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Radiolysis of water generates hydroxyl radical
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Depending on the status of the cell, hydroxyl radical can
- Cause DNA damage in PROLIFERATING CELLS -> Inability to replicate
- Cause Lipid peroxidation of membrane phospholipids in NONPROLIFERATING CELLS -> Loss of membrane integrity
- Both lead to CELL DEATH
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Polyenoic fatty acid is susceptible damage by hydroxyl radical and (initiation) and O2 (peroxidation), and self-propagation, resulting low molecular weight aldehydes.
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PMNs, macrophages -> Inflammation
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PMNs, Xanthine oxidase -> Reperfusion injury after ischemia
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Mixed function oxidases, Redox reactions -> Chemical toxicity
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Radiotherapy -> Ionizing radiation
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Initiators, promoters -> Chemical carcinogenesis
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OXIDATIVE STRESS comes from:
- (1) ROS (Reactive oxygen species)
- (2) RNOS (Reactive nitrogen oxide species) - Peroxynitrite (ONOO-·), Nitroxyl (NO-)
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Actions of superoxide
- O2 + e -> O2-• (superoxide)
- O2-• + O2-• + 2H -> H2O2 + O2 (with enzyme SOD, superoxide dismutase, protect from too much superoxide)
- 2H2O2 -> O2 + 2H2O (with enzyme catalase; foam forms when O2 is released)
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Cellular defense mechanisms against free radicals
vit A, C, E
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Intracellular accumulations
- Water- cellular edema or swelling, reversible
- Lipids- steatosis or fatty change, reversible
- Proteins- usually aggregates in the cytoplasm providing clues to disease, diagnostic
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Ischemia leads to
- decreased oxidative phosphorylation in mitochondria and decreased ATP production
- decreased ATPase Na+ pump and less efflux of Na+ -> swelling of ER and cells, blebs
- decreased glycogen and pH, clumping of nuclear chromatin
- decreased protein synthesis
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The principal biochemical mechanisms and sites of damage in cell injury
- Mitochondria - less ATP w/ consequences; more ROS, damaging to lipids, DNA and proteins
- Increased entry of Ca2+ -> increased permeability of mitochondria and activation of cellular enzymes
- Membrane damage - cell contents leaking out; lysosome leakage, digesting cellular components
- Protein misfolding and DNA damamge -> apoptosis
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The production of ROS (_______) is increased by many injurious stimuli, eg _____. These free radicals are removed by ________ and by ________. Excessive production or inadequate removal leads to accumulation of free radicals in cells, which may damage lipids (by _______), proteins, and DNA, resulting in cell injury.
- superoxide, hydrogen peroxide, hydroxyl radical
- radiation, toxin, reperfusion
- spontaneous decay
- specialized enzymatic systems
- peroxidation
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Important consequences of hypoxia :
- Lowered production of ATP
- Interference with Na+/K+ pump
- Recruitment of secondary metabolic paths - glycogen; lactic acid
- Distortion of cellular organelles - mitochondria
- Accumulation of fat, CHO etc.
- Clumping of chromatin
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reversible cell injury and irreversible necrosis.
- ischemic injury - surface blebs, increased eosinophilia of cytoplasm, and swelling
- Necrosis - loss of nuclei, fragmentation of cells, and leakage of contents
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Mechanisms of fatty change in liver cells
- Oxidation of fatty acids
- Accumulation of triglycerides
- Triglycerides are transferred out by lipid acceptor proteins
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________ due to chronic passive congestion
- Nutmeg liver
- Nodularity present
- Fat can burst & damage surrounding tissues and vascular tissue
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Diphtheritic myocarditis show fatty change
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Fatty change in endocardium giving a ________ appearance.
- patchy “thrush breast”
- accumulated fat droplets
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_____ bodies in _______ hepatitis
- Mallory
- alcoholic
- - Accumulation of protein in the liver, Suggests alcohol
- - Accumulation of cytoskeletal elements in the heart
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________ droplets in renal tubules indicating ______ diseases
- Protein re-absorption
- glomerular
- protein leaking out of glomerular and resorpted by tubules
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__________ nuclei in uncontrolled diabetes
Glycogen distending cell
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Swollen __________, with deposits, in necrosis
mitochondria
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Mechanisms of membrane damage in cell injury.
- Decreased O2 and increased cytosolic Ca2+ are typically seen in ischemia but may accompany other forms of cell injury. Reactive oxygen species, which are often produced on reperfusion of ischemic tissues, also cause membrane damage
- ROS -> lipid peroxidation
- decreased O2 -> decreased ATP -> decreased phospholipid synthesis
- increased Ca2+ -> phospholipase activation -> increased phospholipid degradation -> lipid breakdown products
- increased Ca2+ -> protease activation -> cytoskeletal damage
- lipid peroxidation, decreased phospholipid synthesis, lipid breakdown products -> phospholipid loss
- phospholipid loss, cytoskeletal damage, lipid breakdown products -> membrane damage
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Cellular Responses to Stress and Toxic Insults - hypertrophy
- Mechanical sensors arevthe major triggers for physiologic hypertrophy
- Agonists and growth factors more important in pathologic states
- All activate certain pathway -> transcription factors -> hypertrophy -> increased mechanical performance
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Altered physiologic stimuli; some nonlethal injurious stimuli ->
Cellular adaptations
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Increased demand, increased stimulation (e.g., by growth factors, hormones) ->
Hyperplasia, hypertrophy
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Decreased nutrients, decreased stimulation ->
Atrophy
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Chronic irritation (physical or chemical) ->
Metaplasia
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Nutritional deprivation ->
Autophagy
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Cumulative sublethal injury over long life span ->
Cellular aging
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