoptotic bodies derived from pancreas acinar cell after subcutaneous cerulein injection(x8,300). Well preserved large apoptotic body with characteristic nuclear fragment phagocytosed by a tubular epithelial cell in rat kidney after ureteric ligation(x4500)
  • 10.
    XI’AN JIAOTONG UNIVERSITY Page 10 Partlydegraded apoptotic bodies, one with nuclear fragments(arrow), in intraepithelial macrophage in rat pancreas after duct ligation(x7500) Well-preserved hepatocyte-derived apoptotic body with condensed cytoplasm, crowded organelles, and characreistic nuclear fragment phagocytosed by Kupffer cell in rat liver after portal vein branch ligation
  • 11.
    XI’AN JIAOTONG UNIVERSITY Page 11 Multiplepartly degraded apoptotic bodies in intraepithelial macrophage in rat pancreas after duct ligation(x6700) Residual bodies in cytoplasm of intraepithelial macrophage in rat pancreas after duct ligation(x7500)
  • 12.
    XI’AN JIAOTONG UNIVERSITY Page 12 Luminalapoptotic bodies in lactating mouse breast after weaning(A),intact apoptotic bodies with characteristic nuclear fragment. (B), Partly degraded apoptotic body with nuclear fragment showing decreased density and loss of membrane integrity. (C) , Degraded apoptotic body showing membrane loss and dispersal of nuclear fragments(arrows) and organelles.(x3000, 3900, 5200)
  • 13.
    XI’AN JIAOTONG UNIVERSITY Page 13 Apoptoticcells and bodies in rat liver after portal vein branch ligation. Note apoptotic hepatocyte with characteristic crescentic chromatin clumps in nucleus(1), budding cells(2), and typic apoptotic body with basophilic chromatin dot(3). Also note numerous small inconspicuous phagocytosed apoptotic bodies without nuclear fragments in the backgroud Clusters of apoptotic bodies in rat parotid after duct ligation. Some small clusters may represent bodies derived from a single cell(short arrow). Larger clusters are likely to be phagocytosed apoptotic bodies within intraepithelial macrophages(long arrow)
  • 14.
    XI’AN JIAOTONG UNIVERSITY Page 14 Aoptosisof epithelial cells(arrow) in ductules of normal human breast Apoptotic bodies in intraepithelial macrophages in late secretory human endometrium
  • 15.
    XI’AN JIAOTONG UNIVERSITY Page 15 Causeof apoptosis Apoptosis in physiologic situations Death by apoptosis is a normal phenomenon that serves to eliminate cells that are no longer needed, and to maintain a steady number of various cell populations in tissue The destruction of cells during embryogenesis Fetal development involves the sequential appearance and regression of many evolutionary relics.
  • 16.
    XI’AN JIAOTONG UNIVERSITY Page 16 Involutionof hormone-dependent tissue upon hormone withdrawal menstrual cycle, lactating breast after weaning Cell loss in proliferating cell populations turnover of intestinal crypt epithelia, bone marrow lymphocytes, Elimination of potentially harmful self-reactive lymphocytes either before or after they have completed their maturation Death of host cells that have served their useful purpose neutrophils, lymphocytes at the end of response Cell death induced by cytotoxic T lymphocytes.
  • 17.
    XI’AN JIAOTONG UNIVERSITY Page 17 Apoptosisin pathologic situations Apoptosis eliminates cells that are injured beyond repair without eliciting a host reaction, thus limiting collateral tissue damage. DNA damage radiation, cytotoxic anticancer drugs, hypoxia, either directly or via free radicals Accumulation of misfolded proteins excessive amount of these proteins in ER leads to a condition called ER stress, which culminates in apoptotic cell death, which may cause several degenerative disease of CNS
  • 18.
    XI’AN JIAOTONG UNIVERSITY Page 18 Celldeath in certain infections Directly such as adenovirus –cytolysis,indirectly cell mediated immune response ； Conversly, HPV infection Pathologic atrophy in parenchymal organs after duct obstruction, such as in pancreas, paroit gland, and kidney
  • 19.
    XI’AN JIAOTONG UNIVERSITY Page 19 Mechanismof Apoptosis Apoptosis results from the activation of enzymes called caspase. Two distinct pathways converge on caspase activation: the mitochondrial pathway and the death receptor pathway
  • 20.
    XI’AN JIAOTONG UNIVERSITY Page 20 Thetwo pathways of apoptosis differ in their induction and regulation, and both culminate in the activation of "executioner" caspases. The induction of apoptosis is dependent on a balance between pro- and anti-apoptotic signals and intracellular proteins. The figure shows the pathways that induce apoptotic cell death, and the anti-apoptotic proteins that inhibit mitochondrial leakiness and cytochrome c-dependent caspase activation and thus function as regulators of mitochondrial apoptosis.
  • 21.
    XI’AN JIAOTONG UNIVERSITY Page 21 Necroptosis Ahybrid form of cell death that shares aspects of both necrosis and apoptosis （ programmed necrosis) Morphologically, and to some extent biochemically, it resembles necrosis, both characterized by loss of ATP, swelling of the cell and organelles, generation of ROS, release of lysosomal enzymes and ultimately rupture of the plasma membrane as discussed early
  • 22.
    XI’AN JIAOTONG UNIVERSITY Page 22 Mechanistically,it is triggered by genetically programmed signal transduction events that culminate in cell death. In this respect it resembles programmed cell death---the hallmark of apoptosis. In sharp contrast to apoptosis, the genetic program that drives necroptosis does not result in caspase activation (caspase independent programmed cell death)
  • 23.
    XI’AN JIAOTONG UNIVERSITY Page 23 TNF-inducedformation of apoptotic and necroptotic signaling complexes. nature immunology 2011,12(12):1143
  • 24.
    XI’AN JIAOTONG UNIVERSITY Page 24 Necroptosisis induced by various stimuli. Different necroptotic stimuli are recognized or sensed by specific receptors or sensors on the cell surface or inside cells
  • 25.
    XI’AN JIAOTONG UNIVERSITY Page 25 Pyroptosis Bearingsome biochemical similarities with apoptosis and releasing fever producing cytokine IL-1 Initially described in immune cells during antimicrobial response, is a caspase-1 or caspase-11- dependent regulated type of cell death that plays a central role in inflammation and immunity
  • 26.
    XI’AN JIAOTONG UNIVERSITY Page 26 Anoikis Activatedby Loss of Cell Attachments Anoikis (Greek: “homelessness”) is a variety of apoptosis that occurs in epithelial cells and is caused by loss of cell adhesion or inappropriate cell adhesion Correct binding of a cell to the ECM helps to determine whether that cell is in its appointed location
  • 27.
    XI’AN JIAOTONG UNIVERSITY Page 27 Mechanismsof anoikis. A. Normal. Under normal circumstances, epithelial cells are bound to their native ECM by transmembrane molecules, including α- and β-integrins. These molecules activate survival signals and block both intrinsic and extrinsic apoptotic signaling pathways. B. Loss of attachment. When the cell’s integrins are not bound, or not bound by the appropriate ECM moieties, their survival signals are eliminated. Then, activation of apoptosis by death receptor signaling is no longer blocked, and apoptosis may proceed.
  • 28.
    XI’AN JIAOTONG UNIVERSITY Page 28 EntosisIs a Cell-Eat-Cell Form of Cell Death Entosis is a type of cellular cannibalism in which cells that are not professional phagocytes engulf nearby living cells. Aggressor cells may engulf cells of either the same or other lineages. For example, hepatocytes may ingest and destroy autoreactive T lymphocytes, thus inhibiting experimental autoimmune liver disease. More often, Entosis is seen in tumors
  • 29.
    XI’AN JIAOTONG UNIVERSITY Page 29 SUMMARY: MorphologicAlterations in Injured Cells Reversible cell injury: Cell swelling, fatty change, plasma membrane blebbing and loss of microvilli, mitochondrial swelling, dilation of ER, eosinophilia (due to decreased cytoplasmic RNA).
  • 30.
    XI’AN JIAOTONG UNIVERSITY Page 30 Irreversiblecell injury Necrosis: increased eosinophilia; nuclear shrinkage, fragmentation, and dissolution; breakdown of plasma membrane and organellar membranes; leakage and enzymatic digestion of cellular contents(tissue pattern/ inflammation). Apoptosis: nuclear chromatin condensation; formation of apoptotic bodies (fragments of nuclei and cytoplasm)
  • 31.
    XI’AN JIAOTONG UNIVERSITY Page 31 Keyconcepts on apoptosis ● Regulated mechanism of cell death that serves to eliminate unwanted and irreparably damaged cells, with the least possible host reaction ● Characterized by enzymatic degradation of proteins and DNA, initiated by caspases; and by recognition and removal of dead cells by phagocytes
  • 32.
    XI’AN JIAOTONG UNIVERSITY Page 32 ●Initiated by two major pathways: Mitochondrial (intrinsic) pathway is triggered by loss of survival signals, DNA damage and accumulation of misfolded proteins (ER stress); associated with leakage of pro-apoptotic proteins from mitochondrial membrane into the cytoplasm, where they trigger caspase activation; inhibited by anti-apoptotic members of the Bcl family, which are induced by survival signals including growth factors. Death receptor (extrinsic) pathway is responsible for elimination of self-reactive lymphocytes and damage by cytotoxic T lymphocytes; is initiated by engagement of death receptors (members of the TNF receptor family) by ligands on adjacent cells.
  • 33.
    XI’AN JIAOTONG UNIVERSITY Page 33 Keyconcepts on necroptosis and pyroptosis ● Necroptosis resembles necrosis morphologically and apoptosis mechanistically as a form of programmed cell death ● Necroptosis is triggered by ligation of TNFR1, and viral proteins of RNA and DNA viruses ● Necroptosis is caspase-independent but dependent on signalling by the RIP1 and RIP3 complex (receptor-interacting protein 1/3, RIP1/3)
  • 34.
    XI’AN JIAOTONG UNIVERSITY Page 34 ●RIP1-RIP3 signally reduces mitochondria ATP generation, cause production of ROS, and permeabilize lysosomal membranes, thereby causing cellular swelling and membrane damage as occurs in necrosis. ● Release of cellular contents evokes an inflammatory reaction as in necrosis ● Pyroptosis occurs in cells infected by microbes. It involves activation of caspase-1 which cleaves the precursor form of IL- 1 to generate biologically active IL-1. Caspase-1 along with closely related caspase-11 also cause death of the infected cell.
  • 35.
    XI’AN JIAOTONG UNIVERSITY Page 35 Autophagy Aprocess in which a cell eat its own content, based on both the cargoes involved and how they arrive at Lysosomes, Autophagic degradation is generally divided into three categories ● Chaperone-mediated autophage (direct translocation across the lysosomal membrane by chaperone proteins) ● Microautophagy (inward invagination of lysosomal membrane for delivery) ● Macroautophagy ( the major form of autophagy involving the sequestration and transportation of protein of cytosol in a double membrane bound autophagic vacuole
  • 36.
    XI’AN JIAOTONG UNIVERSITY Page 36 Typesof autophagy. A. Macroautophagy. Cytoplasmic organelles are partially sequestered by an open membrane, the phagophore. Upon closure by fusion, the phagophore becomes an autophagosome, which then delivers its contents to a lysosome. Lysosomal enzymes degrade the contents to small molecules for reutilization. B. Microautophagy. Cytosolic cargoes are engulfed by invagination of the lysosomal membrane.The contents are then degraded by lysosomal enzymes. C. Chaperone-mediated autophagy. Proteins conjugated to chaperones (e.g., Hsc70) are recognized by lysosomal receptor proteins (LAMP-2A) and translocated to the lysosomal interior, where they are received by a second chaperone and then degraded. The original, extralysosomal chaperone survives to work further.
  • 37.
    XI’AN JIAOTONG UNIVERSITY Page 37 Autophagy.Cellular stresses, such as nutrient deprivation, activate autophagy genes (Atg genes), which initiate the formation of membrane- bound vesicles in which cellular organelles are sequestered. These vesicles fuse with lysosomes, in which the organelles are digested, and the products are used to provide nutrients for the cell. The same process can trigger apoptosis, by mechanisms that are not well defined.
  • 38.
  • 39.
  • 40.
    XI’AN JIAOTONG UNIVERSITY Page 40 Oxygendeprivation ----Hypoxia Cause of Hypoxia: Reduced blood flow—ischemia Inadequate oxygenation—cardiorespiratory failure Decreased oxygen-carrying capacity of the blood---anemia or CO poisoning or severe blood loss Hypoxia → ATP synthesis↓ (affects oxidative phosphorylation and ATP synthesis) → membrane damage → cell injury.
  • 41.
    XI’AN JIAOTONG UNIVERSITY Page 41 Physicalagents  Mechanical trauma; Extremes of temperatures Abrasion(scratch) represents the tearing away of epidermal cells by fraction or crushing, such a defect may or may not penetrate the corium Multiple Laceration of liver caused by laterial compression of thorax. There were no external wounds of fracture. Death resulted from hemoperitoneum contusion Solar Dermatitis
  • 42.
    XI’AN JIAOTONG UNIVERSITY Page 42 Mechanismsby which ionizing radiation at low and high doses causes cell death Radiation
  • 43.
    XI’AN JIAOTONG UNIVERSITY Page 43 p53-mediatedapoptosis. p53 is recruited to areas of DNA damage following external irradiation. Activated p53 activates p21WAF/CIP1, which halts cell cycle progression at the G1/S and G2/M transition points. If DNA damage is irreparable, p53 activates transcription of NOXA and PUMA, which alter the balance of proapoptotic and antiapoptotic Bcl-2 family proteins at the mitochondrial membrane in favor of apoptosis. The MPTP is opened leading to apoptosis.
  • 44.
    XI’AN JIAOTONG UNIVERSITY Page 44 Chemicalagents  Any chemical substance can cause injury, even normal substances such as glucose or salt.  Poisons can cause severe damage at the cellular level by altering membrane permeability, osmotic homeostasis, or the integrity of an enzyme and result in the death of the whole organism.  eg.: air pollutants, insecticides, carbon monoxide, strong acids or alkali, and social “stimuli” such as alcohol, and other poisons such as arsenic, cyanide, melamine, even therapeutic drugs.
  • 45.
    XI’AN JIAOTONG UNIVERSITY Page 45 Infectiousagents Virus, Rickettsiae, Bacteria, Fungi, Parasites. Immunologic reactions May be lifesaving or lethal. Immune system defends against biologic agents; may lead to cell injury. e.g., hypersensitivity: anaphylaxis (asthma), autoimmune diseases (systemic lupus erythematosus, SLE), etc.
  • 46.
    XI’AN JIAOTONG UNIVERSITY Page 46 Nutritionalimbalances Protein-calorie insufficiency; Specific vitamin deficiency; The excesses of nutrition: e.g. obesity markedly increases the risk for type 2 diabetes, AS and many disorders.
  • 47.
    XI’AN JIAOTONG UNIVERSITY Page 47 Geneticabnormalities Chromosome abnormality -Down syndrome Single base pair mutation– sickle cell anemia Mutations may cause alteration of functional proteins, influencing metabolism Somatic mutations involved in activation of proto-oncogene and deletion of tumor suppressor gene may lead to cellular malignant transformation.
  • 48.
    XI’AN JIAOTONG UNIVERSITY Page 48 Mechanismsof cell injury ● The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity. ● The consequences of cell injury depend on the type, status and adaptability of the injured cell. ● Cell injury results from different biochemical mechanisms acting on several essential cellular components
  • 49.
    XI’AN JIAOTONG UNIVERSITY Page 49 Theprincipal biochemical mechanisms and sites of damage in cell injury. (1) ATP generation, largely via mitochondrial aerobic respiration; (2) Cell membrane integrity, critical to cellular ionic and osmotic homeostasis ;(3) Protein synthesis (4) The integrity of the genetic apparatus
  • 50.
    XI’AN JIAOTONG UNIVERSITY Page 50 Mitochondriadamage Mitochondria are critical players in cell injury and cell death by all pathways. Three major consequences of mitochondria damage ● Mitochondria damage often results in the formation of a high- conductance channel in the mitochondria membrane, called mitochondrial permeability transition pore ● Abnormal oxidative phosphorylation also leads to the formation of reactive oxygen species, ● The mitochondria sequester between their outer and inner membranes several proteins that are capable of activating apoptotic pathway.
  • 51.
    XI’AN JIAOTONG UNIVERSITY Page 51 Roleof mitochondria in cell injury and death. Mitochondria are affected by a variety of injurious stimuli and their abnormalities lead to necrosis or apoptosis.
  • 52.
    XI’AN JIAOTONG UNIVERSITY Page 52 Influxof Sources and consequences of increased cytosolic calcium in cell injury. ● The accumulation of Ca2+ in mitochondria results in opening of the mitochondria permeability transition pore ●increased cytosolic Ca2+ activates a number of enzymes with potentially deleterious effects on cells ●increased intracellular Ca2+ levels also result in the induction of apoptosis by direct activation of caspases and by increasing mitochondrial permeability.
  • 53.
    XI’AN JIAOTONG UNIVERSITY Page 53 Thegeneration, removal, and role of reactive oxygen species (ROS) in cell injury. The production of ROS is increased by many injurious stimuli. These free radicals are removed by spontaneous decay and by specialized enzymatic systems. Excessive production or inadequate removal leads to accumulation of free radicals in cells, which may damage lipids (by peroxidation), proteins, and deoxyribonucleic acid (DNA), resulting in cell injury.
  • 54.
    XI’AN JIAOTONG UNIVERSITY Page 54 Defectsin membrane permeability Mechanisms of membrane damage in cell injury. Decreased O2 and increased cytosolic Ca2+ typically are seen in ischemia but may accompany other forms of cell injury. Reactive oxygen species, which often are produced on reperfusion of ischemic tissues, also cause membrane damage
  • 55.
    XI’AN JIAOTONG UNIVERSITY Page 55 Damageto DNA and proteins Cells have mechanisms that repair damage to DNA, but if DNA damage is too severe to be corrected(e.g., after exposure to DNA damaging drugs, radiation, or oxidative stress), the cell initiates a suicide program that results in death by apoptosis
  • 56.
    XI’AN JIAOTONG UNIVERSITY Page 56 Aging Biologicalaging can be defined as a constellation of deleterious functional and structural changes that are inevitable consequences of longevity. Importantly, aging must be distinguished from disease. Although the aging process may increase vulnerability to many diseases, it is independent of the pathogenesis of any specific illness. Biological longevity is generally interpreted as the extension of life well beyond the period of reproduction and childrearing
  • 57.
    XI’AN JIAOTONG UNIVERSITY Page 57 Lifespan of animals in their natural environment compared with that in a protected habitat. Note that both curves reach the same maximal life span. Decrease in human physiologic capacities as a function of age.
  • 58.
    XI’AN JIAOTONG UNIVERSITY Page 58 Cellularaging the result of a progressive decline in the life span and functional capacity of cells. The Hallmarks of Aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication
  • 59.
    XI’AN JIAOTONG UNIVERSITY Page 59 1960Leonard Hayflik’s work by counting the number of times that population of cells had doubled . When the cells enter into senescence , they could remain viable but nonproliferating for as long as a year
  • 60.
    XI’AN JIAOTONG UNIVERSITY Page 60 BarbaraMcClintock 1983 Nobel Prize Telomeres detected by FISH(left),( right) karyotype seen in left compared with that of cells have been deprived of TRF2
  • 61.
    XI’AN JIAOTONG UNIVERSITY Page 61 Roleof large T antigen in circumventing senescence Inactivation of both pRB and p53 is needed to ensure that these cells do not senesce in culture. This can be archived through the expression of the SV40 large T antigen in the target cells
  • 62.
    XI’AN JIAOTONG UNIVERSITY Page 62 Hutchinson-Guilfordprogeria. A 10-year-old girl shows the typical features of premature aging associated with progeria.
  • 63.
    XI’AN JIAOTONG UNIVERSITY Page 63 Interventionsthat Might Extend Human Health span The nine hallmarks of aging are shown together with those therapeutic strategies for which there is proof of principle in mice