1. Mechanism of Cell Injury By Dr.Ghaus

2. Objectives:  Explain important general principles of cell injury  List the causes of cell injury  List the differences between ischemia and hypoxia  Explain the mechanism of reversible & irreversible cell injury using ischemic and chemical injury as models  List effects of excess entry calcium in the cytosol  Discuss the point of no return

3. Causes of Cell Injury Hypoxia Physical Agents Chemicals and Drugs Microbiologic Agents Immunologic Reactions Genetic Defects Nutritional Imbalances

4. Role of oxygen in cell injury (Final common pathway) Causes of cell injury ← Thrombus blocking an artery

5. General principles of cell injury The cellular response to injurious stimuli depends on: 1. Type of injury, its duration, and its severity 2. Type, status, adaptability, metabolic demand & genetic makeup of the injured cell 3. Nutritional (or hormonal) status of the cell : A cell rich in glycogen (hepatocyte) will tolerate ischemia much better than one that has just burned its last glucose molecule

6. 4 weak points of the cell  Cell membrane integrity, critical to cellular ionic and osmotic homeostasis  ATP synthesis, largely via mitochondrial aerobic respiration  Protein synthesis (RER)  Integrity of the genetic apparatus (nucleus)

7.  The structural and biochemical components of a cell are so integrally connected that regardless of the initial locus of injury, multiple secondary effects rapidly occur (Ripple effect)

8. Cell Injury Loss of cell functions e.g. myocardial cells lose power of contraction after 1-2 minutes of injury Death of cells e.g. myocardial cells die after 20 to 30 minutes of ischemia Ultrastructural (electron microscopic ) changes in the dead myocardium become visible 2-3 hrs after ischemic injury Light microscopic changes in the dead myocardium become visible 6-12 hrs Time lag between different events after cell injury Gross (Naked-eye) changes occur after another few hours

10. Reversible cell injury Changes limited mainly to the cytoplasm Nucleus still viable The only changes seen in the nucleus with the light microscope are swelling and mild clumping of the nuclear chromatin With electron microscope we may also see some myelin figures and small amorphous densities

11. Irreversible cell injury leads to Cell Death and then light microscopically visible changes: Necrosis Apoptosis

12. Mechanisms of Cell Injury: Two models: a. Ischemic injury b. Chemical injury

13. Ischemia vsHypoxia Loss of blood supply (↓ed O2 as well as ↓ed delivery of other nutrients & ↓ed removal of toxic waste products of the cells so there is accumulation of toxic substances, e.g Lactic acid Quicker and More severe injury than with just lack of Oxygen Lack of Oxygen in tissues Maybe due to ischemia or due to other causes like due to less RBCs in the blood, or less Oxygen in the atmosphere etc. Less severe injury than with Ischemia

14. Mechanism of Ischemic injury

18. Effects of excess calcium in the cytosol Cut-off point between reversible cell injury and cell death??

19. Seen just before cell death

24. Mechanism of chemical injury: Most chemicals do not produce cell injury directly by themselves, but once they are metabolized in the body, the metabolites are the injurious agent: Example is Carbon tetrachloride poisoning

25. ↓ed apoprotein protein synthesis means lipids cannot be transported out of liver cells and will therefore accumulate inside hepatocytes