Cell Injury and Cell Death PDF

Cell Injury and Cell Death Pmed-Pdent-Pphrm Pathology Team By the end of this session students should be able to: ◦ Recognize cell interactions and causes of cell injury. Session’s Objectives ◦ Identify biochemical mechanisms involved in cell injury. ◦ Differentiate between reversible and irreversib...

Cell Injury and Cell Death Pmed-Pdent-Pphrm Pathology Team By the end of this session students should be able to: ◦ Recognize cell interactions and causes of cell injury. Session’s Objectives ◦ Identify biochemical mechanisms involved in cell injury. ◦ Differentiate between reversible and irreversible injury. Part 1 ◦ Recognize cellular changes in the reversible and irreversible injury. Normal cell The Cell and the Environment Adaptive Responses: when exposed to physiological stresses and pathological stimuli , cell undergo adaptations to achieve a new steady state to preserve viability and function Cell Injury: Occur in response of harmful stimuli when cells are unable or exceed limits to adapt or external stress is severe enough, then cell injury ensue Reversible Irreversible Atrophy Hypertrophy Hyperplasia Metaplasia Robbins Pathology 10th edition ◦ Reversible cell injury: ◦ Within certain limits, functional & morphological (gross and microscopic) changes are reversible if ◦ damaging stimulus is removed and cell returns to stable state. ◦ No membrane damage & nucleus is intact Cell Injury ◦ Irreversible cell injury (Cell Death): ◦ If stress is severe, persistent and rapid then cell unable to restore normal function and progress eventually to cell death. ◦ Cell Death either: ◦ Necrosis ◦ Apoptosis Stages in the cellular response to stress and injurious stimuli Stress increase demand and cell shows Normal cell (homeostasis) Adaptations Injurious stimulus if continuous can lead to Cell Injury Reversible Cell injury Irreversible Cell injury Necrosis Damage to membrane Apoptosis Damage to DNA or proteins ◦ Oxygen deprivation ◦ Hypoxia, most common ◦ Ischemia Causes of Cell Injury ◦ Physical Agents ◦ Chemicals and Drugs ◦ Microbiologic Agents ◦ Immunologic Reactions ◦ Genetic Derangements ◦ Nutritional Imbalances ◦ Aging ◦ Cellular response to injurious stimuli depends on: ◦ Type, duration, and severity of injury. General Principles of Cell Injury ◦ Consequences of cell injury depend on: ◦ Type, state, & adaptability of injured cell. ◦ The most important targets of injurious stimuli are: ◦ Mitochondria, the sites of ATP generation ◦ Cell membranes, homeostasis of cell depends ◦ Endoplasmic reticulum/Ribosomes (Protein synthesis) ◦ Cytoskeleton ◦ Genetic apparatus of the cell Biochemical mechanisms & sites of damage in cell injury Mechanism of cell injury 1. Depletion of ATP Blood Clot  ATP is the main cause of necrotic cell death  O2 ATP Major causes of ATP depletion: Reduced supply of oxygen, hypoxia. Reduce supply of nutrients Mitochondrial damage Toxins (Cyanide) 1. Mechanism of Ischemic / Hypoxic injury Mechanism of Ischemic / Hypoxic injury Intracellular ATP depletion Sodium pump failure (Na+-K+ ATPase) Increased anaerobic glycolysis Detachment of ribosomes ↑Ca2+,↑Na+, & H2O Influx Loss of K+ Cellular & ER swelling, mitochondria swelling Glycogen depletion, Accumulation of lactic acid causing low pH (enzyme activity) Reduce protein synthesis Mechanism of cell injury 2. Influx of Calcium: ◦ Causes of increase cytosolic Ca+2 : ◦ Ischemia ◦ Toxins ◦ Influx of Ca+2 in cells can: ◦ Activate enzymes which can damage the cells (Phospholipase, ATPase, protease, endonuclease) ◦  ATP generation ◦ Induce Apoptosis (Caspases) Mechanism of cell injury ◦ Causes of mitochondrial injury: ◦  cytosolic Ca+2 ◦ Reactive oxygen species ◦ Ischemia ◦ Consequences: ◦ Formation of channels in mitochondrial membrane ◦  oxidative phosphorylation and depletion of ATP leading to necrosis ◦ Release of cytochrome c inducing apoptosis Mechanism of cell injury 4. Accumulation of Oxygen derived Free Radicalsoxidative stress ◦ Free radicals are unstable molecules, which react with cell organelles and cause damage. ◦ Reactive oxygen species (ROS) are O2 derived free radicals ◦ Ischemia- reperfusion ◦ Chemicals ◦ Radiations Causes of ROS ◦ Toxins/ microbes Cell injury mediated by free radicals by: ◦ Damage to lipid contents of cell membrane ◦ Protein Fragmentation ◦ Damage DNA Robbins Pathology 10th edition Mechanism of cell injury 5. Defects in membrane permeability ◦ Factors that can lead to defect in membrane permeability ◦ Hypoxia (ATP) ◦ ROS (Lipid peroxidation) ◦ Increase Ca+2 (Activation of enzymes) ◦ Most important site of membrane damage during cell injury: ◦ Mitochondrial membrane damage ◦ Plasma membrane damage ◦ Injury to lysosomal membrane which release digestive enzymes and degradation of cellular contents Mechanism of cell injury 6. Damage to DNA and Proteins ◦ Cells can repair minor DNA damages ◦ If the damage is severe that cannot be corrected, the cell initiates its suicide program and die by apoptosis. ◦ Causes of DNA damage: ◦ Radiation and chemical injury ◦ Reactive oxygen species Mechanism of cell injury, summary 1. ATP depletion (mitochondrial injury) injury necrosis. Na+ pump failure 2. Mitochondrial injury 3. Influx of Ca+2 activation of enzymes 4. Reactive Oxygen species(free radicals) especially DNA. 5. Increase membrane permeability membranes necrosis 6. Accumulation of damaged DNA reversible cell necrosis or apoptosis cell damage/ apoptosis damage to cell structure mitochondria, Lysosome, and cell apoptosis Effects of stresses on cells Stresses affect normal cell functions Continuous stress and ineffective adaptation Cell Injury Adaptive changes 1. 2. 3. 4. Atrophy Hypertrophy Hyperplasia Metaplasia Reversible cell Injury Irreversible cell Injury Apoptosis Necrosis ◦ The changes which are produced in a cell in response to injury are still reversible if the cause of injury is removed. Reversible Cell Injury ◦ Two main morphologic correlates of reversible cell injury: ◦ Cellular swelling due to loss of Na+ K+ ATPase pump activity, so influx of water ◦ Fatty changes Reversible changes: structural Earliest changes on microscopy : ◦ Pinched off segments of ER, appear as small clear vacuoles within cytoplasm called as hydropic changes or vacuolar degeneration ◦ Appearance of lipid filled vacuoles in cytoplasm fatty changes. Commonly seen in Kidney, liver and heart as these organs are involved in fat metabolism (mainly in hypoxic & toxic injury). Ultrastructural changes in reversible injury: ◦ Plasma membrane alteration: stretched, bulges, bleb formation but membrane remains intact. ◦ Mitochondrial changes: Water accumulation leads to swelling ◦ ER: Detachment of polysomes & dilatation. ◦ Nuclear alterations: Clumping of chromatin otherwise nuclei remain almost unchanged Reversible Cell Injury ◦ Persistent and excessive severe cell injury in which cell Irreversible cell injury changes and necrosis can not restore normal functions. ◦ Cell membrane rupture ◦ Mitochondria shows structural distortion, focal deposits of Ca+2 and loss of ribosomes ◦ Lysosome rupture releases enzymes & autodigestion ◦ Nuclear changes i.e. condensation is the most important indicator of irreversible injury