Chapter Two adaptation Chapter Two adaptation and injuryand injury

Chapter Two adaptation Chapter Two adaptation and injuryand injury

Adaptation & Cellular Injury :

• Normal cell is in a steady state “Homeostasis”

• Cells constantly adjust structure and function to accommodate changing demands and extracellular stress.

• But within a relatively narrow range of physiologic parameter.

• Change in Homeostasis due to stimuli - Injury

Irreversible Injury (cell death)

Reversible Injury

adaptation

normal

When cells encounter physiological stresses or pathological stimuli, they undergo adaptation, achieving a new a steady state and preserving viability.

If the adaptive capacity is exceeded, cell injury develops. Within certain limits, injury is reversible.

with severe and persistent stress, irreversible injury results.

adaptation

A state that between normal, unstressed cell and the injured, overstressed cell.

General principles

• 1. The cellular response to injurious stimuli depends on the type of injury.

Incomplete occlusion of coronary artery

Complete or prolonged occlusion

hypertesion

Prolonged starvation

General principles

• 2.The consequences of an injurious stimulus depend on the type, status, adaptability, and genetic makeup of injured cell.

• Skeletal muscle accommodates complete ischemia for 2 to 3 hours without irreversible injury.

• cardiac muscle dies after 20 to 30 minutes.

• Neuron dies after a few minutes.

General principles

• 3.Cellular function is far before cell death occurs, and the morphologic changes of cell injury(or death) lag far behind both.

General principles

• Cell membrane integrity, critical to cellular ionic and osmotic homeostasis;

• ATP generation, largely via mitochondrial aerobic respiration;

• Protein synthesis;

• Intergrity of the genetic apparatus.

4. four intracellular systems are particularly vulnerable.

General biochemical mechanisms

• Defects in plasma membrane permeability.

• Oxygen deprivation or generation of reactive oxygen species(free radical).

• Loss of calcium homeostasis.

• Mitochondrial damage.

• Chemical injury

• Genetic variation

Cellular adaptation:Cellular adaptation: AtrophyAtrophy HypertrophyHypertrophy HyperplasiaHyperplasia MetaplasiaMetaplasia

Types of adaptationTypes of adaptation

CELLULAR ADAPTATIONCELLULAR ADAPTATION

• Excessive physiologic stresses.

• Some pathologic stimuli.

A new, but altered state preserving

the viability of the cell.

ATROPHYATROPHY

Decrease in mass of the cellDecrease in mass of the cell

HYPERTROPHY HYPERTROPHY

Increase in mass of the cellIncrease in mass of the cell

ATROPHY ATROPHY • Inadequate nutrition.• Diminished blood supply.• Increased compression• Loss of innervation.• Decreased workload• Loss of endocrine stimulation.• Aging

malnutrational

Denervative

endocrineDisuse

compressive

Aging

Morphology of atrophyMorphology of atrophy

Brown atrophyBrown atrophy

Reduction in the number of cell Reduction in the number of cell organelles.organelles.

Increase in the number of autophagic Increase in the number of autophagic vacuoles.vacuoles.

Lipofuscin granules (Brown atrophy)Lipofuscin granules (Brown atrophy)

Fig 2-5

Cerebral atrophy - Alzheimers:

Atrophy of Brain

o The left part of the brain diminishes in size.The gyrus is narrower and the gauge is widen.

Hydropic change in ischemic - kidney

Microvilli

Muscle ischemic atrophy:

Hydronephrosis

• Hormonal hypertrophyHormonal hypertrophy : : Specific hormonal stimulation

•Compensatory hypertrophyCompensatory hypertrophy : : Increased functional demand

HYPERTROPHYHYPERTROPHY

Fig 2-6

Heart hypertrophy in hypertension:

Left VentricleLeft Ventricle

HYPERPLASIAHYPERPLASIA

HYPERPLASIA

• Physiologic hyperplasia:Physiologic hyperplasia:

Hormonal hyperplasiaHormonal hyperplasia

Compensatory hyperplasiaCompensatory hyperplasia

• Pathologic hyperplasia:Pathologic hyperplasia:

Excessive hormonal stimulation.Excessive hormonal stimulation.

Effects of locally produced GFs on target cells. Effects of locally produced GFs on target cells.

female breast and uterus at puberty and pregnancy.

• Fig 2-1

PARTIAL HEPATECTOMYPARTIAL HEPATECTOMY

PrimingPriming

ProliferationProliferation

Growth lnhibitionGrowth lnhibition

GROWTH FACTORSGROWTH FACTORSAND CYTOKINESAND CYTOKINES HGF HGF TGF-TGF- EGFEGF TNF-TNF- IL-6IL-6 OthersOthers

ADJUVANTSADJUVANTSNorepinephrineNorepinephrineInsulinInsulinGlucagonGlucagonThyroid hormoneThyroid hormone

GROWTH INHIBITORSGROWTH INHIBITORS TGF-TGF- OthersOthers

Growth factorsGrowth factors

AdjuvanisAdjuvanis

Matrix degradationMatrix degradation

MetaplasiaMetaplasia

• One adult cell type is replaced by One adult cell type is replaced by another.another.

• Genetic reprogramming of stem Genetic reprogramming of stem cells.cells.

• Epithelial and mesenchymal Epithelial and mesenchymal metaplasia.metaplasia.

Intestinal glandular epithelium

•Squamous metaplasiaSquamous metaplasia

•Glandular metaplasiaGlandular metaplasia

•Intestinal metaplasia of gastric epitheliaIntestinal metaplasia of gastric epithelia

Bronchial epitheliaBronchial epithelia

Epithelia in bile ductEpithelia in bile duct

Cervical epitheliaCervical epithelia

Epithelial metaplasia Epithelial metaplasia

Columnar epithelium Squamous epithelium

Squamous epithelium

Gastric glandular epithelium

Barrett esophagitis

4. Connective tissue metaplasia• Bone metaplasia.Bone metaplasia.

• cartilige metaplasia.metaplasia. Inmatured fibroblasts

Osteocytes

Chondrocytes

mesenchymal metaplasia mesenchymal metaplasia

significance of metaplasia

o A two-edged sword

o An undesirable change

o Survive but some important protective mechanism is lost.

o The influences that predispose to such squamous metaplasia, if persistent, may promote cancer transformation in metaplastic epithelium.

Cell injuryCell injury

Causes of cell injury and diseaseCauses of cell injury and disease

• Oxygen deprivation ( hypoxia, ischemia)Oxygen deprivation ( hypoxia, ischemia)• Nutritional imbalancesNutritional imbalances• Physical agentsPhysical agents• Chemical agents and drugsChemical agents and drugs• Infectious agentsInfectious agents• Immunologic reactionsImmunologic reactions• Genetic derangementsGenetic derangements

HYPOXIAHYPOXIA

Ischemia ( loss of blood supply ).Ischemia ( loss of blood supply ).

Inadequate oxygenationInadequate oxygenation

( cardiorespiratory failure ).( cardiorespiratory failure ).

Loss of oxygen-carrying capacity of the Loss of oxygen-carrying capacity of the blood ( anemia or CO poisoning ).blood ( anemia or CO poisoning ).

HYPOXIC INJURYHYPOXIC INJURY

• Loss of oxidative phosphorylation and ATP Loss of oxidative phosphorylation and ATP generation by mitochondria.generation by mitochondria.

• Decreased ATP (with increase in AMP): stimulating Decreased ATP (with increase in AMP): stimulating fructokinase and phosphorylation, resulting in fructokinase and phosphorylation, resulting in aerobic glycolysis.aerobic glycolysis.

• Depleted glycogen.Depleted glycogen.• Reduced intracellular pH: Lactic acid and inorganic Reduced intracellular pH: Lactic acid and inorganic

phosphate.phosphate.• Clumping of nuclear chromatin.Clumping of nuclear chromatin.

Four biochemical themesFour biochemical themes

• Oxygen-derived free radicals.Oxygen-derived free radicals.

• Loss of calcium homeostasis and increased Loss of calcium homeostasis and increased intracellular calcium.intracellular calcium.

• ATP depletion.ATP depletion.

• Defects in membrane permeability.Defects in membrane permeability.

PHYSICAL AGENTSPHYSICAL AGENTS

• TraumaTrauma

• HeatHeat

• ColdCold

• RadiationRadiation

• Electric shockElectric shock

CHEMICAL AGENTS AND DRUGS

•Endogenous products: urea

•Exogenous agents:

Therapeutic drugs: hormones

Nontherapeutic agents:

lead or alcohol

MECHANISMS OF CHEMICAL INJURYMECHANISMS OF CHEMICAL INJURY

• Directly:Directly: Mercury of mercuric chloride Mercury of mercuric chloride binds to SH groups of cell membrane binds to SH groups of cell membrane proteins, causing increased permeability proteins, causing increased permeability and inhibition of ATPase-dependent and inhibition of ATPase-dependent transport.transport.

• By conversion to reactive toxic metabolites By conversion to reactive toxic metabolites which in turn cause cell injury either by which in turn cause cell injury either by direct covalent binding to membrane protein direct covalent binding to membrane protein and lipid, or more commonly by the and lipid, or more commonly by the formation of free radicals.formation of free radicals.

MECHANISMS OF CHEMICAL INJURYMECHANISMS OF CHEMICAL INJURY

CClCCl44 in SER of liver cell (P-450) – CCl in SER of liver cell (P-450) – CCl33. . – lipid – lipid

peroxidation and autocatalytic reactions – peroxidation and autocatalytic reactions –

swelling and breakdown of ER, dissociation of swelling and breakdown of ER, dissociation of

ribosome, and decreased hepatic protein synthesis ribosome, and decreased hepatic protein synthesis

( loss of lipid acceptor protein – fatty change of ( loss of lipid acceptor protein – fatty change of

liver cell) – progressive cellular swelling, plasma liver cell) – progressive cellular swelling, plasma

membrane damage, and cell death.membrane damage, and cell death.

FREE RADICAL INITIATIONFREE RADICAL INITIATION

• Absorption of energy (UV light and x-rays)Absorption of energy (UV light and x-rays)• Oxidative metabolic reactionsOxidative metabolic reactions• Enzymatic conversion of exogenous chemicals Enzymatic conversion of exogenous chemicals

or drugs (CClor drugs (CCl44>CCl>CCl33..))

• Oxygen-derived radicalsOxygen-derived radicals• SuperoxideSuperoxide

Cell injury caused by free radicals throughCell injury caused by free radicals through

• Peroxidation of lipids.Peroxidation of lipids.

• Cross linking proteins by the formation of Cross linking proteins by the formation of disulfide bonds.disulfide bonds.

• Induction of DNA damage that has been Induction of DNA damage that has been implicated both in cell killing and malignant implicated both in cell killing and malignant transformation.transformation.

INFECTIOUS AGENTSINFECTIOUS AGENTS

• VirusesViruses

• RickettsiaeRickettsiae

• BacteriaBacteria

• FungiFungi

• ParasitesParasites

Marfan syndromeMarfan syndromeFibrillin, a scaffolding on which tropoelastinFibrillin, a scaffolding on which tropoelastin is is

deposited to form elastic fibers.deposited to form elastic fibers.FBN1, 15q21, mutations in Marfan syndrome.FBN1, 15q21, mutations in Marfan syndrome.FBN2, 5q3, mutations in congenital contractual FBN2, 5q3, mutations in congenital contractual

arachnodactyly. arachnodactyly.

Genetic derangementsGenetic derangements

Adenomatous polyposis coliAdenomatous polyposis coliAPC loci, 5q21APC loci, 5q21Adenomatous polyposis in colons (in teens).Adenomatous polyposis in colons (in teens).100% malignant transformation ( 100% malignant transformation ( 40ys ). 40ys ).APC protein in the cytoplasm.APC protein in the cytoplasm.Several partners, including Several partners, including -catenin.-catenin. -catenin -catenin entering the nucleusentering the nucleusactivating activating

transcription of growth-promoting genes.transcription of growth-promoting genes.Causing degradation of Causing degradation of -catenin-cateninmaintainingmaintaining low level of low level of -catenin in the cytoplasm.-catenin in the cytoplasm.

CELLS REACT TO ADVERSE CELLS REACT TO ADVERSE INFLUENCESINFLUENCES

• ADAPTINGADAPTING

• SUSTAINING REVERSIBLE INJURYSUSTAINING REVERSIBLE INJURY

• SUFFERING IRREVERSIBLE INJURY AND SUFFERING IRREVERSIBLE INJURY AND DYINGDYING

CELL INJURY AND NECROSISCELL INJURY AND NECROSIS

General mechanisms:General mechanisms:• Maintenance of the integrity of cell membranes. Maintenance of the integrity of cell membranes. • Aerobic respiration and production of ATP. Aerobic respiration and production of ATP. • Synthesis of enzymes and structure proteins. Synthesis of enzymes and structure proteins. • Preservation of the integrity of the genetic apparatus.Preservation of the integrity of the genetic apparatus.

Irreversible Injury

Reversible Injury

adaptation

normal

Types of cell injury

• reversible

• irreversible necrosisapoptosis

Reversible injury

• Cellular swelling

• Fatty change

• Hyaline change

Cellular swelling

• Excessive entry of free fatty acids into the liver (starvation, corticosteroid therapy).• Enhanced fatty acid synthesis.• Decreased fatty acid oxidation.• Increased esterification of fatty acid to triglycerides (alcohol).• Decreased apoprotein synthesis (CCl4).• Impaired lipoprotein secretion from the liver (alcohol).

FATTY CHANGE

•Morphology of fatty change

Sudan III, Oil red O, Osmic acid

•Liver

•Heart

•Kidney

•Intracellular hyaline changes

•Hyaline degeneration of arterioles

•Hyaline degeneration of connective tissue

Hyaline changes (degeneration)

• Absorption of protein causing hyaline Absorption of protein causing hyaline droplets in proximal epithelial cells indroplets in proximal epithelial cells in the kidney.the kidney.• Russel bodies in plasma cells.Russel bodies in plasma cells.• Viral inclusions in the cytoplasm orViral inclusions in the cytoplasm or the nucleus.the nucleus.• Masses of altered intermediate filaments Masses of altered intermediate filaments (Mallory bodies).(Mallory bodies).

Intracellular hyaline changesIntracellular hyaline changes

Hyaline change of the central artery of the spleen(spleen of hypertension disease)

• The narrowing of the lumina with thickened vessel wall. Homogeneous pink hyaline material deposits under the intima.

5) Mucoid Degeneration

• mucopolysaccharide deposition in the stroma of connective tissue.

mucoid degeneration

•A heterogeneous group of pathogenic A heterogeneous group of pathogenic fibrillar proteins accumulating in fibrillar proteins accumulating in

tissuestissues and organs.and organs.•Excess synthesisExcess synthesis•Resistance to catabolismResistance to catabolism

AMYLOIDOSIS AMYLOIDOSIS

Chemical nature of amyloid fibrilsChemical nature of amyloid fibrilsTwo major forms:Two major forms:

AL (amyloid light chain protein)AL (amyloid light chain protein)

AA (amyloid-associated protein):AA (amyloid-associated protein):

Derived from serum AA (12kd) Derived from serum AA (12kd)

synthesized in liver and elevated in synthesized in liver and elevated in

inflammatory states.inflammatory states.

Minor forms of amyloid fibrils:Minor forms of amyloid fibrils:Transthyretin (TTR): A mutant form of a Transthyretin (TTR): A mutant form of a

serum protein in familial amyloid serum protein in familial amyloid

polyneuropathy.polyneuropathy.

A variant of TTR in aging.A variant of TTR in aging.

Beta-2-microglobulin (the component of Beta-2-microglobulin (the component of

class I MHC molecules) in long-termclass I MHC molecules) in long-term

hemidialysis.hemidialysis.

Minor forms of amyloid fibrils: Beta-2-amyloid protein forms the core of

cerebral plaques and deposits within

cerebral vessel walls in Alzheimer

disease, deriving from a transmembrane

glycoprotein precursor.

Minor forms of amyloid fibrils:Minor forms of amyloid fibrils:Transthyretin (TTR): A mutant form of a Transthyretin (TTR): A mutant form of a

serum protein in familial amyloid serum protein in familial amyloid

polyneuropathy.polyneuropathy.

A variant of TTR in aging.A variant of TTR in aging.

Beta-2-microglobulin (the component of Beta-2-microglobulin (the component of

class I MHC molecules) in long-termclass I MHC molecules) in long-term

hemidialysis.hemidialysis.

Minor forms of amyloid fibrils: Beta-2-amyloid protein forms the core of

cerebral plaques and deposits within

cerebral vessel walls in Alzheimer

disease, deriving from a transmembrane

glycoprotein precursor.

• primary (B-cell dyscrasia, AL)primary (B-cell dyscrasia, AL)• Secondary or reactive (AA): Secondary or reactive (AA): Collagen diseases, bronchiectasis, chronic Collagen diseases, bronchiectasis, chronic osteomyelitis.osteomyelitis.• Hemodialysis-related: Beta-2-microglobulin Hemodialysis-related: Beta-2-microglobulin deposition.deposition.• Hereditary (AA)Hereditary (AA)

Clinical forms of amyloidosis Systemic amyloidosis:

• Nodular (tumor-forming deposits,

B-cell dyscrasia, AL) • Endocrine amyloidosis (procalcitonin)• Amyloidosis of aging: Heart, lung,

pancreas, spleen, brain.

Localized amyloidosis

• Exogenous:Exogenous: CarbonCarbon TattooingTattooing•Endogenous:Endogenous: LipofuscinLipofuscin MelaninMelanin HemosiderinHemosiderin BilirubinBilirubin

PigmentationPigmentation

• Dystrophic calcificationDystrophic calcification

• Metastatic calcificationMetastatic calcification

Pathologic calcificationPathologic calcification

• Necrotic tissuesNecrotic tissues• AtheromaAtheroma• Damaged heart valvesDamaged heart valves

Dystrophic calcificationDystrophic calcification

• Fig 2-13

• Increased secretion of parathyroid Increased secretion of parathyroid hormonehormone• Destruction of bone tissueDestruction of bone tissue• Vitamin D-related disorders: Vitamin D-related disorders: SarcoidosisSarcoidosis• Renal failureRenal failure

Metastatic calcificationMetastatic calcificationHypercalcimiaHypercalcimia

Metastatic calcification AffectingMetastatic calcification Affecting

Interstitial tissue of gastric mucosaInterstitial tissue of gastric mucosaKidneysKidneysLungsLungsPulmonary veins Pulmonary veins Systemic arteriesSystemic arteries

CELL DEATHCELL DEATH

TYPES OF CELL DEATHTYPES OF CELL DEATH• necrosisnecrosis Coagulation necrosisCoagulation necrosis

Caseous necrosisCaseous necrosis

GangreneGangrene

Liquefaction necrosis( fat necrosis)Liquefaction necrosis( fat necrosis)

Fibrinoid necrosisFibrinoid necrosis

• ApoptosisApoptosis

•Swelling, denaturation and coagulation Swelling, denaturation and coagulation

of proteinsof proteins•Breakdown of cellular organellesBreakdown of cellular organelles•Cell ruptureCell rupture

Common type of necrosis after Common type of necrosis after exogenous stimuli.exogenous stimuli.

NECROSISNECROSISThe sum of the morphologic changesThe sum of the morphologic changes that follow cell death in living tissuethat follow cell death in living tissue and organ:and organ:

• Denaturation of proteins.• Enzymatic digestion of organelles and cytosol.

• Enzymatic digestion by lysosomal Enzymatic digestion by lysosomal enzymes of the dead cells enzymes of the dead cells themselves.themselves.

AUTOLYSISAUTOLYSIS

HETEROLYSISHETEROLYSIS

• Digestion by lysosomal enzymes of Digestion by lysosomal enzymes of immigrant leukocytes.immigrant leukocytes.

1) Nucleus changes:

The hallmarks of cell death in three patterns:

Basic Pathologic Change of Necrosis

Normal cell Chromatinmargination

karyorrhexispyknosis karyolysis

Nuclear Alteration of Necrosis

1)Three pattern of nuclear 1)Three pattern of nuclear changeschanges

Karyolysis (DNase activity)Karyolysis (DNase activity)

Pyknosis (DNA condensation)Pyknosis (DNA condensation)

Karyorrhexis (fragmentationKaryorrhexis (fragmentation

of pyknotic nucleus)of pyknotic nucleus)

• Pyknosis: nuclear shrinkage and increased basophilia, and the DNA apparently condenses into a solid, shrunken basophilic mass.

• Karyorrhexis: nucleus undergoes fragmentation, scattered about the cytoplasm.

• Karyolysis: the basophilia of the chromatin may fade and the nucleus disappears.

2)2)Cytoplasm change:Cytoplasm change:

• increased eosinophilium and a more glassy homogeneous appearance and even vacuolated cytoplasm.

The Necrosis of heptocytes

Types of Necrosis

Coagulative Necrosis

Liquefactive Necrosis

Fibrinoid Necrosis

Necrosis

Gangrenous Necrosis

Morphologic appearance of necrosisMorphologic appearance of necrosis

• Increased eosinophilia:Increased eosinophilia: Loss of RNA in the cytoplasm Loss of RNA in the cytoplasm Increased binding of eosin to denatured Increased binding of eosin to denatured

cytoplasmiccytoplasmic protein protein • More glassy homogeneous appearance More glassy homogeneous appearance Loss of glycogen particlesLoss of glycogen particles• Vacuolated and moth-eaten cytoplasmVacuolated and moth-eaten cytoplasm• Calcification of necrotic cellsCalcification of necrotic cells

Coagulation necrosisCoagulation necrosis

Denatures of both structural and Denatures of both structural and

enzymatic proteins by injury or the enzymatic proteins by injury or the

subsequent increasing intracellular subsequent increasing intracellular

acidosis.acidosis.

Renal Infarction - Coagulative

Splenic Infarction - Coagulative necrosis

Infarction - Adrenal gland:

Caseous necrosisCaseous necrosisA subtype of coagulation necrosisA subtype of coagulation necrosisWhite and cheesyWhite and cheesyTuberculosisTuberculosisCompletely obliterated tissue Completely obliterated tissue architecturearchitecture

Caseous necrosis of kidney

• The necrosis area is soft, white-yellow cheesy appearance.

Extensive Caseous necrosis

Tuberculosis

Liquefactive necrosisBacterial or fungal infections

Central nervous system

Amebiasis

Liver abscess: Liquifactive necrosis

Stroke- Liquifactive necrosis

Fat necrosisTraumatic

Activated pancreatic lipases

Fat necrosis(Steatonecrosis)

• Only shadowy outlines of necrotic fat cells may be seen, with basophilic calcium deposits and a surrounding inflammatory reaction.

Fibrinoid degeneration Deeply eosinophilic

• Collagen diseases• Necrotic vasculitis• Malignant hypertension

Fibrinoid Necrosis

• homogeneous, deeply eosinophilic in necrosis.

GangreneGangreneA subtype of coagulation necrosisA subtype of coagulation necrosis

Dry gangreneDry gangrene

Wet gangreneWet gangrene

Gas gangreneGas gangrene

Caseous necrosis - Tuberculosis

Gangrene - Amputated Diabetic foot

Gangrene Intestine - Thrombosis.

• AbsorptionAbsorption• Discharge: Erosion UlcerDischarge: Erosion Ulcer Sinus Fistula CavitationSinus Fistula Cavitation• OrganizationOrganization• EncapsulationEncapsulation• CalcificationCalcification

Fates of necrosisFates of necrosis

APOPTOSISAPOPTOSIS

APOPTOSIS (Programmed cell death)

• Programmed destruction of cells during Programmed destruction of cells during embryogenesis.embryogenesis.• Hormone dependent involution of tissues Hormone dependent involution of tissues in the adult.in the adult.• Cell deletion in proliferating cell popula- Cell deletion in proliferating cell popula- tions (intestinal crypt epithelium), tions (intestinal crypt epithelium), tumors, and lymphoid organs.tumors, and lymphoid organs.

• Pathologic atrophy in parenchymal Pathologic atrophy in parenchymal

organs after duct obstruction.organs after duct obstruction.• Cell death by cytotoxic T cells.Cell death by cytotoxic T cells.• Cell injury in certain viral diseases.Cell injury in certain viral diseases.• Cell death produced by a variety of Cell death produced by a variety of

injurious stimuli given in low dosesinjurious stimuli given in low doses

(e.g. mild thermal injury).(e.g. mild thermal injury).

MORPHOLOGICAL FEATURES MORPHOLOGICAL FEATURES OF APOPTOSISOF APOPTOSIS

• Cell shrinkageCell shrinkage• Chromatin condensation and fragmentation.Chromatin condensation and fragmentation.• Formation of cytoplasmic blebs and apoptoticFormation of cytoplasmic blebs and apoptotic bodies.bodies.• Phagocytosis of apoptotic bodies by adjacent Phagocytosis of apoptotic bodies by adjacent healthy cells or macrophages.healthy cells or macrophages.• Lack of inflammation.Lack of inflammation.

NecrosisNecrosis ApoptosisApoptosisStimuliStimuli Hypoxia Physical Hypoxia Physical Toxins PathologicalToxins PathologicalHistologyHistology Cell swelling Single cell Cell swelling Single cell Coagulation N ChromatinCoagulation N Chromatin Disruption of condensationDisruption of condensation organelles Apoptotic bodiesorganelles Apoptotic bodiesDNADNA Random Internucleosomal Random Internucleosomalbreakdownbreakdown Diffuse Diffuse

NecrosisNecrosis ApoptosisApoptosis

Mechanism Mechanism ATP depletion Gene activation ATP depletion Gene activation

Membrane EndonucleaseMembrane Endonuclease

injuryinjury

Free radicalsFree radicals

Tissue Tissue Inflammation No inflammation Inflammation No inflammation

reactionreaction Phagocytosis of Phagocytosis of

apoptotic bodiesapoptotic bodies

• Fig 1-18

Biochemical features of apoptosisBiochemical features of apoptosis

1.PROTEIN CLEAVAGE:1.PROTEIN CLEAVAGE: Caspases (cysteine protease)Caspases (cysteine protease) Nuclear scaffoldNuclear scaffold Cytoskeletal proteinCytoskeletal protein2.PROTEIN CROSS-LINKING:2.PROTEIN CROSS-LINKING: TransglutaminaseTransglutaminase Cytoplasmic proteinCytoplasmic proteinshrunken shallsshrunken shalls apoptotic bodiesapoptotic bodies Biochemical features of apoptosisBiochemical features of apoptosis

3. DNA breakdown:3. DNA breakdown: 50-300 kb pieces 50-300 kb pieces Ca2+, Mg2+ dependent endonucleasesCa2+, Mg2+ dependent endonucleases DNA oligonucleosomesDNA oligonucleosomes DNA ladders (also seen in necrosis)DNA ladders (also seen in necrosis)4. PHAGOCYTIC RECOGNITION4. PHAGOCYTIC RECOGNITION Receptors on macrophages for the Receptors on macrophages for the surface components surface components (phosphatidylserine, thrombospondin) (phosphatidylserine, thrombospondin) on apoptotic bodies.on apoptotic bodies.

• Fig 1-19

• Apoptosis-associated genesApoptosis-associated genes

bcl-2, c-myc, p53bcl-2, c-myc, p53

• Fig 1-20

• Occuring conditions

1. during embryogenesis and development;

2. as a homeostatic mechanism to maintain normal cell populations of tissue in the face of cell turnover;

3. as a defense mechanism such as in immune reactions;

4. when cells are damaged by diseases or noxious agents, such as injury, tumors and inflammation;

5. reduction cell during atrophy;

6. in aging.

A. Morphologic features

1. Cell shrinkage.

2. Chromatin condensation

3. Apoptotic bodies formation

4. Phagocytosis of apoptotic bodies by adjacent cells or macrophages.

5. Intacted membrane.

•Morphology Biochemistry of Apoptosis

B. A specific biochemical feature

breakdown of DNA into large 180 to 200-kilobase pieces, by Ca2+/Mg2+ dependent endogenous nucleases.

normalcellCellular swelling,

chromatin cluping Membrane damage

Nuclear chromatin condensation and

fragmentation

Cytoplasmic budding and apoptosisi body

Phagocytosisi of apoptosis body

The sequential ultrastructual changes in necrosis and apoptosis

Apotosis of hepatocytes

Comparison of cell death by apoptosis and necrosis

Terminology:

• Necrosis: Morphologic changes seen in dead cells within living tissue.

• Autolysis: Dissolution of dead cells by the cells own digestive enzymes. (not seen)

• Apoptosis: Programmed cell death. Physiological, for cell regulation.

Types of Necrosis:

• Coagulative – Eg. Infarction

• Liquifactive - Brain, abscess

• Fibrinous - colleagen

• Caseous - Bacterial / Tuberculosis

• Gangrene - With infection

Ageing:

“Progressive time related loss of structural and functional capacity of

cells leading to death”

• Senescence, Senility, Senile changes.

• Ageing of a person is intimately related to cellular ageing.

Factors affecting Ageing:

• Genetic – Clock genes, (fibroblasts)

• Diet – malnutrition, obesity etc.

• Social conditions -

• Diseases – Atherosclerosis, diabetes etc.

• Werner’s syndrome.

Cellular mechanisms of ageing

• Cross linking proteins & DNA.

• Accumulation of toxic by-products.

• Ageing genes.• Loss of repair mechanism.• Free radicle injury• Telomerase shortening.

Telomerase in ageing:

GermCells

SomaticCells

Ageing –changes:• Gradual atrophy of tissues and organs.

• Dementia

• Loss of skin elasticity

• Greying and Loss of hair

• BV damage – atherosclerosis/bruising.

• Loss of Lens elasticity opacity vision

• Lipofuscin pigment deposition – Brown atrophy in vital organs.

Pathology of elderly

Factors affecting ageing:

• Stress• Infections• Diseases• Malnutrition• Accidents

• Diminished stress response.

• Diminished immune response.

• Good health.

Conclusions:

• Cellular Injury - Various causes• Reversible Injury Adaptations

– Hypertrophy, Hyperplasia, Atrophy– Accumulations - Hydropic, hyaline, fat..

• Irreversible Injury - Necrosis– Coagulative, Liquifactive, Caseous

• Ageing - Causes, Changes, Factors