SHS 301 Lect-4

COURSE CODE: 301
Dr. Uzma Naz

OVERVIEW
Cellullar response to stress
Necrosis
Apoptosis
For every cell, there is a time to live
and a time to die.
There are two ways in which cells
die:
1)They are killed by injurious agents.
2)They are induced to commit
suicide.
DEFINITION OF NECROSIS
Necrosis is the type of cell death that is associated

with loss of membrane integrity and leakage of
cellular contents culminating in dissolution of cells,
largely resulting from the degradative action of
enzymes on lethally injured cells.
CAUSES OF NECROSIS
• ISCHEMIA
• PHYSICAL AGENTS
• CHEMICAL AGENTS
• IMMUNOLOGICAL INJURY
MORPHOLOGY OF NECROSIS
Necrosis is characterized by changes in the cytoplasm and

nuclei of the injured cells.
• CYTOPLASMIC CHANGES.
Necrotic cells show:
1. increased eosinophilia (i.e., pink staining from the eosin
dye),
2. loss of the basophilia that is normally imparted by the
ribonucleic acid (RNA) in the cytoplasm (basophilia is
the blue staining from the hema-toxylin dye).
When enzymes have digested cytoplasmic organelles, the
cytoplasm becomes vacuolated and appears “moth-eaten
NUCLEAR CHANGES
Nuclear changes assume one of three patterns,
all due to breakdown of DNA and chromatin.
• The basophilia of the chromatin may
fade (karyolysis),presumably secondary to
deoxyribonuclease (DNase)activity.
• A second pattern is pyknosis, characterized
bynuclear shrinkage and increased
basophilia; the DNA con-denses into a solid
shrunken mass.
• In the third pattern, karyorrhexis, the
pyknotic nucleus undergoes fragmen-tation.
MORPHOLOGY
• Increased eosinophilia of cytoplasm

• Glassy form
• Cytoplasm is vacuolated
• Appearance of myelin figures
• Generation of calcium soaps
FATE OF NECROTIC CELLS
Necrotic cells may persist for some time or
may be digested by enzymes and disappear.
• Dead cells may be replaced by

myelin figures, which are either
phagocytosed by other cells or further
degraded into fatty acids.
• These fatty acids bind calcium salts, which

may result in the dead cells ultimately
becoming calcified.
TYPES OF NECROSIS
• Coagulative necrosis
• Liquefactive necrosis
• Caseous necrosis
• Fat necrosis
• Fibrinoid necrosis
COAGULATIVE NECROSIS
• Coagulative necrosis is a form of necrosis

in which the underlying tissue architecture is
preserved for at least several days typically
caused by ischemia.
• Coagulative necrosis is characteristic

of infarcts (areas of ischemic necrosis) in all
of the solid organs except the brain.
Example
– Heart, kidney, spleen.
LIQUIFACTIVE NECROSIS
Liquefactive necrosis is seen in focal bacterial
or,occasionally, fungal infections, because
microbes stimulate the accumulation of
inflammatory cells and the enzymes of
leukocytes digest (“liquefy”) the tissue.
• The tissue becomes liquid viscous mass

• Material is creamy yellow in color
• Seen in brain, abscess
GANGRENOUS NECROSIS
• Gangrenous necrosis is not a distinctive pattern of cell

death, the term is still commonly used in clinical
practice.
• It usually refers to the condition of a limb,generally
the lower leg, that has lost its blood supply and has
undergone coagulative necrosis involving multiple
tissue layers.
• When bacterial infection is superimposed,coagulative
necrosis is modified by the liquefactive actionof the
bacteria and the attracted leukocytes (resulting inso-
called wet gangrene).
TYPES OF GANGRENE
1. Wet gangrene
2. Dry gangrene
3. Gas gangrene
1. WET GANGRENE
Occurs in moist tissues like mouth, bowel, lung, cervix,

Diabetic foot Bed sores
2. DRY GANGRENE
Toes and feet due to arteriosclerosis
• Thromboangitis obliterans
• Raynaud disease
• Trauma
3. GAS GANGRENE
Gangrene caused by gram positive anaerobic

bacteria (Clostridium perferinges)
• Seen in muscle and in colon

CASEOUS NECROSIS
• Type of coagulative necrosis

• Seen in tuberculous infections
• Tissue is cheesy white in appearance
• The tissue architecture is preserved
FAT NECROSIS
It refers to focal areas of fat destruction, typically

resulting from release of activated pancreatic
lipases into the substance of the pancreas and the
peritoneal cavity.
This occurs in acute pancreatitis
• Grossly visible chalky white areas

• Presence of shadowy outlines of necrotic cells
FIBRINOID NECROSIS
A special form of necrosis, visible by light

microscopy, usually in immune reactions in which
complexes of antigens and antibodies are deposited
in the walls of arteries.
The deposited immune complexes,together

with fibrin that has leaked out of vessels, produce a
bright pink and amorphous appearance on H&E
preparations called fibrinoid (fibrin-like)
FIBRINOID NECROSIS
Seen in
• immunologic cell injury,
• hypertension
• peptic ulcer
TREATMENT OF NECROSIS
1. Debridement: referring to the removal of dead tissue

by surgical method
2. Antibiotics
3. Anti-inflammatory drugs
4. Keeping the wound clean from infection also prevents

necrosis.
APOPTOSIS
DEFINITION
• Regulated mechanism of cell death that

serves to eliminate unwanted and irreparably
damaged cells, with the least possible host
reaction
• Characterized by enzymatic degradation of

proteins and DNA, initiated by caspases; and
by recognition and removal of dead cells by
phagocytes
APOPTOSIS
Apoptosis in physiologic
situations
Apoptosis in pathologic
situations
APOPTOSIS
Apoptosis in physiologic situations
Vaux and Korsmeyer, 1999,Cell

Apoptosis in physiologic situations
Programmed cell death during embryogenesis
Formation of Development
free and Development of
independent of the brain reproductive
digits organs
APOPTOSIS IN PATHOLOGIC CONDITIONS
Apoptosis eliminates cells that are genetically altered

or injured beyond repair and does so without eliciting
a severe host reaction,thereby keeping the extent of
tissue damage to a minimum.
Death by apoptosis is responsible for loss of
cells in a variety of pathologic states:
• DNA damage.
Radiation, cytotoxic anticancer drugs,extremes of
temperature, and even hypoxia can damage DNA
• Accumulation of misfolded proteins
Improperly folded proteins may arise because of

mutations in the genes encoding these proteins
• Cell injury in certain infections particularly viral
infections
• Pathologic atrophy
In parenchymal organs after duct obstruction, such as

occurs in the pancreas, parotid gland, and kidney
MORPHOLOGY
Cell shrinkage
Chromatin condensation
Formation of cytoplasmic cells and apoptotic bodies
Phagocytosis by macrophages
Apoptosis triggered by internal signals:
1. THE INTRINSIC OR MITOCHONDRIAL PATHWAY
Mitochondrial (intrinsic) pathway is triggered by loss of

survival signals, DNA damage and accumulation of mis-
folded proteins (ER stress); associated with leakage of
pro-apoptotic proteins from mitochondrial membrane
into the cytoplasm, where they trigger caspase
activation; inhibited by anti-apoptotic members of the
Bcl family, which are induced by survival signals
including growth factors.
2. APOPTOSIS TRIGGERED BY EXTERNAL SIGNALS:
THE EXTRINSIC OR DEATH RECEPTOR PATHWAY
Death receptor (extrinsic) pathway is responsible for

elimination of self-reactive lymphocytes and damage by
cytotoxic T lymphocytes
Is initiated by engagement of death receptors (members

of the TNF receptor family)by ligands on adjacent cells
• Extrinsic
pathway
The death
receptor
pathway
3. APOPTOSIS-INDUCING FACTOR (AIF)
Neurons, and perhaps other cells, have another way

to self-destruct that — unlike the two paths
described above — does not use caspases.
Apoptosis-inducing factor (AIF) is a protein that is
normally located in the intermembrane space of
mitochondria. When the cell receives a signal telling
it that it is time to die,
AIF is released from the mitochondria  migrates

into the nucleus  binds to DNA  triggers the
destruction of the DNA and cell death.
POINT TO PONDER!!
What happens if apoptosis is inhibited

Inhibition of apoptosis
can result in a number of cancers,

autoimmune diseases,
 inflammatory diseases,
viral infections
Treatment
To stimulate apoptosis, one can

increase the number of death
receptor ligands

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SHS 301 Lect-4

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COURSE CODE: 301

Dr. Uzma Naz

Necrosis is the type of cell death that is associated

Necrosis is characterized by changes in the cytoplasm and

• Increased eosinophilia of cytoplasm

• Dead cells may be replaced by

• These fatty acids bind calcium salts, which

• Coagulative necrosis is a form of necrosis

• Coagulative necrosis is characteristic

• The tissue becomes liquid viscous mass

• Gangrenous necrosis is not a distinctive pattern of cell

Occurs in moist tissues like mouth, bowel, lung, cervix,

Toes and feet due to arteriosclerosis

Gangrene caused by gram positive anaerobic

• Seen in muscle and in colon

• Type of coagulative necrosis

It refers to focal areas of fat destruction, typically

This occurs in acute pancreatitis

• Grossly visible chalky white areas

A special form of necrosis, visible by light

The deposited immune complexes,together

1. Debridement: referring to the removal of dead tissue

4. Keeping the wound clean from infection also prevents

• Regulated mechanism of cell death that

• Characterized by enzymatic degradation of

Apoptosis in physiologic situations

Vaux and Korsmeyer, 1999,Cell

Apoptosis eliminates cells that are genetically altered

• Accumulation of misfolded proteins

Improperly folded proteins may arise because of

In parenchymal organs after duct obstruction, such as

1. THE INTRINSIC OR MITOCHONDRIAL PATHWAY

Mitochondrial (intrinsic) pathway is triggered by loss of

Death receptor (extrinsic) pathway is responsible for

Is initiated by engagement of death receptors (members

Neurons, and perhaps other cells, have another way

AIF is released from the mitochondria  migrates

What happens if apoptosis is inhibited

can result in a number of cancers,

To stimulate apoptosis, one can

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