Studies mechanisms of disease development (pathogenesis)
Studies progression of disease (pathophysiology)
Causes of Cell Injury
-- Mechanical trauma
-- Electric shock
-- Changes in
-- Vitamin deficiency
Causes of Cell Injury
Hypoxia (oxygen deficiency)
-- Carbon monoxide (CO) poisoning
-- Ischemia (poor blood flow)
-- Infarction (loss of blood supply)
-- Autoimmune diseases (self-allergy, loss of tolerance)
Genetic defects (DNA alterations)
-- Congenital malformations
-- Inborn errors of metabolism
-- Cellular senescence
Biochemical Mechanisms of Injury
ATP depletion via:
a- mitochondrial oxidative phosphorylation
b- anaerobic glycolysis
Oxygen deprivation (ischemia, infarction)
-- partially reduced O 2 >> free radicals
Loss of calcium homeostasis
Defects in cell membrane permeability
The most vulnerable intracellular systems:
Cell membrane integrity
mitochondrial aerobic respiration
Free Radical-Induced Cellular Injury Highly reactive, unstable species, interact with proteins, lipid, carbohydrates causing cellular injury. Generation of free radicals 1- Absorption of radiant energy (ultraviolet light & x-rays): H2O OH* & H* 2- Enzymatic metabolism of exogenous chemicals or drugs: CCL4 CCL3 3- Reduction-oxidation reaction during normal metabolic processes: O2 - , H2O2, OH* 4- Transition metals (Iron & Copper), Fenton reaction, superoxide& iron maximal oxidative cellular damage 5- Nitric oxide.
Free Radicals in Injury Generation, Injury and Neutralization by Antioxidants GSSG = oxidized glutathione; NADPH = reduced nicotinamide adenine dinucleotide phosphate; NO = nitric oxide
Lipid peroxidation of
membranes yield peroxides
and begin an autocatalytic
Single-strand DNA breaks
Cross-linking of proteins
enhances degradation rate
and loss of enzyme activity
Superoxide dismutase (SOD)
Glutathione (GSH) peroxidase
Catalase (in peroxisomes)
Vitamins E, A, C and
Free ionized iron and copper
Removal of Free Radicals
Decay: Superoxide O2 & H2O2
Antioxidants: lipid soluble vitamins, ascorbic acid glutathion block initiation of FR, inhibition, termination of radical damage.
Binding of storage or transport proteins.
Enzymes acting as a free radical-Scavenging system: Catalase, Superoxide dismutases, Glutathione peroxidases.
Chemical Injury Mechanisms of chemical injury: I- Direct : binding to some critical molecular component: mercury of mercuric chloride+SH group of cell membrane Increase permeability and inhibition of ATP-ase dependent transport II- Indirect: conversion to reactive toxic metabolites cell injury by direct covalent binding to membrane ptns and lipids or formation by reactive free radicals (CCL4, actetaminphen. CCL4: dry cleaning, CCL3 in SER of liver, initiate lipid peroxidation and autocatalytic reaction Swelling and breakdown of ER, dissociation of ribosomes, decrease hepatic ptn synthesis (e.g. apoprotein), reduced lipid transport fatty change, progressive heptocyte swelling, plasma membrane damage, death Acetaminophen : Analgesic, metabolized by liver, toxic metabolites inactivated by GSH, large doses acc. of metabolites due to GSH depletion binding to ptns & nucleic acids- increase drug toxicity & massive liver damage
Ischemia/Reperfusion Injury Significant in myocardial and cerebral infarctions
Restoration of blood flow brings concentrated calcium when cells
aren’t healthy enough to regulate it
Recruits inflammatory cells, which release many free radicals
-- membrane damage
-- mitochondrial permeability transition
Damaged mitochondria cannot reduce oxygen well
-- free radicals are produced
Compromised antioxidant defense mechanisms
Problem? Vasoconstrictors in local anesthetics produce ischemia and reperfusion each time they are used.
Mitochondrial Dysfunction with Injury
Are targets of most injuries
Nonselective pores allow
protons out >> prevents ATP
Cytochrome c (electron
transport protein) leaks out
>> activates apoptotic death
Apoptosis = programmed cell death
Reversible Ischemic Injury Sequence of Events Accumulation of inorganic phosphates, lactic acid (hydrolysis of phosphate esters)
from rough endoplasmic
Polysomes dissociate into
Increased Cytosolic Calcium in Cell Injury
Usually 10,000x lower than
Ischemic/toxins >> influx of
calcium across membrane
Activates phospholipases >>
Activates proteases >>
structural and membrane
Activates endonucleases >>
May be irreversible
May kill the cell
Membrane Damage If severe enough, may stimulate external attack
Cell Responses to Injury
The cell adapts (reversible damage)
The cell is injured and heals (reversible damage)
The cell is injured and remains injured (atypical adaptation; usually irreversible damage)
Resistance of degradation : Mallory body (alcoholic hyalin; prekeratin intermediate filaments
Intracellular Protein Accumulation Kidney (top), liver (bottom) Much less common than lipid accumulations. Kidney: albumin in pinocytic vesicles -- vesicles fuse with lysosomes -- result: hyalin droplets in cells -- nephrotic syndrome; proteinuria -- is reversible Liver: alcohol hyalin ( Mallory bodies ) -- intermediate filaments aggregate -- chronic alcohol abuse Plasma cells: Russell bodies -- immunoglobulins in RER
Abnormalities in the metabolism of glucose or glycogen
Diabetes Mellitus: Glycogen accumulation in renal tubular epithelium, cardiac myocytes, beta cells of pancreas
Enzyme defects: synthesis or breakdown of glycogen Glycogen storage disease
Pigments (Exogenous or Endogenous)
Anthracosis : Acc. of carbon in the macrophages of lungs and Lymph nodes Heavy acc. emphysema or coal workers pneumoconiosis.
most common exogenous pigment (anthracosis)
-- smoking, coal mining, urban living
-- alveolar macrophages take it o tracheobronchial lymph nodes
-- may induce emphysema and coal miner’s pneumoconiosis
Tattooing: Macrophages, extracellularly (persist for life)
Lipofuscin, melanine, certain hemoglobin derivatives
Lipofuscin (the wear-and tear pigment): Intra- cytoplasmic yellowbrown fine pigment (Brown atrophy) lipid& phospholipids & proteins (peroxidation of polyunsaturated lipids of cellular membrane )
Melanine : Non-hemoglobin-derived brown- black pigment formed by melanocytes by the oxidation of tyrosine.
Lipofuscin granules in a cardiac myocyte as shown by A, light microscopy (deposits indicated by arrows), and B, electron microscopy (note the perinuclear, intralysosomal location).
Hemosiderin : A hemoglobin-derived, golden-yellow to brown granular pigment composed of aggregates of ferritin micelles
Localized or systemic
Gross hemorrhage or rupture of small vessels (congestion)
Lysosomal enzymes in macrophages convert hemoglobin to hemosiderin
Increased absorption of dietary iron (primary hemochromatosis)
Impaired utilization of iron (Thalassemia)
Repeated transfusion (exogenous load of iron)
Hemosiderin granules in liver cells. A, H&E section showing golden-brown, finely granular pigment. B, Prussian blue reaction, specific for iron.
Abnormal deposition of calcium salts in soft tissues
Dystrophic calcification : Non-viable or dying tissues, normal calcium serum level.
(Atherosclerosis, Damaged heart valves, areas of coagulative, liquifactive or caseous necrosis).
Gross picture : fine, white granules or clumps, gritty deposits.
Microscopic picture : intracellular or extracellular basophilic deposits, by time heterotropic bone formation.
Pathogenesis of Dystrophic Pathological Calcification
Initiation : Extracellularly or intracellularly
Extracellular initiation: membrane- bound vesicles derived from dead or dying cells that concentrate calcium by their affinity for acidic phospholipids.
Phosphates accumulation by the action of membrane bound phosphatases.
The cycle of calcium and phosphate binding is repeated- deposits
Initiation of intracellular calcification occurs in mitochondria of dead or dying tissue.
Propagation of crystal formation: depends on conc. of calcium and phosphates, the presence of inhibitors, structural components of extra-cellular matrix (collagen) as well as other matrix protein (osteonectin and others).
Calcific Valves in Aortic Stenosis Thick, fibrotic cusps; masses of dystrophic calcification
Causes of Metastatic Calcification (Hypercalcemia) A: Excessive mobilization of calcium from bone: 1- Hyperparathyroidism (primary or secondary). 2- Bony destructive lesions such as myelomas and metastatic carcinomas. 3- Disuse atrophy of bones. B- Excessive absorption of calcium from the gut: 1- Hypervitaminosis D. 2- Excessive oral calcium intake. 3- Hypercalcemia of infancy. Metastatic calcification affects Kidney (basement membrane of tubules), Alveolar wall of lungs, Stomach (fundal glands0, Blood vessels especially internal elastic lamina and cornea. It is based on that sites have relatively alkaline pH which favors precipitation of calcium.
Metastatic Calcification Calcification in the wall of a blood vessel Calcification in the gastric submucosa
Cellular Adaptation to Injury
A state that lies between the normal, unstressed cell and the injured over stressed cell.
Up- or down-regulation of specific cellular receptors
Induction of new protein synthesis : heat shock protein (protection)
Switch from one type of protein to another
marked over-production of one type of protein (collagen)
Atrophy, Hypertrophy, Hyperplasia, Metaplasia
Reversible Cell Adaptation Adaptation Result Atrophy Decrease in cell size Hypertrophy Increased cell size of an organ due to increase in the size of cells. Hyperplasia Increased cell size of an organ due to increase in the number of cells. Metaplasia Stable change from one cell type to another cell type Dysplasia Abnormal cell or tissue growth
Cellular adaptations to stress: 1. Hyperplasia (more cells) 2. Hypertrophy (bigger cells) 3. Atrophy (smaller cells) 4. Metaplasia ( different type of cells)
An increase in the number of organelles and the size of the cells with subsequent increase in the size of organ due to an increase in the functional demands.
physiological : Uterus in pregnancy, muscle in athletes
Irritation hyperplasia: lymphoid tissue in infection and toxemia
Mechanism of hyperplasia Cell proliferation via increased production of TRANSCRIPTION FACTORS due to: * Increased production of GF * Increased levels of GF receptors * Activation of intracellular signaling Results in larger organ
Hyperplasia Endometrial hyperplasia in response to estrogen Hyperplastic Glands
Hyperplasia Nodular hyperplasia of the prostate gland Normal
Thyroid hyperplasia Normal Thyroid Hyperplastic Thyroid
Metaplasia A reversible change in which one differentiated adult cell type is replaced by another (epithelial or mesenchymal) of the same type (during postnatal life) - Columnar to squamous epithelium (most common epithelial type of metaplasia) - Chronic irritation i.e. (in trachea and bronchi of smokers) - Vit A deficiency squamous metaplasia in respirastory epithelium - May be some loss of function and predispose to malignancy
Mechanism of Metaplasia Reprogramming 1. of stem cells present in normal tissues 2. of undifferentiated mesenchymal cells in connective tissue Mediated by signals from: cytokines, GF or ECM Leading to induction of specific transcription factors
Metaplasia Original Tissue Stimulus Metaplastic Tissue Ciliated columnar epithelium of bronchial tree Cigarette smoke Squamous epithelium Transitional epithelium of bladder Trauma of bladder calculus Squamous epithelium Columnar epithelium of gland ducts Trauma of calculus Squamous epithelium Esophageal squamous epithelium Gastric acid Columnar epithelium Fibrocollagenous tissue Chronic trauma Bone (osseous) tissue Columnar glandular epithelium Vitamin A deficiency Squamous epithelium
Epithelial Metaplasia, the normal respiratory epithelium at the right and the squamous epithelium at the left .
Photomicrograph of the junction of normal epithelium (1) with metaplastic transitional epithelium (2).
Photomicrograph of the trachea from a smoker. Note that the columnar ciliated epithelium has been replaced by squamous epithelium.
This biopsy of the lower esophagus in a patient with chronic gastroesophageal reflux disease (GERD) shows columnar metaplasia (Barrett's esophagus), and the goblet cells are typical of an intestinal type of epithelium. Squamous epithelium typical of the normal esophagus appears at the right.
Atrophy I t is the shrinkage in the size of the cell by loss of cell substance ( Balance between synthesis and degradation)
Decreased synthesis and Increased catabolism
-- thyroid-stimulating hormone
Two systems for regulation of protein degradation ☺
-- lysosomal proteases and other enzymes
degrade endocytosed molecules
-- ubiquitin-proteasome pathway, primarily for
cytosolic and nuclear proteins (senescent organelles)
Often accompanied by autophagic vacuoles
-- some debris resists digestion: membrane-bound residual bodies
Types/Causes of Atrophy Physiologic v. Pathologic
-- Ablation of pituitary gland>>less ACTH>>adrenal cortex atrophy
-- Endometrial atrophy during menopause
-- Myometrial atrophy post partum
-- Thymus atrophy during adolescence
-- Parathyroid atrophy with increasing age
-- Old age>>reduced gonadotrophins>>testicular atrophy
-- Leg in cast
-- Long-term hospitalization
-- Brain atrophy after stroke
-- Spinal cord injury
-- Mucosal atrophy in pernicious anemia (vitamin B 12 deficiency)
Mechanism of Atrophy Reduction in structural components Decreased number of mitochondria, myofilaments, ER via proteolysis (lysosomal proteases; ubiquitin-proteosome system) Increase in number of autophagic vacuoles Residual bodies (i.e. lipofuscin brown atrophy) NB: diminished function but not dead
Muscle fiber atrophy. The number of cells is the same as before the atrophy occurred, but the size of some fibers is reduced. This is a response to injury by "downsizing" to conserve the cell. In this case, innervation of the small fibers in the center was lost. This is a trichrome stain.
Atrophy Atrophic Adrenal Gland from Corticosteroid Use Normal Atrophied
Brain Atrophy An aging process 82 y/o male 25 y/o male
Dysplasia means abnormal organization of cells
At the cellular level, morphologically, it is characterized by variations in size and shape of the cell (pleomorphism), disorderly arrangement within the epithelium (loss of polarity) and nuclear changes, consisting of enlargement, irregular borders, and hyperchromasia of individual cell nuclei and increased number of mitotic figures.
It is considered pre-malignant (often arises in previously metaplastic epithelium), and can progress to malignant squamous cell carcinoma, unless treated.
Basement membrane is always intact
In early stages it is reversible
HISTOLOGICAL CRITERIA FOR DYSPLASIA
Pleomorphism of both cells & nuclei.
Increased nuclear cytoplasmic ratio.
Hyperchromatic or vesicular nuclei with prominence of nucleoli
Increased and specially presence of atypical mitotic figures
Loss of polarity
INTACT BASEMENT MEMBRANE
(INTRAEPITHELIAL NEOPLASIA-GRADE I)
These changes are confined to lower 1/3 of the thickness of the epithelium.
(INTRAEPITHELIAL NEOPLASIA-GRADE II)
These changes are confined to lower 1/2 of the thickness of the epithelium.
(INTRAEPITHELIAL NEOPLASIA-GRADE III)
These changes are confined to lower 2/3 of the thickness of the epithelium.
CARCINOMA IN SITU
(INTRAEPITHELIAL NEOPLASIA-GRADE III)
These changes involve the entire thickness of the epithelium.
At high magnification, the normal cervical squamous epithelium at the left merges into the dysplastic squamous epithelium at the right in which the cells are more disorderly and have darker nuclei with more irregular outlines.
Normal cervix Severe dysplasia
Irreversible cell injury caused by severe injury of long duration and includes:
Sublethal v. Lethal Cell Damage
Nuclear Events in Necrosis Pyknosis, Karyorrhexis, Karyolysis 1- Karyopyknosis means shrinkage and increased basophilia of the nucleus. 2- Karyorrhexis means fragmentation of the nucleus. 3- Karyolysis means fading of the nucleus Karyolysis Karyorrhexis Normal
Proteins Liberated into Blood Following Necrosis Released enzymes can help with diagnosis
Cytoplasmic Changes in Necrosis
- Dead cells show increased acidophilia.
Cells may have glassy appearance.
Cytoplasm become vacuolated and appear moth- eaten.
-- focal bacterial and some fungal infection (attract neutrophils)
-- brain death
Caseous necrosis : tuberculosis (“cheesy”)
-- granulomatous inflammation (granulomas)
-- loss of architecture centrally (structureless, amorphus granular debris).
Fat necrosis (liquefied fat, released fatty acids)
-- acute pancreatitis
-- trauma/ischemia to fatty tissue - calcific fat necrosis
--Shadowy outlines of necrotic fat cells with basophilic Ca and inflam. Cells.
Preservation of structure
Hypoxic tissue death (except brain)
This is an example of coagulative necrosis. This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia). Here, there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney.
The liver shows a small abscess here filled with many neutrophils. This abscess is an example of localized liquefactive necrosis
Not a specific pattern
Focal areas of fat digestion
Ususally via release of lipases from pancreas
FFA combine with Ca to produce “soaps”
This is fat necrosis of the pancreas. Cellular injury to the pancreatic acini leads to release of powerful enzymes which damage fat by the production of soaps, and these appear grossly as the soft, chalky white areas seen here on the cut surfaces.
Fat Necrosis (Acute pancreatitis)
Gangrene Def : Gangrene is massive tissue necrosis followed by putrefaction Causes: 1- Necrosis : sudden ischemia or bacterial toxins 2- Putrefaction : Saprophytic bacteria that breaks down the protein of necrotic tissue liberation of hydrogen sulphide (H2S) foul odour , H2S + iron (derived from hemoglobin iron sulphide staining of gangrenous tissue black. Types of Gangrene 1- Dry gangrene 2- Moist gangrene 3- Infective gangrene 4- Gas gangrene
Classification of gangrene
According to the amount of blood and tissue fluids in the part affected at the time of its death
I- Dry gangrene II- Moist gangrene
I- Dry Gangrene
Dry gangrene of limb results from occlusion of its artery by thrombus, embolus, thromboangitis obliterans (Buerger’s disease), Ergot poisoning and Raynaud’s disease (spastic occlusion ), surgical ligature.
Main arterial supply is cut off + poor collateral circulation= gangrene
Low body resistance due to nutritional disturbance, nephritis, anemia, etc..
Pathological features : the gangrenous process follows the following steps:
1- Arterial occlusion: spontaneous or initiated by slight injury caused by tight shoes
2- Massive necrosis distal to occlusion (pale, cold due to ischemia ), sensations are lost. Later on, the necrotic are stains red (blood escaped from necrotic blood vessels), Drainage and evaporation of blood and tissue fluid dryness of dead part Shrunken & mummified
4- Gangrenous process advances slowly along limb (gangrenous part irritates living one inflammation of tissue with thrombosis of the vessels more tissue necrosis & extension of gangrene.
5- At level of good blood supply gangrene stops. Toxic products act as an irritant acute inflammation in the neighboring healthy part narrow red line between healthy and gangrenous part line of demarcation .
6- from healthy side granulation tissue grow towards gangrenous part with formation of groove on the surface (line of separation ) deepening of the groove conical stump
II Moist Gangrene (Wet gangrene)
Caused by sudden arterial and venous occlusion, mainly in internal organs (intestine; no evaporation of fluid).
Excess tissue fluid rapid putrefaction rapid spread of gangrene (line of demarcation is poor and line of separation is absent, severe toxemia)
1- Moist gangrene of intestine : strangulated hernia, intussusception, volvulus (venous occlusion occur first) and mesenteric arterial occlusion.
Affected loop: congestion & edema, dark red and swollen arterial occlusion necrosis invasion by putrefactive bacteria (lumen) putrefaction (rapid) black color (iron sulphide)
Severe toxemia, acute intestinal obstruction & peritonitis.
2- Moist gangrene of limb : severe crushing injury (occlusion of artery and vein by thrombosis and hematoma), diabetic patients.
3- Diabetic gangrene : more common in diabetic female after 45 years (diabetic hyperlipaemia early atherosclerosis Arterial occlusion.
Pathology: initiated by mild injury, starts on big toe or sole of foot, at first dry moist (tissue hyperglycemia, poor body resistant multiplication of bacteria inflammation and occlusion of vessels), rapid spread, poor line of demarcation, severe toxemia, little tendency to self limitation.
III Infective gangrene: A subtype of moist gangrene (bacteria cause tissue destruction and putrefaction).
Cancrum oris: Cheeks of debilitated children, Treponema vincenti and Bacillus fusiformis , severe toxemia, bronchopneumonia.
Noma pudendi: subcutaneous tissue of inguinal region.
Phagenda: gangrene on top of syphilitic chancer.
Synergistic gangrene: wounds draining deep seated abscesses
IV Gas Gangrene : Moist gangrene of muscles in deep wounds contaminated by manured soil containing anaerobic spores. Tissue destruction local ischemia germination of spores.
Saccharolytic bacteris & proteolytic bacteria
Putrefaction with excess production of gases, highly fatal, severe toxemia degeneration and necrosis of parenchymatous organs.
Complications of Gangarene 1-Toxemia : circulation of bacterial toxins in the blood causing pathological and clinical manifestations (acute & chronic) constitutional symptoms, degeneration of parenchymatous organs, Amyloidosis in chronic forms, necrosis and hemorrhage of adrenal cortex, anemia. 2- Bacteremia: Transient presence of small number of bacteria in the blood stream without toxic manifestations (tooth extraction) Fate: 1- phagocytosis by RES (small number). 2- localization pathological lesions (carbuncle, acute osteomyelitis, subacute bacterial endocarditis)
3- Septicemia: the circulation and multiplication of large amount of virulent bacteria and their toxins in blood stream, highly fatal Causes: pyogenic bacteria as staph, strept, pneumococci, gonococci) & Bacilli (proteus, anthrax) Septic wound, puerperal sepsis, acute osteomyelitis + low body resistance 4- Pyemia : Circulation of septic emboli in the blood stream and their arrest in different organs causing multiple abscess, high mortality rate. 5- Sapremia : Presence of toxic metabolites in blood stream derived from action of saprophytic bacteria on necrotic tissue (gangrene).
Somatic death = death of the body as a whole
Rigor mortis = stiffening of muscles (proteins precipitate)
-- begins in involuntary muscles
-- voluntary muscles in 4-10 hours
-- passes off in 3-4 days
-- unreliable as indicator of time of death
Livor mortis = red discoloration from pooling of blood at low points
Algor mortis = cooling of the body
-- occurs gradually and rather evenly
Autolysis = self-digestion of tissues (no inflammation)
Putrefaction = gas and green color, from saprophytes in body (GI)
Post mortem clot – differs from antemortem clot (thrombus)
-- “currant jelly” clot = rapid formation
-- “chicken fat” clot = slow formation
Apoptosis (Falling away)
Def.: A programmed cellular death occurs when a cell within an organism dies through activation of an internal suicide program.
Function : Elimination of unwanted cells selectively with minimal disturbance to surrounding cells and the host
Programmed destruction of cells during embryogenesis.
Hormone- dependent involution of tissues.
Cell deletion in proliferating cell populations (duct obstruction, intestinal crypts)
Cell death by cytotoxic T cells.
Deletion of auto-reactive T cells in thymus.
A variety of mild injurious stimuli (heat, radiation, etc) irreparable DNA damage trigger cell suicide pathways (p53).
Morphological Features of Apoptosis - Cell shrinkage. - Chromatin condensation and fragmentation. - Cellular blebbing and fragmentation into apoptotic bodies. - Phagocytosis of apoptotic bodies by adjacent healthy cells or macrophages.
Apoptosis and necrosis can occur together depending on the severity of stimuli.
Apoptosis is not easy to be demonstrated in histological sections.
Mechanisms of Apoptosis
1- Signaling : Stimuli generates signals
* transmitted across the plasma membrane to intracellular regulatory molecules (e.g.FAS)
addressed directly at targets present within the cells
2- Control and Integration Death signals Execution program 1- Adaptor protein : connection * Mitochondrial permeability transitions: pore in inner mitochondrial membrane. * Death signals cytochrome c release from outer membrane to cytoplasm apoptosis. 2- bcl-2 family members : Regulate mitochondrial function and suppress apoptosis.
* Direct action on mitochondria to prevent increased permeability
Effects mediated by interaction with other protein.
3- Execution Phase Signaling and regulatory mechanisms 1- final proteolytic cascade ( caspase family) Caspases (inactive) active Initiators and executors Executive caspases are responsible for the morphological changes characteristic of apoptosis. 2- Extensive protein cross- linking (cytoskeleton) fragmentation (apoptotic bodies). 3- DNA breakdown by endonucleases.
4- Removal of Dead Cells
Recognition: Marker molecules on the surface of apoptotic fragments.
Mechanism of Apoptosis Programmed Cell Death
Necrosis v. Apoptosis Usually: single cell Endonucleases activated Necrosis Apoptosis 1- hypoxia Physiologic or Pathologic 2- Cell swelling Single cell 3- Nuclear changes Condensation 4-Diffuse DNA breakdown Internucleosomal 5- ATP depletion Gene activation Membrane injury, Endonucleases, proteases 6- Inflammation No inflammation, Phagocytosis, apoptotic bodies