Cell Injury Pathogenesis AIU 2024 PDF

Normal cells are in a state of Homeostasis = equilibrium with their environment and able to maintain normal physiologic demands. Chapter I: Cell Injury Dr Maram Allam Lecturer of Pathology Cell Injury Cellular Responses to Injury Cellular Atrophy...

Normal cells are in a state of Homeostasis = equilibrium with their environment and able to maintain normal physiologic demands. Chapter I: Cell Injury Dr Maram Allam Lecturer of Pathology Cell Injury Cellular Responses to Injury Cellular Atrophy -Hypertrophy Hyperplasia -Metaplasia Adaptations Acute Cell Reversible Cell Injury swelling – Fatty changes) (Cloudy Injury Irreversible Cell Injury (Necrosis - Apoptosis) Intracellular Pigments - Calcification accumulations Aging  All tissues in the body are composed of parenchymal interstitial cells connective specialized to perform tissue elements which the function of that act as the supporting particular tissue framework of the tissue. Injurious agents may act on parenchymal cells or interstitial connective tissue causing biochemical and/or structural changes leading to disease. parenchymal cells interstitial connective interstitial connective  Cell injury Definition: A set of biochemical and morphological changes that occur when the state of homeostasis is disturbed by injurious agents Of cell injury  Causes of cell injury Aging Hypoxia Nutritional disorders Physical Genetic agents abnormalities Chemical Immunological agents agents Biological agents  Causes of Cell Injury 1. Hypoxia (deficiency of oxygen) 2. Physical Agents 3. Biologic agents e.g. viruses, bacterial toxins, fungi and parasites. 4. Chemical agents and drugs e.g. arsenic, cyanide, insecticides, alcohol, simple chemicals as glucose or salts in hypertonic solutions. 5. Immunologic reactions : autoimmunity = immune reaction may cause cell injury. 6. Nutritional imbalance such as protein calorie malnutrition, vitamin deficiency. 7. Genetic abnormalities as in Down syndrome & sickle cell anemia 8. Aging Hypoxic Injury  Physical Agent Extremes of temperature Mechanical Injury Electrical or Radiation Injury Changes in atmospheric pressure  Chemical Agent Insecticides Alcohol Cyanide Acids and Alkali Affecting Cell response to injurious agents  Cell response to injurious agents depends upon: Type, Duration,& Type, state & Severity of the stress adaptability of cell  Cell response to injurious agents depends upon: Type, Duration,& Type, state & Severity of the stress adaptability of cell  Partial or a brief period of ischaemia leading to reversible cell changes.  Complete or prolonged period of ischaemia leading to irreversible cell changes.  Cell response to injurious agents depends upon: Type, Duration,& Type, state & Severity of the stress adaptability of cell e.g. Neurons tolerate ischaemia for 5 minutes only While bones and skeletal muscles can tolerate ischaemia for several hours.  Do you remember cell organelles? Cell organelles Protein DNA ATP Degradation Protein  Mitochondria Nucleus Lysosome Cell membrane Endoplasmic reticulum Golgi  Mechanism of cell injury (Pathogenesis) Cell systems vulnerable to injury 1- ATP generation produced by aerobic respiration 2- Integrity of cell membrane 3- Enzymatic and structural protein synthesis 4- Integrity of the genetic apparatus Pathogenesis of cell injury Damage to cell Loss of integrity of membrane genetic Apparatus ATP Depletion Pathogenesis of cell injury Damage to cell Loss of integrity of membrane genetic Apparatus ATP Depletion  Causes of ATP depletion 1. Hypoglycemia 2. Hypoxia 3. Chemical toxicity inhibition of enzymes of oxidative phosphorylation e.g. cyanide poisoning  Effects of ATP depletion Switch to Increased Failure of anaerobic cytosolic Na-K pump glycolysis calcium (reversible) (irreversible) (irreversible) Effects of ATP depletion Failure of Na-K pump Normal Sodium Potassium Effects of ATP depletion Failure of Na-K pump Decreased ATP Sodium Increased Na in cell  Effects of ATP depletion Failure of Na-K pump Increased intracellular sodium Intracellular accumulation of water and electrolytes Distension of Mitochondrial swelling Cellular swelling Endoplasmic Reticulum resulting in cessation of (cloudy swelling/hydropic and detachment of oxidative phosphorylation change). ribosomes. and decreased ATP synthesis. Interferes with protein synthesis  Effects of ATP depletion Failure of Na-K pump Mitochondrial swelling  Effects of ATP depletion Failure of Na-K pump At this point, changes are reversible  Effects of ATP depletion Switch to Increased Failure of anaerobic cytosolic Na-K pump glycolysis calcium (reversible) (irreversible) (irreversible) Effects of ATP depletion Switch to anaerobic glycolysis Aerobic and anaerobic glycolysis Effects of ATP depletion Switch to anaerobic glycolysis Anaerobic glycolysis Accumulation of lactic acid and inorganic phosphate decrease pH 1. Chromatin clumping 2. Disruption of cell organelles including lysosomes. 3. Loss of ribosomes (protein synthesis)  Switch to anaerobic glycolysis Lysosome Disruption of cell Nucleus organelles including Chromatin lysosomes. clumping Endoplasmic reticulum Loss of ribosomes (protein synthesis)  Effects of ATP depletion Switch to anaerobic glycolysis Irreversible  Effects of ATP depletion Switch to Increased Failure of anaerobic cytosolic Na-K pump glycolysis calcium (reversible) (irreversible) (irreversible) Effects of ATP depletion Increased cytosolic calcium Due to failure of CA pump Effects of ATP depletion Increased cytosolic calcium It activates enzymes : degrade the membrane Phospholipases phospholipids. degrade structural and Proteases membranous proteins degrade the nucleus. Endonucleases accelerates ATP depletion. ATPase  Increased cytosolic calcium Cell membranes Proteases and phospholipase Nucleus Endonucleas Mitochondria Atpase Effects of ATP depletion Increased cytosolic calcium Irreversible  Effects of ATP depletion Switch to Increased Failure of anaerobic cytosolic Na-K pump glycolysis calcium (reversible) (irreversible) (irreversible) Pathogenesis of cell injury Damage to cell Loss of integrity of membrane genetic Apparatus ATP Depletion  II- Impaired Integrity of the plasma membrane Cell membrane  II- Impaired Integrity of the plasma membrane Causes: 1. ATP depletion. 2. Ca+ modulated-activation of phospholipases. 3. Direct damage by: 1. bacterial toxins, 2. viral proteins 3. activated complement pathway 4. Production of free radicals  Effects of cell membrane damage 1. Loss of the structural integrity and function of cell membrane leading to changes in the cell membrane permeability. 2. Liberation of intracellular enzymes  Effects of cell membrane damage Cell membrane Liberation of intra cellular enzymes Pathogenesis of cell injury Damage to cell Loss of integrity of membrane genetic Apparatus ATP Depletion  III- Genetic apparatus and protein synthesis 1. Failure of synthesis of structural proteins 2. Failure of mitosis 3. Failure of synthesis of growth regulating proteins and enzymes.  Effects of genetic apparatus and protein synthesis affection Nucleus 1. Failure of synthesis of structural proteins 2. Failure of mitosis 3. Failure of synthesis of growth regulating proteins and enzymes.  Morphology of cell injury Reversible Irreversible  Reversible ATP depletion damage to NA K pump  1. Hydropic swelling and other membrane changes. 2. Reduced protein synthesis 2nd to dispersed ribosomes 3. Nuclear chromatin clumping 2nd to decreased PH (intracellular lactic acidosis)  Reversible ATP depletion damage to NA K pump  1. Hydropic swelling and other membrane changes. 2. Reduced protein synthesis 2nd to dispersed ribosomes 3. Nuclear chromatin clumping 2nd to decreased PH (intracellular lactic acidosis) Cell Chromatin swelling clumpting Irreversible 1. Inability to reverse mitochondrial dysfunction 2. Disturbance in cell membrane – function-in general and in plasma membrane in particular Irreversible 1. Mitochondrial damage due to calcium influx 2. Membrane damage due to activation of phospholipases 3. Cytoskeleton damage due to intracellular protease 4. Nuclear damage due to activated endonuclease 5. Lysosomal damage -cell death and phagocytosis 2nd to rupture lysosomes and release of the enzymes. Reversible Irreversible 59