Cell injury
Dr Heyam AwadFRCPath
Causes of cell injury/ 1
• Chemica agents• Infections.• Immunologic• Genetic factors• Nutritional imbalances• Physical agents• Aging.
Causes of cell injury/ 2
Oxygen deprivation.. Hypoxia and ischemia.
Hypoxia= oxygen deficiencyIschemia = 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 non-contractile) 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 energy-dependent 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
• ATP depletion• Mitochondrial damage• Calcium influx• Oxygen derived free radicals• membrane defects• Damage to DNA and protein
mechanisms
Mitochondrial damage