Mechanisms of cell injury

Made from Cotran and Robbins textbook of Pathology.
Dr. Amnah Shaukat, Mirpur AJK.

1. Mechanisms of Cellular Injury Dr. Amnah Shaukat

2. introduction;: Cellular Injury occurs when stress exceeds the cell’s ability to adapt. Reaction of cell to injury depends on; Type of injury Duration of injury Severity of the injurious stimuli Type , State & A daptability of the cell

3. Causes of Cell Injury: Oxygen deprivation – hypoxia Physical agents Chemical agents & drugs Infectious agents Immunologic reactions Genetic derangements Nutritional imbalances

4. Mechanisms of cell injury: 1.ATP Depletion 2.Mitochondrial Damage 3.Loss of Ca ++ H omeostasis 4.Accumulation of Reactive Oxygen S pecies 5.Defects in Membrane P ermeability 6.Damage to DNA and proteins 7.Examples of cell injury and N ecrosis -Ischemic cell injury -Ischemia-reperfusion injury -Chemical (toxic injury)

5. 1.ATP DEPLETION: ATP in humans is produced via two pathways; 1.Oxidative Phosphorylation 2.Glycolytic Pathway (anaerobic glycolysis) ATP is required for virtually all synthetic and degradative processes in the cell and its depletion results in; Na-K ATPase failure Stimulation of A naerobic Glycolysis Disruption of Protein S ynthesis Apparatus

6. 2.Mitochondrial damage: Mitochondria; the power house of the cell are sensitive to a wide range of injurious stimuli including hypoxia, toxins, genetic mutations in mitochondrial genes, etc. Two major consequences of mitochondrial damage are; Formation of Mitochondrial Permeability Transition Pore Activation of Apoptotic Pathways

7. 3.Loss of calcium homeostasis: ATP depletion leads to failure of Calcium Pump which causes influx of extracellular Calcium. Increased calcium influx leads to following; Accumulation of Ca ++ in mitochondria leads to opening of mitochondrial transition permeability pore. Activation of enzymes ( ATPases , Phospholipases, Proteases , Endonucleases and Caspases - leading to apoptosis)

8. 4.Accumulation of oxygen derived free radicals : Free Radicals are extremely unstable, highly reactive chemical species with a single unpaired electron in their outer orbit. SOURCES : Normal redox reactions generate free radicals Nitric oxide (NO) can act as a free radical Ionizing radiation (UV, X-rays) can hydrolyze water into hydroxyl (OH) and hydrogen (H) free radicals Metabolism of exogenous chemicals such as CCl4 can generate free radicals Fenton Reaction: M etals like copper and iron also catalyze free-radical formation

9. REMOVAL: Spontaneous decay Superoxide dismutase(SOD) 2O2 + 2H →O2+ H2O2 Glutathione peroxidase: (2OH+2GSH→ 2H2O + GSSG) Catalase: (2H2O2 →O2+ H2O) Endogenous and exogenous antioxidants (Vitamins E, A, C and β- carotene)

10. They initiate autocatalytic reactions i.e. molecules that react with free radicals are converted into free radicals via Redox reactions. If not adequately neutralized , free radicals can damage cells by three basic mechanisms : Lipid Peroxidation of membranes: double bonds in polyunsaturated membrane lipids are vulnerable to attack by oxygen free radicals DNA fragmentation: Free radicals react with thymine in nuclear and mitochondrial DNA to produce single strand breaks Protein cross-linking: Free radicals promote sulfhydryl-mediated protein cross-linking, resulting in increased degradation or loss of activity

11. 5.Defects in membrane permeability : Causes : Direct damage by toxins ( bacterial , viral, complement, physical or chemical injury) Damage secondary to ATPase loss or from calcium- mediated phospholipase activation. Consequences: Mitochondrial permeability transition pore leads to Apoptosis Plasma membrane damage leads to loss of Osmotic balance Injury to lysosomal membrane Leakage of Rnases , Dnases ,proteases ,phosphatases , glucosidases leading to enzymatic digestion and Necrosis

12. 6.Damage to dna and proteins: Clumping of DNA and other M isfolded Proteins leads to irreversible damage that can not be corrected leading to Apoptosis. Reversible cell injury: cell swelling, detachment of ribosomes from granular ER , plasma membrane blebbing , myelin figures, mitochondrial swelling. Irreversible cell injury: mitochondria swell and are unable to synthesize ATP, lysosomes swell, damage to plasma membrane and lysosomal membranes leads to enzyme leakage; acidosis. This is the point of no return.

13. EXAMPLES OF CELL INJURY AND NECROSIS: 1.Ischemic and Hypoxic Injury: deficient oxygen(hypoxia) and loss of blood supply(ischemia) that all cuts off nutrients lead to more rapid cell injury than hypoxia alone e.g coronary artery occlusion 2.Ischemia/Reperfusion Injury : new damage on reperfusion mediated by oxygen free radicals and cytokines causing immune mediated injury e.g reperfusion after myocardial or cerebral infarction. Free radicals cause injury by: lipid peroxidation of membranes , oxidative modification of proteins, lesions in DNA (single strand breaks ).Inactivated by: antioxidants ( vit A, E, glutathione), binding to storage and transfer proteins (transferrin, ferritin, lactoferrin , ceruloplasmin ), enzymes (catalase, SOD, glutathione peroxidase ) 3.Chemical Injury: mercuric chloride - binds sulfhydryl groups of proteins cyanide - poisons mitochondrial cytochrome oxidase CCl4 - conversions to free radical CCl3· causing lipid peroxidation Acetaminophen - P450 catalyzed oxidation to toxic metabolite

14. SUMMARY