Download cell injury lecture 2

Cell injury
Dr Heyam Awad
FRCPath
Causes of cell injury/ 1
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Chemica agents
Infections.
Immunologic
Genetic factors
Nutritional imbalances
Physical agents
Aging.
Causes of cell injury/ 2
Oxygen deprivation.. Hypoxia and ischemia.
Hypoxia= oxygen deficiency
Ischemia = loss of blood supply due to impaired arterial
flow or reduced venous return.
-Ischemia is the most common cause of hypoxia.
-Other causes of hypoxia:
*reduced oxygen carrying capacity in anemia or carbon
monoxide deficiency.
*inadequate oxygenation of the blood as in pnumonia.
Rules and principles/ 1
• Cell response to injurious stimuli depend on
type, duration and severity of the injury.
• Example: low dose of a toxin can cause
reversible injury whereas larger dosed can
cause cell death.
• Short-lived ischemia.. Reversible
• Ischemia of long duration… death
Rules and principles/ 2
• Response to injury also depends on type, status,
adaptability and genetic makeup of the injured
cell.
• Example: skeletal muscle cells can stand 2-3
hours of ischemia without irreversible injury but
cardiac muscles die in 20-30 minutes .
• Glycogen content in hepatocytes can determine
their response to injury.. How?
• Genetic polymorphism in cytochrome P-450
influences response to toxins.
Rules and principles/ 3
Cell injury results from functional and
biochemical changes in essential cellular
components, mainly:
• Mitochondrial function
• Calcium homeostasis
• Cell and organelle membranes
• DNA
• Protein synthesis and folding.
Rules and principles/ 4
• All injurious stimuli first affect the molecular
or biochemical level.
• Cellular functions lost before cell death
occurs.
• The morphologic changes of cell injury (or cell
death) occur very late.
Rules/4 example
• Ischemia of the heart… coronary artery
occlusion.
• Myocardial cells loose function ( become noncontractile) after 1-2 minutes of ischemia.
• They die 20-30 minutes after ischemia.
• It takes 2-3 hours to recognise ultrastructural
changes of death (EM)
• 6-12 hours by light microscope to appear
dead.
Morphology of reversible cell injury
• Cellular swelling : due to failure of energydependent ion pumps in the plasma
membrane causing inability to maintain ion
and fluid homeostasis.
• Fatty change : small or large lipid vacuoles
(hepatocytes and myocardial cells)
Cell swelling
• The first manifestation of almost all forms of
cell injury.
• Reversible.
• Grossly: organ affected becomes pale and
gains weight.
• Micro: small clear cytoplasmic vacuoles …
which are distended endoplasmic reticulum.
Cell swelling
Cell swelling
Fatty change
• In cells participating in fat metabolism:
hepatocytes and myocardial cells)
• Reversible
• Fat droplets.
Fatty change
Ultrastructural changes of reversible
injury (EM)
• (1) plasma membrane changes such as blebbing,
blunting or distortion of microvilli, and loosening
of intercellular attachments.
• (2) mitochondrial changes such as swelling and
the appearance of phospholipid-rich amorphous
densities.
• (3) dilation of the ER with detachment of
ribosomes and dissociation of polysomes.
• (4) nuclear alterations, with clumping of
chromatin.
EM changes
Mechanisms of cell injury
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ATP depletion
Mitochondrial damage
Calcium influx
Oxygen derived free radicals
membrane defects
Damage to DNA and protein
mechanisms
Mitochondrial damage