AdaptedCell

+ Stress

InjuryInjury

Normal cell

Reversibly injured cell

Irreversibly Injured cell

Dead cell

+Stress

ApoptosisApoptosis

NecrosisNecrosis

- Stress

- Stress

OverviewOverview

Causes of Cell Injury

• Oxygen Deprivation• Physical Agents• Chemical Agents and Drugs• Infectious Agents• Immunologic Reactions• Genetic Derangements• Nutritional Imbalances

Oxygen Deprivation

• Hypoxia – deficiency of oxygen• Ischemia – loss of blood supply (arterial flow

or reduced venous drainage)

Physical Agents

• Mechanical trauma• Extremes of temperature – burns, deep cold• Radiation• Electric shock

Chemical Agents and Drugs

• Hypertonic concentration of salt – deranging electrolyte homeostasis

• Poisons – arsenic, cyanide, or mercuric salts• Insecticides and Herbicides• Air pollutant – carbon monoxide• Occupational hazard – asbestos• Alcohol and Narcotic drugs

Infectious Agents

• Parasites• Fungi• Bacteria• Rickettsiae• Viruses

Immunologic Reactions

• Anaphylactic reaction to foreign protein or drug

• Reactions to endogenous self-antigens – autoimmune diseases

Genetics Derangements

• Congenital malformation – Down syndrome• Decreased life of red blood cell – Thalassemia,

Sickle cell anemia• Inborn errors of metabolism

Nutritional Imbalances

• Protein-calorie deficiencies• Vitamin deficiencies• Anorexia nervosa• Excesses of lipids – Obesity, Atherosclerosis• Metabolic diseases – Diabetes

Mechanisms of Cell Injury• Depletion of ATP• Mitochondrial Damage• Influx of Intracellular Calcium and Loss of Calcium

Homeostasis• Accumulation of Oxygen-Derived free radical

(Oxidative stress)• Defects in Membrane Permeability

Depletion of ATP

Na+K+ATPase (Na-pump), Ca2+Mg2+ ATPases (Ca-pump)

CausesCauses

Hypoxia, Ischemia

Chemical Injury

Membrane transport

Protein synthesis, Lipogenesis etc

ATP

Na+

K+

Ca2+

Depletion of ATPDepletion of ATP

Mitochondrial DamageCausesCauses

Hypoxia, Toxins

Cytosolic Ca2+

Oxidative stress

Lipid breakdown product

Mitochondrial Damage

• Mitochondrial permeability transition of inner membrane (formation of high-conductance high-conductance channelchannel)

• Leakage of Cytochrome cCytochrome c into cytosol

ATP productionATP production

Mitochondrial Oxidative Phosphorylation

Mitochondrial Mitochondrial DamageDamage

Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)

• The Oxidation-Reduction reaction (normal metabolic processes)

-superoxide anion (O2-)

-hydrogen peroxide (H2O2)

-hydroxyl ion (OH )

Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)

• Absorption of radiant energy (ultraviolet light: UV, X-ray)

HH2200

Ionizing radiationIonizing radiation

OHOH HH

Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)

• Transition Metals – iron, copper

HH220022 OHOH--OHOHFe3+Fe2+

“Fenton reaction”

Effects of the free radicals on cell injury

• Lipid peroxidation of Membranes - Plasma membrane - Organellar membrane

Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)

Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids

membrane damagemembrane damage

Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)

Effects of the free radicalsEffects of the free radicals

• Oxidative modification of proteins -Oxidation of amino acid side chains

Protein-protein cross-linkages -Oxidation of the protein backbone

Protein fragmentation

Accumulation of Oxygen-Derived Free Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)Radicals (Oxidative Stress)

Effects of the free radicalsEffects of the free radicals• Lesions in DNA

Reaction with Thymine

DNA single-stranded break

DNA fragmentation

Superoxide dismutase Superoxide dismutase (SOD)(SOD)

Defects in Membrane Permeability

• Mitochondrial Dysfunction -Decreased phospholipid synthesis -Phospholipase activation• Loss of Membrane phospholipid

Mechanism of Membrane damage in Cell Injury

Defects in Membrane Permeability

• Cytoskeletal Abnormality

• Reactive Oxygen species

• Lipid breakdown products (detergen effect on membrane)

Mechanism of Membrane damage in Cell Injury

Cytosolic Ca+ proteaseprotease

Cellular and biochemical Cellular and biochemical sites of damage in cell sites of damage in cell

injuryinjury