Chapter 1-Cell Injury Summarized

7/29/2019 Chapter 1-Cell Injury Summarized

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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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Chapter 1-Cell Injury Summarized

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