Pathology is the study of diseases through identifying changes in tissues and cells. It examines the patterns, causes, mechanisms, and effects of diseases. Pathology bridges clinical practice and basic science. Cell injury can result from physical, chemical, infectious, or environmental factors and causes damage through mechanisms like ATP depletion, oxygen deprivation, calcium dysregulation, and mitochondrial dysfunction. Cells respond to injury through reversible or irreversible changes, repair, or death by necrosis or apoptosis.

1. 1
PathologyPathology
The 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)

2. 2
 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)

3. 3
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

4. 4
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

5. 5
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

6. 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 radicals
1- 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& iron4- Transition metals (Iron & Copper), Fenton reaction, superoxide& iron 
maximal oxidative cellular damagemaximal oxidative cellular damage
5- Nitric oxide.5- Nitric oxide.

7. 7
Free Radicals in InjuryFree Radicals in Injury
Generation, 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

8. Removal of Free RadicalsRemoval of Free Radicals
•Decay: SuperoxideDecay: Superoxide O2 & H2O2O2 & H2O2
• Inactivation:Inactivation:
• Antioxidants: lipid soluble vitamins, ascorbic acidAntioxidants: lipid soluble vitamins, ascorbic acid
glutathionglutathion block initiation of FR, inhibition, terminationblock 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, GlutathioneCatalase, Superoxide dismutases, Glutathione
peroxidases.peroxidases.

9. Chemical InjuryChemical Injury
Mechanisms of chemical injury:Mechanisms of chemical injury:
I- DirectI- Direct:: binding to some critical molecular component: mercury of mercuricbinding to some critical molecular component: mercury of mercuric
chloride+SH group of cell membranechloride+SH group of cell membrane Increase permeability and inhibition of ATP-Increase permeability and inhibition of ATP-
ase dependent transportase dependent transport
II- Indirect:II- Indirect: conversion to reactive toxic metabolitesconversion to reactive toxic metabolites cell injury by directcell injury by direct
covalent binding to membrane ptns and lipids or formation by reactive free radicalscovalent binding to membrane ptns and lipids or formation by reactive free radicals
(CCL4, actetaminphen.(CCL4, actetaminphen.
CCL4:CCL4: dry cleaning, CCL3 in SER of liver, initiate lipid peroxidation and autocatalyticdry cleaning, CCL3 in SER of liver, initiate lipid peroxidation and autocatalytic
reactionreaction Swelling and breakdown of ER, dissociation of ribosomes, decrease hepaticSwelling and breakdown of ER, dissociation of ribosomes, decrease hepatic
ptn synthesis (e.g. apoprotein), reduced lipid transportptn synthesis (e.g. apoprotein), reduced lipid transportfatty change, progressivefatty change, progressive
heptocyte swelling, plasma membrane damage, deathheptocyte swelling, plasma membrane damage, death
AcetaminophenAcetaminophen: Analgesic, metabolized by liver, toxic metabolites inactivated by: Analgesic, metabolized by liver, toxic metabolites inactivated by
GSH, large dosesGSH, large doses acc. of metabolites due to GSH depletionacc. of metabolites due to GSH depletion binding to ptns &binding to ptns &
nucleic acids-nucleic acids- increase drug toxicity & massive liver damageincrease drug toxicity & massive liver damage

10. 10
Ischemia/Reperfusion InjuryIschemia/Reperfusion Injury
Significant 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.

11. 11
MitochondrialMitochondrial
DysfunctionDysfunction
with 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

12. 12
Reversible IschemicReversible 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

13. 13
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

14. 14
Membrane DamageMembrane Damage
If severe enough, may stimulate external attackIf severe enough, may stimulate external attack

15. 15
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

16. 16
Adapted
Cell
+ Stress
Injury
Normal
cell
Reversibly
injured cell
Irreversibly
Injured cell
Dead cell
+Stress
Apoptosis
Necrosis
- Stress
- Stress
Overview

17. 17
Reversible vs irreversible cell injury
Reversible injury
* Decreased ATP
levels
* Ion imbalance
* Swelling
* Decreased pH
* Fatty change
(liver)
Irreversible injury
* Amorphous
densities in
mitochondria
* Severe membrane
damage
* Lysosomal rupture
Extensive DNA
damage

18. 18
 Reversible cell injuryReversible cell injury ((degeneration)degeneration) casedcased
by mild injury of short duration andby mild injury of short duration and
includes:includes:
1 Cell or Cloudy
Swelling. Then can
proceed to
2- Hydropic or Vacular
Degeneration

19. 19
Cell Swelling or HydropicCell Swelling or Hydropic
DegenerationDegeneration
 Characterized by:-Characterized by:- Swelling of cells -Swelling of cells -
Granulation of cytoplasm.Granulation of cytoplasm.
** Organs affectedOrgans 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 normal
Fate:Fate: ReversibleReversible

20. 20
Reversible Ischemic InjuryReversible Ischemic Injury
Microscopic ChangesMicroscopic Changes
Accumulation of
inorganic
phosphates,
lactic acid
(hydrolysis of
phosphate
esters)
Hydropic DegenerationHydropic Degeneration
Cellular 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

21. 21Hydropic change (viral hepatitis)

22. 22
Subcellular response to injurySubcellular response to injury
 Lysosomes (heterophagy; autophagy)
 Smooth ER (induction)
 Mitochondria (D number, size and shape)
 Cytoskeleton (D phagocytosis, locomotion)
 Nucleus (karyolysis, karyorrhexis,
pyknosis)
 Membranes (cellular and subcellullar)

23. 23
Subcellular Response to InjurySubcellular Response to Injury
 Lyzosomal CatabolismLyzosomal Catabolism::
 Primary lyzosomes are membrane- bound intracellularPrimary lyzosomes are membrane- bound intracellular
organells containing a variety of hydrolytic enzymes.organells containing a variety of hydrolytic enzymes.
 These fuse with vacuoles containing materials neededThese fuse with vacuoles containing materials needed
for digestion.for digestion.
 They form Secondary lyzosomes or phagolyzosomes.They form Secondary lyzosomes or phagolyzosomes.
 Lyzosomes are involved in the breakdown of ingestedLyzosomes are involved in the breakdown of ingested
materials in one of two ways:materials in one of two ways: HeterophagyHeterophagy oror
AutophagyAutophagy

24. 24
Autophagy v. HeterophagyAutophagy v. Heterophagy
DegeneratingDegenerating
mitochondria withmitochondria with
amorphousamorphous
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.

25. 25
Autophagy and Cell AtrophyAutophagy and Cell Atrophy

26. 26
Intracellular AccumulationsIntracellular Accumulations
Reversible cellular adaptationReversible cellular adaptation
 Lipids (TG and Cholesterol)Lipids (TG and Cholesterol)
 ProteinsProteins
 PigmentsPigments
 Glycogen (genetic disease)Glycogen (genetic disease)

27. 27
Intracellular Accumulations (ReversibleIntracellular Accumulations (Reversible
Cellular Adaptaion)Cellular Adaptaion)
Three mechanisms by which the cell can acquireThree mechanisms by which the cell can acquire
intracellular accumulations:intracellular 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)

28. 28
Fatty Change (Liver)Fatty Change (Liver)
Many ways to get to sublethal cell damageMany ways to get to sublethal cell damage
-Fatty Change refersFatty Change refers
to any abnormalto any abnormal
accumulation ofaccumulation of
triglycerides withintriglycerides within
parenchymal cells.parenchymal cells.
- It is reversibleIt is reversible
process.process.
-When mild: noWhen mild: no
effect.effect.
-Severe cases:Severe cases:
impair the cellularimpair the cellular
function transiently.function transiently.
-Micro: ClearMicro: Clear
cytoplasmiccytoplasmic
vacuoles that needsvacuoles that needs
specific stains.specific stains.

29. 29
Intracellular AccumulationsIntracellular Accumulations
.
Fatty LiverFatty Liver
Lipofuscin in Heart MuscleLipofuscin in Heart Muscle

30. 30
Fatty ChangeFatty Change
 Characterized byCharacterized 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 livera- 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.

31. 31
Fatty change

32. 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 cellslipids accumulate in smooth muscle cells
and in macrophages of the wall of arteries.and in macrophages of the wall of arteries.
*Cells:*Cells: vacuolesvacuoles
*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 derivedphagocytosis of membrane lipids derived
from injured cellsfrom injured cells Foamy macrophagesFoamy macrophages

33. 33
Cholesterolosis. Cholesterol-laden macrophages (foam cells)
from a focus of gallbladder cholesterolosis (arrow).

34. 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 bodiesRussell 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: NeurodegenerativeNeurodegenerative
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; prekeratinprekeratin
intermediate filamentsintermediate filaments

35. 35
Intracellular ProteinIntracellular 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

36. GlycogenGlycogen
•Abnormalities in the metabolism of glucose or glycogenAbnormalities in the metabolism of glucose or glycogen
• Diabetes Mellitus:Diabetes Mellitus: Glycogen accumulation in renal tubularGlycogen 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 glycogensynthesis or breakdown of glycogen
Glycogen storage diseaseGlycogen storage disease

37. 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 Lymphlungs 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 yellowbrownIntra- cytoplasmic yellowbrown
fine pigment (Brown atrophy) lipid& phospholipids & proteins (peroxidationfine 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 byNon-hemoglobin-derived brown- black pigment formed by
melanocytes by the oxidation of tyrosine.melanocytes by the oxidation of tyrosine.

38. 38
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).

39. • HemosiderinHemosiderin:: A hemoglobin-derived, golden-yellow to brownA 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 systemic
Local HemosidrosisLocal Hemosidrosis
•Gross hemorrhage or rupture of small vessels (congestion)Gross hemorrhage or rupture of small vessels (congestion)
• Lysosomal enzymes in macrophages convert hemoglobin toLysosomal 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)

40. 40
Hemosiderin granules in liver cells. A, H&E section showing
golden-brown, finely granular pigment. B, Prussian blue
reaction, specific for iron.

41. 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.

42. Pathogenesis of Dystrophic Pathological CalcificationPathogenesis of Dystrophic Pathological Calcification
•InitiationInitiation:: Extracellularly or intracellularlyExtracellularly or intracellularly
•Extracellular initiation: membrane- bound vesicles derived from dead orExtracellular initiation: membrane- bound vesicles derived from dead or
dying cells that concentrate calcium by their affinity for acidicdying cells that concentrate calcium by their affinity for acidic
phospholipids.phospholipids.
•Phosphates accumulation by the action of membrane boundPhosphates 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- depositsdeposits
• Initiation of intracellular calcification occurs in mitochondria of dead orInitiation 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 anddepends 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 andcellular matrix (collagen) as well as other matrix protein (osteonectin and
others).others).

43. 43
Calcific Valves in Aortic StenosisCalcific Valves in Aortic Stenosis
Thick, fibrotic cusps; masses of dystrophic calcificationThick, fibrotic cusps; masses of dystrophic calcification

44. 44
Chronic Calcific PulpitisChronic Calcific Pulpitis
Chronic Ischemic Pulpitis?Chronic Ischemic Pulpitis?
DystrophicDystrophic
CalcificationCalcification

45. Causes of Metastatic CalcificationCauses 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 especiallyAlveolar 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 favorsIt is based on that sites have relatively alkaline pH which favors
precipitation of calcium.precipitation of calcium.

46. 46
Metastatic CalcificationMetastatic Calcification
Calcification in the wall of a
blood vessel
Calcification in the gastric
submucosa

47. Cellular Adaptation to InjuryCellular Adaptation to Injury
A state that lies between the normal, unstressed cell andA 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 proteinInduction 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

48. 48
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 theIncreased 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 theIncreased 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

49. 49
Cellular adaptations to stress:
1. Hyperplasia (more cells)
2. Hypertrophy (bigger cells)
3. Atrophy (smaller cells)
4. Metaplasia (different type of cells)

50. HypertrophyHypertrophy
An increase in the number of organelles and the size ofAn increase in the number of organelles and the size of
the cells with subsequent increase in the size of organ duethe 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 partialHollow 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)

51. 51
Hypertrophy
* Larger cells
* Not due to swelling
* Increased synthesis of structural components
* Results in larger organ
* May occur with hyperplasia

52. 52
Mechanism of HypetrophyMechanism of Hypetrophy
•Increased synthesis of structural proteins via:
•Transcription factors (i. e. c-fos and c-jun)
•Growth factors (TGF-β, IGF-1, FGF)
•Vasoactive agents (endothelien-1, AII)

53. 53
HypertrophyHypertrophy
Physiologic hypertrophy ofPhysiologic hypertrophy of
myometrium during pregnancy due tomyometrium during pregnancy due to
estrogen stimulationestrogen stimulation
Physiologic hypertrophy of skeletalPhysiologic hypertrophy of skeletal
musclemuscle
from exercisefrom exercise
Normal muscleNormal muscle

54. 54
HypertrophyHypertrophy
Enlargement 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

55. 55
Normal Hypertrophied
Cardiac smooth muscle hypertrophy

56. 56
HyperplasiaHyperplasia
 It is an increase in the number of cells in anIt 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 and1- Hormonal as in breast due to puberty and
pregnancypregnancy
2- Compensatory occurs when a portion of the2- 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

57. Mechanism of hyperplasiaMechanism of hyperplasia
Cell proliferation
via increased production of
TRANSCRIPTION FACTORS
due to:
* Increased production of GF
* Increased levels of GF receptors
* Activation of intracellular signaling
Results in larger organ

58. 58
HyperplasiaHyperplasia
Endometrial hyperplasia in response to estrogenEndometrial hyperplasia in response to estrogen
Hyperplastic GlandsHyperplastic Glands

59. 59
HyperplasiaHyperplasia
Nodular hyperplasia of the prostate glandNodular hyperplasia of the prostate gland
NormalNormal

60. 60
Thyroid hyperplasiaThyroid hyperplasia
Normal ThyroidNormal Thyroid Hyperplastic ThyroidHyperplastic Thyroid

61. Metaplasia
A reversible change in which one differentiated adult cellA 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

62. Mechanism of MetaplasiaMechanism of Metaplasia
ReprogrammingReprogramming
1. of stem cells present in normal tissues1. of stem cells present in normal tissues
2. of undifferentiated mesenchymal cells2. of undifferentiated mesenchymal cells
in connective tissuein connective tissue
Mediated by signals from:Mediated by signals from:
cytokines, GF or ECMcytokines, GF or ECM
Leading to induction ofLeading to induction of specific transcriptionspecific transcription
factorsfactors

63. 63
MetaplasiaMetaplasia
Original TissueOriginal Tissue StimulusStimulus Metaplastic TissueMetaplastic Tissue
Ciliated columnarCiliated columnar
epithelium of bronchialepithelium of bronchial
treetree
Cigarette smokeCigarette smoke Squamous epitheliumSquamous epithelium
Transitional epitheliumTransitional epithelium
of bladderof bladder
Trauma of bladderTrauma of bladder
calculuscalculus
Squamous epitheliumSquamous epithelium
Columnar epithelium ofColumnar epithelium of
gland ductsgland ducts
Trauma of calculusTrauma of calculus Squamous epitheliumSquamous epithelium
Esophageal squamousEsophageal squamous
epitheliumepithelium
Gastric acidGastric acid Columnar epitheliumColumnar epithelium
Fibrocollagenous tissueFibrocollagenous tissue Chronic traumaChronic trauma Bone (osseous) tissueBone (osseous) tissue
Columnar glandularColumnar glandular
epitheliumepithelium
Vitamin A deficiencyVitamin A deficiency Squamous epitheliumSquamous epithelium

64. 64
Epithelial Metaplasia, the normal respiratory epithelium at the
right and the squamous epithelium at the left .

65. 65
Photomicrograph of the junction of normal epithelium (1) with
metaplastic transitional epithelium (2).

66. 66
Photomicrograph of the trachea from a smoker. Note that the columnar
ciliated epithelium has been replaced by squamous epithelium.

67. 67
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.

68. 68
AtrophyAtrophy
IIt is the shrinkage in the size of the cell by loss of cellt 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

69. 69
Types/Causes of AtrophyTypes/Causes of Atrophy
Physiologic 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)

70. 70
Mechanism of Atrophy
Reduction in structural components
Decreased number of mitochondria, myofilaments, ER
via
proteolysis (lysosomal proteases; ubiquitin-proteosome
system)
Increase in number of autophagic vacuoles
Residual bodies (i.e. lipofuscin  brown atrophy)
NB: diminished function but not dead

71. 71
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.

72. 72
AtrophyAtrophy
Atrophic Adrenal Gland from Corticosteroid UseAtrophic Adrenal Gland from Corticosteroid Use
NormalNormal
AtrophiedAtrophied

73. 73
Brain AtrophyBrain Atrophy
An aging processAn aging process
82 y/o male82 y/o male 25 y/o male25 y/o male

74. 74

75. 75
DysplasiaDysplasia
Dysplasia meansDysplasia means abnormal organization of cellsabnormal organization of cells
 At the cellular level, morphologically, it is characterized byAt 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, irregularand nuclear changes, consisting of enlargement, irregular
borders, and hyperchromasia of individual cell nuclei andborders, 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 previouslyIt is considered pre-malignant (often arises in previously
metaplastic epithelium), and can progress to malignantmetaplastic 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

76. 76
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

77. 77
 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.

78. 78

79. 79
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.

80. 80
Normal cervix
Severe dysplasia

81. 81
•Irreversible cell injury caused by severe
injury of long duration and includes:
1- Necrosis
2- Apoptosis

82. 82
Sublethal v. Lethal Cell DamageSublethal v. Lethal Cell Damage

83. 83
Nuclear Events in NecrosisNuclear Events in Necrosis
Pyknosis, 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
KaryorrhexisKaryorrhexis
NormalNormal

84. 84
Proteins Liberated into BloodProteins 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)
Hepatocyte
Alanine transaminase
(ALT)
Striated muscle
Creatine kinase (MM
isoform)
Exocrine
pancreas
Amylase
CytoplasmicCytoplasmic
Changes inChanges in
NecrosisNecrosis
--Dead cells showDead cells show
increased acidophilia.increased acidophilia.
-Cells may have glassyCells may have glassy
appearance.appearance.
- Cytoplasm becomeCytoplasm become
vacuolated and appearvacuolated and appear
moth- eaten.moth- eaten.
- Calcification of the deadCalcification of the dead
cells may occur.cells may occur.

85. 85
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
☺☺

86. 86
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.
☺☺

87. 87
Coagulative necrosisCoagulative necrosis
 Preservation of structurePreservation of structure
 FirmFirm
 Protein denaturationProtein denaturation
 Hypoxic tissue death (except brain)Hypoxic tissue death (except brain)

88. 88
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.

89. 89
Coagulative Necrosis
(Myocardial Infarction-heart attack)

90. 90
Caseous necrosisCaseous necrosis
 Subset of coagulative necrosisSubset of coagulative necrosis
 TBTB
 Cheesy, whiteCheesy, white
 Surrounded by inflammatory cellsSurrounded by inflammatory cells
(granulomatous reaction)(granulomatous reaction)
 Complete destruction of tissueComplete destruction of tissue

91. 91
Caseation Necrosis
Tuberculosis of hilar lymph node

92. 92
Caseous NecrosisCaseous Necrosis
Tuberculosis of Lung, LiverTuberculosis of Lung, Liver
GranulomaGranuloma

93. 93
Liquefactive necrosisLiquefactive necrosis
 Enzymatic digestionEnzymatic digestion
 Liquid, viscous massLiquid, viscous mass
 May contain pusMay contain pus
 Bacterial infections (via inflammation)Bacterial infections (via inflammation)
 Hypoxic brain injuryHypoxic brain injury

94. 94
MeningitisMeningitis
Liquefactive Necrosis of Central Nervous SystemLiquefactive Necrosis of Central Nervous System
Loss of cell outlinesLoss of cell outlines

95. 95
Liquefactive Necrosis
(Cerebral Infarction-stroke)

96. 96
The liver shows a small abscess here filled with many
neutrophils.
This abscess is an example of localized liquefactive necrosis

97. 97
Fat necrosisFat necrosis
 Not a specific patternNot a specific pattern
 Focal areas of fat digestionFocal areas of fat digestion
 Ususally via release of lipases from pancreasUsusally via release of lipases from pancreas
 FFA combine with Ca to produce “soaps”FFA combine with Ca to produce “soaps”

98. 98
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.

99. 99
Fat Necrosis
(Acute pancreatitis)

100. GangreneGangrene
DefDef: 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 ofSaprophytic 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 hemoglobinH2S + iron (derived from hemoglobin  iron sulphideiron sulphide  staining ofstaining 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

101. Classification of gangreneClassification of gangrene
According to the amount of blood and tissue fluids in theAccording 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 gangreneII- 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 poisoningembolus, thromboangitis obliterans (Buerger’s disease), Ergot poisoning
and Raynaud’s diseaseand 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)+ surfaceArtery (occluded) + venous and lymphatic drainage (open)+ surface
evaporationevaporation dry gangrenedry gangrene
• Commonest example of dry gangrene:Commonest example of dry gangrene: Senile gangrene of limbSenile gangrene of limb..

102. SenileSenile GangreneGangrene 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 pressurelow blood pressure  vascular stasisvascular 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 occlusion2- 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 arenecrotic are stains red (blood escaped from necrotic blood vessels),stains red (blood escaped from necrotic blood vessels), Drainage and evaporation ofDrainage and evaporation of
blood and tissue fluidblood and tissue fluid dryness of dead partdryness of dead part Shrunken & mummifiedShrunken & mummified
3- saprophytic bacteria (bacillus subtitis & diphteroids) invade necrotic tissue3- saprophytic bacteria (bacillus subtitis & diphteroids) invade necrotic tissue  putrefaction (bacteriaputrefaction (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 one4- 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 ofmore 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 irritantgangrene stops. Toxic products act as an irritant  acuteacute
inflammation in the neighboring healthy partinflammation in the neighboring healthy part narrow red line between healthy and gangrenousnarrow red line between healthy and gangrenous
partpart  line of demarcationline of demarcation..
6- from healthy side granulation tissue grow towards gangrenous part with formation of groove on the6- from healthy side granulation tissue grow towards gangrenous part with formation of groove on the
surfacesurface (line of separation(line of separation)) deepening of the groovedeepening of the groove conical stumpconical stump

103. 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 putrefactionrapid putrefaction rapid spread of gangrenerapid 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 (venousstrangulated 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 occlusionarterial occlusion 
necrosisnecrosis invasion by putrefactive bacteria (lumen)invasion by putrefactive bacteria (lumen) putrefaction (rapid)putrefaction (rapid) black colorblack 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 bysevere 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 atherosclerosisearly 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 moistmoist
(tissue hyperglycemia, poor body resistant(tissue hyperglycemia, poor body resistant  multiplication of bacteriamultiplication of bacteria inflammation andinflammation and
occlusion of vessels), rapid spread,occlusion of vessels), rapid spread, poor line of demarcation, severe toxemia, littlepoor line of demarcation, severe toxemia, little
tendency to self limitation.tendency to self limitation.

104. III Infective gangrene:III Infective gangrene: A subtype of moist gangrene (bacteria causeA 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 BacillusTreponema 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: Moist gangrene of muscles in deep wounds contaminated by
manured soil containing anaerobic spores. Tissue destructionmanured soil containing anaerobic spores. Tissue destruction local ischemialocal 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.

105. 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 parenchymatousconstitutional symptoms, degeneration of parenchymatous
organs, Amyloidosis in chronic forms, necrosis andorgans, 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 bacteriaTransient presence of small number of bacteria
in the blood stream without toxic manifestations (toothin the blood stream without toxic manifestations (tooth
extraction)extraction)
Fate:Fate: 1- phagocytosis by RES (small number).1- phagocytosis by RES (small number).
2- localization2- localization  pathological lesions (carbuncle, acutepathological lesions (carbuncle, acute
osteomyelitis, subacute bacterial endocarditis)osteomyelitis, subacute bacterial endocarditis)

106. 3- Septicemia:3- Septicemia: the circulation and multiplication of large amount ofthe 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 bodySeptic wound, puerperal sepsis, acute osteomyelitis + low body
resistanceresistance
4- Pyemia4- Pyemia:: Circulation of septic emboli in the blood stream and theirCirculation of septic emboli in the blood stream and their
arrest in different organs causing multiple abscess, high mortalityarrest 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).

107. 107
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

108. Apoptosis (Falling away)Apoptosis (Falling away)
Def.: A programmed cellular death occurs when a cell within anDef.: 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 minimalElimination 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, intestinalCell 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 DNAirreparable DNA
damagedamage trigger cell suicide pathways (p53).trigger cell suicide pathways (p53).

109. 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 theApoptosis 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.

110. Mechanisms of ApoptosisMechanisms of Apoptosis
1- Signaling1- Signaling: Stimuli generates signals: Stimuli generates signals
** transmitted across the plasma membrane to intracellulartransmitted 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

111. 2- Control and Integration2- Control and Integration
Death signalsDeath signals Execution programExecution program
1- Adaptor protein : connection1- Adaptor protein : connection
** Mitochondrial permeability transitions: pore in inner mitochondrialMitochondrial permeability transitions: pore in inner mitochondrial
membrane.membrane.
* Death signals* Death signals  cytochrome c release from outer membrane tocytochrome c release from outer membrane to
cytoplasmcytoplasm 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 increasedDirect action on mitochondria to prevent increased
permeabilitypermeability
• Effects mediated by interaction with other protein.Effects mediated by interaction with other protein.

112. 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 morphologicalExecutive 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.

113. 4- Removal of Dead Cells4- Removal of Dead Cells
• Recognition: Marker molecules on theRecognition: Marker molecules on the
surface of apoptotic fragments.surface of apoptotic fragments.
• PhagocytosisPhagocytosis

114. 114
Mechanism of ApoptosisMechanism of Apoptosis
Programmed Cell DeathProgrammed Cell Death

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Necrosis v. ApoptosisNecrosis v. Apoptosis
Usually: single cellUsually: single cell
EndonucleasesEndonucleases
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
↓ProstateProstate

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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 AgingCellular 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
changeschanges

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