Cell Injury:

Cellular Injury
(year 2010 )

Dr. Huda M.Zahawi, FRC.Path.

Cell Injury:

Topic Outline
 Causes of cell injury
 Types of Injury
 Priciples & Mechanisms of cell injury
 Outcome : ?Reversible ? Irreversible
 Morphology
 Adaptation to Injury
 Patterns & types of Cell Death
 Process of Aging
Cell Injury:

Cellular Injury & Adaptation

 Normal cell is in a steady dynamic state

“Homeostasis” :

 The ability or tendency of an organism or

cell to maintain internal equilibrium by
adjusting its physiological processes.
Cell Injury:
 Cells are constantly exposed to stresses.

 Normal physiologic stress

 Severe stresses: injury results, and alters

the normal steady state of the cell,

consequently,
 It can survive in a damaged state and
adapt to the injury
(reversible injury or adaptation)
 It can die

(irreversible injury or cell death).

 STRESS INJURY

NORMAL
CELL

Reversible Irreversible
Adaptation
injury injury
Atrophy
Hypertophy
Hyperplasia Cellular swelling Necrosis
Metaplasia Vacuolar change
Fatty change Apoptosiss
Cell Injury:

Causes of Cell Injury

 Hypoxia and ischemia

 Free radicals
 Chemical agents
 Physical agents
 Infections
 Immunological reactions
 Genetic defects
 Nutritional defects
 Aging
Cell Injury:

TYPES OF INJURY
Cell Injury:

1- Hypoxia & Ischemia

 Causes of Hypoxia

 low levels of oxygen in the air

 poor or absent Hemoglobin function

 decreased erythropoiesis

 respiratory or cardiovascular diseases,

or ischemia (reduced supply of blood)

Cell Injury:

 Ischemia & Hypoxia induce mitochondrial

damage.

 This results in decreased ATP which in

turn reduces energy for all cell functions !

 If persistent  CELL DEATH

Cell Injury:

 Hypoxia is a common cause of cell injury

 Result : Cell resorts to anaerobic glycolysis
 Ischemia is the commonest cause of
hypoxia, & injures the cells faster than pure
hypoxia
 Why ??
 Restoration of blood may lead to recovery
OR Ischemia/ Reperfusion injury 
 Progressive cell damage
 Examples : Myocardial & Cerebral infarction
Cell Injury:

Ischemia/Reperfusion Injury
 Restoration of blood flow influx of high
levels of calcium
 Reperfusion increases recruitment of
inflammatory cells  free radical injury
 Damaged mitochondria induce free radical
production & compromise antioxidant defense
mechanisms
 Dead tissue becomes antigenicAB 
activation of complement immune response
Cell Injury:

 Recommendation :

 In some cases , high oxygen therapy to

improve hypoxia is NOT given because it
generates oxygen derived FREE RADICALS
( Reactive Oxygen Species ROS)
Cell Injury:

2- Free Radicals
 Free radicals are chemical species with a
single unpaired electron in an outer orbital,
they are chemically unstable and therefore
readily react with other molecules, resulting in
chemical damage.
 To gain stability, the radical gives up or steals
an electron.
 Radicals can bind to proteins, carbohydrates
lipids, producing damage.
Cell Injury:

Sources of Free Radicals in pathology

 Chemical injury
 Physical injury
 Inflammation
 Oxygen toxicity
 Reperfusion injury
 Malignant transformation
 Aging
Cell Injury:

Formation of Free Radicals :

 Endogenous from normal metabolism
 Reduction Oxidation reaction (REDOX) in

mitochondria
 Transition metals (Copper, Iron) catalyze

Free Radicals formation by donating or

accepting free electrons
(Fenton reaction)
superoxide
Ferric iron Ferrous iron
Cell Injury:

 Exogenous formation :
 Ionizing radiation

 Drug metabolism
Cell Injury:

Free Radicals (Examples)

 Reactive Oxygen Species (ROS) generated
by mitochondrial respiration :
 Oxygen Superoxide
 H2O2 (Hydrogen peroxide)
 OH (hydroxyl group)
 Inflammation :
 Accumulation of leucocytes
 NO (Nitric oxide) reactive nitrite
Cell Injury:

Mechanism of injury by Free Radicals

 1-Lipid peroxidation
(oxidative degradation of lipids):

 Destruction of unsaturated fatty acids

by binding to methylene groups (CH2)
that posses reactive hydrogen
molecules
Cell Injury:

 2-Protein destruction:
By cross linking proteins forming disulfide
bonds (S-S) → inactivate enzymes, &
polypeptide degradation

 3- DNA alteration:
By producing single strand breaks in DNA
 Induce mutation that interfere with cell

growth
Cell Injury:

Inactivation Free Radicals

 Spontaneous decay
 Enzymes

 Superoxide dismutase,

 glutathione peroxidase, and catalase

 Antioxidants

 Block synthesis or inactivate free radicals

 Include Vitamin E, Vitamin C, albumin,

ceruloplasmin, and transferrin

Cell Injury:

3- Chemical Agents
 Chemical agents can cause cellular injury
by:

 direct contact of the chemical with

molecular components of the cell.
 Indirect injury

 formation of free radicals, or lipid

peroxidation.
Cell Injury:

Examples of injurious chemicals

 Cyanide disrupts cytochrome oxidase.
 Mercuric chloride binds to cell

membrane in cell resulting in increased

permeability.
 Chemotherapeutic agents & antibiotics

may act in the same way.

 Carbon Monoxide (CO)

 Ethanol

 Lead
Cell Injury:

Action of Carbon Monoxide :

 Has a very high affinity to hemoglobin

(carboxyhemoglobin: COHb)
 The effect of large quantities of COHb is

death (carbon monoxide poisoning).

 Smaller quantities of COHb leads to

tiredness,dizziness & unconsciousness.

Cell Injury:

Action of Ethanol :

 The conversion of ethanol to acetaldehyde

leads to formation of free radical.
 Acetaldehyde initiates changes in liver
 Fatty change

 Liver enlargement

 Liver cell necrosis.

Cell Injury:

liver enlargement with deposition of fat

Cell Injury:

Action of Lead :

 Mimics other metals (calcium, iron and zinc)

which act as cofactors in many catalyzing
enzymatic reactions.
 Acts on the CNS by interfering with
neurotransmitters, blocking glutamate
receptor.
(May cause wrist, finger,&foot paralysis).
 Affects hemoglobin synthesis
Cell Injury:

Indirect injury of some chemicals :

 Activation in the liver by the P- 450 mixed function
oxidases in SER .
 CCL4  CCL3 (FR)  membrane
phospholipid peroxidation & ER destruction:
 ↓ protein ↓ lipid  No apoproteins for lipid
transport  Fatty liver
 Mitochondrial injury  ↓ATP  Failure of

cell function  increased cytosolic Ca+ 

cell death
 Acetaminophen may act similarly
Cell Injury:

4- Physical agents
 Mechanical injury resulting in tearing, or
crushing of tissues.
e.g.: blunt injuries , car accidents….

 Ionizing Radiation
 Water and DNA are the most vulnerable

target
Cell Injury:

Physical agents (cont……)

 Extreme temperatures
 Hypothermia

 Hyperthermia

 Atmospheric Pressure
 Blast injuries

 Water pressure – increased or decreased

Cell Injury:

5-Infectious Agents
 Bacteria: produce toxins
 Endotoxin

 Exotoxin

 Viruses :
 Decrease the ability to synthesize proteins

 Change host cell’s antigenic properties

Cell Injury:

5-Immunological reactions
 Cell membranes are injured by contact
with immune components such as
lymphocytes, macrophages….etc

 Exposure to these agents causes changes

in membrane permeability
Cell Injury:

6- Genetic Diseases
 Genetics play a substantial role in cellular
structure and function.
 A genetic disorder can cause a dramatic
change in the cell’s shape, structure,
receptors, or transport mechanisms.eg :
 Enzyme deficiencies

 Sickle Cell Anemia

Cell Injury:

7- Nutritional Imbalances
 Adequate amounts of proteins, lipids,
carbohydrates are required.
 Low levels of plasma proteins, like
albumin, encourages movement of water
into the tissues, thereby causing edema.
 Hyperglycemia, hypoglycemia,

 Vitamin deficiencies (vitamins E, D, K, A,

and folic acid)

 Excess food intake is also classified as a
nutritional imbalance
Cell Injury:

 Mechanism of cell injury &

sites of damage
Cell Injury:

General Considerations:

 Function is lost before morphological

changes occur
 EM changes
 Microscopic changes
 Gross changes
Cell Injury:

Result of injury depends on :

 Injury : Type
Duration
Severity
 Type of cell:
 Specialization

 Adequacy of blood supply, hormones,

nutrients
 Regenerative ability or adaptability

 Genetic make up
Cell Injury:

Steps & Cellular targets in Injury :

Cell Injury:

1- Mitochondria:
Interruption of oxidative metabolism
 Loss of energy due to formation of

mitochondrial permeability transition

pore (MPT)  loss of membrane
potential  prevents ATP generation
(ATP depletion)
 Cytochrome c released into cytosol 

activates apoptosis.
 O2 depletion  ROS
Cell Injury:

2- Cell Membranes
 Important sites of damage :
 Mitochondrial membrane ATP

 Plasma membrane failure of Na pump

leads to cellular amounts of water

 Lysosomal membrane  enzyme release,

activation & digestion of cell components

Cell Injury:

3- Influx of Calcium:
 Ca stability is maintained by ATP
 Loss of Ca homeostasis  cytosolic Ca+

 activation of:

 phospholipases
 proteases

 ATPases

 Endonucleases
Cell Injury:

4-Protein synthesis:
High fluid levels cause ribosomes to
separate from the swollen endoplasmic
reticulum  protein synthesis,
glycolysis
Metabolic acidosis
5- Genetic apparatus
DNA defects & mutations
Cell Injury:

 Injury at one locus leads to wide

ranging secondary effects

 Cascading effect
Cell Injury:

 Subcellular response to injury

Cell Injury:

1- Hypertrophy of Smooth Endoplasmic

Reticulum in liver induced by some drugs
 e.g. barbiturates , alcohol…. etc.
2-Mitochondrial alterations in size & number
 e.g. in atrophy, hypertrophy, alcoholic
liver
3-Cytoskeletal abnormalities
 e.g. microtubule abnormality involved
in cell mobility
Cell Injury:

4- Lysosomal Catabolism:
Enzymatic digestion of foreign material
(Heterophagy / pinocytosis & phagocytosis)
or intracellular material (Autophagy).

 Persistent debris → residual body

(Undigestible lipid peroxidation products
→ Lipofuscin pigment.
Cell Injury:

Morphology of reversible cell injury:

Ultrastructurally :
• Generalized swelling of the cell and its
organelles
• Blebbing of the plasma membrane
• Detachment of ribosomes from the
endoplasmic reticulum
• Clumping of nuclear chromatin.
Cell Injury:

Transition to irreversible cell injury :

• Increasing swelling of the cell

• Swelling and disruption of lysosomes
• Severe swelling & dysfunction of mitochondria
with presence of large calcium rich densities
in swollen mitochondria
• Disruption membranes→ phospholipase
• Irreversible nuclear changes
 Ultra structural changes in irreversible injury

Cell membrane Breaks in cell & organelles membranes

Amorphous density,bizarre forms,

mitochondria calcification

lysosomes rupture

Endoplastic retic fragmentation

Nucleus See by light mic

 Nuclear changes in irreversible changes
by light microscopy

Pyknosis

Nuclear shrinkage+Increased
basophilia

Pyknotic nucleus
karyolysis karyorrhexis

Anucleated cell
Cell Injury:

After death
 Cellular constituents are digested by lysosomal
hydrolases → enzymes & proteins leak into
extracellular space → useful in diagnosis
 Myocardial Infarction ( creatine kinase &

troponins)
 Liver injury (biliary obstruction): Alkaline

phosphatase
 Dead cells converted to phospholipid masses
(Myelin Figures) → Phagocytosis or degraded to
fatty acids → calcification
Summary
Cell Injury:

 IF INJURED CELLS DON’T DIE, THEY

MAY ADAPT TO PROTECT THEMSELVES !
Cell Injury:

Cellular Adaptations

 Cells change to
 Adapt to a new environment

 Escape from injury

 Protect themselves
Cell Injury:

Cellular Adaptations:
 Growth adaptations:
 Hyperplasia, Hypoplasia,
 Hypertrophy, Atrophy,
 Metaplasia , Dysplasia.

 Degenerations: (Accumulations)
 Hydropic change (water collection in cell /edema)
 Fatty Change
 Hyaline Change
 Pigment storage – wear & tear..
Cell Injury:

Cellular Adaptation to Injury

 The most common morphologically
apparent adaptive changes are

– Atrophy (decrease in cell size)

– Hypertrophy (increase in cell size)
– Hyperplasia (increase in cell number)
– Metaplasia (change in cell type)
Cell Injury:

Atrophy
 Decrease in cell size due to loss of cell substance
(protein degradation & lysosomal proteases digest
extracellular endocytosed molecules )
 Often hormone dependent (insulin, TSH, etc…).
 Atrophic cells have diminished function.
Cell Injury:

Atrophy
 Physiologic:
Uterus following parturition
 Pathologic:
 Decreased workload (Disuse atrophy)
 Loss of innervation (Denervation atrophy)

 Decreased blood supply (Brain atrophy)

 Malnutrition (Marasmus).

 Lack of hormonal stimulation.

 Ageing:
 Senile atrophy
Cell Injury:

Disuse atrophy of muscle fibers

Cell Injury:

Atrophy of frontal lobe

Cell Injury:

Atrophy: Undescended testes

Cell Injury:

Hypertrophy
 Hypertrophy is an increase in cell size by gain of
cellular substance
 With the involvement of a sufficient number of
cells, an entire organ can become hypertrophic
 Hypertrophy is caused either by increased
functional demand or by specific endocrine
stimulations
 With increasing demand, hypertrophy can reach a
limit beyond which degenerative changes and
organ failure can occur
Cell Injury:

Hypertrophy
 Physiological & Pathological

 Skeletal muscles in manual workers &

athletes
 Smooth muscles in pregnant uterus

(Hyperplasia accompanies hypertrophy here)

 Cardiac muscles in hypertension
 Remaining kidney after nephrectomy
Cell Injury:

Left ventricle hypertrophy - HPTN

Compare normal & pregnant uterus
Cell Injury:

Hyperplasia

 Hyperplasia is an increase in the number of

cells of a tissue or organ, from an increased
rate of cell division.
 If cells have mitotic ability and can
synthesize DNA, both hyperplasia and
hypertrophy can occur.
 Hyperplasia may be a predisposing condition
to neoplasia
Cell Injury:

 Cells differ in their capacity to divide :

 High capacity: Epidermis, intestinal epithelium

hepatocytes, bone marrow, fibroblasts.

 Low capacity: Bone cartilage, smooth muscles

 Nil capacity: Neurons, cardiac muscle, skeletal

muscle….
Cell Injury:

Types of Hyperplasia

 Physiological Hyperplasia
(hormonal or compensatory), Examples:

 Uterine enlargement during pregnancy

 Female breast in puberty & lactation

 Compensatory hyperplasia in the liver

Cell Injury:

 Pathological

 Hyperplasia of the endometrium

(excessive hormone stimulation).
 Wound healing

(Effects of growth factors).

 Infection by papillomavirus
Cell Injury:

Endometrial Hyperplasia
Cell Injury:

Metaplasia
 Metaplasia is a “reversible” change
(adaptation ) in which one adult cell type
is replaced by another adult cell type that
are better suited to tolerate a specific
abnormal environment.

 May occur in epithelial or mesenchymal

tissue. e.g. Bronchial , gastric, & cervical
epith., and bone in injured soft tissue
Cell Injury:

Some disadvantages occur :

 Because of metaplasia, normal protective
mechanisms may be lost.

 Persistence of signals that result in

metaplasia often lead to progression from
metaplasia to dysplasia and possibly to
adenocarcinoma.
Cell Injury:

Example of Metaplasia
 Replacement of ciliated columnar
epithelium with stratified squamous
epithelium in respiratory tract of a smoker.
Cell Injury:
Columnar (gastric) metaplasia in
esophageal squamous epithelium
Cell Injury:

Dysplasia

 Abnormal changes in size, shape,

appearance, and organizational structure
of the cells
 Sometimes atypical hyperplasia can
progress to neoplasia
 Caused by persistent injury or irritation
 Cervix, oral cavity, gallbladder, and
respiratory tract

“Cells having disordered arrangement”

Cell Injury:

Cervical dysplasia
Cell Injury:

Intracellular Accumulations
& Deposits
Cell Injury:
May occur in any one of the
following ways :
 Excessive production of a normal product
but metabolic function is inadequate

 Normal or abnormal substance

accumulates but there is genetic or
acquired defective enzyme mechanism for
removal

 Abnormal exogenous substance

accumulates because the cell does not
possess a mechanism for removal
Cell Injury:

Accumulations include
 Water
 ( Hydropic degeneration/cloudy swelling)
 Fatty change
 Cholestrol & cholestrol esters
 Proteins
 Glycogen
 Pigments
 Calcium
 Amyloid deposition
Cell Injury:

Hydropic degeneration
Cell Injury:

1- Fatty change

 Accumulation of excessive lipid in cells

 The liver is the main organ involved, to

lesser extent heart and kidney

 Fatty acids → hepatocytes → triglyceride

+ apoproteins → lipoprotein → exit liver

 Excess accumulation may result from

defect in any of the above steps
Cell Injury:

Causes of fatty change :

 Toxins including alcohol

 Starvation and protein malnutrition

 Diabetes mellitus

 Oxygen lack (anemia & ischemia )

 Drugs, Complicate pregnancy & Obesity

Cell Injury:

Morphology of fatty liver

 Gross appearance in liver depends on severity
 Normal to large size, looks yellow and greasy
when severe
 Histology
 Fat accumulates in hepatocytes as small vacuoles
in cytoplasm with nucleus in the center
(Microvesicular fatty change ).
 The whole cytoplasm is replaced by fat and
nucleus is pushed to one side of the cell
(Macrovesicular fatty change).
Cell Injury:

Fatty Liver (Alcoholism)

Cell Injury:

2- Cholestrol & Cholestrol esters

 Accumulate in macrophages ( foam cells )

& in foreign body giant cells :
 Atherosclerosis

 Hereditary & Acquired hyperlipidemia →

Xanthomas (a yellow nodule or plaque,

especially of the skin, composed of lipid-
laden histiocytes).
Cell Injury:

3- Protein accumulation:

 kidney in the nephrotic syndrome.

 Plasma cells as immunoglobulins.

 Mallory Bodies: Alcoholic liver disease as

(Eosinophilic intracellular hyaline body)

 Glycogen accumulation in Glycogen

Storage Diseases.
Liver - Mallory hyaline - Alcoholism
Cell Injury:

4- Pathologic Calcification
 A- Dystrophic calcification :
Abnormal deposition of calcium phosphate in
dead or dying tissue
 Dystrophic calcification is an important
component of the pathogenesis of
atherosclerotic disease and valvular heart
disease.
 Areas of caseous, coaggulative or fat
necrosis.
 Dead parasites & their ova
Cell Injury:

cont…
 B- Metastatic calcification :
Calcium deposition in normal tissues as a
consequence of hypercalcemia:
 Increased PTH with subsequent bone

resorption
 Bone destruction: METASTATIC BONE
CANCERS
 Vitamin D disorders Renal failure

 Organs affected:
 Kidney, stomach, lungs….
Cell Injury:

Dystrophic calcification - Stomach.

Cell Injury:

5-Pigments
Pigments

EXOGENOUS ENDOGENOUS

Anthracosis
Hb-derived Non Hb -derived
Tattooing
Iron Melanin

Bilirubin Lipofuscin
Cell Injury:

Exogenous pigment :
 Anthracosis :

Accumulation of carbon, black pigment

 Smokers

 Tatooing
Cell Injury:

Exogenous pigment : Anthracosis

Cell Injury:

Endogenous pigments :
 1- Melanin pigment :
Brown pigment synthesized in melanocytes.
 Melanin protects the nuclei of cells in

basal layer of epidermis against effects of

UV light
 Lesions associated with melanocytes

 Moles (nevi)…..benign
 Melanoma…….malignant

 Lesions can occur anywhere

e.g.rectum,eye.
Cell Injury:

2- Lipofuscin pigment
 Brown pigment in cytoplasm of cells,
represents residue of oxidized lipid derived
from digested membranes of organelles.
 It is called “wear and tear”pigment
accumulates as a part of the aging process
and atrophy, in which lipid peroxidation
take part in it.
 It is harmless to the cell.
 Large amounts in atrophic organs gives
rise to “Brown atrophy” e.g brown
atrophy of the heart.
Cell Injury:

Lipofuscin
Cell Injury:

3- Bile pigment (Bilirubin )

 Derived from heme of Hb from destroyed RBC in
reticuloendothelial system.
 Conjugated in hepatocytes with glucuronic acid
and excreted as bile.
 Hyperbilirubinemia may present clinically as
jaundice
 Causes may be hemolysis, liver diseases or
obstruction to the outflow of bile
Cell Injury:

4- Excess iron accumulation

 Total body iron….. 2 - 4gm.
 Functional pool
 Hb, myoglobin, cytochromes & catalase

 Storage pool
 in macrophages of RES in the ferric form as

ferritin & / or hemosiderin which is golden

brown.
 Potasium ferrocyanide + hemosiderin = ferric

ferrocyanide. This is known as ” Prussian

Blue reaction” or Perl`s reaction.
Cell Injury:

Iron overload: Localized or systemic

 Local increase of iron in tissues
 Localized hemorrhage in tissues

 Chronic venous congestion of lung in heart

failure
 Systemic increase of iron
 Hemosiderosis ….. Iron in RES without much

damage
 Occurs in:

 Excessive hemolysis

 Multiple blood transfusions

 Intravenous administration of iron

Cell Injury:

Hemosiderin granules in liver cells.

A- H&E section showing golden-brown, finely
granular pigment.
B- Prussian blue reaction, specific for iron.
Cell Injury:

Idiopathic Hemochromatosis
 Abnormality is lack of regulation of iron
absorption & defect in the monocyte -
macrophage system.
 Iron accumulates in liver, pancreas, other
parenchymal cells & to lesser extent in
RES.
 Induce fibrosis, secondary diabetes,
cirrhosis & liver cancer
Cell Injury:

5- Amyloidosis
 Extracellular deposition of an abnormal fibrillar
proteins in various tissues and organs (kidney,
heart, brain, liver…etc.)
 The abnormal protein is called Amyloid.
 Many types associated with different diseases or
primary forms
 H & E … Hyaline-like acellular eosinophilic material
 Congo red stains amyloid pink or red and under
polarizing microscopy gives apple green
birefringence .
Cell Injury:

Amyloid deposition in kidney

Cell Injury:

Congo Red Stain

Cell Injury:

Classification of amyloidosis
 Localized amyloid deposition
 larynx,lungs,urinary bladder,etc..

 Systemic amyloidosis
 multiple myeloma associated …. AL amyloid

 Reactive (secondary amyloidosis) …

AA amyloid
 RHEUMATOID ARTHRITIS,

 INFLAMMATORY BOWEL DISEASE,

 OSTEOMYELITIS,

 HODGKIN’S DISEASE AND RENAL CELL

CARCINOMA.
 Hereditary amyloidosis
Cell Injury:

CELL DEATH
Cell Injury:

CELL DEATH
 Ultimate result of injury, following
ischemia, infection, toxins, immune
reactions……

 Physiologically seen in embryogenesis,

lymphoid tissue development, hormonally
induced involution.

 Therapeutically in cancer radiotherapy and

chemotherapy.
Cell Injury:

Types :

 Necrosis: Morphologic changes seen

in dead cells within living tissue.
 Autolysis: Dissolution of dead cells by
the cells own digestive enzymes. (not
seen)
 Apoptosis: Programmed cell death.
Physiological, cell regulation.
Cell Injury:

NECROSIS

 Irreversible

 Necrosis is local cell death and cellular

dissolution in living tissues.

 Necrosis involves the process of self/auto

digestion and lysis.
Cell Injury:

Morphologic changes :

 Increased eosinophilia of cells

 Pyknosis of nuclei

 Karyorrhexis

 Karyolysis: dissolution of the nucleus

from hydrolytic enzymes

 Release of catalytic enzymes from

lysosomes cause either autolysis or

heterolysis
Cell Injury:
 Morphologic appearance of necrosis is
due to:
 Enzymic digestion of the cell

 Denaturation of proteins

 Types: coagulative, liquefactive, caseous,

fat necrosis, gummatous necrosis and
fibrinoid necrosis.
 Sequels of Necrosis:
 Autolysis

 Phagocytosis

 Organization & fibrous repair

 Dystrophic calcification
Cell Injury:

1- Coagulative necrosis

 Commonest type of necrosis, usually ischemic

 Infarction specially in heart (Myocardial
Infarction) Also in kidney & in adrenals….
 Variable appearance mostly firm texture.
 It is suspected that high levels of intracellular
calcium plays a role in coagulative necrosis.
 Results from denaturation of all proteins
including enzymes .
Cell Injury:

 Histology:

 Preservation of the tissue architecture &

cellular outlines.
 The necrotic area stains more

eosinophilic, often devoid of nuclei.

Cell Injury:
Renal Infarction: Coagulative
Necrosis
Cell Injury:

2- Liquefactive Necrosis
 Autolysis predominates and results in liquefied
mass e.g. hypoxia in brain, bacterial infections
(abscess).
 Brain cells have a large amount of hydrolytic

digestive enzymes (hydrolases). These

enzymes cause the neural tissue to become
soft and liquefy.
 Liquefactive necrosis is what causes pus to

form.
 Hydrolytic enzymes are released from neutrophils to
fight an invading pathogen.
 E. Coli, Staphylococcus, and Streptococcus
Cell Injury:

Stroke- Liquifactive necrosis

Cell Injury:

Lung abscess:
Liquefactive
necrosis
Cell Injury:

Liver abscess: Liquefactive necrosis

Cell Injury:

3- Caseous Necrosis
 Grossly “cheese-like”, appearance, being soft and
white.
 Histology:
 Central cheesy material , rimmed by chronic
inflammatory cells, epitheloid cells & Langhans giant
cells ( GRANULOMA)
 Typical of tuberculosis, may be seen in others
 Is a distinctive form of coagulative necrosis
modified by capsule lipopolysacchride of TB bacilli
Cell Injury:

Caseous necrosis in Tuberculosis

Cell Injury:

Caseous necrosis - Tuberculosis

Cell Injury:

4- Fat Necrosis
 Two types :
 Traumatic fat necrosis → foreign body giant

cells → calcification → hard lump

 Enzymatic fat necrosis due to acute

pancreatitis
 Acute Pancreatitis :
 Medical emergency

 Enzymes released, digests fat

 Adipose tissues → triglycerides & fatty acids

→ saponification & calcification

Cell Injury:
Foci of fat necrosis with saponification
in the mesentery
Cell Injury:

Fat Necrosis - Peritoneum.

Cell Injury:

Gangrene
 Necrosis plus putrefaction (rotting) by saprophytes.
 Wet gangrene: Coagulative necrosis due to

ischemia and liquifactive necrosis due to

superimposed infection.
 Dry gangrene: Drying of dead tissue, is a form

of coagulative necrosis, applied to necrosis of the

lower limbs distally, associated with peripheral
vascular disease.
Necrosis is separated by a line of demarcation from
viable tissue.
 Gas gangrene: This caused by wound
contamination by anaerobic bacteria (Clostridia
perfringes)
Cell Injury:

Toes - Dry Gangrene

Cell Injury:
Wet Gangrene
Amputated Diabetic foot
Cell Injury:

APOPTOSIS
 Programmed cell death by suicide
 The cell’s membrane remains intact
 Apoptosis is characterised by death of single
cells or clusters and results in cell shrinkage, not
lysis and swelling without an inflammatory
reaction,
 unlike necrosis where there is death of large

amounts of the tissue and there is an

associated inflammatory reaction.
 Cell death involved in normal and pathologic
conditions.
Cell Injury:

APOPTOSIS
 Apoptosis depends on cellular signals, these
signals cause protein cleavage (proteases)
within the cell, causing cell death.
 Programmed and energy dependent process
designed to switch cell off and eliminate them
 Cell shrinkage

 Chromatin condensation- most characteristic

 Formation of cytoplasmic blebs and apoptotic

bodies
 Phagocytosis of apoptotic cells or bodies
Cell Injury:

Two main pathways

 Intrinsic ‘mitochondrial’ pathway:
Increased permeability of mitochondrial
membrane results in release of pro-apoptotic
factors (cytochrome c and AIF) that activate
downstream caspases  death .

 Extrinsic ‘death receptor pathway’:

FAS and TNF1 receptor families with death
domain.
Cell Injury:
Cell Injury:

Physiologic apoptosis
 During development, embryogenesis.
 Homeostatic mechanism to maintain cell
population(Cell turnover in intestinal crypts).
 Immune reaction - defense mechanism.
 In aging.
 Shedding of menstrual endometrium.
 Involution of breast after weaning.
Cell Injury:

Pathologic apoptosis
 Prostatic ‘atrophy’ after castration.
 Death of inflammatory cells after inflammation
 When cells are damage by disease or injurious
agents
 DNA damage e.g. radiation, chemotherapy,

Cytotoxic drugs
 Viral infections e.g. viral hepatitis

 Neoplasia: tumours that regress or involution

 Deletion of autoreactive T cells in thymus

 Others including rejection of transplants

Cell Injury:

A, Apoptosis of epidermal cells in an immune-mediated reaction. The

apoptotic cells are visible in the epidermis with intensely eosinophilic
cytoplasm and small, dense nuclei. H&E stain.
B, High power of apoptotic cell in liver in immune-mediated hepatic cell
injury.
Cell Injury:

Comparison of apoptosis with necrosis

 Apoptosis  Necrosis
 Active process  Passive process

 Occur in single cells  Affects mass of

cells
 Physiological &
pathological  Always pathological

 No inflammatory  stimulates
reaction Inflammation
Cell Injury:

Aging and Cellular Death

 Theories
 Aging is caused by accumulations of injurious

events
 Aging is the result of a genetically controlled

developmental program.
 Mechanisms
 Genetic, environmental, and behavioral

 Changes in regulatory mechanisms

 Degenerative alterations
Cell Injury:

Cellular aging
 Genetic e.g. failure of repair mechanisms , Clock
genes overexpression of antioxidative enzymes
Telomerase activity …….etc
Telomerase activity stops in somatic cells, but
continues in stem cells & germ cells
 Environmental: generation of FR, diet
 Accumulation of multiple defects Aging
 Aged cells show Lipofuscin pigment , abnormally
folded proteins & advanced glycosylation end
products ( AGES’s)