Post on 07-Apr-2018
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Mechanisms of cell injury
Hussam Telfah,MBBS,FRCPath
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Defects in membranepermeability
Selective and overt membranedamage is a constant feature in allforms of cell injury except apoptosis.
Causes include ischemia (ATPdepletion and calcium mediatedactivation of phospholipases), direct
damage (bacterial toxins, viralproteins, lytic complementcomponents, physical and chemical
agents).
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Mechanisms of membranedamage
Reactive oxygen species: lipidperoxidation.
Decreased phospholipids synthesis: as a
consequence of defective mitochondrialfunction or hypoxia. This affects allcellular membranes including
mitochondria themselves. Increased phospholipids breakdown:
activation of endogenousphospholipases due to Ca resultingin accumulation of li id breakdown
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Mechanisms of membranedamage
Lipid Breakdown products includeunesterified free fatty acids, acylcarnitine and lysophospholipids
which have a detergent effect onmembranes causing changes inpermeability and electrophysiologicalterations.
Cytoskeletal abnormalities:activation of proteases by high Cacauses damage to the elements of
cytoskeleton.
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Consequences of membranedamage
Most important sites of membranedamage: mitochondrial, plasmamembrane and lysosomal.
Lysosomes contain many degradingenzymes like RNases, DNases,proteases.....
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Damage to DNA andproteins
Usually cells have mechanisms torepair DNA damage but if thedamage is severe the cells initiate a
suicide program results in cell deathby apoptosis.
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Concluding points
The identification of factors thatdetermine when reversible injurybecomes irreversible and progresses to
cell death would be very useful so wemay be able to identify strategies toprevent permanent consequences of cell
injury. Leakage of intracellular proteins into
blood through damaged membranesprovides a means of detecting tissue
damage. CK & troponin in MI and ALT,
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Ischemic and hypoxic injury
Most common type of injury inclinical medicine.
Hypoxia: anaerobic glycolysis
Ischemia: delivery of substrates isalso compromise.
Ischemia is more rapidly damagingthan hypoxia in the absence ofischemia.
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Mechanisms of ischemicinjury
Low O2 leads to loss of oxidativephosphorylation and decreasedgeneration of ATP.
Na/K and Ca pumps failure.
Progressive loss of glycogen anddecreased protein synthesis.
Loss of function though the cell is notyet dead.
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Mechanisms of ischemicinjury
Cytoskeleton abnormalities; blebsand 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 tothe plasma membranes, myelinfigures formation and swelling oflysosomes.
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Mechanisms of ischemicinjury
Large densities develop in themitochondria.
Massive influx of Ca happens
especially if the ischemic area isreperfused.
Death is mainly by necrosis but
apoptosis also takes place. Dead cells may become replaced by
large masses of myelin figures whichare either phagocytosed or degraded
more into fatty acids.
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Mechanisms of ischemicinjury
Protective responses: Hypoxia-inducible factor-1; promotes newblood vessel formation, stimulates
cell survival pathways and enhancesanaerobic glycolysis.
Still no reliable therapeutic measureto reduce consequences of ischemiaclinically.
Induction of hypothermia (33.4 ) inischemic brain and spinal injuries
may help in reducing the effects of
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Ischemia- reperfusion injury
Restoration of blood flow to ischemictissues can promote recovery if theyare reversibly injured.
In certain situations, reperfusionparadoxically exacerbates injury(more dead cells in addition to the
already irreversibly injured cells).
Mechanisms:
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Ischemia- reperfusion injury
Reoxygenation: increasedregeneration of reactive oxygen andnitrogen species from parenchymal
and endothelial cells and leukocytes.Ca influx.
Inflammation response mediated bycytokines which recruits moreleukocytes and more injury. Applyingof Anti-cytokines might aid indecreasing the unwanted effects of
inflammation.
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Ischemia- reperfusion injury
Activation of the complementsystem: Some IgM antibodies aredeposited in ischemic tissues for
unknown reasons and once the bloodis restored complement proteins bindto those antibodies and lead to more
injury.
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Chemical injury
Major problem. Drugs.
Liver as a major site of drugmetabolism is a target for drug
toxicity. Mechanisms:
Directly by combining with critical
molecular component. Examplemercuric chloride poisoning bind tothe sulfhydryl groups of cellmembrane proteins causing
increased permeability. More in GIT
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Chemical injury
Cyanide poisons mitochondrialcytochrome oxidase and inhibitsoxidative phosphorelation
Most chemicals are not biologicallyactive and need to be converted intoactive forms (toxic metabolites)which usually takes place in liver( cytochrome P-450 mixed-functionoxidases). Free radical formation andlipid peroxidation. CCl4 is converted
to CCl3 which causes lipid
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Chemical injury
Acetaminophen (paracetamol)converted to to toxic products in liverleading to injury.
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Apoptosis
Pathway of cell death induced by asuicide program in which activationof degrading enzymes takes place.
Apoptotic cells break up intofragments called apoptotic bodieswhich contain portions of thecytoplasm and nucleus. Becometargets for phagocytosis before theircontents leak out and so there wouldbe no inflammatory reaction.
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Apoptosis
Occurs normally during developmentand adulthood and in pathologicconditions.
Physiologic situations:
Embryogenesis, involution ofhormone-dependent tissues uponhormone withdrawal, cell loss inproliferating cell populations anddeath of host cells after serving their
usful function.
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Apoptosis
Pathologic situations: (no hostreaction)
DNA damage, accumulation ofmisfolded proteins (Excessiveaccumulation of these proteins in theER called ER stress), certain
infections (viral ones), pathologicatrophy in parenchymal organs afterduct obstruction (pancreas, parotid
and kidney)