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PathologyPathologyThe study of diseases (patterns, causes, mechanisms, effects)The study of diseases (patterns, causes, mechanisms, effects)

Bridges clinical practice and basic science

Identifies changes in morphology (shape, patterns) -- Clinical (clinical pathology, laboratory pathology) -- Gross (anatomic pathology, autopsy, necropsy) -- Microscopic (histopathology, surgical pathology) -- Molecular (molecular pathology, cellular pathology)

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Renders an histopathologic diagnosis May require immunohistochemistry, molecular

markers Studies causes (etiology, pathoetiology,

etiopathology) -- Genetics -- Environment (including iatrogenic) -- Idiopathic (“idiot pathologists”?!) Studies mechanisms of disease development

(pathogenesis) Studies progression of disease

(pathophysiology)

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Causes of Cell InjuryCauses of Cell Injury

Physical agents -- Mechanical trauma -- Temperature -- Radiation -- Electric shock -- Changes in atmospheric pressure

Chemical agents Infectious agents

Inflammation

Nutritional imbalances -- Starvation -- Obesity -- Vitamin deficiency

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Causes of Cell InjuryCauses of Cell Injury Hypoxia (oxygen deficiency) -- Pneumonia -- Anemia -- Carbon monoxide (CO) poisoning -- Ischemia (poor blood flow) -- Infarction (loss of blood supply) Immunologic reactions -- Allergy -- Anaphylaxis -- Autoimmune diseases (self-allergy, loss of tolerance)

Genetic defects (DNA alterations) -- Congenital malformations -- Inborn errors of metabolism

Aging -- Degeneration -- Cellular senescence

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Biochemical Mechanisms of InjuryBiochemical Mechanisms of Injury

ATP depletion via: a- mitochondrial oxidative phosphorylation b- anaerobic glycolysis Oxygen deprivation (ischemia, infarction) Oxygen damage -- partially reduced O2 >> free radicals Loss of calcium homeostasis Defects in cell membrane permeability Mitochondrial damage

The most vulnerable intracellular systems:The most vulnerable intracellular systems: Cell membrane integrity mitochondrial aerobic respiration Protein synthesis Gene integrity

Free Radical-Induced Cellular InjuryFree Radical-Induced Cellular Injury

Highly reactive, unstable species, interact with proteins, lipid, Highly reactive, unstable species, interact with proteins, lipid, carbohydrates causing cellular injury.carbohydrates causing cellular injury.

Generation of free radicalsGeneration of free radicals1- Absorption of radiant energy (ultraviolet light & x-rays): H2O1- Absorption of radiant energy (ultraviolet light & x-rays): H2O OH* & H* OH* & H*

2- Enzymatic metabolism of exogenous chemicals or drugs: CCL42- Enzymatic metabolism of exogenous chemicals or drugs: CCL4 CCL3CCL3

3- Reduction-oxidation reaction during normal metabolic processes: O23- Reduction-oxidation reaction during normal metabolic processes: O2 --, , H2O2, OH*H2O2, OH*

4- Transition metals (Iron & Copper), Fenton reaction, superoxide& iron 4- Transition metals (Iron & Copper), Fenton reaction, superoxide& iron maximal oxidative cellular damagemaximal oxidative cellular damage

5- Nitric oxide.5- Nitric oxide.

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Free Radicals in InjuryFree Radicals in InjuryGeneration, Injury and Neutralization by AntioxidantsGeneration, Injury and Neutralization by Antioxidants

GSSG = oxidized glutathione; NADPH = reduced nicotinamide adenine dinucleotide phosphate; NO = nitric oxide

Major injuries: Lipid peroxidation of membranes yield peroxides and begin an autocatalytic chain reaction Single-strand DNA breaks (thymine) Cross-linking of proteins (sulfhydryl-mediated) enhances degradation rate and loss of enzyme activity

Antioxidants: Superoxide dismutase (SOD) Glutathione (GSH) peroxidase Catalase (in peroxisomes) Vitamins E, A, C and beta-carotene Free ionized iron and copper

Removal of Free RadicalsRemoval of Free Radicals

•Decay: SuperoxideDecay: Superoxide O2 & H2O2 O2 & H2O2

• Inactivation:Inactivation:

• Antioxidants: lipid soluble vitamins, ascorbic acid Antioxidants: lipid soluble vitamins, ascorbic acid glutathionglutathion block initiation of FR, inhibition, termination block initiation of FR, inhibition, termination of radical damage.of radical damage.

• Binding of storage or transport proteins.Binding of storage or transport proteins.

• Enzymes acting as a free radical-Scavenging system: Enzymes acting as a free radical-Scavenging system: Catalase, Superoxide dismutases, Glutathione Catalase, Superoxide dismutases, Glutathione peroxidases.peroxidases.

Chemical InjuryChemical Injury

Mechanisms of chemical injury:Mechanisms of chemical injury:

I- DirectI- Direct: : binding to some critical molecular component: binding to some critical molecular component: mercury of mercuric chloride+SH group of cell membranemercury of mercuric chloride+SH group of cell membrane Increase permeability and inhibition of ATP-ase dependent Increase permeability and inhibition of ATP-ase dependent transporttransport

II- Indirect: II- Indirect: conversion to reactive toxic metabolitesconversion to reactive toxic metabolites cell cell injury by direct covalent binding to membrane ptns and lipids or injury by direct covalent binding to membrane ptns and lipids or formation by reactive free radicals (CCL4, actetaminphen.formation by reactive free radicals (CCL4, actetaminphen.

CCL4:CCL4: dry cleaning, CCL3 in SER of liver, initiate lipid dry cleaning, CCL3 in SER of liver, initiate lipid peroxidation and autocatalytic reactionperoxidation and autocatalytic reaction Swelling and Swelling and breakdown of ER, dissociation of ribosomes, decrease hepatic ptn breakdown of ER, dissociation of ribosomes, decrease hepatic ptn synthesis (e.g. apoprotein), reduced lipid transportsynthesis (e.g. apoprotein), reduced lipid transportfatty change, fatty change, progressive heptocyte swelling, plasma membrane damage, progressive heptocyte swelling, plasma membrane damage, deathdeath

AcetaminophenAcetaminophen: Analgesic, metabolized by liver, toxic : Analgesic, metabolized by liver, toxic metabolites inactivated by GSH, large dosesmetabolites inactivated by GSH, large doses acc. of metabolites acc. of metabolites due to GSH depletiondue to GSH depletion binding to ptns & nucleic acids- binding to ptns & nucleic acids- increase drug toxicity & massive liver damageincrease drug toxicity & massive liver damage

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Ischemia/Reperfusion InjuryIschemia/Reperfusion InjurySignificant in myocardial and cerebral infarctionsSignificant 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?Problem? Vasoconstrictors in local anesthetics produce

ischemia and reperfusion each time they are used.

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Mitochondrial Mitochondrial DysfunctionDysfunctionwith Injurywith Injury

Are targets of most injuries Nonselective pores allow protons out >> prevents ATP generation Cytochrome c (electron transport protein) leaks out >> activates apoptotic death

Apoptosis = programmed cell death

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Reversible Ischemic Reversible Ischemic InjuryInjury

Sequence of EventsSequence of Events

Accumulation of inorganic phosphates, lactic acid

(hydrolysis of phosphate

esters)

Ribosomes detach from rough endoplasmic reticulum Polysomes dissociate into monosomes

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Increased Cytosolic Calcium in Cell InjuryIncreased Cytosolic Calcium in Cell Injury

Usually 10,000x lower than extracellular calcium ATP-dependent Ischemic/toxins >> influx of calcium across membrane Activates phospholipases >> membrane damage Activates proteases >> structural and membrane proteins catabolized Activates endonucleases >> chromosomes fragment May be irreversible May kill the cell

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Membrane DamageMembrane DamageIf severe enough, may stimulate external attackIf severe enough, may stimulate external attack

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Cell Responses to InjuryCell 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) The cell dies (irreversible damage)

These are tempered by:These are tempered by: Genetic factors Immune factors Environmental factors Strength of the outside attack Duration of the outside attack

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AdaptedCell

+ Stress

Injury

Normal cell

Reversibly injured cell

Irreversibly Injured cell

Dead cell

+Stress

Apoptosis

Necrosis

- Stress

- Stress

Overview

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Reversible vs irreversible cell injuryReversible injury* Decreased ATP levels* Ion imbalance* Swelling * Decreased pH* Fatty change (liver)

Irreversible injury* Amorphous densities in mitochondria* Severe membrane damage* Lysosomal ruptureExtensive DNA damage

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Reversible cell injuryReversible cell injury ((degeneration)degeneration) cased by mild cased by mild injury of short duration and injury of short duration and includes:includes:

1 Cell or Cloudy Swelling. Then can proceed to2- Hydropic or Vacular Degeneration

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Cell Swelling or Cell Swelling or Hydropic Hydropic

DegenerationDegeneration Characterized by:-Characterized by:- Swelling of cells - Swelling of cells -

Granulation of cytoplasm.Granulation of cytoplasm.** Organs affected Organs affected: : parenchymatous organsparenchymatous organs

* * Microscopic appearanceMicroscopic appearance::• Cytoplasm is fine red and granularCytoplasm is fine red and granular• Vacuolation of cytoplasm.Vacuolation of cytoplasm. Nuclei are normalNuclei are normalFate:Fate: Reversible Reversible

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Reversible Ischemic InjuryReversible Ischemic InjuryMicroscopic ChangesMicroscopic Changes

Accumulation of inorganic

phosphates, lactic acid

(hydrolysis of phosphate

esters)

Hydropic DegenerationHydropic DegenerationCellular swelling in alcohol liver damageCellular swelling in alcohol liver damage

Summary:Summary: Swollen mitochondria Swollen endoplasmic reticulum Swollen cell (poor Na+ pump) Release of ribosomes from rough ER Mitochondrial densities Membrane blebs (poor structure) Autophagic vacuoles accumulate Nuclear clumping

21Hydropic change (viral hepatitis)

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Subcellular response to Subcellular response to injuryinjury

Lysosomes (heterophagy; autophagy) Smooth ER (induction) Mitochondria (D number, size and

shape) Cytoskeleton (D phagocytosis,

locomotion) Nucleus (karyolysis, karyorrhexis,

pyknosis) Membranes (cellular and subcellullar)

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Subcellular Response to Subcellular Response to InjuryInjury

Lyzosomal CatabolismLyzosomal Catabolism:: Primary lyzosomes are membrane- bound Primary lyzosomes are membrane- bound

intracellular organells containing a variety of intracellular organells containing a variety of hydrolytic enzymes.hydrolytic enzymes.

These fuse with vacuoles containing These fuse with vacuoles containing materials needed for digestion.materials needed for digestion.

They form Secondary lyzosomes or They form Secondary lyzosomes or phagolyzosomes.phagolyzosomes.

Lyzosomes are involved in the breakdown of Lyzosomes are involved in the breakdown of ingested materials in one of two ways: ingested materials in one of two ways:

HeterophagyHeterophagy or or AutophagyAutophagy

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Autophagy v. HeterophagyAutophagy v. Heterophagy

Degenerating Degenerating mitochondria with mitochondria with

amorphous amorphous materialmaterial

Autophagy:Autophagy: Intracellular organelles and cytosol are sequestered (autophagic vacuoles) In area of smooth ER fuse with preexisting lyzosomes to form autophagolysosomes. Especially common is cell differentiation and removal of damaged organells. Lipids, especially, may not be digested Undigested debris: exocytosis or residual bodies, i.e. lipofuscin pigment, carbon

Heterophagy:Heterophagy: Outside stuff undergoes: endocystosis or phagocytosis (large particles) or pinocytosis (Soluble macromolecules) Endocysted vacuoles fuse with lysosomes Ex: phagocyteso of bacteria by neutrophil and necrotic tissues by macrophages.

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Autophagy and Cell AtrophyAutophagy and Cell Atrophy

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Intracellular Intracellular AccumulationsAccumulations

Reversible cellular Reversible cellular adaptationadaptation

Lipids (TG and Cholesterol)Lipids (TG and Cholesterol) ProteinsProteins PigmentsPigments Glycogen (genetic disease)Glycogen (genetic disease)

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Intracellular Accumulations (Reversible Intracellular Accumulations (Reversible Cellular Adaptaion)Cellular Adaptaion)

Three mechanisms by which the cell can acquire intracellular Three mechanisms by which the cell can acquire intracellular accumulations:accumulations:

Too much of a normal endogenous substance -- usually decreased metabolism from cell damage, e.g. fatty liver

Genetic or acquired defect of metabolism (inborn error of metabolism)

-- errors of metabolism, packaging, transport, secretions -- storage diseases, alpha1-antitrypsin deficiency (protein folding &

transport)

Exogenous deposits accumulate in cell (can’t degrade or transport it) -- carbon (black lung disease) -- silica (silicosis)

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Fatty Change (Liver)Fatty Change (Liver)Many ways to get to sublethal cell damageMany ways to get to sublethal cell damage

-Fatty Change refers Fatty Change refers to any abnormal to any abnormal accumulation of accumulation of triglycerides within triglycerides within parenchymal cells.parenchymal cells.- It is reversible It is reversible process.process.-When mild: no When mild: no effect.effect.-Severe cases: Severe cases: impair the cellular impair the cellular function transiently.function transiently.-Micro: Clear Micro: Clear cytoplasmic cytoplasmic vacuoles that needs vacuoles that needs specific stains.specific stains.

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Intracellular AccumulationsIntracellular Accumulations

.

Fatty LiverFatty Liver

Lipofuscin in Heart MuscleLipofuscin in Heart Muscle

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Fatty ChangeFatty Change Characterized by Characterized by - Accumulation of excess neutral fat in the cells.Accumulation of excess neutral fat in the cells.

* * Causes:Causes:

* * Hypoxia * Toxins * Chemicals * In the liver may be due to: Hypoxia * Toxins * Chemicals * In the liver may be due to: a- Excess fat brought to liver b- Diseases of liver a- Excess fat brought to liver b- Diseases of liver

c- Deficiency of lipotropic factors.c- Deficiency of lipotropic factors.

Gross pictureGross picture: : The affected organ is enlarged, soft,The affected organ is enlarged, soft,

Microscopic picture:Cells are:Microscopic picture:Cells are:pale yellow, rounded borders, pale yellow, rounded borders,

*Swollen * Cytoplasm show cut surface bulges and greesy. *Swollen * Cytoplasm show cut surface bulges and greesy. multiple tiny fat globulesmultiple tiny fat globules

* Nucleus is compressed, flattened* Nucleus is compressed, flattened against cell membrane. against cell membrane.

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Fatty change

Cholesterol and Cholesterol EstersCholesterol and Cholesterol Esters

•Synthesis of cell membranesSynthesis of cell membranes

• Accumulations manifested by intracellular vacuolesAccumulations manifested by intracellular vacuoles

• Atherosclerosis:Atherosclerosis: lipids accumulate in smooth muscle cells lipids accumulate in smooth muscle cells and in macrophages of the wall of arteries.and in macrophages of the wall of arteries.

*Cells: *Cells: vacuoles vacuoles

*Extracellular: *Extracellular: Rhomboid cleft-like cavitiesRhomboid cleft-like cavities•Hereditary hyperlipidemiaHereditary hyperlipidemia: : in macrophages and mesenchymal cells-in macrophages and mesenchymal cells- XanthomasXanthomas

• Inflammation and necrosis: Inflammation and necrosis: phagocytosis of membrane lipids derived phagocytosis of membrane lipids derived from injured cellsfrom injured cells Foamy macrophagesFoamy macrophages

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Cholesterolosis. Cholesterol-laden macrophages (foam cells) from a focus of gallbladder cholesterolosis (arrow).

Intracellular Protein Accumulation•Excessive synthesis or Absorption or Defect in cellular transportExcessive synthesis or Absorption or Defect in cellular transport

• Rounded eosinophilic droplets or masses in the cytoplasmRounded eosinophilic droplets or masses in the cytoplasm

•Excessive AbsorptionExcessive Absorption: Protracted proteinuria : Protracted proteinuria

•Excessive synthesisExcessive synthesis:: Russell bodies Russell bodies

•Defective intracellular transport and secretion of critical proteins: Defective intracellular transport and secretion of critical proteins: Alpha-1-Alpha-1-antitrypsin deficiency & Cystic fibrosisantitrypsin deficiency & Cystic fibrosis

• Toxicity of aggregated abnormally folded protein: Toxicity of aggregated abnormally folded protein: Neurodegenerative Neurodegenerative disorders (Alzheimer dis; microtubule-associated ptn & neurofilament) & disorders (Alzheimer dis; microtubule-associated ptn & neurofilament) & amylodosisamylodosis

• Resistance of degradationResistance of degradation: Mallory body (alcoholic hyalin; : Mallory body (alcoholic hyalin; prekeratin prekeratin intermediate filamentsintermediate filaments

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Intracellular Protein Intracellular Protein AccumulationAccumulation

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

GlycogenGlycogen•Abnormalities in the metabolism of glucose or glycogenAbnormalities in the metabolism of glucose or glycogen

• Diabetes Mellitus:Diabetes Mellitus: Glycogen accumulation in renal tubular Glycogen accumulation in renal tubular epithelium, cardiac myocytes, beta cells of pancreasepithelium, cardiac myocytes, beta cells of pancreas

• Enzyme defects:Enzyme defects: synthesis or breakdown of glycogen synthesis or breakdown of glycogen Glycogen storage diseaseGlycogen storage disease

Pigments (Exogenous or Endogenous)Pigments (Exogenous or Endogenous)

•Exogenous pigments: Exogenous pigments:

•AnthracosisAnthracosis: Acc. of carbon in the macrophages of : Acc. of carbon in the macrophages of lungs and Lymph lungs and Lymph nodes Heavy acc.nodes Heavy acc. emphysema or coal workers pneumoconiosis. 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:Tattooing: Macrophages, extracellularly (persist for life)Macrophages, extracellularly (persist for life)

• Endogenous pigments:Endogenous pigments:

•Lipofuscin, melanine, certain hemoglobin derivativesLipofuscin, melanine, certain hemoglobin derivatives

•Lipofuscin (the wear-and tear pigment):Lipofuscin (the wear-and tear pigment): Intra- cytoplasmic yellowbrown Intra- cytoplasmic yellowbrown fine pigment (Brown atrophy) lipid& phospholipids & proteins (peroxidation fine pigment (Brown atrophy) lipid& phospholipids & proteins (peroxidation of polyunsaturated lipids of cellular membraneof polyunsaturated lipids of cellular membrane))

• MelanineMelanine: : Non-hemoglobin-derived brown- black pigment formed by Non-hemoglobin-derived brown- black pigment formed by melanocytes by the oxidation of tyrosine.melanocytes by the oxidation of tyrosine.

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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).

• HemosiderinHemosiderin: : A hemoglobin-derived, golden-yellow to brown A hemoglobin-derived, golden-yellow to brown granular pigment composed of aggregates of ferritin micellesgranular pigment composed of aggregates of ferritin micelles

Localized or systemicLocalized or systemicLocal HemosidrosisLocal Hemosidrosis

•Gross hemorrhage or rupture of small vessels (congestion)Gross hemorrhage or rupture of small vessels (congestion)

• Lysosomal enzymes in macrophages convert hemoglobin to Lysosomal enzymes in macrophages convert hemoglobin to

hemosiderinhemosiderin

Systemic HemosiderosisSystemic Hemosiderosis

•Increased absorption of dietary iron (primary hemochromatosis)Increased absorption of dietary iron (primary hemochromatosis)

• Impaired utilization of iron (Thalassemia)Impaired utilization of iron (Thalassemia)

•Hemolytic anemiasHemolytic anemias

•Repeated transfusionRepeated transfusion (exogenous load of iron) (exogenous load of iron)

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Hemosiderin granules in liver cells. A, H&E section showing golden-brown, finely granular pigment. B, Prussian blue reaction, specific for iron.

Pathologic CalcificationPathologic Calcification

•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).

• Metastatic calcification: Vital tissue, hypercalcemia

• 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 CalcificationPathogenesis of Dystrophic Pathological Calcification

•InitiationInitiation: : Extracellularly or intracellularlyExtracellularly or intracellularly

•Extracellular initiation: membrane- bound vesicles derived from dead or Extracellular initiation: membrane- bound vesicles derived from dead or dying cells that concentrate calcium by their affinity for acidic dying cells that concentrate calcium by their affinity for acidic phospholipids.phospholipids.

•Phosphates accumulation by the action of membrane bound Phosphates accumulation by the action of membrane bound phosphatases.phosphatases.

• The cycle of calcium and phosphate binding is repeated-The cycle of calcium and phosphate binding is repeated- deposits deposits

• Initiation of intracellular calcification occurs in mitochondria of dead or Initiation of intracellular calcification occurs in mitochondria of dead or dying tissue.dying tissue.

•Propagation of crystal formation:Propagation of crystal formation: depends on conc. of calcium and depends on conc. of calcium and phosphates, the presence of inhibitors, structural components of extra-phosphates, the presence of inhibitors, structural components of extra-cellular matrix (collagen) as well as other matrix protein (osteonectin and cellular matrix (collagen) as well as other matrix protein (osteonectin and others).others).

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Calcific Valves in Aortic StenosisCalcific Valves in Aortic StenosisThick, fibrotic cusps; masses of dystrophic calcificationThick, fibrotic cusps; masses of dystrophic calcification

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Chronic Calcific PulpitisChronic Calcific PulpitisChronic Ischemic Pulpitis?Chronic Ischemic Pulpitis?

Dystrophic Dystrophic CalcificationCalcification

Causes of Metastatic Calcification Causes of Metastatic Calcification (Hypercalcemia)(Hypercalcemia)

A: Excessive mobilization of calcium from bone:A: Excessive mobilization of calcium from bone:

1- Hyperparathyroidism (primary or secondary).1- Hyperparathyroidism (primary or secondary).

2- Bony destructive lesions such as myelomas and metastatic carcinomas.2- Bony destructive lesions such as myelomas and metastatic carcinomas.

3- Disuse atrophy of bones.3- Disuse atrophy of bones.

B- Excessive absorption of calcium from the gut:B- Excessive absorption of calcium from the gut:

1- Hypervitaminosis D.1- Hypervitaminosis D.

2- Excessive oral calcium intake.2- Excessive oral calcium intake.

3- Hypercalcemia of infancy.3- Hypercalcemia of infancy.

Metastatic calcification affects Kidney (basement membrane of tubules), Metastatic calcification affects Kidney (basement membrane of tubules), Alveolar wall of lungs, Stomach (fundal glands0, Blood vessels especially Alveolar wall of lungs, Stomach (fundal glands0, Blood vessels especially internal elastic lamina and cornea.internal elastic lamina and cornea.

It is based on that sites have relatively alkaline pH which favors It is based on that sites have relatively alkaline pH which favors precipitation of calcium.precipitation of calcium.

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Metastatic CalcificationMetastatic Calcification

Calcification in the wall of a blood vessel

Calcification in the gastric submucosa

Cellular Adaptation to InjuryCellular Adaptation to Injury

A state that lies between the normal, unstressed cell and A state that lies between the normal, unstressed cell and the injured over stressed cell.the injured over stressed cell.

Mechanisms:Mechanisms:

•Up- or down-regulation of specific cellular receptorsUp- or down-regulation of specific cellular receptors

• Induction of new protein synthesis : heat shock protein Induction of new protein synthesis : heat shock protein (protection)(protection)

•Switch from one type of protein to anotherSwitch from one type of protein to another

• marked over-production of one type of protein (collagen)marked over-production of one type of protein (collagen)

Atrophy, Hypertrophy, Hyperplasia, MetaplasiaAtrophy, Hypertrophy, Hyperplasia, Metaplasia

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Reversible Cell AdaptationReversible Cell Adaptation

AdaptationAdaptation ResultResult

AtrophyAtrophy Decrease in cell sizeDecrease in cell size

HypertrophyHypertrophy

Increased cell size of an organ due to increase in the Increased cell size of an organ due to increase in the size of cells.size of cells.

HyperplasiaHyperplasia

Increased cell size of an organ due to increase in the Increased cell size of an organ due to increase in the number of cells.number of cells.

MetaplasiaMetaplasia Stable change from one cell type to another cell typeStable change from one cell type to another cell type

DysplasiaDysplasia Abnormal cell or tissue growthAbnormal cell or tissue growth

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Cellular adaptations to stress:

1. Hyperplasia (more cells)

2. Hypertrophy (bigger cells)

3. Atrophy (smaller cells)

4. Metaplasia (different type of cells)

HypertrophyHypertrophyAn increase in the number of organelles and the size of An increase in the number of organelles and the size of the cells with subsequent increase in the size of organ due the cells with subsequent increase in the size of organ due to an increase in the functional demands.to an increase in the functional demands.

Types:Types:

•physiologicalphysiological:: Uterus in pregnancy, muscle in athletesUterus in pregnancy, muscle in athletes

•PathologicalPathological::

•Adaptive:Adaptive: Hollow muscular organs above a chronic partial Hollow muscular organs above a chronic partial obstruction (Heart, stomach, intestine, bladder)obstruction (Heart, stomach, intestine, bladder)

•Compensatory: Compensatory: Paired organ (kidney, lung) Paired organ (kidney, lung)

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Hypertrophy

* Larger cells

* Not due to swelling

* Increased synthesis of structural components

* Results in larger organ

* May occur with hyperplasia

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Mechanism of HypetrophyMechanism of Hypetrophy

•Increased synthesis of structural proteins via:

•Transcription factors (i. e. c-fos and c-jun)

•Growth factors (TGF-, IGF-1, FGF)

•Vasoactive agents (endothelien-1, AII)

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HypertrophyHypertrophy

Physiologic hypertrophy of Physiologic hypertrophy of myometrium during pregnancy due to myometrium during pregnancy due to estrogen stimulationestrogen stimulation

Physiologic hypertrophy of skeletal Physiologic hypertrophy of skeletal musclemuscle

from exercisefrom exercise

Normal muscleNormal muscle

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HypertrophyHypertrophyEnlargement of cardiac muscle in response to valve diseaseEnlargement of cardiac muscle in response to valve disease

Normal HeartNormal Heart

Hypertrophied Left VentricleHypertrophied Left Ventricle

Normal Heart MuscleNormal Heart Muscle

Hypertrophied Heart MuscleHypertrophied Heart Muscle

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Normal Hypertrophied

Cardiac smooth muscle hypertrophy

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HyperplasiaHyperplasia It is an increase in the number of cells in an It is an increase in the number of cells in an

organ or tissue.organ or tissue. Physiologic Types:Physiologic Types:1- Hormonal as in breast due to puberty and 1- Hormonal as in breast due to puberty and

pregnancypregnancy2- Compensatory occurs when a portion of the 2- Compensatory occurs when a portion of the

tissue is removed or diseased.tissue is removed or diseased.

PathologicPathologic::• Compensatory hyperplasia: Bone marrow, liver cirrhosisCompensatory hyperplasia: Bone marrow, liver cirrhosis

• Hormonal hyperplasia: thyroid, breast, endometriumHormonal hyperplasia: thyroid, breast, endometrium

• Irritation hyperplasia: lymphoid tissue in infection and toxemiaIrritation hyperplasia: lymphoid tissue in infection and toxemia

Mechanism of Mechanism of hyperplasiahyperplasiaCell 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

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HyperplasiaHyperplasiaEndometrial hyperplasia in response to estrogenEndometrial hyperplasia in response to estrogen

Hyperplastic GlandsHyperplastic Glands

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HyperplasiaHyperplasiaNodular hyperplasia of the prostate glandNodular hyperplasia of the prostate gland

NormalNormal

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Thyroid hyperplasiaThyroid hyperplasia

Normal ThyroidNormal Thyroid Hyperplastic ThyroidHyperplastic Thyroid

Metaplasia A reversible change in which one differentiated adult cell A reversible change in which one differentiated adult cell type is replaced by another (epithelial or mesenchymal) type is replaced by another (epithelial or mesenchymal) of the same type (during postnatal life)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 Mechanism of MetaplasiaMetaplasia

Reprogramming Reprogramming 1. of stem cells present in 1. of stem cells present in

normal tissuesnormal tissues

2. of undifferentiated 2. of undifferentiated mesenchymal cells mesenchymal cells in in connective tissueconnective tissue

Mediated by signals from:Mediated by signals from:

cytokines, GF or ECMcytokines, GF or ECM

Leading to induction ofLeading to induction of specific specific transcription transcription factorsfactors

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MetaplasiaMetaplasia

Original TissueOriginal Tissue StimulusStimulus Metaplastic TissueMetaplastic Tissue

Ciliated columnar Ciliated columnar epithelium of bronchial epithelium of bronchial treetree

Cigarette smokeCigarette smoke Squamous epitheliumSquamous epithelium

Transitional epithelium Transitional epithelium of bladderof bladder

Trauma of bladder Trauma of bladder calculuscalculus Squamous epitheliumSquamous epithelium

Columnar epithelium of Columnar epithelium of gland ductsgland ducts Trauma of calculusTrauma of calculus Squamous epitheliumSquamous epithelium

Esophageal squamous Esophageal squamous epitheliumepithelium Gastric acidGastric acid Columnar epitheliumColumnar epithelium

Fibrocollagenous tissueFibrocollagenous tissue Chronic traumaChronic trauma Bone (osseous) tissueBone (osseous) tissue

Columnar glandular Columnar glandular epitheliumepithelium Vitamin A deficiencyVitamin A deficiency Squamous epitheliumSquamous epithelium

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Epithelial Metaplasia, the normal respiratory epithelium at the right and the squamous epithelium at the left .

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Photomicrograph of the junction of normal epithelium (1) with

metaplastic transitional epithelium (2).

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Photomicrograph of the trachea from a smoker. Note that the columnar ciliated epithelium has been replaced by squamous epithelium.

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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.

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AtrophyAtrophy

IIt is the shrinkage in the size of the cell by loss of cell t is the shrinkage in the size of the cell by loss of cell substancesubstance ((Balance between synthesis and degradation)Balance between synthesis and degradation)

Decreased synthesis and Increased catabolism

Influenced by: -- insulin -- thyroid-stimulating hormone -- glucocorticoids

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

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Types/Causes of AtrophyTypes/Causes of AtrophyPhysiologic v. PathologicPhysiologic v. Pathologic

Hormone-related atrophy -- 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

Disuse atrophy -- Leg in cast -- Long-term hospitalization

Ischemic atrophy -- Brain atrophy after stroke Denervation atrophy -- Spinal cord injury

Nutritional atrophy -- Mucosal atrophy in pernicious anemia (vitamin B12 deficiency)

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Mechanism of Atrophy

Reduction in structural components

Decreased number of mitochondria, myofilaments, ER

viaproteolysis (lysosomal proteases; ubiquitin-proteosome system)

Increase in number of autophagic vacuoles

Residual bodies (i.e. lipofuscin brown atrophy)

NB: diminished function but not dead

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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.

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AtrophyAtrophyAtrophic Adrenal Gland from Corticosteroid UseAtrophic Adrenal Gland from Corticosteroid Use

NormalNormal

AtrophiedAtrophied

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Brain AtrophyBrain AtrophyAn aging processAn aging process

82 y/o male82 y/o male 25 y/o male25 y/o male

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DysplasiaDysplasiaDysplasia means Dysplasia means abnormal organization of cells abnormal organization of cells At the cellular level, morphologically, it is characterized by At the cellular level, morphologically, it is characterized by

variations in size and shape of the cell (pleomorphism), variations in size and shape of the cell (pleomorphism), disorderly arrangement within the epithelium (loss of polarity) disorderly arrangement within the epithelium (loss of polarity) and nuclear changes, consisting of enlargement, irregular and nuclear changes, consisting of enlargement, irregular borders, and hyperchromasia of individual cell nuclei and borders, and hyperchromasia of individual cell nuclei and increased number of mitotic figures.increased number of mitotic figures.

It is considered pre-malignant (often arises in previously It is considered pre-malignant (often arises in previously metaplastic epithelium), and can progress to malignant metaplastic epithelium), and can progress to malignant squamous cell carcinoma, unless treated.squamous cell carcinoma, unless treated.

Basement membrane is always intactBasement membrane is always intact In early stages it is reversibleIn early stages it is reversible

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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

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MILD DYSPLASIA (INTRAEPITHELIAL NEOPLASIA-GRADE I) These changes are confined to lower 1/3 of the

thickness of the epithelium.

MODERATE DYSPLASIA (INTRAEPITHELIAL NEOPLASIA-GRADE II) These changes are confined to lower 1/2 of the

thickness of the epithelium.

SEVERE DYSPLASIA (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.

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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.

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Normal cervixSevere dysplasia

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•Irreversible cell injury caused by severe injury of long duration and includes:

1- Necrosis 2- Apoptosis

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Sublethal v. Lethal Cell DamageSublethal v. Lethal Cell Damage

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Nuclear Events in NecrosisNuclear Events in NecrosisPyknosis, Karyorrhexis, KaryolysisPyknosis, 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

KaryolysisKaryolysis

KaryorrhexisKaryorrhexisNormalNormal

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Proteins Liberated into Blood Proteins Liberated into Blood Following NecrosisFollowing Necrosis

Released enzymes can help with diagnosisReleased enzymes can help with diagnosis

Cell DamagedCell Damaged Enzyme ReleasedEnzyme Released

Cardiac muscle Creatine kinase (MB isoform)

Aspartate transaminase (AST)

Lactate dehydrogenase (LDH-1)

HepatocyteAlanine transaminase (ALT)

Striated muscleCreatine kinase (MM isoform)

Exocrine pancreas

Amylase

Cytoplasmic Cytoplasmic Changes in Changes in NecrosisNecrosis--Dead cells show Dead cells show increased acidophilia.increased acidophilia.

-Cells may have glassy Cells may have glassy appearance.appearance.

- Cytoplasm become Cytoplasm become vacuolated and appear vacuolated and appear moth- eaten.moth- eaten.

- Calcification of the dead Calcification of the dead cells may occur.cells may occur.

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Mechanisms of Irreversible Injury (NECROSIS)Mechanisms of Irreversible Injury (NECROSIS)

Two main characteristics of irreversible damage:Two main characteristics of irreversible damage: Inability to reverse mitochondrial dysfunction Profound membrane disturbances

Cell membrane damage is the single most important problem:Cell membrane damage is the single most important problem: Loss of membrane phospholipids Lipid breakdown products are catabolic

-- also: detergent effect on membranes Cytoskeletal abnormalities

-- from activate proteases (>Ca++ in cell)

-- detachment of cell membrane from cytoskeleton Toxic oxygen radicals cause additional damage and recruit leukocytes

☺☺

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Types of NecrosisTypes of Necrosis Coagulative necrosis: denatured proteins -- most common type -- cell outlines remain

Gangrenous necrosis (form of ischemic coagulative necrosis) -- wet and dry (superimposed liquefactive necrosis) -- gas necrosis (Clostridium perfringens)

Liquefactive necrosis: enzymatic digestion (proteolysis) -- 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.

☺☺

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Coagulative necrosisCoagulative necrosis

Preservation of structurePreservation of structure Firm Firm Protein denaturationProtein denaturation Hypoxic tissue death (except Hypoxic tissue death (except

brain)brain)

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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.

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Coagulative Necrosis(Myocardial Infarction-heart attack)

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Caseous necrosisCaseous necrosis

Subset of coagulative necrosisSubset of coagulative necrosis TBTB Cheesy, white Cheesy, white Surrounded by inflammatory Surrounded by inflammatory

cells (granulomatous reaction)cells (granulomatous reaction) Complete destruction of tissue Complete destruction of tissue

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Caseation NecrosisTuberculosis of hilar lymph node

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Caseous NecrosisCaseous NecrosisTuberculosis of Lung, LiverTuberculosis of Lung, Liver

GranulomaGranuloma

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Liquefactive necrosisLiquefactive necrosis

Enzymatic digestionEnzymatic digestion Liquid, viscous massLiquid, viscous mass May contain pusMay contain pus Bacterial infections (via Bacterial infections (via

inflammation)inflammation) Hypoxic brain injuryHypoxic brain injury

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MeningitisMeningitisLiquefactive Necrosis of Central Nervous SystemLiquefactive Necrosis of Central Nervous System

Loss of cell outlines Loss of cell outlines

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Liquefactive Necrosis(Cerebral Infarction-stroke)

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The liver shows a small abscess here filled with many neutrophils. This abscess is an example of localized liquefactive necrosis

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Fat necrosisFat necrosis

Not a specific patternNot a specific pattern Focal areas of fat digestionFocal areas of fat digestion Ususally via release of lipases Ususally via release of lipases

from pancreasfrom pancreas FFA combine with Ca to produce FFA combine with Ca to produce

“soaps”“soaps”

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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.

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Fat Necrosis(Acute pancreatitis)

GangreneGangreneDefDef: Gangrene is massive tissue necrosis followed by putrefaction: Gangrene is massive tissue necrosis followed by putrefaction

Causes:Causes:

1- Necrosis1- Necrosis: : sudden ischemia or bacterial toxinssudden ischemia or bacterial toxins

2- Putrefaction2- Putrefaction: : Saprophytic bacteria that breaks down the protein of Saprophytic bacteria that breaks down the protein of necrotic tissuenecrotic tissue liberation of hydrogen sulphide (H2S) liberation of hydrogen sulphide (H2S) foul odourfoul odour, ,

H2S + iron (derived from hemoglobin H2S + iron (derived from hemoglobin iron sulphide iron sulphide staining of staining of gangrenous tissue black.gangrenous tissue black.

Types of GangreneTypes of Gangrene

1- Dry gangrene1- Dry gangrene 2- Moist gangrene2- Moist gangrene

3- Infective gangrene3- Infective gangrene 4- Gas gangrene4- Gas gangrene

Classification of gangreneClassification of gangrene

According to the amount of blood and tissue fluids in the According to the amount of blood and tissue fluids in the part affected at the time of its deathpart affected at the time of its death

I- Dry gangreneI- Dry gangrene II- Moist gangrene II- Moist gangrene

I- Dry GangreneI- Dry Gangrene

•Dry gangrene of limb results from occlusion of its artery by thrombus, Dry gangrene of limb results from occlusion of its artery by thrombus, embolus, thromboangitis obliterans (Buerger’s disease), Ergot poisoning embolus, thromboangitis obliterans (Buerger’s disease), Ergot poisoning and Raynaud’s disease and Raynaud’s disease (spastic occlusion(spastic occlusion), surgical ligature.), surgical ligature.

• Main arterial supply is cut off + poor collateral circulation= gangreneMain arterial supply is cut off + poor collateral circulation= gangrene

• Artery (occluded) + venous and lymphatic drainage (open)+ surface Artery (occluded) + venous and lymphatic drainage (open)+ surface evaporationevaporation dry gangrene dry gangrene

• Commonest example of dry gangrene: Commonest example of dry gangrene: Senile gangrene of limbSenile gangrene of limb..

Senile Senile Gangrene Gangrene Usually affects old malesUsually affects old males

Predisposing factors:Predisposing factors:

1)1) Atherosclerosis: common in old age, predispose to arterial thrombosis & poor collateral circulationAtherosclerosis: common in old age, predispose to arterial thrombosis & poor collateral circulation

2)2) Weak heart actionWeak heart action low blood pressure low blood pressure vascular stasis vascular stasis

3)3) Low body resistance due to nutritional disturbance, nephritis, anemia, etc..Low body resistance due to nutritional disturbance, nephritis, anemia, etc..

Pathological featuresPathological features: the gangrenous process follows the following steps:: the gangrenous process follows the following steps:

1- Arterial occlusion: spontaneous or initiated by slight injury caused by tight shoes1- Arterial occlusion: spontaneous or initiated by slight injury caused by tight shoes

2- Massive necrosis distal to occlusion 2- Massive necrosis distal to occlusion (pale, cold due to ischemia(pale, cold due to ischemia), sensations are lost. Later on, the ), sensations are lost. Later on, the necrotic are necrotic are stains red (blood escaped from necrotic blood vessels), stains red (blood escaped from necrotic blood vessels), Drainage and evaporation of Drainage and evaporation of blood and tissue fluidblood and tissue fluid dryness of dead partdryness of dead part Shrunken & mummified Shrunken & mummified

3- saprophytic bacteria (bacillus subtitis & diphteroids) invade necrotic tissue 3- saprophytic bacteria (bacillus subtitis & diphteroids) invade necrotic tissue putrefaction (bacteria putrefaction (bacteria + dead tissue)+ dead tissue) H2S (bad odour) & iron sulphide (black color) H2S (bad odour) & iron sulphide (black color)

4- Gangrenous process advances slowly along limb (gangrenous part irritates living one 4- Gangrenous process advances slowly along limb (gangrenous part irritates living one inflammation of tissue with thrombosis of the vesselsinflammation of tissue with thrombosis of the vessels more tissue necrosis & extension of more tissue necrosis & extension of gangrene.gangrene.

5- At level of good blood supply5- At level of good blood supply gangrene stops. Toxic products act as an irritant gangrene stops. Toxic products act as an irritant acute acute inflammation in the neighboring healthy partinflammation in the neighboring healthy part narrow red line between healthy and gangrenous narrow red line between healthy and gangrenous part part line of demarcation line of demarcation..

6- from healthy side granulation tissue grow towards gangrenous part with formation of groove on the 6- from healthy side granulation tissue grow towards gangrenous part with formation of groove on the surface surface (line of separation(line of separation)) deepening of the groove deepening of the groove conical stumpconical stump

II Moist Gangrene (Wet gangrene) II Moist Gangrene (Wet gangrene)

- Caused by sudden arterial and venous occlusion, mainly in internal organs (intestine; Caused by sudden arterial and venous occlusion, mainly in internal organs (intestine;

no evaporation of fluid).no evaporation of fluid).

- Excess tissue fluidExcess tissue fluid rapid putrefaction rapid putrefaction rapid spread of gangrene rapid spread of gangrene (line of demarcation (line of demarcation is poor and line of separation is absent, severe toxemia)is poor and line of separation is absent, severe toxemia)

1- Moist gangrene of intestine1- Moist gangrene of intestine:: strangulated hernia, intussusception, volvulus (venous strangulated hernia, intussusception, volvulus (venous occlusion occur first) and mesenteric arterial occlusion.occlusion occur first) and mesenteric arterial occlusion.

- Affected loop: congestion & edema, dark red and swollenAffected loop: congestion & edema, dark red and swollen arterial occlusion arterial occlusion necrosisnecrosis invasion by putrefactive bacteria (lumen) invasion by putrefactive bacteria (lumen) putrefaction (rapid) putrefaction (rapid) black color black color (iron sulphide)(iron sulphide)

- Severe toxemia, acute intestinal obstruction & peritonitis.Severe toxemia, acute intestinal obstruction & peritonitis.

2- Moist gangrene of limb2- Moist gangrene of limb:: severe crushing injury (occlusion of artery and vein by severe crushing injury (occlusion of artery and vein by thrombosis and hematoma), diabetic patients.thrombosis and hematoma), diabetic patients.

3- Diabetic gangrene3- Diabetic gangrene: more common in diabetic female after 45 years (diabetic : more common in diabetic female after 45 years (diabetic hyperlipaemiahyperlipaemia early atherosclerosis early atherosclerosis Arterial occlusion. Arterial occlusion.

Pathology: Pathology: initiated by mild injury, starts on big toe or sole of foot, at first dryinitiated by mild injury, starts on big toe or sole of foot, at first dry moist moist (tissue hyperglycemia, poor body resistant (tissue hyperglycemia, poor body resistant multiplication of bacteria multiplication of bacteria inflammation and inflammation and occlusion of vessels), rapid spread, occlusion of vessels), rapid spread, poor line of demarcation, severe toxemia, little poor line of demarcation, severe toxemia, little tendency to self limitation. tendency to self limitation.

III Infective gangrene: III Infective gangrene: A subtype of moist gangrene (bacteria cause A subtype of moist gangrene (bacteria cause tissue destruction and putrefaction). tissue destruction and putrefaction).

Pathological bacteria (necrosis) + saprophytic bacteria (putrefaction)Pathological bacteria (necrosis) + saprophytic bacteria (putrefaction)

Types:Types:

a)a) Lung gangreneLung gangrene

b)b) Cancrum oris: Cheeks of debilitated children, Cancrum oris: Cheeks of debilitated children, Treponema vincenti and Bacillus Treponema vincenti and Bacillus fusiformisfusiformis, severe toxemia, bronchopneumonia., severe toxemia, bronchopneumonia.

c)c) Noma pudendi: subcutaneous tissue of inguinal region.Noma pudendi: subcutaneous tissue of inguinal region.

d)d) Phagenda: gangrene on top of syphilitic chancer.Phagenda: gangrene on top of syphilitic chancer.

e)e) Synergistic gangrene: wounds draining deep seated abscessesSynergistic gangrene: wounds draining deep seated abscesses

f)f) Bed soresBed sores

IV Gas GangreneIV Gas Gangrene: Moist gangrene of muscles in deep wounds contaminated by manured : Moist gangrene of muscles in deep wounds contaminated by manured soil containing anaerobic spores. Tissue destructionsoil containing anaerobic spores. Tissue destruction local ischemia local ischemia germination of spores.germination of spores.

• Saccharolytic bacteris & proteolytic bacteriaSaccharolytic bacteris & proteolytic bacteria

• Putrefaction with excess production of gases, highly fatal, severe toxemiaPutrefaction with excess production of gases, highly fatal, severe toxemia degeneration and necrosis of parenchymatous organs.degeneration and necrosis of parenchymatous organs.

Complications of GangareneComplications of Gangarene

1-Toxemia1-Toxemia: circulation of bacterial toxins in the blood causing : circulation of bacterial toxins in the blood causing pathological and clinical manifestations (acute & chronic)pathological and clinical manifestations (acute & chronic)

constitutional symptoms, degeneration of parenchymatous constitutional symptoms, degeneration of parenchymatous organs, Amyloidosis in chronic forms, necrosis and organs, Amyloidosis in chronic forms, necrosis and hemorrhage of adrenal cortex, anemia.hemorrhage of adrenal cortex, anemia.

2- Bacteremia:2- Bacteremia: Transient presence of small number of bacteria Transient presence of small number of bacteria in the blood stream without toxic manifestations (tooth in the blood stream without toxic manifestations (tooth extraction)extraction)

Fate: Fate: 1- phagocytosis by RES (small number). 1- phagocytosis by RES (small number).

2- localization 2- localization pathological lesions (carbuncle, acute pathological lesions (carbuncle, acute osteomyelitis, subacute bacterial endocarditis)osteomyelitis, subacute bacterial endocarditis)

3- Septicemia:3- Septicemia: the circulation and multiplication of large amount of the circulation and multiplication of large amount of virulent bacteria and their toxins in blood stream, highly fatalvirulent bacteria and their toxins in blood stream, highly fatal

Causes: pyogenic bacteria as staph, strept, pneumococci, Causes: pyogenic bacteria as staph, strept, pneumococci, gonococci) & Bacilli (proteus, anthrax)gonococci) & Bacilli (proteus, anthrax)

Septic wound, puerperal sepsis, acute osteomyelitis + low body Septic wound, puerperal sepsis, acute osteomyelitis + low body resistanceresistance

4- Pyemia4- Pyemia:: Circulation of septic emboli in the blood stream and their Circulation of septic emboli in the blood stream and their arrest in different organs causing multiple abscess, high mortality arrest in different organs causing multiple abscess, high mortality rate. rate.

5- 5- SapremiaSapremia: Presence of toxic metabolites in blood stream derived : Presence of toxic metabolites in blood stream derived from action of saprophytic bacteria on necrotic tissue (gangrene). from action of saprophytic bacteria on necrotic tissue (gangrene).

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Postmortem ChangesPostmortem Changes

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)Apoptosis (Falling away)

Def.: A programmed cellular death occurs when a cell within an Def.: A programmed cellular death occurs when a cell within an organism dies through activation of an internal suicide program.organism dies through activation of an internal suicide program.

•FunctionFunction: : Elimination of unwanted cells selectively with minimal Elimination of unwanted cells selectively with minimal disturbance to surrounding cells and the hostdisturbance to surrounding cells and the host

ExamplesExamples

•Programmed destruction of cells during embryogenesis.Programmed destruction of cells during embryogenesis.

•Hormone- dependent involution of tissues.Hormone- dependent involution of tissues.

•Cell deletion in proliferating cell populations (duct obstruction, intestinal Cell deletion in proliferating cell populations (duct obstruction, intestinal crypts)crypts)

•

•Cell death by cytotoxic T cells.Cell death by cytotoxic T cells.

• Deletion of auto-reactive T cells in thymus.Deletion of auto-reactive T cells in thymus.

• A variety of mild injurious stimuli (heat, radiation, etc)A variety of mild injurious stimuli (heat, radiation, etc) irreparable DNA irreparable DNA damagedamage trigger cell suicide pathways (p53). trigger cell suicide pathways (p53).

Morphological Features of ApoptosisMorphological Features of Apoptosis

- - Cell shrinkage.Cell shrinkage.

- Chromatin condensation and fragmentation.- Chromatin condensation and fragmentation.

- Cellular blebbing and fragmentation into apoptotic bodies.- Cellular blebbing and fragmentation into apoptotic bodies.

- Phagocytosis of apoptotic bodies by adjacent healthy cells or - Phagocytosis of apoptotic bodies by adjacent healthy cells or macrophages.macrophages.

•No Inflammation.No Inflammation.

• Apoptosis and necrosis can occur together depending on the Apoptosis and necrosis can occur together depending on the severity of stimuli.severity of stimuli.

• Apoptosis is not easy to be demonstrated in histological sections.Apoptosis is not easy to be demonstrated in histological sections.

Mechanisms of ApoptosisMechanisms of Apoptosis

1- Signaling1- Signaling: Stimuli generates signals: Stimuli generates signals

** transmitted across the plasma membrane to intracellular transmitted across the plasma membrane to intracellular regulatory molecules (e.g.FAS)regulatory molecules (e.g.FAS)

•addressed directly at targets present within the cellsaddressed directly at targets present within the cells

2- Control and Integration2- Control and Integration

Death signalsDeath signals Execution program Execution program

1- Adaptor protein : connection1- Adaptor protein : connection

* * Mitochondrial permeability transitions: pore in inner mitochondrial Mitochondrial permeability transitions: pore in inner mitochondrial

membrane.membrane.* Death signals * Death signals cytochrome c release from outer membrane to cytochrome c release from outer membrane to cytoplasm cytoplasm apoptosis.apoptosis.

2- bcl-2 family members2- bcl-2 family members: Regulate mitochondrial function and : Regulate mitochondrial function and suppress apoptosis.suppress apoptosis.

* * Direct action on mitochondria to prevent increased Direct action on mitochondria to prevent increased permeabilitypermeability

• Effects mediated by interaction with other protein.Effects mediated by interaction with other protein.

3- Execution Phase3- Execution Phase

Signaling and regulatory mechanismsSignaling and regulatory mechanisms

1- final proteolytic cascade (1- final proteolytic cascade (caspase family)caspase family)

Caspases (inactive) activeCaspases (inactive) active

Initiators and executorsInitiators and executors Executive caspases are responsible for the morphological Executive caspases are responsible for the morphological

changes characteristic of apoptosis.changes characteristic of apoptosis.2- 2- Extensive protein cross- linking (cytoskeleton) Extensive protein cross- linking (cytoskeleton) fragmentation (apoptotic bodies).fragmentation (apoptotic bodies).

3- DNA breakdown by endonucleases.3- DNA breakdown by endonucleases.

4- Removal of Dead Cells4- Removal of Dead Cells

• Recognition: Marker molecules on the Recognition: Marker molecules on the surface of apoptotic fragments.surface of apoptotic fragments.

• PhagocytosisPhagocytosis

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Mechanism of ApoptosisMechanism of ApoptosisProgrammed Cell DeathProgrammed Cell Death

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Necrosis v. ApoptosisNecrosis v. Apoptosis

Usually: single cellUsually: single cell

Endonucleases Endonucleases activatedactivated

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

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APOPTOSIS

Shrinkage

Condensation

Fragmentation

Phagocytosis

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Apoptosis ← Liver

Prostate↓Prostate Prostate

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Cellular Aging (Senescence)Cellular Aging (Senescence)Progressive accumulation of sublethal injury; diminished capacity to respond to injuryProgressive accumulation of sublethal injury; diminished capacity to respond to injury

With increasing age:With increasing age: Less oxidative phosphorylationLess oxidative phosphorylation Less protein synthesis (structure, enzymes, receptors)Less protein synthesis (structure, enzymes, receptors) Less ability to respond to stressLess ability to respond to stress

Cell appearance with age:Cell appearance with age: Irregular nucleusIrregular nucleus Pleomorphic vacuolated mitochondriaPleomorphic vacuolated mitochondria Less endoplasmic reticulumLess endoplasmic reticulum Distorted Golgi apparatusDistorted Golgi apparatus More lipofuscin pigment and fatty vesiclesMore lipofuscin pigment and fatty vesicles More abnormally folded proteinsMore abnormally folded proteins More glycosylation products (can cross-link with proteins)More glycosylation products (can cross-link with proteins)

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Cellular Aging (Senescence)Cellular Aging (Senescence)Why? How?Why? How?

Predetermined by genetic programmingPredetermined by genetic programming -- adult fibroblasts stop dividing after 50 divisions-- adult fibroblasts stop dividing after 50 divisions -- neonatal fibroblasts stop after 65 divisions-- neonatal fibroblasts stop after 65 divisions -- Progeria (premature aging) fibroblasts stop-- Progeria (premature aging) fibroblasts stop after 35 divisionsafter 35 divisions -- Worms: can increase lifespan 5X genetically-- Worms: can increase lifespan 5X genetically

Telomere shortening (nontranscribed DNA on ends)Telomere shortening (nontranscribed DNA on ends) -- -- new chromosome is slightly shorter than originalnew chromosome is slightly shorter than original -- somatic cells: severe truncation >> senescence-- somatic cells: severe truncation >> senescence -- germ cells: telomerase restores telomere after each division -- germ cells: telomerase restores telomere after each division -- stem cells: telomerase restores telomere after each division-- stem cells: telomerase restores telomere after each division -- cancer cells: telomerase restores telomere after each division-- cancer cells: telomerase restores telomere after each division

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Cellular Aging Cellular Aging (Senescence)(Senescence)

Why? How?Why? How?

Wear-and-tearWear-and-tear -- Less recognition and repair of DNA damage -- Less recognition and repair of DNA damage -- DNA errors accumulate-- DNA errors accumulate -- Premature aging:-- Premature aging: -- Progeria (Werner syndrome)-- Progeria (Werner syndrome) -- Cockayne syndrome-- Cockayne syndrome -- Ataxia telangiectasia-- Ataxia telangiectasia

Free radical damageFree radical damage -- -- evidenced by more lipofuscin with ageevidenced by more lipofuscin with age -- DNA damage: 10,000 base modifications/cell/day-- DNA damage: 10,000 base modifications/cell/day -- more radicals >> shorter life (animal models)-- more radicals >> shorter life (animal models) -- more antioxidants >> longer life (animal models)-- more antioxidants >> longer life (animal models) -- fewer calories/day >> fewer radicals >> slows age-related -- fewer calories/day >> fewer radicals >> slows age-related

changes changes

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