Cell InjuryCell Injury
Robert Low MD PhDRobert Low MD PhD
•sites within cells that are easily injured
•reversibility of injury and complete recover
•adaptation to chronic injury
•cell death-necrosis vs apoptosis
Hypoxic injury-starving cells/tissues for oxygen;problems of too much oxygen and cell damagefrom oxygen radicals
Cell and tissue injuryproduce human disease
Injury-acute vs chronic
#1
•Human disease occurs because ofinjury to cells/tissue
Cell Injury– Damage or alteration of one or more cellular componentsCell Injury– Damage or alteration of one or more cellular components
1.Many types of injury we incur are tissue specificbecause of anatomic relationships and thetissue tropism of chemical and infectious agents.1.Many types of injury we incur are tissue specificbecause of anatomic relationships and thetissue tropism of chemical and infectious agents.
2.Cell injury perturbs cell physiology; the cell doesnot function at full capacity.2.Cell injury perturbs cell physiology; the cell doesnot function at full capacity.
Basic Types of TissuesBasic Types of Tissues
1.Epithelium1.Epithelium
2.Muscle (skeletal, smooth, cardiac)2.Muscle (skeletal, smooth, cardiac)
3.Nerve (CNS, PNS)3.Nerve (CNS, PNS)
4.Connective (bone, cartilage, softtissue, adventitia, ligaments, bloodand lymph, etc)4.Connective (bone, cartilage, softtissue, adventitia, ligaments, bloodand lymph, etc)
#2
•Most human disease results from injuryto Epithelium
Epithelium arises from eachof three germ layersEpithelium arises from eachof three germ layers
1.Cells cover external surfaces (skin); lineinternal closed cavities, secretory glandsand tubes- -GI, respiratory, GU tracts- -thatcommunicate with external surfaces1.Cells cover external surfaces (skin); lineinternal closed cavities, secretory glandsand tubes- -GI, respiratory, GU tracts- -thatcommunicate with external surfaces
2.Also includes liver, exocrine pancreas,parotid glands, thyroid, parathyroid,epithelium of kidney2.Also includes liver, exocrine pancreas,parotid glands, thyroid, parathyroid,epithelium of kidney
3.Also: vascular endothelium, mesothelium3.Also: vascular endothelium, mesothelium
#3
•Injury to one tissue usually affects theadjacent or underlying tissue as well
Cell Injury Produces:Cell Injury Produces:
1.Signs- abnormal physical findings1.Signs- abnormal physical findings
2.Symptoms- complaints experienced2.Symptoms- complaints experienced
by the patientby the patient
Cell Injury Produces: (cont)Cell Injury Produces: (cont)
3.Morphologic change- A visualchange in the cell shape or appearance,seen when cells are stained and viewedby light microscopy; or examined byE.M. in the injured tissue; or seen“grossly” with the naked eye.3.Morphologic change- A visualchange in the cell shape or appearance,seen when cells are stained and viewedby light microscopy; or examined byE.M. in the injured tissue; or seen“grossly” with the naked eye.
Outcomes from cell injurydepend upon:Outcomes from cell injurydepend upon:
1.Type of injury1.Type of injury
2.Severity of the injury2.Severity of the injury
3.Duration of the damage3.Duration of the damage
4.Type of cell being injured- Some celltypes sustain injury better than others;some tissues (e.g. liver) have acapacity to regenerate.4.Type of cell being injured- Some celltypes sustain injury better than others;some tissues (e.g. liver) have acapacity to regenerate.
Cell Injury: Vulnerable SitesCell Injury: Vulnerable Sites
1.Cell membranes1.Cell membranes
2.Mitochondria2.Mitochondria
3.Endoplasmic reticulum3.Endoplasmic reticulum
4.Nucleus4.Nucleus
Cell Membrane- why so easily injuredCell Membrane- why so easily injured
1.Membrane faces the external environment:sustains “trauma”, extracellular oxidants,proteases, etc.1.Membrane faces the external environment:sustains “trauma”, extracellular oxidants,proteases, etc.
2.Requires a constant supply of ATP fornormal function (ion pumps).2.Requires a constant supply of ATP fornormal function (ion pumps).
3.Lipid molecules in the membrane are easilyoxidized and support and oxidative chainreaction called lipid peroxidation.3.Lipid molecules in the membrane are easilyoxidized and support and oxidative chainreaction called lipid peroxidation.
Consequences of InjuryConsequences of Injury
1.No long term effects- - the celldamage is repaired, the effects of theinjury are reversible.1.No long term effects- - the celldamage is repaired, the effects of theinjury are reversible.
2.The cell ”adapts” to the damagingstimulus.2.The cell ”adapts” to the damagingstimulus.
3.The cell dies, undergoing necrosis.The damage is irreversible.3.The cell dies, undergoing necrosis.The damage is irreversible.
Reversible Cell InjuryReversible Cell Injury
Examples:Examples:
1.Cell swelling – usually accompanies alltypes of injury. Results from an increase inwater permeability. Reverses oncemembrane function is restored.1.Cell swelling – usually accompanies alltypes of injury. Results from an increase inwater permeability. Reverses oncemembrane function is restored.
2.Increase in extracellular metabolitebecause of a biochemical derangement.Ex.: Increase in extracellular glycogen indiabetes.2.Increase in extracellular metabolitebecause of a biochemical derangement.Ex.: Increase in extracellular glycogen indiabetes.
Reversible Cell Injury (cont)Reversible Cell Injury (cont)
Examples:Examples:
3.Fatty change in liver. Vacuoles of fataccumulate within the liver cell following manytypes of injury: alcohol intoxication, chronicillness, diabetes mellitus, etc.3.Fatty change in liver. Vacuoles of fataccumulate within the liver cell following manytypes of injury: alcohol intoxication, chronicillness, diabetes mellitus, etc.
Due to: An increase in entry of free fatty acids.Due to: An increase in entry of free fatty acids.
An increase in synthesis of free fatty acids. An increase in synthesis of free fatty acids.
A decrease in fatty acid oxidation. A decrease in fatty acid oxidation.
Adaptation- the cell respondssuccessfully to the injurious stimulusAdaptation- the cell respondssuccessfully to the injurious stimulus
Examples:Examples:
1.Hypertrophy- the cell increases insize. Ex.: cardiac myocytes of the leftventricle increase in size fromessential hypertension.1.Hypertrophy- the cell increases insize. Ex.: cardiac myocytes of the leftventricle increase in size fromessential hypertension.
2.Atrophy- the cell decreases in sizebecause of a loss of cell substance.2.Atrophy- the cell decreases in sizebecause of a loss of cell substance.
Causes of Cell AtrophyCauses of Cell Atrophy
1.Loss of blood supply or innervation1.Loss of blood supply or innervation
2.Loss of endocrine factors (ex. TSH)2.Loss of endocrine factors (ex. TSH)
3.Decrease in the workload3.Decrease in the workload
4.Aging, chronic illness4.Aging, chronic illness
Cell Death
•Necrosis
•Apoptosis
Morphology of NecrosisMorphology of Necrosis
Coagulative NecrosisCoagulative Necrosis
•Dead cell remains a ghost-likeremnant of its former self-classicallyseen in an MI.•Dead cell remains a ghost-likeremnant of its former self-classicallyseen in an MI.
PyknosisPyknosis
Intensely dark staining and shrunkennucleus, seen in a necrotic (dead) cell.Intensely dark staining and shrunkennucleus, seen in a necrotic (dead) cell.
KaryorrhexisKaryorrhexis
Fragmentation of pyknotic nucleus.Fragmentation of pyknotic nucleus.
KaryolysisKaryolysis
Extensive hydrolysis of the pyknoticnucleus with loss of staining.Represents breakdown of thedenatured chromatin.Extensive hydrolysis of the pyknoticnucleus with loss of staining.Represents breakdown of thedenatured chromatin.
Liquefactive NecrosisLiquefactive Necrosis
The dead cell undergoes extensiveautolysis, caused by the release oflysosomal hydrolases (proteinases,DNases, RNases, lipases, etc.)The dead cell undergoes extensiveautolysis, caused by the release oflysosomal hydrolases (proteinases,DNases, RNases, lipases, etc.)
Seen classically in the spleen andbrain following infarction. Seen classically in the spleen andbrain following infarction.
Caseous NecrosisCaseous Necrosis
Seen in Tuberculosis (mycobacteriumtuberculosis).Seen in Tuberculosis (mycobacteriumtuberculosis).
Type of necrosis seen within infectedtissues characterized as soft, friable,whitish-grey (resembles the milkprotein casein).Type of necrosis seen within infectedtissues characterized as soft, friable,whitish-grey (resembles the milkprotein casein).
Fat NecrosisFat Necrosis
Leakage of lipases from dead cells attacktriglycerides in surrounding fat tissue andgenerate free fatty acids and calcium soaps.Leakage of lipases from dead cells attacktriglycerides in surrounding fat tissue andgenerate free fatty acids and calcium soaps.
These soaps have a chalky-whiteappearance.These soaps have a chalky-whiteappearance.
Seen in the pancreas following acuteinflammation.Seen in the pancreas following acuteinflammation.
Causes of Cell and Tissue InjuryCauses of Cell and Tissue Injury
1.Physical agents1.Physical agents
2.Chemicals and drugs2.Chemicals and drugs
3.Infectious pathogens3.Infectious pathogens
4.Immunologic reactions4.Immunologic reactions
5.Genetic mutations5.Genetic mutations
6.Nutritional imbalances6.Nutritional imbalances
Causes of Cell and Tissue Injury (cont)Causes of Cell and Tissue Injury (cont)
7.Hypoxia and Ischemia-7.Hypoxia and Ischemia-
cell injury resulting from inadequate levelsof oxygen.cell injury resulting from inadequate levelsof oxygen.
Many important causes:Many important causes:
A. Inadequate blood supplyA. Inadequate blood supply
B. Lung diseaseB. Lung disease
C. Heart failureC. Heart failure
D. ShockD. Shock
Why So Important?Why So Important?
All cells in the body require a continuoussupply of oxygen in order to produce ATPvia oxidative phosphorylation inmitochondria.All cells in the body require a continuoussupply of oxygen in order to produce ATPvia oxidative phosphorylation inmitochondria.
ATP is absolutely critical for life.ATP is absolutely critical for life.
Susceptibility of specificcells to ischemic injury- -Susceptibility of specificcells to ischemic injury- -
Neurons: 3 to 5 min.Neurons: 3 to 5 min.
Cardiac myocytes, hepatocytes, renalepithelium: 30 min. to 2 hr.Cardiac myocytes, hepatocytes, renalepithelium: 30 min. to 2 hr.
Cells of soft tissue, skin, skeletal muscle:many hoursCells of soft tissue, skin, skeletal muscle:many hours
Hypoxic Injury- changes which are reversibleHypoxic Injury- changes which are reversible
1.Decrease in extracellular ATP levels1.Decrease in extracellular ATP levels
2.Decrease in the Na pump, with cellswelling2.Decrease in the Na pump, with cellswelling
3.Increase in glycolysis, with a decreasein intracellular pH3.Increase in glycolysis, with a decreasein intracellular pH
4.Decrease in protein synthesis4.Decrease in protein synthesis
Hypoxic Injury- changes which are irreversibleHypoxic Injury- changes which are irreversible
1.Activation of lysosomal enzymes.(recall that lysosomal enzymes areactive at low pH, ca. pH 4-5)1.Activation of lysosomal enzymes.(recall that lysosomal enzymes areactive at low pH, ca. pH 4-5)
2.Degradation of DNA and protein.2.Degradation of DNA and protein.
3.Influx of calcium. (recall that calciumactivates many lipases and proteases)3.Influx of calcium. (recall that calciumactivates many lipases and proteases)
Hypoxic cells are exposed todamage from oxygen radicals-Hypoxic cells are exposed todamage from oxygen radicals-
1.Hypoxic patients are given high levelsof oxygen. This oxygen is toxic to thecells lining the alveolar spaces in thelung because the high 02 producesoxygen radicals.1.Hypoxic patients are given high levelsof oxygen. This oxygen is toxic to thecells lining the alveolar spaces in thelung because the high 02 producesoxygen radicals.
Hypoxic cells are exposed todamage from oxygen radicals-(cont)Hypoxic cells are exposed todamage from oxygen radicals-(cont)
2.Hypoxic tissues are often infiltratedwith PMNs. PMNs have enzymes,myleoperoxidases, which produceactivated oxygen2.Hypoxic tissues are often infiltratedwith PMNs. PMNs have enzymes,myleoperoxidases, which produceactivated oxygen
Hypoxic cells are exposed todamage from oxygen radicals-(cont)Hypoxic cells are exposed todamage from oxygen radicals-(cont)
3.Hypoxic tissues are often reperfusedonce the blood supply is restored.Xanthine oxidase, produced fromproteolysis during hypoxia, generatesfree radicals when the 02 is broughtback to normal levels.3.Hypoxic tissues are often reperfusedonce the blood supply is restored.Xanthine oxidase, produced fromproteolysis during hypoxia, generatesfree radicals when the 02 is broughtback to normal levels.
02- + 02- + 2H+H202 + 0202- + 02- + 2H+H202 + 02
SODSOD
GOOD/BAD REACTIONGOOD/BAD REACTION
BAD REACTIONSBAD REACTIONS
1
2
3
H202 H. + 0H. (very reactive)H202 H. + 0H. (very reactive)
FE++ + H202 FE +++ + 0H. + 0H-FE++ + H202 FE +++ + 0H. + 0H-
H202 + 02- 0H. + 0H- + 02H202 + 02- 0H. + 0H- + 02
FENTON REACTIONFENTON REACTION
HABER-WEISS REACTIONHABER-WEISS REACTION
GOOD REACTIONSGOOD REACTIONS
1
2
GLUTATHIONE PEROXIDASEGLUTATHIONE PEROXIDASE
2 H202 02 + 2H20
2 0H. + 2 GSH2 H20 + GSSG
H202 + 2 GSH 2 H20 + GSSG
