Aspirin Resistance 2003 08 13

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1 : Mechanisms of cell injury BY DR. SHANKAR LAL RATHI M.B;B.S, M C P S , M.Phil
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3 : Key Concepts Normal cells have a fairly narrow range of function or steady state: Homeostasis Excess physiologic or pathologic stress may force the cell to a new steady state: Adaptation Too much stress exceeds the cell’s adaptive capacity: Injury
4 : Adapted Cell + Stress Injury Normal cell Reversibly injured cell Irreversibly Injured cell Dead cell +Stress Apoptosis Necrosis - Stress - Stress Overview
5 : Causes of Cell Injury Hypoxia Ischemia Hypoxemia Loss of oxygen carrying capacity Free radical damage Chemicals, drugs, toxins Infections Physical agents Immunologic reactions Genetic abnormalities Nutritional imbalance
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7 : General principles The cellular response to injurious stimuli depends on the nature of the injury, its duration and its severity. The consequences of cell injury depend on the type, state, and adaptability of the injured cell. Cell injury results from different biochemical mechanisms acting on several essential cellular components.
8 : General principles Any injurious stimulus may simultaneously trigger multiple interconnected mechanisms that damage cells.
9 : 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
10 : Biochemical mechanisms Depletion of ATP: Usually in hypoxic and chemical injuries. Sources : oxidative phosphorylation of ADP in the mitochondria and Glycolytic pathway using Glucose. The major causes of ATP depletion are reduced supply of oxygen and nutrients, mitochondrial damage and the actions of some toxins (Cyanide).
11 : Depletion of ATP Tissues with a greater glycolytic capacity (liver) are more able to survive loss of oxygen and decreased oxidative phosphorylation better than are tissues with limited capacity for glycolysis (brain).
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13 : Depletion of ATP Low oxygen situation results in misfolding of proteins which trigger a cellular response called the unfolded protein response that may lead to cell death.
14 : Mitochondrial damage Supplies ATP (energy) to the cell. Damaged by Calcium influx, reactive oxygen species, oxygen deprivation and toxins and mutations in mitochondrial genes. Consequences of mitochondrial damage: Formation of mitochondrial permeability transition pore which leads to loss of membrane potential, failure of phosphorylation and ATP depletion and then necrosis. Cyclosporine acts on cyclophilin D.
15 : Mitochondrial damage Consequences of mitochondrial damage: Release of cytochrome c and caspases into the cytosol that activate apoptosis (death).
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17 : Influx of calcium and loss of calcium homeostasis Depleting Ca protects the cell from injury. Cytosolic Ca is very low and is present intracellularly in mitochondria and ER. Injury will lead to increase cytosolic Ca Consequences of the increase are: opening of mitochondrial permeability transition pore, activation of a number of enzymes (phospholipases, proteases, endonucleases & ATPases)
18 : Influx of calcium and loss of calcium homeostasis Consequences of the increase are: and induction of apoptosis by direct activation of caspases and increasing mitochondrial permeability.
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20 : Accumulation of oxygen derived free radicals It is important in chemical and radiation injuries, ischemia-reperfusion injury, cellular aging and microbial killing by phagocytosis. Free radicals: chemical species that have a single unpaired electron in the outer orbit. Unstable atoms, react with inorganic and organic chemicals (proteins, lipids, carbohyd.) Initiate autocatalytic reactions..... Creation of more radicals.
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22 : Reactive oxygen species (ROS) One of the oxygen derived free radicals. Produced normally in small amounts and removed by defence mechanisms. Once the ROS amount increased this will lead to what so called oxidative stress. Oxidative stress : cell injury, cancer, aging and some degenerative diseases like Alzheimer. Also ROS are produced by leukocytes and macrophages in inflammation.
23 : Generation of free radicals Reduction oxidation reactions. Normal respiration; molecular Oxygen is reduced by reacting with H2 to generate two water molecules. By products are: superoxide anion, hydrogen peroxide (H2O2) and hydroxyl ions (OH). Absorption of radiant energy. UV light and X-rays. Hydrolyze water into OH & H free radicals.
24 : Generation of free radicals Production by leukocytes. Plasma membrane multiprotein complex using NADPH oxidase. Intracellular oxidases such as xanthine oxidase generate superoxide anion. Enzymatic metabolism of exogenous chemicals or drugs. Not ROS but similar. Ex CCL4 ---- CCL3
25 : Generation of free radicals Transition metals. Iron and copper. Fenton reaction (H2O2+Fe²? Fe³?+OH•+OH?) Ferric iron should be reduced to ferrous iron to participate in Fenton reaction. This reaction is enhanced by superoxide anion and so sources of iron and superoxides may participate in oxidative cell damage.
26 : Generation of free radicals Nitric oxide (NO). Endothelial cells, macrophages, neurons and other cell types. Can act as a free radical and can also be converted to highly reactive peroxynitrite anion as well as NO2 and NO3.
27 : Removal of free radicals Decay spontaneously. Antioxidants: Vitamin E and A, ascorbic acid and glutathione in the cytosol. Binding proteins. Enzymes: Catalase-----H2O2 ----- O2 and H2O, Superoxide dismutase------ superoxide anion ----H2O2, Glutathione peroxidase---- H2O2---H2O or OH------ H2O. Reduced Glutathione level is important in cell safety.
28 : Pathological effects of free radicals Lipid peroxidation in membranes. Oxidative damage of the double bonds in the polyunsaturated fatty acids resulting in formation of peroxides which are unstable and lead to membrane damage. Oxidative modification of proteins. Damage the active sites on enzymes, change the structures of proteins and enhance proteosomal degradation of unfolded proteins.
29 : Pathological effects of free radicals Lesions in DNA. Single and double strand breaks in DNA. Oxidative DNA damage has been implicated in cell aging and in malignant transformation of cells. Radicals are involved in both necrosis and apoptosis.
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31 : Defects in Membrane Permeability Mitochondrial Dysfunction -Decreased phospholipid synthesis -Phospholipase activation Loss of Membrane phospholipid Mechanisms of Cell Injury Mechanism of Membrane damage in Cell Injury
32 : Cytoskeletal Abnormality Reactive Oxygen species Lipid breakdown products (detergen effect on membrane) Defects in Membrane Permeability Mechanisms of Cell Injury Mechanism of Membrane damage in Cell Injury Cytosolic Ca+ protease
33 : Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
34 : Clinical Correlation Injured membranes are leaky Enzymes and other proteins that escape through the leaky membranes make their way to the bloodstream, where they can be measured in the serum
35 : Defects in membrane permeability Selective and overt membrane damage is a constant feature in all forms of cell injury except apoptosis. Causes include ischemia (ATP depletion and calcium mediated activation of phospholipases), direct damage (bacterial toxins, viral proteins, lytic complement components, physical and chemical agents).
36 : Mechanisms of membrane damage Reactive oxygen species: lipid peroxidation. Decreased phospholipids synthesis: as a consequence of defective mitochondrial function or hypoxia. This affects all cellular membranes including mitochondria themselves. Increased phospholipids breakdown: activation of endogenous phospholipases due to Ca?² accumulation resulting in lipid breakdown products.
37 : Mechanisms of membrane damage Lipid Breakdown products include unesterified free fatty acids, acyl carnitine and lysophospholipids which have a detergent effect on membranes causing changes in permeability and electrophysiologic alterations. Cytoskeletal abnormalities: activation of proteases by high Ca?² causes damage to the elements of cytoskeleton.
38 : Consequences of membrane damage Most important sites of membrane damage: mitochondrial, plasma membrane and lysosomal. Lysosomes contain many degrading enzymes like RNases, DNases, proteases.....
39 : Damage to DNA and proteins Usually cells have mechanisms to repair DNA damage but if the damage is severe the cells initiate a suicide program results in cell death by apoptosis.
40 : Concluding points The identification of factors that determine when reversible injury becomes irreversible and progresses to cell death would be very useful so we may be able to identify strategies to prevent permanent consequences of cell injury. Leakage of intracellular proteins into blood through damaged membranes provides a means of detecting tissue damage. CK & troponin in MI and ALT, AST &ALK in liver.
41 : Ischemic and hypoxic injury Most common type of injury in clinical medicine. Hypoxia: anaerobic glycolysis Ischemia: delivery of substrates is also compromise. Ischemia is more rapidly damaging than hypoxia in the absence of ischemia.
42 : Mechanisms of ischemic injury Low O2 leads to loss of oxidative phosphorylation and decreased generation of ATP. Na/K and Ca?² pumps failure. Progressive loss of glycogen and decreased protein synthesis. Loss of function though the cell is not yet dead.
43 : Mechanisms of ischemic injury Cytoskeleton abnormalities; blebs and loss of villi. Formation of myelin figures and swollen organelles. To this point changes are reversible. After that, severe swelling to the mitochondria, extensive damage to the plasma membranes, myelin figures formation and swelling of lysosomes.
44 : Mechanisms of ischemic injury Large densities develop in the mitochondria. Massive influx of Ca?² happens especially if the ischemic area is reperfused. Death is mainly by necrosis but apoptosis also takes place. Dead cells may become replaced by large masses of myelin figures which are either phagocytosed or degraded more into fatty acids.
45 : Mechanisms of ischemic injury Protective responses: Hypoxia-inducible factor-1; promotes new blood vessel formation, stimulates cell survival pathways and enhances anaerobic glycolysis. Still no reliable therapeutic measure to reduce consequences of ischemia clinically. Induction of hypothermia (33.4°) in ischemic brain and spinal injuries may help in reducing the effects of injury.
46 : Ischemia- reperfusion injury Restoration of blood flow to ischemic tissues can promote recovery if they are reversibly injured. In certain situations, reperfusion paradoxically exacerbates injury (more dead cells in addition to the already irreversibly injured cells).


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