1. Cell injury By Dr. Abdelaty Shawky Dr. Gehan Mohamed

2. Learning objectives: Understand the definition of cell injury. Outline Mechanisms of Cell Injury Recognize the variability in Cellular response to injury which include : - Cellular adaptation - Reversible cell injury ( nonlethal hit) - Irreversible injury and cell death (apoptosis, necrosis ). -Identify the differences between apoptosis and necrosis. - Recognize the different types of necrosis.

3.  Cells are constantly exposed to a variety of stresses.  At first cells try to adapt themselves to overcome this stressful condition, but When stress is too severe or for prolonged duration, injury results.  Injury of the cell may be; 1. Reversible: 1. Reversible: if the affected cells recover from the injury. 2. irreversible: 2. irreversible: injury: cell may die

4. * Causes of cellular injury:  Hypoxia: inadequate oxygenation of tissues  Physical agents: mechanical trauma, burns, frostbite, sudden changes in pressure, radiations, electric shock  Chemical agents: poisons (toxins), insecticides, CO, asbestos, alcohol, tobacco, glucose, salt, oxygen  Infectious agents: prions, viruses, rickettsiae, bacteria, fungi, parasites  Immunologic reactions: anaphylaxis, autoimmune disease.  Nutritional imbalances: protein calorie deficiency, vitamin deficiencies, excess food intake (obesity, atherosclerosis)  Genetic derangements: congenital malformations, abnormal proteins (hemoglobinopathies), abnormal or absent enzymes (storage disorders).

5. - The cellular response to injurious stimuli depends on : 1. Type, duration and severity of injurious agent. 2. The type, status, adaptability, and genetic makeup of the injured cell.

6. AdaptationReversible Irreversible Cell death Etiologic agent Point of no return The precise moment of transition from reversible injury to irreversible injury is known as the POINT OF NO RETURN.

7. The relationships between normal, adapted, reversibly injured, and dead myocardial cells

8. Adaptation

9. a. Hyperplasia: b. Hypertrophy: c. Atrophy: d. Metaplasia: a. Hyperplasia: increase in cell number. e.g. benign prostatic hyperplasia. b. Hypertrophy: increase in cell size. Hypertrophied uterine muscle in pregnancy. c. Atrophy: decrease in cell mass e.g. atrophy of the breast after menopause. d. Metaplasia: change of type of cell to another e.g. squamous metaplasia of urinary bladder epithelium in response to bilharziasis.

10. Reversible cell injury

11. * Mechanisms of reversible cell injury: 1- Decrease ATP production: so Plasma membrane energy-dependent sodium pump is reduced, resulting in cell swelling. 2. Cell membrane damage: leading to Loss of structural integrity and Loss of function. 3. Mitochondrial damage: leading to inadequate aerobic respiration. 4. Ribosomal damage: leading to altered protein synthesis. 5. Nuclear change: leading to abnormal proliferation.

12. 6. increase intra cellular calcium. 7. Production of oxygen derived free radicals.

13. * Examples of cell injury: 1.Hypoxic cell injury 2.Ischemia- reperfusion injury 3.Chemical injury

14. Hypoxic cell injury

15. - Most common cause of cell injury. * Definition: inadequate oxygenation of tissue. * Causes: 1.Ischemia: decreased arterial blood flow to tissues. – Most common cause of hypoxia. – Ex: Atherosclerosis (lesion in intima = atheroma) in coronary arteries. 2.Hypoxemia: decrease in the amount of oxygen dissolved in plasma. Seen in: Atelectasis, pulmonary embolus and interstitial fibrosis of lung. 3.Hemoglobin related abnormalities – Anemia – Carbon monoxide poisoning (CO has high affinity for hemoglobin).

16. * Consequences of tissue hypoxia: Decreased synthesis of ATP by oxidative phosphorylation causing ATP depletion. This leads to; 1.Impaired Na + /K + -ATPase pump – Diffusion of Na + and water into cells  cellular swelling. 2. Shifting to anaerobic glycolysis: leads to; Depletion of glycogen stores. Accumulation of lactic acid. Decrease in intracellular pH  denaturation of proteins  decreased activity of many enzymes  clumping of nuclear chromatin.

17. 3. Decreased protein synthesis: - Due to detachment of ribosomes from the rough endoplasmic reticulum. - ↓protein synthesis. – Reflected as accumulation of lipid in the cell = fatty change. – Since you’re not synthesizing proteins, you’re not synthesizing apolipoproteins (lipid carriers) either! ↓ protein synthesis  ↓ synthesis of apolipoproteins (lipid carriers in blood)  accumulation of lipid in the cell. 4. Impaired calcium ATPase pump: – Increased cytosolic calcium.

18. Ischemia ↓ oxidative phosphorylation  Na pump Influx of Na, H 2 O & Ca 2+ Efflux of K Cell Swelling  Glycolysis  Glycogen  Lactic acid  pH Ribosomal Detachment  Protein Synthesis Nuclear chromatin clumping ↓↓ ATP

19. * Morphology of reversible cell Injury: 1.Cell Swelling: 1.First manifestation of cell injury. 2.Occurs when cells fail to maintain ionic and fluid homeostasis. 3.Manifests as small clear vacuoles. 4.Also known as hydropic change or vacuolar degeneration. 2.Fatty change: 1.Manifested by appearance of lipid vacuoles in the cytoplasm. 2.Seen in kidney, heart and liver.

20. Normal cell Reversible injury Injury (hypoxia) Recovery Cell swelling, Swelling of ER and mitochondria Chromatin clumping

21. Cell swelling - Light Microscopy Normal epithelium Cellular Swelling = hydropic change

22. Myocardium: cell swelling= hydropic change

23. Normal liver histology Hepatocytes showing fatty change

24. Endoplasmic reticulum Mitochondria Nucleus Lysosome Normal cell

25. Good luck