1. Cell injury
Dr Heyam Awad
FRCPath

2. Causes of cell injury/ 1 Chemica agents Infections. Immunologic
Genetic factors
Nutritional imbalances
Physical agents
Aging.

3. 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.

4. 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

5. 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 minutes .
Glycogen content in hepatocytes can determine their response to injury.. How?
Genetic polymorphism in cytochrome P-450 influences response to toxins.

6. 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.

7. 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.

8. 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 minutes after ischemia.
It takes 2-3 hours to recognise ultrastructural changes of death (EM)
6-12 hours by light microscope to appear dead.

10. 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)

11. 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.

12. Cell swelling

13. Cell swelling

14. Fatty change
In cells participating in fat metabolism: hepatocytes and myocardial cells)
Reversible
Fat droplets.

15. Fatty change

16. 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.

17. EM changes

18. Mechanisms of cell injury
ATP depletion
Mitochondrial damage
Calcium influx
Oxygen derived free radicals
membrane defects
Damage to DNA and protein

19. mechanisms

20. Mitochondrial damage