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See above: Injurious stimulus or inability to adapt lead to reversible cell injury. If point of irreversibility is reached necrosis.

Types of Cell Death y Apoptosis: o Usually a regulated, controlled process o Plays a role in embryogenesis o A method of controlled cell population o Programmed cell death o Necessary for maturation of cell development y Necrosis: o Always pathologic the result of irreversible injury o Numerous causes o The sum of all morphologic changes occurring after cell death o Types:  Coagulative (most common)  Liquefactive  Caseous: combination of liquefactive and coagulative necrosis  Fat necrosis  Gangrenous necrosis: combination of liquefactive and coagulative necrosis Coagulative Necrosis y Cell s basic outline is preserved, but not nucleus. y Homogeneous, glassy eosinophlic appearance due to loss of cytoplasmic RNA (basophilic) and glycogen (granular) y Nucleus may show pyknosis, karyloysis, or karyorrhexis (definitions from last lecture)

SY 2011-2012

Subject: Pathology Topic: Cell Injury and Death 2 & Cell Growth Lecturer: Dr. Luis Cruz Date of Lecture: 06/14/2011 Transcriptionist: CELLOmapas Editor: kChristel Paok Pages: 17

Liquefactive Necrosis y Usually due to enzymatic dissolution of necrotic cells (usually due to release of proteolytic enzymes from neutrophils) y Most often seen in CNS and in abscesses (aka, pus, purulence, or liquefaction)

See above: cross section of kidney with pale wedge shaped lesion necrosis. Kidney is an end organ, ie supplied by one artery, so should that artery occlude infarct. Infarct is wedge shaped because of occlusion of the artery and its various branches.

See above: lung with abscess

See above: abscess of lung histologically. An abscess, plain and simple, is a collection of neutrophils.

See above: the blue region is the viable area, whereas the pink is the non-viable area.

Fatty acids released via hydrolysis react with calcium to form chalky white areas saponification

See above: Pancreatitis, grossly

See both diagrams above: liquefactive necrosis of brain, grossly, usually brought about by occlusion of blood supply to area.

See above: chalky white deposits

See above: typical appearance of enzymatic fat necrosis. Fat cells surrounded by liquefaction because of action of lipases on fat tissue.

See both diagrams above: liquefactive necrosis under microscope.

Enzymatic Fat Necrosis y Results from hydrolytic action of lipases on fat y Most often seen in and around the pancreas; can also be seen in other fatty areas of the body, usually due to trauma

Caseous Necrosis y Grossly: resembles cheese y Microscopically: amorphous, granular eosinophilic material surrounded by a rim of inflammatory cells o No visible cell outlines tissue architecture is obliterated y Usually seen in infections (esp, mycobacterial and fungal infections)

See above: Caseous necrotic lesion in upper right corner

See above: Pediatric lung. Note centrally located TB lesion, aka, Gohn s lesion. In adults, TB is usually located apically.

Gangrenous Necrosis y Most often seen on extremities, usually due to trauma or physical injury y Dry gangrene no bacterial superinfection; tissue appears dry y Wet gangrene bacterial superinfection has occurred; tissue looks wet and liquefactive

Above: dry gangrene in diabetic foot

Above: wet gangrene with associated abscess

See above: Apically located caseous lesions in elderly patient. These are granulomatous lesions.


 Most often due to decreased production of apoproteins for fat transport Decreased use of fat by cells Overproduction of fat in cells

Above: Note the presence of WBC s wet gangrene. Osteomyelitis with associated panniculitis.

Fibrinoid Necrosis y Usually seen in the walls of blood vessels (eg, in vasculitidies) y Glassy, eosinophilic fibrin like material is deposited within the vascular walls Reversible Cellular Changes and Accumulations y Hydropic degeneration (hydropic change) o Only the cytoplasm is involved o Water accumulation and the cell swells  Large vacuoles in the cytoplasm o Light microscopy:  Cytoplasm is pink and granular o Electron microscopy (ultrastructural):  Organelles are swollen  Ribosomes displaced  Lysosomal activity very apparent y Fatty change (steatosis, fatty metamorphosis) o Characterized by accumulation of intracellular parenchymal triglycerides, nucleus is displaced and the cell swells. Resembles signet ring. o Observed frequently in liver, heart, and kidney  Eg, in liver secondary to alcoholism, diabetes mellitus, malnutrition, obesity, poisoning o Results from imbalance among the uptake, utilization, and secretion of fat  Increased transport of triglycerides (fatty acids) to affected cells  Decreased mobilization of fat from cells

Intracellular Accumulations y Steatosis (aka, fatty change) o Accumulation of lipids within hepatocytes o Causes include EtOH, drugs, toxins o Accumulation can occur at any step in the pathway from entrance of fatty acids into cell to packaging and transport of triglycerides out of cell y Cholesterol (usually seen as needle like clefts in tissue; washes out with processing so looks cleared out). Eg,: o Atherosclerotic plaque in arteries o Accumulation within macrophages (called foamy macrophage) seen in xanthomas, areas of fat necrosis, cholesterolosis in gall bladder

y y

See above: steatosis of liver. Hyaline change o Homogeneous, glassy, eosinophilic appearance in H & E stained tissue sections

Caused most often by nonspecific accumulations of proteinaceous material Eg, glomeruli tufts in diabetic glomerulosclerosis

Above: note the glassy pink appearance of hyaline change

Intracellular Accumulations y Morphologically visible protein accumulations are much less common than lipid accumulations; they may occur because excesses are presented to the cells or because the cells synthesize excessive amounts. In the kidney, for example, trace amounts of albumin filtered through the glomerulus are normally reabsorbed by pinocytosis in the proximal convoluted tubules. However, in disorders with heavy protein leakage across the glomerular filter (e.g., nephrotic syndrome), there is a much larger reabsorption of the protein. Pinocytic vesicles containing this protein fuse with lysosomes, resulting in the histologic appearance of pink, hyaline cytoplasmic droplets. The process is reversible; if the proteinuria abates, the protein droplets are metabolized and disappear. Pigment Accumulation Cells may acquire (either transiently or permanently) various substances that arise either from the cell itself or from nearby cells y Normal cellular constituents accumulated in excess (eg, from increased production or decreased/inadequate metabolism) eg, lipid accumulation in hepatocytes y Abnormal substances due to defective metabolism or excretion (eg, storage diseases, -1-AT deficiency) y Pigments due to inability of cell to metabolize or transport them (eg, carbon, silica/talc)

Reversible Cellular Changes and Accumulations (cont.) y Accumulation of exogeneous pigments o Naturally colored substances not requiring tissue stain to be seen  Pulmonary accumulations of carbon, silica, and iron dust  Plumbism (lead poisoning)  Algeria (silver poisoning)  May cause a permanent gray discoloration of the skin and conjunctiva  See below: anthracosis, inhalation of carbon particles common in city dwellers

Accumulation of endogenous (produced by body) pigments o Melanin


Most common, brown pigment Formed from tyrosine via tyrosinase Synthesized in melanosome of melanocytes within the basement membrane of the epidermis and choroid of the eye Transferred by melanocytes to adjacent clusters of keratinocytes and macrophages (melanophores) in the subjacent dermis See below: melanoma

Found in:  Week old hemorrhage  Hemolysis  Inborn errors of metabolism affecting transport and absorption as in the liver and pancreas

Bilirubin o Catabolic product of the heme moiety of hemoglobin and myoglobin  In pathologic conditions, accumulates, and stains the blood, sclera, mucosae, and internal organs producing a yellow discoloration (jaundice)  Hemolytic jaundice  Destruction of RBCs  Obstructive jaundice  Intra- or extrahepatic obstruction of the biliary tract  Hepatocellular jaundice  Parenchymal liver damage Hemosiderin o Iron containing pigment, aggregates of ferritin o In tissue, appears as golden brown amorphous aggregates  Prussian blue dye special dye results in positive blue color stain reaction o Exists normally in small amounts as physiologic iron stores within tissue macrophages of the bone marrow, liver, and spleen

Accumulates pathologically in tissue in excess amounts (sometimes massive)  Hemosiderosis vs. hemochromatosis Hemosiderosis  Accumulaton of hemosiderin, primarily within tissue macrophages, without associated tissue or organ damage  Local: most often from hemorrhage into tissue; derived from breakdown of hemoglobin  Systemic: generalized; from hemorrhage, multiple blood transfusions, hemolysis, excessive dietary intake; often accompanied by alcohol consumption Hemochromatosis  Extensive accumulation of hemosiderin, often within parenchymal cells, with accompanying tissue damage, scarring, and organ dysfunction  Hereditary type (primary)  Most often caused by mutation of Hfe gene, chromosome #6  Characterized by liver, pancreas, myocardium, and multiple endocrine glands damage; melanin deposition in skin  Triad: micronodular cirrhosis, diabetes

mellitus, bronze diabetes  Elevated serum iron, decreased total iron binding capacity  Secondary type  Most often caused by multiple blood transfusion for conditions such as thalassemia major (a hereditary hemolytic anemia) Lipofuscin o Yellowish to light brown, fat soluble pigment; end product of membrane lipid peroxidation by free radicals o Wear and tear pigment o Commonly accumulates in elderly patients  Found most often within hepatocytes and at the poles of nuclei of myocardial cells o Brown atrophy  Accumulation of lipofuscin and atrophy of organs

Calcification y Pathologic calcifications o Abnormal deposition of calcium salts in soft tissue

Deep blue purple in nondecalcified H & E stained tissue o May stimulate further bone deposition o Calcifications of dead tissue dystrophic o Calcifications of live tissue metastatic Metastatic calcifications o Caused by hypercalcemia  Most often from hyperparathyroidism  Osteolytic tumors with mobilization of Ca2+ and PO4 Hypervitaminosis D: Ca2+ absorption in ileum  Excess calcium intake  Eg, milk alkali syndrome nephrocalcinosis, renal stones caused by milk and antacid self therapy for peptic ulcer o May occur in normal, viable tissues in the setting of hypercalcemia due to any of a number of causes  Calcification most often seen in kidney, cardiac muscle and soft tissue Dystrophic calcifications o Intracellular or extracellular; gritty o Deposition of calcium in tissue altered by injury  Areas of old trauma  Tuberculosis lesions  Affects crucial organs, heart valves, vessels  Second heart valves  Atherosclerosis  Not caused by hypercalcemia but calcium attracted by released membrane phosphates  Serum calcium concentration normal  Occurs in areas of nonviable or dying tissues in the setting of normal serum calcium  Gross: hard, gritty, tan white, lumpy  Micro: deeply basophilic on H & E stain; glassy amorphous appearance; may be either crystalline or noncrystalline o

See above: Increased cell age usually coincides with decreased telomere length.

kkkkkkkkkkkkkkkkkkkkkkkkkk Cellular Aging y Cellular aging is the result of a progressive decline in the proliferative capacity and life span of cells and the effects of continuous exposure to exogenous factors that cause accumulation of cellular and molecular damage y All normal cells have a limited capacity for replication, and after a fixed number of divisions, cells become arrested in a terminally nondividing state, known as replicative senescence. Aging is associated with progressive replicative senescence of cells y In human cells, the mechanism of replicative senescence involves incomplete replication and progressive shortening of telomeres, which ultimately results in cell cycle arrest. Telomeres are short repeated sequences of DNA present at the linear ends of chromosomes that are important for ensuring the complete replication of chromosome ends and for protecting the ends from fusion and degradation. When somatic cells replicate, a small section of the telomere is not duplicated, and telomeres become progressively shortened. As the telomeres become shorter, the ends of chromosomes cannot be protected and are seen as broken DNA, which signals cell cycle arrest.

Cell Growth y Cell Cycle Phases o G1: presynthetic o S: synthetic o G2: premitotic o M: mitotic y Groups of cells according to proliferative potentials o Continuously dividing (labile cells)

o o 

Quiescent cells (stable cells) Nondividing (permanent cells)

Continuously dividing tissues Cells of these tissues (also known as labile tissues) are continuously being lost and replaced by maturation from stem cells and by proliferation of mature cells. These tissues can readily regenerate after injury as long as the pool of stem cells is preserved.

 Permanent tissues The cells of these tissues are considered to be terminally differentiated and non-proliferative in postnatal life. The majority of neurons and cardiac muscle cells belong to this category. Limited stem cell replication and differentiation occurs in some areas of the adult brain, and there is some evidence that heart muscle cells may proliferate after myocardial necrosis.  Stable tissues Cells of these tissues are quiescent(in the G0 stage of the cell cycle) and have only minimal replicative activity in their normal state. However, these cells are capable of proliferating in response to injury or loss of tissue mass. Stable cells constitute the parenchyma of most solid tissues. With the exception of liver, stable tissues have a limited capacity to regenerate after injury. Cell Growth The key processes in the proliferation of cells: y DNA replication y Mitosis Checkpoint controls: prevent DNA replication or mitosis of damaged cells. These are surveillance mechanisms. If damage occurs, cell cycle does not proceed until DNA is repaired.

All somatic eukaryotic cells proceed through four phases in cell cycle: G1 (gap phase 1) in which the cell prepares for the upcoming events of S-phase; S (synthesis phase), in which DNA is replicated; G2 (gap phase 2) in which the cell prepares for the upcoming events of M-phase; and M (mitosis), in which chromosomes are separated over two new nuclei. Progression through the cell cycle determines the rate of proliferation. Growth, repair and maintenance of organisms all rely on the regulation of the cycle.

Checkpoints y Provides surveillance mechanisms for ensuring that critical transitions occur in the correct order with fidelity in their completion. y Cause cell cycle arrests by promoting inhibitory pathways or inhibiting activation pathways y p53 activation in response to DNA damage which in turn activate p21 (CDK inhibitor) y Cyclins accomplish the regulatory functions by complexing with cyclin dependent kinases (CDK) and exert their effects by phosphorylating protein complexes. o Kinase phosphorylate o Phosphatase dephosphorylate y Phosphorylation leads to conformational changes that: o Activate or inactivate an enzymatic activity o Induce or interfere with protein protein interaction


Induce or inhibit binding of a protein to DNA o Induce or prevent the catabolism of a protein Cell proliferation can be stimulated by injury, cell death and mechanical deformation of tissues. Growth can be accomplished by shortening the cell cycle but the most important factors are those that recruit resting or quiescent cells into the cycle. o

Cell Growth Autocrine: y Signaling substance produced by same cells. y Exemplified by cyclins y Plays a role in compensatory epithelial hyperplasia

Cell Growth and Differentiation y General schemes of intercellular signaling o Autocrine o Paracrine o Endocrine

Paracrine y Cells produce molecules that affect only a target cell in close proximity. y Connective tissue repair in healing wounds Endocrine y Hormone production targeting cells distant from site of production.


Signal Transduction y The major intracellular signaling pathways induced by growth factor receptors are similar to those of many other cellular receptors that recognize extracellular ligands. The binding of a ligand to its receptor triggers a series of events by which extracellular signals are transduced into the cell, leading to the stimulation or repression of gene expression. y Receptor proteins are generally located on the cell surface, but they may be intracellular; in the latter case, the ligands must be sufficiently hydrophobic to enter the cell (e.g., vitamin D, or steroid and thyroid hormones). The binding of a ligand to its cell surface receptor leads to a cascade of secondary intracellular events that culminate in transcription factor activation or repression, leading to cellular responses. y Note that not all ligands induce stimulatory signals; in fact, growthinhibitory signals inducing direct inhibition or inhibition caused by cellcell contact (contact inhibition) are equally important. For instance, the TGF- receptor has intrinsic kinase activity, and when in complex with TGFit phosphorylates specific intracellular proteins, which in turn increases the synthesis of CDK inhibitors and block the activity of transcription factors and cell cycle progression. y Systems: o Arranged as networks of sequential protein kinases:  Mitogen activated protein kinase  PI 3 Kinase


Inositol Lipid (IP3) Cyclic adenosine monophosphate Jak-Stat signaling system Stress kinase systems

Receptors with Intrinsic Kinase Activity y Dimeric transmembrane molecules with an extracellular ligand binding domain o Ligand binding causes stable dimerization with subsequent phosphorylation o Phosphorylation can activate other intracellular proteins (eg, RAS, phosphatidylinositol -3 [PI3] kinase, phospholipase C [PLC- ]) and stimulate a cascade of events leading to entry into the cell cycle and cell cycle progression, or induction of other transcriptional programs. y An especially important pathway stimulated by RAS activation is the mitogen-activated protein (MAP) kinase cascade, which is involved in the intracellular signaling of many growth factors, including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF) G protein Coupled Receptors y Seven transmembrane G protein coupled receptors o After ligand binding, the receptors associate with intracellular guanosine triphosphate (GTP) binding proteins (G proteins) that contain guanosine diphosphate (GDP) o Binding of the G proteins causes the exchange of GDP with GTP, resulting in activation of the proteins.  Among the several transduction pathways activated through G protein coupled receptors are those involving cyclic AMP (cAMP)  Generation of inositol - 1, 4, 5 triphosphate (IP3), which releases calcium from the endoplasmic reticulum.


Receptors without Intrinsic Enzymatic Activity y Monomeric transmembrane molecules with an extra cellular ligand binding domain o Ligand interaction induces an intracellular conformational change that allows association with intracellular protein kinases called Janus kinases (JAKs)  Phosphorylation of JAKs activates cytoplasmic transcription factors called STATs (signals transducers and activators of transcription), which shuttle directly into the nucleus. JAK-STAT receptors are usually involved in inflammation.  Ligands for these receptors include many cytokines, the interferons, colony stimulating factors, growth hormone, and erythropoietin. Summary y Polypeptide growth factors bind to and activate their receptors which possess intrinsic kinase activity; subsequently phosphorylation of a number of substrates involved in signal transduction and generation of second messengers is affected. The resultant kinase cascade leads to activation of nuclear transcription factors, initiates DNA synthesis, and ultimately culminates in cell division. The process of cell proliferation is directed by CYCLINS that when complexed with CDK s control the phosphorylation of proteins involved in cell cycle progression


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Cytokine / Growth Factor Epidermal growth factor

Source Activated macrophages, salivary glands, keratinocytes, and many other cells Activated macrophages, T lymphocytes, keratinocytes, and many other cells Mesenchymal cells

Function Mitogenic for keratinocytes and fibroblasts; stimulates keratinocyte migration and granulation tissue formation Similar to EGF; stimulates replication of hepatocytes and many epithelial cells

Transforming growth factor

Hepatocyte growth factor (scatter factor) Vascular endothelial cell growth factor (isoforms A, B, C, D) Keratinocyte growth factor (FGF7) Platelet-derived growth factor (isoforms A, B, C, D)

Enhances proliferation of epithelial and endothelial cells, and of hepatocytes; increases cell motility Increases vascular permeability; mitogenic for endothelial cells (see text)

Mesenchymal cells


Stimulates keratinocyte migration, proliferation, and differentiation Chemotactic for PMNs, macrophages, fibroblasts, and smooth muscle cells; activates PMNs, macrophages, and fibroblasts; mitogenic for fibroblasts, endothelial cells, and smooth muscles cells; stimulates production of MMPs, fibronectin, and HA; stimulates angiogenesis and wound remodeling; regulates integrin expression Chemotactic for fibroblasts; mitogenic for fibroblasts and keratinocytes; stimulates keratinocyte migration, angiogenesis, wound contraction, and matrix deposition Chemotactic for PMNs, macrophages, lymphocytes, fibroblasts, and smooth muscle cells; stimulates TIMP synthesis, angiogenesis, and fibroplasia; inhibits production of MMPs and keratinocyte proliferation; regulates integrin expression and other cytokines

Platelets, macrophages, endothelial cells, keratinocytes, smooth muscle cells

Fibroblast growth factor 1 (acidic), -2 (basic), and family

Transforming growth factor (isoforms 1, 2, 3)

Macrophages, mast cells, T lymphocytes, endothelial cells, fibroblasts, and many tissues Platelets, T lymphocytes, macrophages, endothelial cells, keratinocytes, smooth muscle cells, fibroblasts

kkkkkkkkkkkkkkkkkkkkkkkkkk Definition of Apoptosis y A variety of stimuli result in self programmed, genetically determined, energy dependent sequences of molecular events involving initiation by cell signaling, control, and integration by regulatory molecules, a common execution phase by caspase family genes, and dead cell removal. Apoptosis y This process helps to eliminate unwanted cells by an internally programmed series of events affected by dedicated gene products. It serves

y y

y y y y

several vital functions and is seen under various settings. During development for removal of excess cells during embryogenesis. To maintain cell population in tissues with high turnover of cells, such as skin, bowels. To eliminate immune cells after cytokine depletion and autoreactive T cells in developing thymus. To remove damaged cells by virus To eliminate cells with DNA damage by radiation, cytotoxic agents, etc. Hormone dependent involution: endometrium, ovary, breasts, etc. Cell death in tumors


final phase is the removal of dead cell fragments by phagocytosis without inflammatory reactions.

Morphology of Apoptosis y Shrinkage of cells y Condensation of nuclear chromatin peripherally under nuclear membrane y Formation of apoptotic bodies by fragmentation of the cells and nuclei. The fragments remain membrane bound and contain cell organelles with or without nuclear fragments y Phagocytosis of apoptotic bodies by adjacent healthy cells or phagocytes y Unlike necrosis, apoptosis is not accompanied by inflammatory reaction

Phases of Apoptosis y Initiation phase: caspases (cysteine proteases that cleave aspartic acid residues) become catalytically active by intrinsic and extrinsic paths. Signals from 2 (or more) distinct but convergent pathways: o Extrinsic (death receptor initiated) pathway  Receptor ligand interactions:  TNF receptor (TNFR1). Tumor necrosis factor family.  Fas Fas ligand  Active caspase 8 leads to executioner path  Can be inhibited by FLIP used by some viruses to protect virally infected cells from Fas apoptosis  Fas cross linked to FasL  Death domains (FAD) come together and form binding site for an adaptor protein FADD  FADD attached to death receptors binds inactive caspase 8 (procaspase 8) which come together and is autocatalytically activated to active caspase 8.  Cascade of other caspases activates executioner caspases  Apoptosis initiated

Mechanisms of Apoptosis y Apoptosis can be induced by various factors under both physiological and pathological conditions: It is an energydependent cascade of molecular events which include protein cleavage by a group of enzymes (caspases), protein cross-linking, DNA breakdown. Apoptosis is regulated by a large family of genes some of which are inhibitory (bcl-2) and some are stimulatory (bax). y Apoptosis goes through several complex phases. To put it simple, abnormal mitochondrial membrane permeability is a crucial event which allows escape of cytochrome-c into the cystosol which, in turn, activates proteolytic enzymes (caspases) leading to the execution of the process. The


Intrinsic (mitochondrial) pathway  Result of increased mitochondrial permeabilityand release of pro-apoptotic molecules intocytoplasm (no death receptors)  Initiated by many types of injury: radiation,toxins, free radicals, hypoxia, withdrawal of growth factors or hormones (which stimulateproduction of Bcl-2 (B cell lymphoma) familyanti-apoptotic components (especially Bcl-2 andBcl-x) that reside in mitochondrial membranes.  Can be inhibited by FLIP used by someviruses to protect virally infected cells from Fas apoptosis  Death agonists cause changes in the inner mitochondrial membrane, resulting in the mitochondrial permeability transition (MPT) and release of cytochrome c and other proapoptic proteins into the cytosol, which activate caspases.  AIF: Apoptosis  inducing factor

Execution phase: specific caspase enzymes act to cause cell death o Proteolytic cascade at convergence of other paths o Executioner caspase are caspase 3 and 6

Pro-enzymes are activated by other caspases (e.g. 8 and 9) or autocatalytically o Executioner caspases: cleave cytoskeletal andnuclear matrix proteins, disrupting cytoskeletonand breaking down nucleus. o Nuclear targets of caspase activation;  Transcription proteins  DNA replication  DNA repair  Conversion of cytoplasmic DNAase into active form by caspase 3 cleaving of inhibitor of the enzyme o Effect is induction of internucleosomal cleavage of DNA y Perforin/Granzyme Pathway o Cytotoxic T cells. CD8+ cells kill antigen bearing cells. A variant of type IV hypersensitivity. o A novel pathway in addition to extrinsic and FasL/FasR interaction predominantly used by CTL induced apoptosis o Perforin, a transmembrane poreforming molecule is followed by exophytic release of cytoplasmic granules through the pore into the target cell. Granzyme A and B (serine proteases) are the major component of the granules. o Granzyme B cleaves proteins at aspartate residues andactivates pro-caspase 10 o Granzyme B can also use mitochondrial path to amplifythe death signal by release of cytochrome c. It can alsodirectly activate caspase 3. o Granzyme A activates caspase independent paths,activating DNA nicking via DNAase NM23-H1, a tumorsuppressor gene product. o Effects on virally infected cells, tumor cells, and immune modulation y Removal of dead cells o Phospholipid asymmetry and externalization of phosphatidylserine on the cell surface (flip) is hallmark. o Surface phosphatidylserine and other molecules recruit phagocytes leading to non-inflammatory phagocytic (and adjacent cell) o


recognition (early uptake and disposal without inflammation) o Many macrophage receptors are involved in binding and engulfing apoptotic cells o Macrophages secrete substances that bind to apoptotic but not live cells resulting in opsonization for phagocytosis. o Viable cells prevent engulfment by macrophages by expression of surface molecules (CD3) o The result: no inflammation. Disappearance without a trace. Summary o Initiators of apoptosis: TNF, nitric oxide, Fas ligand, granzyme, viral infection, radiation, corticosteroids, DNA damage o Inhibition of apoptosis: Growth factors, differentiation factors,

o o

adequate intracellular nutrition, insulin, others Extrinsic signaling  Ligand (TNF, CD95L (Fas Ligand), Trail  Activates Pro-caspase 8 to caspase 8 (active) Intrinsic signaling  DNA damage, UV damage, viral infection, cell injury  Cytochrome c release and binds to Apaf-1 to activate caspase 9, Bcl-2and Bcl-x (anti apoptotic) lost and replaced by Bax, Bak, etc. Initiator caspases  2, 8, 9, 10, 12 Effector caspases:  3, 6, 7

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