CELL INJURY AND DEATH
By Dr.K.V.Bharathi
Cell injury
• Results when cells are stressed so severely
that they are no longer able to adapt or when
cells are exposed to damaging agents.
• Cell injury can be reversible or irreversible.
Reversible cell injury
• Functional and morphologic changes are
reversible if the damaging stimulus is
removed.
• The features are:decreased oxidative
phosphorylation,ATP depletion and cellular
swelling.
Irreversible injury and cell death.
• With continuing damage,injury becomes
irreversible.
• Cells undergo morphologic changes
recognisable as cell death.
• Cell death is of 2 types-necrosis and apoptosis.
Reversible
Irreversible
Cell death
Effect
Cell
Function
EM
Changes
LM
Changes
Gross
Changes
Duration of injury
Reversible and irreversible injury
Necrosis
• With severe membrane damage,lysosomal
enzymes enter cytoplasm & digest cell wall.
• Cellular contents leak out.
• Necrosis is always pathologic.
Apoptosis
• Programmed cell death.
• Noxious stimuli that damage DNA result in
nuclear dissolution without complete loss of
cell membrane integrity.
• Can be physiologic or pathologic.
Causes of cell injury
• Oxygen deprivation.
• Physical agents eg:mechanical trauma,burns,deep
cold,barotrauma,electric shock.
• Chemical agents & drugs eg:poisons,environmental
pollutants,CO,asbestos,alcohol,narcotic drugs etc.
• Infectious agents-viruses,rickettsiae,bacteria,fungi,protozoa
and helminths.
• Immunologic reactions-anaphylaxis,autoimmune disorders.
• Genetic derangements.
• Nutritional imbalances-PEM,obesity,specific vitamin
deficiencies etc.
Mechanisms of cell injury
• Depletion of ATP-affects activity of Na,K-ATPase
pump.This results in anaerobic glycolysis.
• Mitochondrial damage-leakage of cytochrome-C into
cytosol,resulting in apoptosis.
• Influx of Ca & loss of Ca homeostasis,leading to
activation of ATPases,phospholipases,proteases &
endonucleases.
ATPases
• Hasten ATP depletion.
• Phospholipases cause membrane damage.
• Proteases breakdown membrane &
cytoskeletal proteins.
• Endonucleases cause DNA & protein
fragmentation.
Free radical injury
• Oxygen derived.
• Free radicals are chemical species that have a
single unpaired electron in an outer orbit.
• Energy created by this unstable configuration
is released through reactions with adjacent
molecules.
• They initiate autocatalytic reactions.
Free radicals are initiated by:
• Absorption of radiant energy(u-v or ionising):Water
is hydrolysed to(OH)&(H) free radicals.
• Enzymatic metabolism of exogenous chemicals or
drugs ,eg:CCl4 converted to CCl3.
• Redox reactions in the cell: (O2),(H2O2) &(OH).
• Transition metals like iron and copper.
• Nitrous oxide.
Effects of free radicals:
• Lipid peroxidation of membranes.
• Oxidative modification of proteins.
• Lesions in DNA.
Inactivation of free radical
reactions.
• Can be enzymatic or non-enzymatic.
• Enzymatic:catalase,superoxide
dismutases,glutathione peroxide.
• Non-enzymatic:-Antioxidants eg: Vitamins A,E,C
& glutathione .
•
-Binding of iron & calcium with
storage & transport proteins
eg:transferrin,lactoferrin,ceruloplasmin.
• Defects in membrane permeability can affect
mitochondria,plasma membrane,other cellular
membranes.
Mechanisms
•
•
•
•
•
Mitochondrial dysfunction.
Loss of membrane phospholipids.
Cytoskeletal abnormalities.
Reactive O2 species.
Lipid breakdown products.
Earliest changes in reversible cell
injury are:
•
•
•
•
•
Decreased generation of ATP.
Loss of cell membrane integrity.
Defects of protein synthesis.
Cytoskeletal damage.
DNA damage.
• Within limits,the cell can compensate for these
derangements.Persistent or excessive injury leads to
irreversible injury.
Ischemia
Cell oxygen tension
Reduced ATP
Membrane injury
Loss of phospholipids,
Increase of free radicals
Lipid breakdown
Incr. Glycolysis
Decr. Protein systhesis
Decr glycogen
Lipid deposition
Leakage of cell enzymes
Calcium influx
Intracellular lysosomal
enzyme release
Reversible injury:
cell swelling
microvlli loss
blebs
ER swelling
myelin figures
chromatin clumping
Irreversible injury
Reduced basophilia
Nuclear changes
Protein digestion
Characteristic phenomena of
irreversibility:
• Inability to reverse mitochondrial dysfunction.
• Development of profound disturbances in membrane
function.
• Therefore,in cardiac muscle death there is leakage of
CKMB & troponin.
• In injury to bile duct epithelium & liver,serum
alkaline phosphatase is raised.
• In hepatocyte injury,transaminases are raised.
Light microscopic patterns of
reversible cell injury:
• Cellular swelling & fatty change.
• Morphology in cellular swellingGross:Pallor,increased turgor & increase in organ
weight.
• Micro:small clear vacuoles seen within cytoplasm.
• Fatty change-seen in injured myocardial cells and
hepatocytes.There is appearance of small or large
lipid vacuoles in the cytoplasm.
Necrosis
• A spectrum of morphologic changes that follow
cell death in living tissue,due to progressive
degradative action of enzymes on the lethally
injured cells.
• Leaked out contents of necrotic cells may elicit
inflammation in the surrounding tissue.
• The morphologic appearance is due to
denaturation of proteins and enzymatic digestion.
• The enzymes are derived from lysosomes of the
dead cells themselves-AUTOLYSIS.
Pathology of necrotic cells
• Increased eosinophilia with a glassy homogeneous
appearance as a result of glycogen particles.
• Moth-eaten appearance in cells with vacuolated
cytoplasm due to enzymatic digestion of cytoplasmic
organelles.
• Calcification of dead cells.
• Replacement of dead cells by whorled phospholipid
masses called myelin figures(ultrastructurally).
Nuclear changes in necrotic cells:
• Karyolysis-basophilia of chromatin may fade.
• Pyknosis-nuclear shrinkage and increased
basophilia.
• Karyorrhexis-nuclear fragmentation.
• Disappearance of nucleus.
Coagulative necrosis
• Denaturation of protein is the primary
pattern.
• Basic cell outline is preserved for some days
eg:acute MI.