5. Mechanisms of Cell Injury

8/3/2019 5. Mechanisms of Cell Injury

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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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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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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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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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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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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)

5. Mechanisms of Cell Injury

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