Mechanism of Cell Injury - Pathology powerpoint

Mechanism of Cell Injury - Pathology powerpoint

1. MECHANISM OF CELL INJURY Dr. P. SHINY LATHA M.B.B.S., M.D.,

2. FOUR ASPECTS OF DISEASE PROCESS Etiology Pathogenesis Morphological changes Clinical manifestations

3. CELLULAR RESPONSE

4. CAUSES OF CELL INJURY Oxygen deprivation Physical agents Chemical agents & drugs Infectious agents and immunologic reactions Genetic Derangements Nutritional imbalances

5. MECHANISM OF CELL INJURY Cellular response to injurious stimuli - type of injury and its duration & Severity Consequences of cell injury – type, state & adaptability of the injured cell Cell injury - results from functional and biochemical abnormalities in one or more of cellular components

6. Cell injury results from Mitochondria cell membranes ER DNA

7. MECHANISMS Mitochondrial Damage Membrane Damage Damage to DNA Oxidative Stress Disturbance in Calcium Homeostasis Endoplasmic Reticulum Stress

8. MITOCHONDRIAL DAMAGE Mitochondria can be damaged by Increase of cytosolic Ca 2+ by oxidative stress Hypoxia ROS

9. Major consequences - ATP depletion - Incomplete oxidative phosphorylation - Leakage of mitochondrial proteins

10. MITOCHONDRIAL DYSFUNCTION

11. MEMBRANE DAMAGE Loss of selective membrane permeability - MC feature of cell injury Membrane damage - by bacterial toxins, viral proteins, complement components, physical and chemical agents

12. Biochemical mechanism that cause membrane damage include mitochondrial dysfunction loss of membrane phospholipids cytoskeletal abnormalities reactive oxygen species lipid breakdown products

13. EFFECTS OF MEMBRANE DAMAGE Mitochondrial membrane damage – Decreased ATP generation Plasma membrane damage – loss of osmotic balance and cellular contents Lysosomal membrane damage – leakage of enzymes into the cytoplasm

14. DISTURBANCE IN CALCIUM HOMEOSTASIS

15. DISTURBANCE IN CALCIUM HOMEOSTASIS Intracellular Ca 2+ - sequestered in mitochondria and ER Ischemia and Toxins - increase in cytosolic Ca 2+ – influx of Ca 2+ across the plasma membrane Sustained release of intracellular Ca 2 + -increases the membrane permeability

16. The enzymes activated by calcium include ATP ases - hasten ATP depletion Phospholipases – degradation of phospholipids Proteases – disruption of membrane and cytoskeletal proteins Endonucleases – DNA and chromatin fragmentation

17. OXIDATIVE STRESS Free radicals that damage lipids, proteins and nucleic acids – reactive oxygen species Free radicals - chemicals having single unpaired electron in an outer orbit Mediate chemical and radiation injury, ischemia –reperfusion injury, cellular aging and microbial killing

18. Free radicals may be initiated by Absorption of radiant energy Enzymatic metabolism of exogenous chemicals or drugs Reduction – oxidation reactions Transition metals Nitric oxide(NO)

19. EFFECTS OF FREE RADICALS (1 ) Lipid peroxidation in membranes Free radicals in the presence of O 2 cause peroxidation of lipids within plasma and organellar membranes An auto catalytic chain reaction ensues (called propagation) leads to extensive membrane, organellar and cellular damage

20. (2 ) Oxidative modification of proteins Promote oxidation of amino acid side chains Formation of protein cross- linkages protein fragmentation (3) Lesions in DNA Mitochondrial DNA produce single / double stranded breaks in DNA

21. ENDOPLASMIC RETICULUM STRESS The accumulation of misfolded proteins in the ER can stress adaptive mechanisms and trigger apoptosis Unfolded or misfolded proteins accumulate in the ER - trigger a number of alterations - unfolded protein response

22. DISEASES CAUSED BY PROTEIN MISFOLDING Cystic fibrosis Familial hypercholesterolemia Tay-sachs disease Alzheimer disease

23. The principal forms and sites of damage in cell injury