3 Lecture D2.pdf

Lecture 3 Mechanisms and morphology of cell injury Year/Level: D2 / Semester 1 Dr Mohammad Shahid Iqbal M.D Assistant Professor of Pathology 1 Learning Outcomes By the end of this lecture, the students must know 1. Mechanisms of cell injury 2. Morp...

Lecture 3 Mechanisms and morphology of cell injury Year/Level: D2 / Semester 1 Dr Mohammad Shahid Iqbal M.D Assistant Professor of Pathology 1 Learning Outcomes By the end of this lecture, the students must know 1. Mechanisms of cell injury 2. Morphological changes in cell injury 2 ETIOLOGY OF CELL INJURY 1. Hypoxia and Ischaemia 2. Physical agents 3. Chemical agents and drugs 4. Microbial agents 5. Immunologic agents 6. Nutritional derangements 7. Ageing 8. Psychogenic diseases 9. Iatrogenic factors 10. Idiopathic diseases 11. Genetic causes 3 Mechanisms and morphology of cell injury Irreversible cell injury The relationship among normal, adapted, reversibly injured, and dead myocardial cells 4 REVERSIBLE CELL INJURY Reversible cell injury is characterized by Functional and structural alterations in early stages or mild forms of injury Are correctable if the damaging stimulus is removed 5 General Mechanisms of Cell Injury ATP Depletion. Mitochondrial Membrane Damages “Permeability Transition” Influx of Ca++ Ions & Loss of Calcium Homeostasis. Generation the Reactive Oxygen Species (ROS) & and other free Radicals. Membrane Damage. Protein misfolding and DNA Damage → triggers apoptosis. 6  The most important targets of injurious stimuli Mitochondria, Cell membranes, Protein synthesis, cytoskeleton, genetic apparatus 7 Depletion of ATP ATP required for membrane transport, protein synthesis, lipogenesis, etc., ATP Depletion: failure of energy-dependent functions → reversible injury → necrosis. Associated with hypoxic & chemical (toxic) injury to cell: Decreased ATP → Failure of Na/K pump. Increased anaerobic glycolysis → Increased lactic acid and phosphate & decrease PH (acidosis). Reduced protein synthesis. 8 Mitochondrial Membrane Damage. Caused by: Increased intracellular Ca++. Oxidative stress. Breakdown of phospholipids through phospholipase A2. Results in formation of MPT (Mitochondrial Permeability Transition): High conductive channel & nonselective pore—loss of membrane potential & leakage of cytochrome C → triggers Apoptosis. 9 Depletion of ATP and mitochondrial membrane damage 10  Influx of Ca++ Ions & Loss of Calcium Homeostasis. Normal intracellular Ca++ < 0.1 mmol, & extracellular Ca++ 1.3 mmol. Intracellular Ca++ is sequestered in Mitochondria & ER. Increased cytosolic Ca++: Activates various enzymes: Examples: ATPases, Phospholipases, Proteases, endonucleases → Membrane Damage Also increases mitochondrial permeability. 11 Oxygen Free Radicals Free radicals: Partially reduced, unavoidable byproducts of mitochondrial respiration. Chemical species with a single unpaired electron in an outer orbit E.g., OH (hydroxyl radical), Ó2 , H2O2, Highly reactive, unstable chemicals. Capable of damaging lipids, proteins & nucleic acids. 12 Oxygen Free Radicals Initiate autocatalytic reactions; Molecules that react with free radicals are in turn converted to free radicals. Imbalance between O2 free radical generating system & radical scavenging system results in OXIDATIVE STRESS. Associated with cell injury of Chemicals/drugs, reperfusion injury, inflammation, irradiation, oxygen toxicity, carcinogenesis. 13 Free Radicals are Removed by: Spontaneous decay By anti-oxidants: Examples: Vitamin E, Vitamin A, Ascorbic acid, Glutathione. Storage proteins: e.g., transferrin, ferritin. (Prevent ROS formation) Free radical scavengers: Enzymes: e.g., Catalase, Superoxide dismutase (SOD), glutathione peroxidase. 14 Membrane Damage. Increased permeability of cellular membranes may affect: Plasma membrane. Lysosomal membranes. Mitochondrial membranes. Typically culminates in necrosis. 15 Protein misfolding: The Unfolded protein Response Unfolded or misfolded proteins accumulate in the ER They trigger a number of alterations that are collectively called the unfolded protein response. The accumulation of misfolded proteins in the ER can stress adaptive mechanisms Trigger apoptosis 17 REVERSIBLE CELL INJURY: Morphology Two features are consistently seen in reversibly injured cells. 1. Early alterations in reversible injury include Generalized swelling of the cell and its organelles (hydropic change or vacuolar degeneration): Earliest manifestation in all forms of cell injury Blebbing of the plasma membrane Detachment of ribosomes from the endoplasmic reticulum (ER) Clumping of nuclear chromatin. 2. Fatty change occurs in organs that are actively involved in lipid metabolism (e.g., liver). 18  REVERSIBLE CELL INJURY: Morphology The cytoplasm of injured cells appears red (eosinophilic) when stained with hematoxylin and eosin (H&E) due to loss of RNA, which binds the blue hematoxylin dye. The eosinophilia becomes more pronounced with progression toward necrosis. (A) kidney tubules (B) Early (reNormalversible) ischemic injury showing surface blebs, increased eosinophilia of cytoplasm, and swelling of occasional cells (C) Necrosis (irreversible injury) 19 Morphologic changes in cell injury 20  References 1. Robbins and Cotran Pathologic Basis of Disease; 10th ed. 2021 2. HarshMohan Textbook of Pathology. 7th edition. 22  Thank You Any questions? [email protected] 23