2. Cellular Injury and Necrosis

7/30/2019 2. Cellular Injury and Necrosis

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CELLULAR INJURY

AND NECROSIS

Dr. Thuaibah Hashim


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CAUSES OF INJURY

1. Oxygen deprivation

2. Physical agents

3. Chemical agents and drugs

4. Infectious agents

5. Immunologic reactions6. Nutritional imbalances

7. Genetic derangements

Acquired


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1. Oxygen deprivation

HYPOXIA

Oxygen deficiency, affects oxidative respiration

common cause of injury and cell death.

eg. respiratory failure

eg. anaemia, CO poisoning

ISCHAEMIA = shortage of blood supply

often due to blockage of artery or veins. Hypoxia + deficiency of metabolic substrate

**Ischaemic tissues are more rapidly and severely

injured than hypoxic tissues.


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2. Physical Agents

Mechanical trauma

Extreme temperatures (burns & cold)

Sudden change in atmospheric pressures

Radiation

Electrical shock


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3. Chemicals & Drugs

The list of chemicals that may produce cell injury defiescompilation.

Caustic agents: Acids & AlkaliAlcohol & narcotic drugs

Therapeutic drugs

Insecticides, Pesticides

Herbicides

Environmental and air pollutants

Simple chemicals eg. glucose and salt in hypertonicconcentrations may cause cell injury directly or by derangingelectrolyte homeostasis.

Even O2, in high concentrations, is severely toxic.


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4. Infectious agents

Viruses (cytopathic effects)

Bacteria

Fungi

ParasitesWorms etc


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5. Immunological Reactions

Bodys defense mechanism, may in fact, cause cellinjury.

eg. anaphylactic reactions (hypersensitivity)

eg. autoimmune diseases


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6. Nutritional imbalances

Deficiencies:

Common protein-calorie malnutrition,

severe degree leads to death of tissues-individuals.

Specific vitamin deficiencies.

Excesses: Excess of lipids predispose to

atherosclerosis.


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7. Genetic Defects

eg. Chromosomal abnormalityDowns syndrome

eg. Single amino acid substitution in Hb Ssicklecell anaemia.

eg. Enzyme abnormality gene defects -- inborn

errors of metabolism (Production of substanceswhich are toxic to cells)


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EFFECTS OF INJURIES ON

CELLS/TISSUESTYPES OF INJURIES EFFECTS ON CELLS

1. SUBLETHALINJURY

(Removal of injurious

agents allows recovery to

normal state)

2. LETHAL INJURY

(No possible recovery)

REVERSIBLE DAMAGE1.1 Hydropic degeneration

1.2 Fatty Change

IRREVERSIBLEDAMAGE

2.1 Apoptosis

2.2 Necrosis


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Mechanisms of cell injury

The biochemical mechanisms responsible for cellinjury are complex.

With most stimuli, multiple mechanisms contributeto injury, and in the case of many injuriousstimuli,the actual biochemical locus of injuryremains unknown.

Basic principles: Depends on type of injury, its duration and severity. Depends on type of injured cells, its status and

adaptability.(eg. Cardiac muscle withstands hypoxia 20-30 mins, Striated muscle withstands hypoxia 2-3 hrs)


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MECHANISM OF INJURY

Interdependance of cellular organelles

Damage of one component leads to secondarydamage of other components.

Cell death occurs when threshold of accumulateddamage is passed

Cell response ranges from recoverable damage toinstant death

Primary targets of damaging stimuli:1. Cell membrane 2. Mitochondria

3. Cytoskeleton 4. Protein synthesis

5. Cellular DNA


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Pathogenesis of

ischaemic/hypoxic injuriesDecreased generation of cellular ATP.

Plasma membrane energy-dependent Na pump fails Naaccumulate intracellular cell swelling, dilated ER.

Anaerobic glycolysis lactic acidosisactivity ofcellular enzymes.

Failure of calcium pump.

Disruption of protein synthetic apparatus.

Damage to mitochondrial and lysosomal membranes.

Proteins may become misfolded unfolded proteinresponse leading to cell injury.


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Ischaemia-Reperfusion injury

Depending upon the duration of ischaemia, restoration of

blood flow may result in 3 different consequences:

1. Short duration, reversible injurycell restored to

normal.

2. Longer durationreperfusion paradoxically deteriorates

the already injured cell = Ischaemia-Reperfusion injury

due to increased generation of oxygen free radicals or

reactive oxygen species (superoxide, H2O2, OH-).

3. Irreversible injury during ischaemia itselfno role of

reperfusion.


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Pathogenesis of chemical injury

Direct cytotoxic effects.

Combine with components of cell.

eg. mercury binds to cell membrane protein

permeability.

Conversion to reactive metabolites

Metabolic activation to yield ultimate toxin.

Target cells may not be the same cells that metabolisethe chemicals

Eg. CCl4 converted to CCl3.causing toxic livernecrosis.


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Pathogenesis of physical injury

Ionizing radiation can hydrolyze water into

H+ and OH- free radicals.

OH- radical produce injury by:

Lipid peroxidation

Protein oxidation

DNA damage


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Morphology of Sublethal Injury

The term degeneration denote morphology

of reversible injury.

Cellular change:HYDROPIC DEGENERATION.

(a.k.a CLOUDY SWELLING,

VACUOLAR DEGENERATION)


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Hydropic degeneration

Commonest and earliest form of cell injury

Results from impaired regulation of cellular

volume esp sodium.

Plasma membrane

Sodium pump

Supply of ATP


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Gross:

Enlarged organs eg kidney, liver

Cut surface bulges outwards, slightly opaque. (hencethe term cloudy swelling)

Microscopic:

Cells swollen

Microvasculature is compressed

Small clear intracytoplasmic vacuoles (represents

distended cisternae of ER.)


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Ultrastructural changes (refer diagram)

Dilated ER

Detachment of polysomes from surface of RERMitochondrial swelling

Blebs on plasma membrane, distortion ofmicrovilli, loosening intercellular attachment,

myelin figures.Nuclear alteration: disaggregation of granular

and fibrillar elements.


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Intracellular Accumulations

Substances in abnormal amounts due to deranged cellmetabolism. Mild degree causes reversible injury.

Normal constituents eg. lipid, carbo, protein Abnormal substances

Exogenous (eg product of infectious agents)

Endogenous (eg inborn error of metabolism, storage

diseases. ) Pigments

Exogenous (eg coal dust)

Endogenous (eg melanin, hemosiderin)


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Process ofintracellular

accumulations


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FATTY DEGENERATION

Fatty change due to hypoxia, toxic substances ormetabolites, infection.

Occurs occasionally in all organs but is most common inthe liver (central role in fat metabolism)

Injured cells are not able to metabolise lipids & hencetriglycerides accumulate in cytoplasm

Gross appearance: Fatty livers are enlarged, yellow, greasy

Microscopically, cells become enlarged, sometimes

nucleus displaced to the side giving crescent shapeappearance. Cytoplasm contain varying amounts of lipid(clear area due to lipid being removed during processing) -microvesicular / macrovesicular.

Fatty cyst, lipogranuloma.


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QuickTimdecomp

are needed to se


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Photomicrograph of normal liver : Liver cell plates & acinar/lobulararran ement :central vein & ortal tracts with sinusoids


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Photomicrograph of normal liver(hi her ma nification)


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Photomicrograph of liver with fatty change due to chronic venous

congestion, changes predominantly around central vein


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Fatty change in liver (high power)


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Cholesterol and cholesterol esters

Accumulation of cholesterol is seen in severalpathologic processes:

Atherosclerosis

Cholesterol accumulates in smooth muscle

cells and macrophages in walls of arteries Xanthomas

Cholesterol accumulates in macrophages andmesenchymal cells in soft tisue due tohyperlipidemia

Foamy (lipid-laden) macrophages

Found in inflammation and necrosis due tophagocytosis of membrane lipids of injuredcells by macrophages


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Proteins

Excess of proteins may cause morphologically

visible accumulations within cells appearing as

rounded eosinophilic droplets or masses in the

cytoplasm

Occurs due to excessive synthesis, absorption or

defects in cellular transport

Example:

Prolonged proteinuria causing reabsorption of protein

and formation of protein droplets in proximal

convoluted tubules


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Morphology of

excess proteinaccumulations


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Glycogen

Excessive intra-cellular glycogen deposits

are seen in abnormalities of glycogen and

glucose metabolism:Eg: Glycogen storage diseases


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Pigments Exogenous pigments:

Anthracosis (accumulation of carbon in macrophages oflungs and lymph nodes)

Tattooing (injected pigment)

Endogenous pigments: Lipofuscin

The wear and tear pigment

Microscopically seen as yellow-brown, fine, intra-cytoplasmicgranules

Usually associated with old age / atrophy (brown atrophy)

Melanin

Derived from melanocytes Microscopically seen as a brown-black pigment

Hemosiderin Derived from hemoglobin

Often seen in hemorrhage, rupture of vessels, vascular

congestion


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Lipofuscin

Lipofuscin deposits in cardiac fibres (brown

atrophy of the heart) in old age

l i


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Melanin

Melanin pigment in a nevus (mole)


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Hemosiderin deposits


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Morphology of Lethal Injury

Necrosis

Apoptosis


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NECROSIS

Spectrum of morphologic changes that follow celldeath in living tissue

Largely resulting from progressive degradativeaction of enzymes on the lethally injured cells.

Autolysis: enzymes derived from ownlysosomes

Heterolysis: enzymes from immigrantleukocytes.

Also results from denaturation of proteins


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Morphology of cell necrosis

Cytoplasm:

increased eosinophilia due to

1. Loss of normal basophilia imparted by RNA

2. increased eosin binding to denatured proteins Vacuolated and moth eaten when cytoplasmic

organelles have been digested

Nucleus:

karyolysis Pyknosis

Karyorrhexis

Ultimately: nucleus disappear, dead cells replaced by myelinfigures or calcified, phagocytosed by other cells.


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PATTERNS OF NECROSIS (mass of cells)

COAGULATIVE NECROSIS

protein denaturation

LIQUEFACTIVE NECROSIS enzyme digestion

CASEOUS NECROSIS

FIBRINOID NECROSIS

FAT NECROSIS


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Coagulative necrosis

refers to preservation of basic outline of thecoagulated cell for a span of at least some

days. is due to denaturation of not only structural

proteins, but also enzymes, thus blockingproteolysis of the cell.

is characteristic of ischaemic death of cellsin all tissues except brain.


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Dead (necrotic) Myocardium.

Cardiac cells appear more

eosinophilic, loss of nuclei, cellular

outlines maintained

Collection of neutrophils

(normally not present) as part

of acute inflammatory process,

reaction to dead tissue

Myocardial infarction: coagulative necrosis


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Liquefactive necrosis

1. Dead tissue becomes liquefied due to digestion of

tissue by enzymes released by dead cells eg abscess

(collection of neutrophils, release of enzymes

destruction of cells & liquefied)

2. Dead tissue becomes liquefied ?due to high content

of water eg Infarction of cerebral tissue

Characteristic of bacterial infections bcos they stimulate

accumulation of inflammatory cells.

.


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Microscopic appearance of necrotic/infarcted brain with dead

neuronal cells becoming disintegrated (n), and intercellular

spaces accumulating fluid (f). Finally becomes pale acellular area

Liquefactive necrosis in brain after an infarction

n

n

f

f


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Liquefactive necrosisSubcutaneous abscess with collections of pus

Kidney: coagulative necrosis


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Kidney: coagulative necrosis

Kidney: Liquefactive necrosis


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Kidney: Liquefactive necrosis


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Caseous necrosis

Combine features of coagulative and

liquefactive necrosis.

Cheesy white gross appearance.

Microscopic: Structureless, eosinophilic

granular debris.

Typically seen in tuberculosis.


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Caseous necrosis

Gross appearance of lung:

Caseation necrosis of lymph node : Friable

fragmented whitish area of necrosis in hilar

lymph node

Microscopic appearance of lungwith caseous/caseation necrosis (c)

appearing as eosinophilic & amorphous

surrounded by viable epithelioid cells,

multinucleated (Langhans) giant

cells (m) & scanty lymphocytes.

c

mm

C ti i


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Caseation necrosis

Cm

l

l

e

e

Microscopic appearance of lung (a high magnification) with caseous necrosis appearing as

eosinophilic & acellular area (c) surrounded by viable epithelioid cells (e), multinucleated

(Langhans) giant cells (m) & scanty lymphocytes (l)


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Fat necrosis

1. ENZYMATIC FAT NECROSISOccurs in the abdomen (peritoneal cavity).Fat tissue lysed by enzymes (pancreatic lipase), released fatty

acids combine with calcium to produce grossly visible chalkywhite areas.

Histo: shadowy outline of necrotic fat cells, with basophiliccalcium deposits, surrounded by inflammatory reaction.

eg fat saponification following Acute Pancreatitis

2. TRAUMATIC FAT NECROSIS

Injury to fatty tissue causes necrosis.

Necrosis of fat cells associated with calcification, may mimiccancer.

eg Traumatic fat necrosis in breast


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Enzymatic fat necrosis

in pancreas andadjacent fatty tissue in

acute pancreatitis

Microscopic appearances of pancreas

(low power) showing residual

pancreatic acini (a) and a area of

necrosis (n) in picture 1. In picture 2necrosis is extensive and

haemorrhagic (n) and viable fat is

present (f)

a

a

n

n

PICTURE 1

PICTURE 2

n

n

f f

Traumatic fat necrosis in the breast


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Microscopic appearance of breast tissue (high power) with traumatic fat

necrosis. The area of necrosis is not obvious now but it demonstrates collections

of foamy macrophages (f) which have engulfed necrotic fat to remove it from

the area in the breast

Traumatic fat necrosis in the breast

f

f

s


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Fibrinoid necrosis

Deposition of fibrin-like material which has

the staining properties of fibrin.

Encountered in various examples ofimmunologic tissue injury, arterioles in

malignant hypertension, peptic ulcer etc.

Histo: Brightly eosinophilic hyaline-likedeposit.

Fibrinoid necrosis


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Fibrinoid necrosis

f

Microscopic appearance of kidney with fibrinoid necrosis of

arteriolar wall in Malignant (accelerated) hypertension,

appearing as eosinophilic acellular area


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Pathologic calcification

Abnormal deposition of calcium salts in

soft tissues

2 types:Dystrophic calcification

Serum calcium isnormal

Metastatic calcification Serum calcium israised(hypercalcemia)


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Dystrophic calcification

Localizedcalcium deposition in non-viableor dying tissues in the presence ofnormal

serum calcium. Occurs in arteries in atherosclerosis,damaged heart valves and areas of necrosis.

Calcium can be intracellular, extracellularor both.

Calcification may be visualised onradiographs.



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Metastatic calcification


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Metastatic calcification

Generalizedcalcium deposition throughout the

body due to increase in serum calcium(hypercalcemia)

4 principal causes:

Increased secretion of parathyroid hormone

(hyperparathyroidism) Eg: Parathyroid tumours or ectopic secretion by other

malignant tumours (eg small cell carcinoma of the lung)

Destruction of bone tissue

Eg: Bone tumours (primary and secondary) Vitamin D related causes

Eg: Vitamin D intoxication

Renal failure

Causing secondary hyperparathyroidism


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Apoptosis

Cell death through activation of an internal suicide

program.

Purpose: Eliminate unwanted cells selectively withminimal disturbance to surrounding cells and host.

Protein cleavage by caspases.

Protein cross-linking by transglutaminase

Internucleosomal cleavage of DNA

Plasma membrane alteration eg flipping of

phosphatidylserine to outer layer recognition of cells

by phagocytes.

Necrosis vs Apoptosis


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Necrosis vs Apoptosis

Feature Necrosis Apoptosis


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p p

Cell size Enlarged (swelling) Reduced (shrinkage)

Nucleus Pyknosis karyorrhexis karyolysis

Fragmentation into

nucleosome size fragments

Plasma

membrane

Disrupted Intact; altered structure, especially

orientation of lipids

Cellular

contents

Enzymatic digestion;

may leak out of cell

Intact; may be released in

apoptotic bodies

Adjacent

inflammation

Frequent No

Physiologic

or pathologic

role

Invariably pathologic

(culmination of

irreversible cell injury)

Often physiologic, means of

eliminating unwanted cells; may

be pathologic after some forms of

cell injury, especially DNA

damage

STRESS


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Increased

functionaldemand

Reversible

cell injury

ADAPTATION

Hypertrophy

Hyperplasia

Atrophy

Metaplasia

Dysplasia

NORMAL CELL

Irreversible

cell injury

NECROSIS

MildSevere

Persistent

Relief of stress


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Learning Objectives

List the causes of cell injury and explaintheir mechanisms.

Define sublethal and lethal injuries.Describe their morphological changes.

Describe the patterns of necrosis withclinical examples.

Describe intracellular accumulations andpathologic calcification.


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2. Cellular Injury and Necrosis

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