1. Cell Injury and Cell Death

2. LO At the end of session student should be able to
Enlist causes of cell injury
Identify effect of injurious agents on cell cytoplasm and nucleus

5. Oxygen Deprivation Hypoxia – deficiency of oxygen
Causes of Cell Injury
Oxygen Deprivation
Hypoxia – deficiency of oxygen
Ischemia – loss of blood supply (arterial flow or reduced venous drainage)

6. Physical Agents Mechanical trauma
Causes of Cell Injury
Physical Agents
Mechanical trauma
Extremes of temperature – burns, deep cold
Radiation
Electric shock

7. Chemical Agents and Drugs
Causes of Cell Injury
Chemical Agents and Drugs
Hypertonic concentration of salt – deranging electrolyte homeostasis
Poisons – arsenic, cyanide, or mercuric salts
Insecticides and Herbicides
Air pollutant – carbon monoxide
Occupational hazard – asbestos
Alcohol and Narcotic drugs

8. Infectious Agents Parasites Fungi Bacteria Rickettsiae Viruses
Causes of Cell Injury
Infectious Agents
Parasites
Fungi
Bacteria
Rickettsiae
Viruses

9. Immunologic Reactions
Causes of Cell Injury
Immunologic Reactions
Anaphylactic reaction to foreign protein or drug
Reactions to endogenous self-antigens – autoimmune diseases

10. Genetics Derangements
Causes of Cell Injury
Genetics Derangements
Congenital malformation – Down syndrome
Decreased life of red blood cell – Thalassemia, Sickle cell anemia
Inborn errors of metabolism

11. Nutritional Imbalances
Causes of Cell Injury
Nutritional Imbalances
Protein-calorie deficiencies
Vitamin deficiencies
Anorexia nervosa
Excesses of lipids – Obesity, Atherosclerosis
Metabolic diseases – Diabetes

13. Mechanisms of Cell Injury
Depletion of ATP
Mitochondrial Damage
Influx of Intracellular Calcium and Loss of Calcium Homeostasis
Accumulation of Oxygen-Derived free radical (Oxidative stress)
Defects in Membrane Permeability

14. Depletion of ATP Causes Hypoxia, Ischemia Chemical Injury
Mechanisms of Cell Injury
Depletion of ATP
Causes
Hypoxia, Ischemia
Chemical Injury
Membrane transport
ATP
Na+K+ATPase (Na-pump), Ca2+Mg2+ATPases (Ca-pump)
Protein synthesis, Lipogenesis etc

15. Mechanisms of Cell Injury
Depletion of ATP
Na+ K+
Ca2+

17. Mitochondrial Damage Causes Hypoxia, Toxins Cytosolic Ca2+
Mechanisms of Cell Injury
Mitochondrial Damage
Causes
Hypoxia, Toxins
Cytosolic Ca2+
Oxidative stress
Lipid breakdown product

18. Mechanisms of Cell Injury
Mitochondrial Damage
Mitochondrial permeability transition of inner membrane (formation of high-conductance channel)
Leakage of Cytochrome c into cytosol
Mitochondrial Oxidative Phosphorylation
ATP production

19. Mechanisms of Cell Injury
Mitochondrial Damage

21. Influx of Intracellular Calcium and Loss of Calcium Homeostasis
Mechanisms of Cell Injury
Influx of Intracellular Calcium and Loss of Calcium Homeostasis

22. Mechanisms of Cell Injury

24. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)
Mechanisms of Cell Injury
Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)
The Oxidation-Reduction reaction (normal metabolic processes)
-superoxide anion (O2-)
-hydrogen peroxide (H2O2)
-hydroxyl ion (OH )

25. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)
Mechanisms of Cell Injury
Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)
Absorption of radiant energy (ultraviolet light: UV, X-ray)
Ionizing radiation
H20 OH H

26. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)
Mechanisms of Cell Injury
Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)
Transition Metals – iron, copper
“Fenton reaction”
H202
Fe2+
Fe3+ OH
OH-

27. Effects of the free radicals on cell injury
Mechanisms of Cell Injury
Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)
Effects of the free radicals on cell injury
Lipid peroxidation of Membranes
- Plasma membrane
- Organellar membrane
Double bonds in unsaturated fatty acids
membrane damage

28. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)
Mechanisms of Cell Injury
Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)
Effects of the free radicals
Oxidative modification of proteins
-Oxidation of amino acid side chains
Protein-protein cross-linkages
-Oxidation of the protein backbone
Protein fragmentation

29. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)
Mechanisms of Cell Injury
Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)
Effects of the free radicals
Lesions in DNA
Reaction with Thymine
DNA single-stranded break
DNA fragmentation

30. Superoxide dismutase (SOD)

32. Defects in Membrane Permeability
Mechanisms of Cell Injury
Defects in Membrane Permeability
Mechanism of Membrane damage in Cell Injury
Mitochondrial Dysfunction
-Decreased phospholipid synthesis
-Phospholipase activation
Loss of Membrane phospholipid

33. Defects in Membrane Permeability
Mechanisms of Cell Injury
Defects in Membrane Permeability
Mechanism of Membrane damage in Cell Injury
Cytoskeletal Abnormality
Reactive Oxygen species
Lipid breakdown products
(detergen effect on membrane)
Cytosolic Ca+
protease

34. Cellular and biochemical sites of damage in cell injury

35. Thanks