1. Week 2 Cell Injury and Cell Death Dr.İ.Taci Cangül Bursa-2008

2. Individual Cell Death Common event in some regenerating tissues: such as skin and gut epithelium and during embryogenesis Not a typical event in developed tissues such as brain Becomes a serious occurrence when many cells are involved in such organs as the liver Programmed cell death: Apoptosis

4. What can cause cell injury?

5. Causes of Cell Injury a) Hypoxia ‑ vascular ischemia b) Physical agents ‑ radiation, heat, cold, trauma c) Chemical & drugs ‑ inorganic/organic d) Biological agents ‑ infectious organisms, etc. e) Immune reactions ‑ autoimmune, hypersensitivity f) Genetic abnormalities g) Nutritional imbalances ‑ protein, mineral, vitamin

6. Tissue Susceptibility Cells that divide rapidly, or have large energy demands, are most susceptible to injury Cells that are poorly nourished, or lack support of an essential hormone, are susceptible to damage

7. What are the important factors on the outcome of injury on cells?

8. Outcome of Injury Severity of injury and duration have a major effect on the outcome of injury

9. Primary Site of Impact 1) Oxidative phosphorylation ‑ ATP generation 2) Membrane integrity ‑ osmotic pump 3) Protein synthesis ‑ cell repair 4) Nuclear integrity ‑ direction of cell functions

10. HYPOXIA AS A CAUSE OF INJURY

11. What can cause hypoxia?

12. Causes of Hypoxia Decreased atmospheric O 2 Brain damage ‑ no breathing Airway obstruction Lung damage Cardiac pump deficiency Arterial vascular obstruction ‑ ischemia Venous obstruction

13. Pathogenesis of Hypoxic Injury Three factors of initial importance after the initial event (decreased O 2 and ATP) The decrease in energy (ATP) leads to the following: 1) Loss of Na + pump (osmotic regulation) 2) Impaired protein synthesis (cell maintenance) 3) Impaired glycolysis/pH (energy source )

14. Sodium Pump Loss Sodium pump is necessary for the integrity of the cell. When this is lost, extracellular fluid flows into the cell and causes edema of the cell and its subcompartments. If it is severe, swelling is accentuated and upon reperfusion of fluid and chemicals, especially the damaging ion calcium, flows in before the regenerated ATP can rescue the cell and restore its functions.

15. Impaired Protein Synthesis Repair of the cell, and also export of substances, such as lipid that requires a protein coat, is inhibited. This leads to obvious fatty changes and potential problems in maintenance of the cell membrane.

16. Impaired Glycolysis When aerobic glycolysis stops, anaerobic metabolism begins. It is "incomplete", i.e. not to CO 2 and water and terminates in the production of lactic acid and pyruvic acid. This drop in pH leads to membrane damage (blebs on mitochondria) and ultimate cell disruption. Finally, the lysosomal membrane breaks, digestive enzymes are released into the cell and this too causes membrane digestion.

17. FREE RADICAL DAMAGE OF MEMBRANES AS A CAUSE OF INJURY

18. When do free radicals form?

19. Origin of Free Radicals Oxygen toxicity O 2 and OH ‑ and H 2 O 2 Irradiation, OH ‑ and -H Microbial killing ‑ leukocytes Inflammation Chemicals, e.g. CCl 4 Aging

20. Mechanism Free radicals contain an unpaired electron and are: 1. Reactive 2. Chemically unstable 3. Low concentration 4. Induce chain reactions by producing more of same

21. Results of Membrane Damage Osmotic regulation loss Influx of calcium into the membrane of the cell Activation of the “membrane lytic” enzyme Phospholipase “A”, with continuing damage to the membrane

22. Cell Death

23. Etiology of Tissue Necrosis 1) Hypoxia 2) Physical injury a) Trauma b) Radiation ‑ U.V., Cosmic, X ‑ ray 3) Chemicals ‑ variable 4) Biological toxins ‑ endotoxins 5) Immunological reactions 6) Inborn genetic disorders 7) Nutritional

24. Mechanisms of Necrosis Basic mechanisms: 1) Impaired oxidative phosphorylation 2) Membrane dissolution 3) Osmotic regulation

25. Major Signs of Necrosis Similar to Apoptosis 1) Nuclear degeneration ‑ Chromatin clumping ‑ Karyopyknosis (shrinking) ‑ Karyolysis (dissolution of chromatin) ‑ Karyorrhexis (fragmentation of chromatin) 2) Cytoplasmic changes

29. Types of Necrosis Liquefactive necrosis: Necrosis in brain, abscessesLiquefactive necrosis: Necrosis in brain, abscesses Coagulative necrosis: Necrosis of kidney, liver, or heart muscle Caseous necrosis: Infection with Mycobacterium tuberculosis Gangrene: Necrosis of an appendage, usually limbs Fat necrosis

32. Types of Necrosis Liquefactive necrosis: Necrosis in brain, abscesses Coagulative necrosis: Necrosis of kidney, liver, or heart muscleCoagulative necrosis: Necrosis of kidney, liver, or heart muscle Caseous necrosis: Infection with Mycobacterium tuberculosis Gangrene: Necrosis of an appendage, usually limbs Fat necrosis

36. Types of Necrosis Liquefactive necrosis: Necrosis in brain, abscesses Coagulative necrosis: Necrosis of kidney, liver, or heart muscle Caseous necrosis: Infection with Mycobacterium tuberculosisCaseous necrosis: Infection with Mycobacterium tuberculosis Gangrene: Necrosis of an appendage, usually limbs Fat necrosis

40. Types of Necrosis Liquefactive necrosis: Necrosis in brain, abscesses Coagulative necrosis: Necrosis of kidney, liver, or heart muscle Caseous necrosis: Infection with Mycobacterium tuberculosis Gangrene: Necrosis of an appendage, usually limbsGangrene: Necrosis of an appendage, usually limbs Fat necrosis

42. Consequences of Necrosis Healing vs. permanent damage Local vs. systemic effects. 1) Type of tissue 2) Size of lesion 3) Location of lesion