Cell Injury: Mechanisms and Examples Flashcards
Causes of cell injury
1) O2 deprivation (hypoxia, iscehmia)
2) physical agents: mechanical truma, extreme temperatures, sudden changes in atmospheric pressure, radiation, electric shock
3) chemicals, toxins, drugs- arsenic, cyanide, mercury, insecticides, benzene, asbestos, CO, drug OD
4) infectious agents: viruses, bacteria, fungi, parasites
5) IR- immune system–injurious reactions to endogenous self-antigens responsible for several autoimmune disease; IR to external agents (microbes and enviro substances) also causes of cell and tissue injury
6) genetic derangements- gene defects resulting in malformations and enzyme defects causing functional impairments
7) nutritional deficiencies and imbalances- undernutrition, vitamins/mineral deficiencies, overnutrition (excess dietary cholesterol, lipids, glucose, vit. A and D)
Structural/biochemical targets and mechanisms in cell injury
1) energy production: decreased ATP production, usually d/t mitochondrial damage–> results in multiple downstream effects
2) calcium homeostasis: excess Ca2+, increased mito permeability and acitvation of multiple cellular enzymes
3) oxidative damage: ROS–> damage to lipids, proteins and DNA
4) membrane integrity: if plasma membrane damaged, loss of cellular components; if lysosomal membrane damaged, get enzymatic digestion of cellular components.
5) protein mis-folding and degradation (ER stress): activation of pro-apoptotic proteins
Role of mitochondrial damage in cell injury and death
Increased cytosolic Ca2+
ROS and lipid peroxidation all result in mito injury or dysfunction–>decreased ATP production–> hydrogen moves out of cell and there’s a transition in mitochondrial permeability–> loss of membrane potential and inability to generate ATP–> necrosis
If cytochrome C or other pro-apoptotic proteins are affected, apoptosis will occur.
Mito damage: decreased ATP leads to 1) impaired function of Na+/K+ pump 2) decreased protein synthesis 3) increased glycolysis (d/t lack of O2 from ox phos) increase in lactic acid, decrease in pH–> chromatin clumping.
Mechanisms of cellular swelling and progression to “vacuolar/hydropic” conditions
With injury/degeneraton–> ATP production decrease–> Na+ and H2O move into cell and K+ moves out–> osmotic pressure increases–> more water moves into cell–> cisternae of ER distends, ruptures and form vacuoles–> extensive vacuolation–> hydropic degeneration
Get a marked over-swelling of cell.
Appearance of hydropic degeneration
Gross: hydropic degeneration due to hypoxia–> organs look enlarged, pale and turgid
Microscopic: cell cytoplasm is pale, finely vacuolated. If hydropic degeneration is extreme=ballooning degeneration. In this case, ctyoplasm is clear.
Pathogenesis of hydropic degeneration
Increased water influx–> cytoplasmic swelling, with organelle swelling and disintegration.
Example: epithelial cell ballooning degeneration in a cow with papular stomatitis due to poxvirus. Very prominent swelling of keratinocytes
Example: Orf (contagious echytema- parapoxvirus): diffuse swelling and ballooning of keratinocytes- results in proliferative lesions on muzzle.
Sequence of events in reversible cell injury
Normal cell–>injury–> swelling of ER and mito–> clumping of chromatin–> recovery–>normal cell
Generalized cell and organelle swelling
blebbing of plasma membrane and detachment of ribosomes from ER
clumping of nuclear chromatin.
these changes are associated with: decreased ATP production, loss of cell membrane integrity, defects in protein synthesis, cytoskeletal damage, DNA damage.
Sequence of events in irreversible cell injury
Normal cell–>injury–>swelling of ER and mitochondrion, clumping of chromatin–> death
Cell death–> swelling of ER and mito, clumping of chromatin–> swollen mito with amorphous densities and nuclear condensation–> necrosis–> fragmentation of cell membrane nucleus.
Severe ER swelling- detachment of ribosomes
Severe mitochondrial swelling- disruption of cristae, presence of amorphous densities in the matrix
Lysosomal rupture- lytic enzymes release in cytoplasm and degrade cellular proteins
Cell membrane blebs progress to membrane fragmentation
Further nuclear shrinkage and condensation with nuclear membrane rupture and chromatin fragmentation
Example of reversible and irreversible cell injury: epithelial cell of proximal convoluted tubule
Normal epithelial cell of PCT with abundant microvilli lining luminal surface
PCT epithelial cell with early cell injury resulting from reperfusion ischemia: microvilli are lost and incorporated in apical cytoplasm. Blebs have formed and are extruded in the lumen. Mito would have been swolling during ischemia; with reperfusion, they rapidly undergo condensation.
PCT epithelial cell with late (irreversible) injury: markedly swollen mito containing electron-dense deposits–> expected to contain precipitated calcium and proteins; disrupted plasma membrane, swelling and fragmentation of organelles, nuclear condensation.
Increased cytosolic calcium in cell injury
excessive level of calcium is toxic to cell
Sources of calcium: extracellular space, mito, smooth ER
Injurious agent–> Ca2+ comes into cell–>activation of cellular enzymes and increase in mito permeability
Increased cytosolic Ca2+ activates: 1) phospholipase-decrease phospholipids–>membrane damage 2) protease-disrupt membrane and cytoskeletal proteins–>membrane damage 3) endonuclease–>nuclear damage 4) ATPase–>decreased ATP production (also decreased ATP due to mito damage)
Oxidative stress
d/t ROS
Generation of free radicals: 1) redox reactions during normal metabolism 2) absorption of radiant energy (UV, X-rays) 3) rapid bursts of ROS by activated leukocytes esp. neutrophils during inflamm. 4) enzymatic metabolism of exogenous checmicals or drugs can generate free radicals that aren’t ROS but have similar effects 5) transition metals (Fe or Cu) donate or accept free electrons during intracellular reactions and catalyze formation of free radicals 6) Nitric oxide, mediator generated by endothelial cells, macs and neurons can act as a free radical and be converted to highly reaction ONOO-
ROS in cell injury: inflammation, radiation, O2 toxicity, chemicals, reperfusion injury. Free radicals can either injure cell or get neutralized and have no effect on cell.
Hypoxia
oxygen deficiency
Partial reduction in O2–>anaerobic glycolysis continues
complete reduction of O2= anoxia
Possible causes of hypoxia: heart or resp. failure, loss of blood supply (ischemia), reduced O2 transport in blood (anemia, CO toxicity), blockage of cell resp. enzymes (cyanide)
Example of cell injury d/t hypoxia: hepatocytes
Zone 1 (near portal triad) is least sensitive to hypoxia. Zone 3 (near central vein) is most sensitive to hypoxic injury.
Passive venous congestion: increased pressure in hepatic veins and venules relative to portal venules.
Possible causes: congestive HF, partial obstruction of larger hepatic veins or caudal VC (abscess, neoplasm, thrombus, heartworm)
Chronic passive congestion results in “nutmeg liver”: red centrilobular zones of congestion with loss of hepatocytes (necrosis), with pale swollen periportal hepatocytes with fatty degeneration.
Acute passive congestion: sudden engorgment with blood- anaphylaxis, shock or other acute insult.
Ischemia
reduction or loss of blood supply
- partial reduction of blood supply caused by local impairment of blood flow
- complete reduction of blood supply caused by total impairment
Possible causes: thrombosis, mechanical intereference with blood flow caused by 1) space occupying lesions compressing BVs 2) displacement of organs causing stretching and torsion of vessels with impairment of blood flow.
Structural changes and biochemical pathway disruption in ischemic cell injury
Thrombus (iscehmia) causes:
–>membrane injury–> loss of phospholipids, cytoskeletal alterations, free radicals, lipid breakdown–> leakage of enzymes and increased Ca2+ influx
–>decreased ox phos d/t injured mito–> decreased ATP
Decrease ATP causes:
–>decreased sodium pump–>increased influx of Ca2+, water and efflux of K+–>cellular swelling, loss of microvilli, blebs, ER swelling, myelin figures
–>increased glycolysis–>decreased pH–>clumping of nuclear chromatin and intracellular release and activation of lysosomal enzymes
–>detachment of ribosomes–>decreased protein synthesis–>lipid deposition.
nb: increased glycolysis–> decreased glycogen.
