3. Cell Injury.ppt in General veterinary Pathology

3. Cell Injury.ppt in General veterinary Pathology

1. Cell Injury and DeathCell Injury and Death

2. Causes of Cell InjuryCauses of Cell Injury

Oxygen Deprivation – hypoxia - ischemiaOxygen Deprivation – hypoxia - ischemia

Nutritional ImbalancesNutritional Imbalances

Chemical agentsChemical agents

Infectious agentsInfectious agents

Immunological Reaction – anaphylaxis, Immunological Reaction – anaphylaxis,
autoimmunity, immunodeficiencyautoimmunity, immunodeficiency

Physical AgentsPhysical Agents

Genetic Defects –Down’s syndrome to Genetic Defects –Down’s syndrome to
substitution of one amino acid in Hb substitution of one amino acid in Hb
resulting in sickle cell anemiaresulting in sickle cell anemia

3. Factors Affecting Cell InjuryFactors Affecting Cell Injury

Cellular response to injurious stimuli Cellular response to injurious stimuli
depends upon type of injury, its depends upon type of injury, its
duration, and its severityduration, and its severity

The consequences of an injurious The consequences of an injurious
stimulus depend on the type of stimulus depend on the type of
injury, status, adaptability, and injury, status, adaptability, and
genetic makeup of the injured cellgenetic makeup of the injured cell

5. Changes following Physiological Changes following Physiological
Stress or Pathological StimuliStress or Pathological Stimuli

Cell injuryCell injury
–ReversibleReversible
–Irreversible – cell deathIrreversible – cell death

Necrosis and ApoptosisNecrosis and Apoptosis

Adaptive changesAdaptive changes

7. General Biochemical MechanismsGeneral Biochemical Mechanisms

ATP depletion – cyanide poisoningATP depletion – cyanide poisoning
–Maintenance of cellular osmolarityMaintenance of cellular osmolarity
–Transport processesTransport processes
–Protein synthesisProtein synthesis
–Basic metabolic pathwaysBasic metabolic pathways

Oxygen deprivation – ischemiaOxygen deprivation – ischemia

Generation of reactive oxygen species – Generation of reactive oxygen species –
Radiation, toxins, chemicalsRadiation, toxins, chemicals
–Lipid per oxidationLipid per oxidation
Cont….

9. Glycolytic PathwayGlycolytic Pathway

10. Tricarboxilic acid cycleTricarboxilic acid cycle

11. 
Loss of calcium homeostasis Loss of calcium homeostasis
–10,000 times less Ca in the 10,000 times less Ca in the
cellscells
–Ischemia or toxinsIschemia or toxins
–Activate Activate phospholipasesphospholipases, ,
proteasesproteases, and , and endonucleasesendonucleases

Defects in plasma membrane Defects in plasma membrane
permeability permeability
–Bacterial toxinsBacterial toxins
–Viral proteinsViral proteins
–Complement componentsComplement components
–Cytotoxic lymphocytesCytotoxic lymphocytes
–A number of pys. & chem. A number of pys. & chem.
AgentsAgents
–Loss of ATP generationLoss of ATP generation
–Calcium mediated Calcium mediated
phospholipase activityphospholipase activity
–Breakdown of concentration Breakdown of concentration
gradientgradient
Cont…….

12. 
Mitochondrial Mitochondrial
dysfunction induced dysfunction induced
by variety of stimuli, by variety of stimuli,
causes a causes a
mitochondrial mitochondrial
permeability permeability
transition, which leads transition, which leads
to to decay of the proton decay of the proton
gradient necessary for gradient necessary for
ATP generation,ATP generation, as as
well as well as releasing releasing
cytochrome C from cytochrome C from
the mitochondria into the mitochondria into
the cytosolthe cytosol

13. Three common forms of cell injuryThree common forms of cell injury

Ischemic and hypoxic injuryIschemic and hypoxic injury

Free radical injuryFree radical injury

Toxic injuryToxic injury

14. Ischemic and Hypoxic InjuryIschemic and Hypoxic Injury

Ischemia injures tissues Ischemia injures tissues
much faster than much faster than
hypoxiahypoxia

Depletion of glycogen, Depletion of glycogen,
accumulation of lactic accumulation of lactic
acid and inorganic acid and inorganic
phosphate, lowering the phosphate, lowering the
pHpH

Ribosomes detach from Ribosomes detach from
RER– reduction in RER– reduction in
protein synthesisprotein synthesis

16. Free Radical-Induced InjuryFree Radical-Induced Injury
How the free radicals are generated:How the free radicals are generated:
–Reduction oxidation reactions, xanthine Reduction oxidation reactions, xanthine
oxidase, fenton reaction,oxidase, fenton reaction,
–Nitric oxideNitric oxide
–Absorption of radiant energy, ionizing radiationAbsorption of radiant energy, ionizing radiation
–Enzymatic metabolism of exogenous chemicals Enzymatic metabolism of exogenous chemicals
(CCl(CCl
44))

Effects:Effects:
–Lipid peroxidationLipid peroxidation
–DNA fragmentation– thymineDNA fragmentation– thymine
–Cross linking of proteins-loss of enzymatic Cross linking of proteins-loss of enzymatic
activityactivity

17. Superoxide dimutase (SOD)

18. Superoxide dimutaseSuperoxide dimutase
2O2O
22
--
2H --- 2H --- H H
22OO
22 + O + O
22
Glutathione peroxidaseGlutathione peroxidase
2OH2OH
--
+2GSH - +2GSH - 2H 2H
22O = GSSGO = GSSG
CatalaseCatalase
2H2H
22OO
22 -- -- O O
22 + H + H
22OO

19. Chemical InjuryChemical Injury

Some chemicals act directly by combining with a Some chemicals act directly by combining with a
critical molecular component or cellular organelle critical molecular component or cellular organelle
–Mercuric chloride-sulfhydral group of various cell Mercuric chloride-sulfhydral group of various cell
membrane proteinsmembrane proteins
–AntibioticsAntibiotics
–antineoplastic therapeutic agentsantineoplastic therapeutic agents

Many chemicals are not intrinsically biologically Many chemicals are not intrinsically biologically
active but must be first converted to reactive active but must be first converted to reactive
metabolites, which then act on target cells. P-450 metabolites, which then act on target cells. P-450
oxidase. oxidase. CClCCl
4 4  CCl CCl
33
(toxic free radical causing (toxic free radical causing
membrane peroxidation)membrane peroxidation)
ATPase dependent transport of ions and increased membrane permeability
Membrane damage by combining directly with lipids and proteins
Main action through formation of free radicals