Cell injury Dr Heyam Awad FRCPath. Causes of cell injury/ 1 Chemica agents Infections. Immunologic Genetic factors Nutritional imbalances Physical agents.

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