1.

CELL INJURY

Normal cell and the

Changes in Reversible
And Irreversible
Cell injury

CELL INJURY
The cellular response to injurious stimuli depends
on the nature of the injury, its duration, and its
severity

The consequences of cell injury depend on the

type, state, and adaptability of the injured cell

Cell injury results from different biochemical

mechanisms acting on several essential cellular
components

MECHANISMS OF CELL INJURY

DEPLETION OF ATP
MITOCHONDRIAL DAMAGE
INFLUX OF CALCIUM AND LOSS OF CALCIUM
HOMEOSTASIS
ACCUMULATION OF OXYGEN-DERIVED FREE
RADICALS (OXIDATIVE STRESS)
DEFECTS IN MEMBRANE PERMEABILITY
DAMAGE TO DNA AND PROTEINS

Mechanism of Cell Injury:

1.
2.
3.
4.
5.

The cellular response to injurious stimuli depends

on type of injury, its duration, & its severity.
Consequences depends on the type, state &
adaptability of the injured cell.
Most important targets of injurious stimuli are
on:
Mitochondrial oxidative phosphorylation and
production of ATP
The integrity of cell membranes
Protein synthesis
The cytoskeleton
Integrity of genetic apparatus of the cell.

INJURIOUS STIMULUS

Decreased
ATP

MEMBRANE DAMAGE

MITOCHONDRIA
DAMAGE

LYSOSOME
RUPTURE

INCREASED
intracellular Ca++

PLASMA
MEMBRANE
RUPTURE
PROTEIN
BREAK
DOWN
DNA
DAMAGE

CELL
DEATH
LOSS OF
ENERGY
DEPENDENT
CELULAR
FUNCTIONS

ENZYMATIC DIGESTION OF
CELL COMPONENTS

REACTIVE
OXYGEN
SPECIES

LOSS OF
CELL
CONTENTS

DEPLETION OF ATP:
ATP generation: 2 pathways
1. Oxidative phosphorylation
2. Glycolytic pathway
ATP required for membrane transport,
protein synthesis, lipogenesis, etc.,
ATP depletion: associated with hypoxic &
chemical (toxic) injury to cell.
Decreased ATP increased anaerobic
glycolysis--accumulation of lactic acidincreased pH- acidosis.

MITOCHONDRIAL DAMAGE:
1.
2.
3.

By increased intracellular Ca++

By oxidative stress
By breakdown of phospholipids through phospholipase
A2
Results in formation of MPT (Mitochondrial Permeability
Transition)high conductive channel & nonselective
poreloss of membrane potential & leakage of
cytochrome Ctriggers Apoptosis.

Influx of Ca++ ions:

Ca++ : most important mediator of cell
injury.
Normal intracellular Ca++ < 0.1 mmol, &
extracellular Ca++ 1.3 mmol.
Intracellular Ca++ is sequestered in
Mitochondria & ER.
Increased cytosolic Ca++ activates various
enzymes: ATPases, Phospholipases,
Proteases, endonucleases.
Also increases mitochondrial permeability.

Oxygen Free Radicals:

Partially reduced, unavoidable byproducts of
mitochondrial respiration. E.g.,OH-, O2-,H2O2,
Have single unpaired electron in outer orbit;
highly unstable configuration.
Capable of damaging lipids, proteins & nucleic
acids.
Imbalance between free O2 radical generating
system & radical scavenging system results in
OXIDATIVE STRESS.
Initiate autocatalytic reactions: molecules with
which they react are themselves convert into
free radicals propagating the chain of reaction.

Production of free radicals:

Absorption of radiant energy: ionizing
radiation, UV rays, X-rays.
Enzymatic metabolism of exogenous
chemicals or drugs
The reduction-oxidation Reaction that occur
during normal metabolic process.
Transition metals :Copper & Iron ; donate or
accept free electrons and catalyze free radical
formation: Fenton Reaction.
Nitric oxide: an important chemical mediator,
that can act as free radical.

Effects of Free Radicals:

Lipid peroxidation of membranes

Oxidative modification of proteins
Single stranded breaks in DNA

ANTIOXIDANTS:

Block the formation or inactivate free

radicals

1. Vitamins: A (Beta carotene), C (Ascorbic

acid)
2. Glutathion peroxidase, catalase
3. SOD (Superoxide dismutase)
4. Ferritin, Ceruloplasmin

Morphology of cell injury:

Cellular swelling
Cytoplasmic small vacuolationrepresent
distended ER: hydropic change or vacuolar
degeneration.
Plasma membrane: blebbing, blunting,
distortion of microvilli, myelin figure formation,
loosening of intracellular attachments.
Mitochondrial changes: swelling, appearance
of phospholipid rich amorphous densities.
Nuclear alterations: disaggregation of granular
& fibrillar material.

Necrosis:
Necrosis refers to a spectrum of
morphologic changes that follow
cell death in living tissue, largely
resulting from progressive
degradative action of enzymes on
the lethally injured cells.

Necrosis
Apoptosis

1. Cell size: enlarged.

2. Nucleus: PyknosisKaryorrhexis- Karyolysis.
3. Plasma membrane:
disrupted
4. Cellular contents: leak
out, enzymatic digestion.
5. Inflammation-+++
6. Role: always pathologic.

1. Reduced.
2. Fragmentation.
3. Intact; altered
structure.
4. Intact; released
into apoptotic
bodies.
5. No inflammation
6. Physiologic/
pathologic.

7. Agarose gel
electrophoresis: diffuse
smearing pattern

7. Ladder pattern

Why Inflammation around it???

Necrotic cells are unable to maintain the
membrane integrity and their contents
often leak out.
This will elicit inflammation in the
surrounding tissue.

Pathogenesis:
Autolysis: Due to enzymatic digestion of
the cell and denaturation of intracellular
proteins.
Enzymes: released from lysosome of dead
cells themselves or from immigrant
leukocytes of inflammation.

Morphology:
Increased Eosinophilia: attributable to
loss of normal basophilia imparted by
RNA in the cytoplasm.
More glassy homogeneous appearance.
Cytoplasmic vacuolation: due to digestion
of cytoplasmic organelles moth eaten
appearance.

Normal Myocardium

Ischemic Myocardium

Morphology:
Dead cells replaced by:
Large,whorled phospholipid masses
called Myelin figures
Calcification
Phospholipids are degraded into fatty
acids which undergo calcification to yield
Calcium soaps.

Electron microscopy:
Discontinuous plasma membrane
Dilatation of mitochondria with
appearance of Large amorphous densities
Intracytoplasmic myelin figures
Amorphous osmiophilic debris
Aggregates of fluffy materialdenatured
protein.

Morphology:
Nuclear changes: 3 forms-1. Karyolysis: Basophilia of the
chromatin may fadeDNase activity+
+
2. Pyknosis: Nuclear shrinkage and
increased basophilia--- DNA is
condensed to solid, basophilic mass.
3. Karyorrhexis: Fragmentation of the
pyknotic nucleus.

Types of Necrosis:
1.
2.
3.
4.
5.

Coagulative Necrosis
Liquefactive Necrosis
Caseous Necrosis
Fat Necrosis
Fibrinoid necrosis

1. Coagulative Necrosis:
Implies preservation of basic outline of
the coagulated cell at least for some
days.
Example: Myocardial infarction
acidophilic, coagulated, anucleate cells
persisting for few weeks.
Ultimately it is removed by phagocytosis
by scavenger leukocytes.

COAGULATIVE
NECROSIS -KIDNEY

INFARCTION CAUSING COAGULATIVE NECROSIS: ADRENAL CORTEX

2. Liquefactive Necrosis:
Most common hypoxic death in CNS.
Transformation of tissue into a liquid
viscous mass.
Seen in fungal/ bacterial infections also.
Pus: creamy yellow material containing
dead white cells.

LIQUEFACTIVE NECROSISBRAIN

LIQUEFACTIVE NECROSISBRAIN

3. Caseous Necrosis:
Most often seen in TUBERCULOSIS.
Cheesy white- gross appearance of the
area of necrosis.
Amorphous, granular debris enclosed
within a distinctive inflammatory border
known as Granulomatous inflammation.

CASEOUS NECROSIS

4. Fat Necrosis:
Due to release of activated pancreatic
lipasesinto pancreatic substances and
peritoneal cavitydestroying the fat.
Most commonly seen in acute
pancreatits.
Lipases split triglycerides into fatty acids
that combine with calcium to produce
grossly visible chalky white areas- FAT
SAPONIFICATION.

Examples:
Acute pancreatitis- release of
pancreatic lipaseliquefy the fat cell
membranes.
Fatty acids+ Ca++ Saponification
Microscopy: foci of necrotic fat cells
surrounded by basophilic calcium
deposits and inflammatory reaction.
Finally may end in dystrophic
calcification.

FAT NECROSIS --PANCREAS

FAT NECROSIS

5. Fibrinoid necrosis
It is characterised by deposition of fibrinlike material which has staining properties
of fibrin
Seen in various examples of immunologic
tissue injury like autoimmune diseases
Microscopy:
Bright eosiniphilic hyaline like deposition
in the vessel wall
Necrotic focus is surrounded by nuclear
debris of neutrophils.

Fibrinoid necrosis