Cell Injury and Cell Death

LO At the end of session student should be able to Enlist causes of cell injury Identify effect of injurious agents on cell cytoplasm and nucleus

Oxygen Deprivation Hypoxia – deficiency of oxygen Causes of Cell Injury Oxygen Deprivation Hypoxia – deficiency of oxygen Ischemia – loss of blood supply (arterial flow or reduced venous drainage)

Physical Agents Mechanical trauma Causes of Cell Injury Physical Agents Mechanical trauma Extremes of temperature – burns, deep cold Radiation Electric shock

Chemical Agents and Drugs Causes of Cell Injury Chemical Agents and Drugs Hypertonic concentration of salt – deranging electrolyte homeostasis Poisons – arsenic, cyanide, or mercuric salts Insecticides and Herbicides Air pollutant – carbon monoxide Occupational hazard – asbestos Alcohol and Narcotic drugs

Infectious Agents Parasites Fungi Bacteria Rickettsiae Viruses Causes of Cell Injury Infectious Agents Parasites Fungi Bacteria Rickettsiae Viruses

Immunologic Reactions Causes of Cell Injury Immunologic Reactions Anaphylactic reaction to foreign protein or drug Reactions to endogenous self-antigens – autoimmune diseases

Genetics Derangements Causes of Cell Injury Genetics Derangements Congenital malformation – Down syndrome Decreased life of red blood cell – Thalassemia, Sickle cell anemia Inborn errors of metabolism

Nutritional Imbalances Causes of Cell Injury Nutritional Imbalances Protein-calorie deficiencies Vitamin deficiencies Anorexia nervosa Excesses of lipids – Obesity, Atherosclerosis Metabolic diseases – Diabetes

Mechanisms of Cell Injury Depletion of ATP Mitochondrial Damage Influx of Intracellular Calcium and Loss of Calcium Homeostasis Accumulation of Oxygen-Derived free radical (Oxidative stress) Defects in Membrane Permeability

Depletion of ATP Causes Hypoxia, Ischemia Chemical Injury Mechanisms of Cell Injury Depletion of ATP Causes Hypoxia, Ischemia Chemical Injury Membrane transport ATP Na+K+ATPase (Na-pump), Ca2+Mg2+ATPases (Ca-pump) Protein synthesis, Lipogenesis etc

Mechanisms of Cell Injury Depletion of ATP Na+ K+ Ca2+

Mitochondrial Damage Causes Hypoxia, Toxins Cytosolic Ca2+ Mechanisms of Cell Injury Mitochondrial Damage Causes Hypoxia, Toxins Cytosolic Ca2+ Oxidative stress Lipid breakdown product

Mechanisms of Cell Injury Mitochondrial Damage Mitochondrial permeability transition of inner membrane (formation of high-conductance channel) Leakage of Cytochrome c into cytosol Mitochondrial Oxidative Phosphorylation ATP production

Mechanisms of Cell Injury Mitochondrial Damage

Influx of Intracellular Calcium and Loss of Calcium Homeostasis Mechanisms of Cell Injury Influx of Intracellular Calcium and Loss of Calcium Homeostasis

Mechanisms of Cell Injury

Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Mechanisms of Cell Injury Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) The Oxidation-Reduction reaction (normal metabolic processes) -superoxide anion (O2-) -hydrogen peroxide (H2O2) -hydroxyl ion (OH )

Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Mechanisms of Cell Injury Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Absorption of radiant energy (ultraviolet light: UV, X-ray) Ionizing radiation H20 OH H

Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Mechanisms of Cell Injury Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Transition Metals – iron, copper “Fenton reaction” H202 Fe2+ Fe3+ OH OH-

Effects of the free radicals on cell injury Mechanisms of Cell Injury Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Effects of the free radicals on cell injury Lipid peroxidation of Membranes - Plasma membrane - Organellar membrane Double bonds in unsaturated fatty acids membrane damage

Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Mechanisms of Cell Injury Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Effects of the free radicals Oxidative modification of proteins -Oxidation of amino acid side chains Protein-protein cross-linkages -Oxidation of the protein backbone Protein fragmentation

Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Mechanisms of Cell Injury Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Effects of the free radicals Lesions in DNA Reaction with Thymine DNA single-stranded break DNA fragmentation

Superoxide dismutase (SOD)

Defects in Membrane Permeability Mechanisms of Cell Injury Defects in Membrane Permeability Mechanism of Membrane damage in Cell Injury Mitochondrial Dysfunction -Decreased phospholipid synthesis -Phospholipase activation Loss of Membrane phospholipid

Defects in Membrane Permeability Mechanisms of Cell Injury Defects in Membrane Permeability Mechanism of Membrane damage in Cell Injury Cytoskeletal Abnormality Reactive Oxygen species Lipid breakdown products (detergen effect on membrane) Cytosolic Ca+ protease

Cellular and biochemical sites of damage in cell injury

Thanks