1. Cellular responses to stress (Adaptations, injury and death) (3 of 5)
Ali Al Khader, MD
Faculty of Medicine
Al-Balqa’ Applied University

2. Differences in responses
Glycogen in hepatocytes make them withstand ischemia more
Striated muscle cell…2-3 hours before irreversible injury
… but cardiac myocyte…20-30 minutes
Genetic polymorphisms in response to toxins/drugs…e.g., P-450 differences
…the study of these is called

3. Essential biochemical abnormalities in cell injury
ATP depletion
Mitochondrial damage
Influx of calcium
Accumulation of oxygen-derived free radicals (oxidative stress)
Cellular membranes, esp. plasma and lysosomal membranes
DNA damage & misfolding of proteins

4. ATP depletion Sodium-potassium pump…swelling
Anaerobic glycolysis lactic acid accumulation pH activity
of enzymes
Ca2+ pump failure influx of calcium into cellular compartments
Detachment of ribosomes and dissociation of polysomes

5. Mitochondrial dysfunction
More in ATP because of oxidative phosphorylation
Formation of reactive oxygen species because of abnormal oxidative phosphorylation
Formation of mitochondrial permeability transition pore
When its proteins get out to the cytoplasm, they induce apoptosis

6. Influx of calcium
Normally: low in the cytosol, due to: -pumping outside the cell
-sequestration in cellular
compartments
When in the cytosol: -activates enzymes: -phospholipases
-proteases
-endonucleases
-ATPases
-activates apoptosis, due to: -activation of
caspases
-increasing
mitochondrial
permeability

7. Oxidative stress Phagocyte when activated in inflammation
Normal cell in oxidative respiration

8. Some causes of increased free radicals
-Ionizing radiation -Catabolism of exogenous chemicals…e.g., carbon tetrachloride -Inflammation -Toxins -Aging -Oxygen toxicity

9. Protective: Glutathione (GSH) peroxidases
Especially GSH peroxidase 1
Protective from free radicals
2GSH + H2O GSSG (oxidized GSH) + 2H2O
More GSSG/GSH means: good activity of GSH peroxidase

10. Catalase…also protective
2H2O O2 + 2H2O
= peroxidase (in peroxisomes)

11. Some vitamins…also protective
Beta-carotene
**By blocking synthesis of free radicals or by scavenging them

12. Effects of ROS
Attacking double bonds of membrane polyunsaturated lipids into:
Peroxides (Lipid peroxidation)
On proteins: -Sulfhydryl-mediated mediated cross-linking
-Direct fragmentation
On DNA: React with thymine single-strand breaks

13. Membrane defects phospholipid synthesis…due to ATP
…it can also exacerbate ATP depletion, How?
degradation of phospholipids…by phospholipases due to increased Ca+2

14. Membrane defects…cont’d
ROS and lipid peroxidation
Cytoskeleton damage by proteases due to increased Ca+2
Effect of phospholipids breakdown products
-un-esterified free fatty acids
-acyl carnitine
-lysophospholipids

15. DNA & proteins damage
The cell typically respond to this by apoptosis

16. Examples of some injury mechanisms
Ischemia & hypoxia…Which does have faster and more severe injury?
Ischemia-reperfusion injury
-The mitochondria is injured so incomplete reduction of O2
-Actions of oxidases in WBCs, endothelial cells and parenchymal cells
-Antioxidant mechanisms are still compromised in injured cells
-Increased WBCs (increased inflammation) and complements
…injurious

17. Chemical (toxic) injury
Directly toxic (examples):
Mercuric chloride
…binds to sulfhydryl groups in membrane proteins (membrane
damage)
Some chemotherapeutic agents

18. Some toxins are not intrinsically active and need modification
CCl4 after processing by cytochrome P-450 in smooth ER in hepatocytes and others:
-direct damage or
-free radicals…CCl3.