Cell Injury and Cell Death. LO At the end of session student should be able to At the end of session...

At the end of session student should At the end of session student should be able tobe able to

Enlist causes of cell injuryEnlist causes of cell injury Identify effect of injurious agents on Identify effect of injurious agents on

cell cytoplasm and nucleuscell cytoplasm and nucleus

Oxygen DeprivationOxygen Deprivation

Hypoxia – Hypoxia – deficiency of oxygendeficiency of oxygen Ischemia – Ischemia – loss of blood supplyloss of blood supply

(arterial flow or reduced venous (arterial flow or reduced venous drainage) drainage)

Causes of Cell InjuryCauses of Cell Injury

Physical AgentsPhysical Agents

Mechanical traumaMechanical trauma Extremes of temperature – Extremes of temperature – burnsburns, ,

deep colddeep cold RadiationRadiation Electric shockElectric shock

Chemical Agents and DrugsChemical Agents and Drugs

Hypertonic concentration of salt – Hypertonic concentration of salt – deranging electrolyte homeostasisderanging electrolyte homeostasis

PoisonsPoisons –– arsenic, cyanide, or arsenic, cyanide, or mercuric saltsmercuric salts

Insecticides and HerbicidesInsecticides and Herbicides Air pollutant – Air pollutant – carbon monoxidecarbon monoxide Occupational hazard – Occupational hazard – asbestosasbestos Alcohol and Narcotic drugsAlcohol and Narcotic drugs

Infectious AgentsInfectious Agents

ParasitesParasites FungiFungi BacteriaBacteria RickettsiaeRickettsiae VirusesViruses

Immunologic ReactionsImmunologic Reactions

Anaphylactic reaction to Anaphylactic reaction to foreign foreign proteinprotein or or drugdrug

Reactions to endogenous self-Reactions to endogenous self-antigens – antigens – autoimmune diseasesautoimmune diseases

Genetics DerangementsGenetics Derangements

Congenital malformation – Congenital malformation – Down Down syndromesyndrome

Decreased life of red blood cell – Decreased life of red blood cell – Thalassemia, Sickle cell anemiaThalassemia, Sickle cell anemia

Inborn errors of metabolismInborn errors of metabolism

Nutritional ImbalancesNutritional Imbalances

Protein-calorie deficienciesProtein-calorie deficiencies Vitamin deficienciesVitamin deficiencies Anorexia nervosaAnorexia nervosa Excesses of lipids – Excesses of lipids – ObesityObesity, ,

AtherosclerosisAtherosclerosis Metabolic diseasesMetabolic diseases –– Diabetes Diabetes

Mechanisms of Cell InjuryMechanisms of Cell Injury Depletion of ATPDepletion of ATP Mitochondrial DamageMitochondrial Damage Influx of Intracellular Calcium and Loss of Influx of Intracellular Calcium and Loss of

Calcium HomeostasisCalcium Homeostasis Accumulation of Oxygen-Derived free Accumulation of Oxygen-Derived free

radical (radical (Oxidative stressOxidative stress)) Defects in Membrane PermeabilityDefects in Membrane Permeability

Mechanisms of Cell InjuryMechanisms of Cell Injury

Depletion of ATPDepletion of ATP

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

CausesCauses

Hypoxia, Ischemia

Chemical Injury

Membrane transport

Protein synthesis, Lipogenesis etc

Depletion of ATPDepletion of ATP

Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury

CausesCauses

Hypoxia, Toxins

Cytosolic Ca2+

Oxidative stress

Lipid breakdown product

Mitochondrial DamageMitochondrial DamageMechanisms of Cell InjuryMechanisms of Cell Injury

• 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

Influx of Intracellular Calcium Influx of Intracellular Calcium and Loss of Calcium and Loss of Calcium

HomeostasisHomeostasis

Accumulation of Oxygen-Accumulation of Oxygen-Derived Free Radicals Derived Free Radicals

(Oxidative Stress)(Oxidative Stress) The Oxidation-Reduction reaction The Oxidation-Reduction reaction

(normal metabolic processes)(normal metabolic processes)

-superoxide anion (O-superoxide anion (O22--))

-hydrogen peroxide (H-hydrogen peroxide (H22OO22))

-hydroxyl ion (OH )-hydroxyl ion (OH )

(Oxidative Stress)(Oxidative Stress) Absorption of radiant energy Absorption of radiant energy

(ultraviolet light: UV, X-ray)(ultraviolet light: UV, X-ray)

HH2200

Ionizing radiationIonizing radiation

OHOH HH

(Oxidative Stress)(Oxidative Stress) Transition Metals – Transition Metals – ironiron, , coppercopper

HH220022 OHOH--OHOHFe3+Fe2+

“Fenton reaction”

Lipid peroxidation of MembranesLipid peroxidation of Membranes

- Plasma membrane- Plasma membrane

- Organellar membrane- Organellar membrane

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

Effects of the free radicals on cell injuryEffects of the free radicals on cell injury

Double bonds in Double bonds in unsaturated fattyunsaturated fatty acids acids

membrane damagemembrane damage

Effects of the free radicalsEffects of the free radicals Oxidative modification of proteinsOxidative modification of proteins --Oxidation of amino acid side chainsOxidation of amino acid side chains

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

Protein fragmentationProtein fragmentation

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

Reaction with Reaction with ThymineThymine

DNA single-stranded breakDNA single-stranded break

DNA fragmentationDNA fragmentation

Superoxide dismutase Superoxide dismutase (SOD)(SOD)

Defects in Membrane Defects in Membrane PermeabilityPermeability

Mitochondrial DysfunctionMitochondrial Dysfunction

-Decreased phospholipid synthesis-Decreased phospholipid synthesis

-Phospholipase activation-Phospholipase activation Loss of Membrane phospholipidLoss of Membrane phospholipid

Mechanism of Membrane damage in Cell Injury

Cytoskeletal AbnormalityCytoskeletal Abnormality

Reactive Oxygen speciesReactive Oxygen species

Lipid breakdown productsLipid breakdown products

(detergen effect on membrane)(detergen effect on membrane)

Defects in Membrane Defects in Membrane PermeabilityPermeability

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

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Cell Injury and Cell Death. LO At the end of session student should be able to At the end of session...

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