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Cell Injury
and
Cell Death
Cell Injury
If the cells fail to adapt under stress, they
undergo certain changes called cell injury.
The affected cells may recover from the injury
(reversible) or may die (irreversible).
Causes of Cell Injury
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Oxygen deprivation (hypoxia)
Physical agents
Chemical agents
Infections agents
Immunologic reactions
Genetic defects
Nutritional imbalances
Hypoxia
&
Ischaemia
Morphology of Cell Injury
Reversible:
• Cellular swelling and vacuoles formation
(Hydropic changes)
• Changes at this stage EM - blebbing of the plasma
membrane, swelling of mitochondria and dilatation of ER
• Nuclear alterations
• Fatty change
Sequence of events in reversible injury
• reduced oxidative phosphorylation and ATP production in the
mitochondria
• increased anaerobic metabolism (glycolysis)  reduced glycogen
stores and increased production of Lactic acid
• decreased intracellular pH - clumping of nuclear DNA
• decreased activity of Na+ pump (ATP-dependent)
• generalized edema (increased intracellular Na+ and H20)
• detachment of ribosomes from ER - reduced protein synthesis
• surface blebs, mitochondrial swelling
Cloudy swelling, Kidney
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Hydropic change or vacuolar degeneration.
Appears whenever cells are incapable of maintaining
ionic and fluid homeostasis.
The first manifestation of almost all forms of cell injury.
Reversible injury.
Fatty Change
• Hepatic lipid accumulation is characterized by intracellular
accumulation of triglycerides, and due to the failure of metabolic
removal.
• Defects in fat metabolism are often induced by alcohol
consumption, and also associated with diabetes, obesity, and
toxins.
• Fatty change is most often seen in the liver (and heart), and is
generally reversible.
Morphology of Cell Injury
Irreversible (Necrosis):
The changes are produced by enzymatic digestion of dead
cellular elements, denaturation of proteins and autolysis (by
lysosomal enzymes)
• Cytoplasm - increased eosinophilia
• Nucleus - nonspecific breakdown of DNA leading to
pyknosis (shrinkage), karyolysis (fading) and karyorrhexis
(fragmentation).
Irreversible Injury
• disruption of plasma membrane
• disintegration of DNA, RNA, and phospholipids
• rupture of lysosomes and leakage of lysosomal
enzymes into the cytoplasm  enzymatic digestion
of cellular components
• influx of Ca+2 into the intracellular space
Irreversibility
Inability to reverse mitochondrial dysfunction
Profound disturbances in membrane function
Reversible Injury:
• Cellular Swelling, Vacuolar Degeneration, “Hydropic Change” –
appearance of clear, vacuolated cytoplasm (due to generalized
edema, mitochondrial edema, dispersion of ribosomes, and
presence of surface blebs)
• “Fatty Change” – appearance of lipid vacuoles in the cell
cytoplasm
Irreversible Injury:
• binding of eosin to denatured proteins causes increased
cytoplasmic eosinophilia  more pink
• loss of DNA, RNA, glycogen causes decreased basophilia  less
blue
• nuclear changes: karyolysis (faded), karyorrhexis
(fragmentation), pyknosis (shrinkage)
MECHANISMS OF FREE RADICAL-INDUCED CELL INJURY
Free radicals are chemical species with a single unpaired electron in an outer
orbit. Free radicals are highly reactive with cell membranes and nucleic acids.
They may by initiated by:
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absorption of radiant energy
enzymatic metabolism of exogenous chemicals or drugs
redox reactions of normal metabolism:
superoxide anion radical from mitochondria and
cytochrome p450
hydrogen peroxide from peroxysome catylases
hydroxyl ions from ionization of water
transition metals
nitric oxide
MECHANISMS OF FREE RADICAL-INDUCED CELL INJURY
Free radicals cause:
• lipid peroxidation of membranes
• oxidation of proteins
• DNA damage
Cells can be damaged by a variety of mechanisms.
Hypoxia causes loss of ATP production secondary to oxygen
deficiency and can be caused by ischemia, cardiopulmonary failure, or
decreased oxygen-carrying capacity of the blood.
The response of cells can range from adaptation to reversible injury to
irreversible injury with cell death.
Intracellular sites and systems particularly vulnerable to injury include
DNA, ATP production, cell membranes, and protein synthesis.
Reversible cell injury is primarily related to decreased ATP synthesis
by oxidative phosphorylation, leading to cellular swelling and
inadequate protein synthesis.
Irreversible cell injury often additionally involves severe damage to
membranes, mitochondria, Iysosomes, and nucleus.