cell injury
TRANSCRIPT
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