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CHAPTER 1-CELLINJURY SUMMARIZED
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Four aspects of disease process:
I. Etiology or cause
II. Pathogenesis
III. Morphologic changes (structural alterationsin cells or tissues)
IV. Functional derangements and clinical
significance
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Definitions:Cellular adaptions: hypertrophy, atrophyWhen the limits of adaptive responses are exceeded cellinjury occurs, initially reversibl, then irreversible leading to celldeath.
Necrosis: severe cell swelling or cell rupture, denaturationand coagulation of cytoplasmic proteins and breakdown ofcell organelles.
Apoptosis: internally controlled cell death, chromtincondensation and fragmentation.
Oncosis: prelethal changes preceding necrotic cell death,characterized by cell swelling
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Causes of Cell Injury:1. Hypoxia (loss of aerobic oxidativerespiration) vs. Ischemia (loss of blood supply:
also cuts off metabolic substrates, injurestissue faster)2. Physical agents (temperature, trauma,radiation)
3. Chemical agents and drugs4. Infectious agents5. Immunologic reactions6. Genetic derangements7. Nutritional imbalances
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General Biochemical Mechanisms
Particularly vulnerable are glycolysis, the citric
acid cycle and oxidative phosphorylation.
ATP depletion: ouabain-sensitive Na+,K+-ATPase in plasma membrane stops working,
Na+ accumulates intracellularly, cell swells;
cell switches to anaerobic metabolism
(glycolysis) and glycogen stores are depleted,
pH goes down.
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Oxygen and oxygen-derived free
radicals/reactive oxygen species
Loss of intracellular calcium homeostasis:
activates phospholopases, proteases,ATPases, endonucleases
Defects in membrane permeability
Irreversible mitochondrial damage: leakage
of cytochrome c triggering apoptotic cell death
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Reversible cell injury: cell swelling, detachmentof ribosomes from granular e.r. and dissociation ofpolysomes into monosomes. Fatty changeencountered in cells invloved in fat metabolism
(hepatocyte, myocardium). Histologicallycharacterized by pallor, hydropic change, vacuolardegeneration. EM: plasma membrane blebbing,blunting, villous distortion, myelin figures,
mitochondrial swelling, rarefaction, nucleardisaggregation of granular and fibrillar elements.
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Irreversible cell injury: mitochondria swell,lysosomes swell, damage to plasmamembrane and lysosomal membranes leads
to enzyme leakage; acidosis somewhatprotective by inhibiting enzymatic reactions.Ischemia/Reperfusion Injury: new damageon reperfusion mediated by oxygen freeradicals and cytokine/adhesion moleculesfurthering immune-mediated injury.
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Free radicals:def. chemical species with a
single unpaired electron in outer orbit.
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)
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Chemical Injury:
mercuric chloride - binds sulfhydryl groups of
proteins
cyanide - poisons mitochondrial cytochromeoxidase
CCl4 - conversions to free radical
CCl3 causing lipid peroxidation
Acetaminophen - P450 catalyzed oxidation to
toxic metabolite
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Necrosis:def. spectrum of morphologicchanges that follow cell death in living tissuethat result from progressive degredative action
of enzymes on the lethally injured cell.Morphologic appearance of necrosis is theresult of enzyme digestion & denaturation ofproteins. Histologically: increased eosinophilia,karyolysis (nuclear pallor), pyknosis (nuclearshrinkage), karyorrhexis (nuclearfragmentation).
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Types:1. Coagulative: e.g. myocardial infarct2. Liquefactive: e.g. bacterial or fungalinfections, CNS hypoxia3. Gangrenous: e.g. limb ischemia (usually acombination of coagulative and liquefactivenecrosis), surgical term4. Caseous: e.g. tuberculosis. characterized bygranular debris w/obliteration of tissuearchitecture (gross: white & cheesy)5. Fat necrosis
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Apoptosis: def. programmed cell death.
Chracterized by cell shrinkage, chromatin
condensation, formation of cytoplasmic blebs
and apoptotic bodies, phagocytosis bymacrophages or adjacent cells. Does notelicit
inflammation (in contrast to necrosis).
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Biochemical features:
1. Protein cleavage (caspases)
2. Protein cross-linking
3. DNA breakdown (endonuclease)4. Phagocytic recognition (mediated by
phosphatidylserine and thrombospondin
expression)
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Cytogenetic features:1. ced genes2. Fas-Fas ligand model: CD95 receptor oncell surface, TNF and TNFR-mediatedapoptosis3. Bcl-2: supresses apoptosis by direct actionon mitochondria (preventing increasedpermeability) & by binding other proteins(Apaf-1)4. caspase (cysteine proteases that cleaveafter aspartic acid) mediated proteolyticcascade
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Lysosomal Catabolismheterophagy and autophagylipofuscin pigment represents undigested materialthat results from lipid peroxidation
cloroquine - raises lysosomal pH inactivating itsenzymesamiodarone - binds lysosomal phospholipidsinhibiting breakdown
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Endoplasmic reticulum
barbiturates - hypertrophy of smooth e.r. and
P450 upregulation
Mitochondria
megamitochondria - liver in alcoholic liver
disease and in nutritional deficiencies
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CytoskeletonThin filaments - actin (6-8 nm), myosin (15nm). Amabita phalloides toxin binds actinfillamentsMicrotubules (20-25 nm) - involved in motility(cilia), leukocyte migration, phagocytosis.Colchicine and vinca alkaloids bind tubulin andprevent assembly.Intermediate filaments (10 nm) - keratin,neurofilaments, desmin, vimentin, glialfilaments. Mallory body composed of keratinintermediate filaments. Alterations in keratinfilament genes cause skin disorder
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