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.

Effect

Duration of injury

Reversible Irreversible

CellFunction

Cell death E M Changes

L M Changes

Gross Changes

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 Membrane injuryLoss of phospholipids,

Increase of free radicalsLipid breakdownReduced ATP

Incr. GlycolysisDecr. Protein systhesisDecr glycogenLipid deposition

Intracellular lysosomal enzyme release

Leakage of cell enzymesCalcium influx

Reversible injury:

cell swellingmicrovlli lossblebsER swellingmyelin figureschromatin 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 swelling-

Gross: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.