F97 Videodisc Lectures

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Todays Quranic verse
But to those who believe and do deeds of
righteousness, He will give their (due) rewards,
and more, out of His bounty But those who are
disdainful and arrogant, He will punish with a
grievous penalty Nor will they find, besides
God, any to protect or help them. 004173 
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CELL INJURY
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Principles of Cell Injury

• Dependent upon the etiology, duration, and
  severity of the inciting injury
• Dependent upon cell type, stage of cell cycle,
  and cell adaptability
• Cellular membranes, mitochondria, endoplasmic
  reticulum, and the genetic apparatus are
  particularly vulnerable
• Injury at one focus often has a cascade effect
• Morphologic reactions occur only after critical
  biochemical (molecular) damage

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• Normal cell is in a steady state Homeostasis
• Change in Homeostasis due to stimuli - Injury
• Response to Injury
• Reversible (adaptation)/ Irreversible (cell
  death)
• Adaptive Responses
• Atrophy
• Hypertrophy
• Hyperplasia
• Metaplasia

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• Reversible vs. Irreversible Injury
• Cell injury is a continuum, and it is not
  possible to identify the exact point at which
  injury becomes irreversible.
• However, some ultrastructural and light
  microscopic changes are associated with each form
  of injury.
• Once an irreversible injury occurs, the cell
  undergoes necrosis, which is the
  light-microscopic hallmark of cell death.

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• In general, permanent organ injury is
  associated with the death of individual cells.
• By contrast, the cellular response to
  persistent sub-lethal injury, whether chemical or
  physical, reflects adaptation of the cell to a
  hostile environment. These changes are, for the
  most part, reversible on discontinuation of the
  stress
• If the acute stress to which a cell must react
  exceeds its ability to adapt, the resulting
  changes in structure and function lead to the
  death of the cell

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Causes of Cell Injury

• Hypoxia
• Physical agents including Radiations
• Chemicals and Drugs
• Microbiologic Agents
• Immunologic Reactions
• Genetic Defects
• Nutritional Imbalances

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Mechanisms of Cell Injury
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Mechanisms of Cell Injury

• Ischemia/Hypoxia
• Activated Oxygen Species(O2.-, H2O2, OH. )
• Radiation
• Inflammation
• Oxygen toxicity
• Chemicals
• Reperfusion injury
• Others
• Chemicals
• Infectious agents
• Mechanical disruption
• Deficiency of essential metabolites
• Damage to DNA

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MECHANISMS OF CELL INJURY
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• ISCHEMIC AND HYPOXIC
• INJURY

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• Reversible Injury
• - Decreased oxidative phosphorylation
• reduced ATP
• increased cytosolic free calcium
• reduced activity of sodium pump
• accumulation of sodium by cell
• is-osmotic gain of water (swelling)
• diffusion of potassium from cell

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• - Increased Cytosolic Calcium (activates enzymes)
• ATPase
• decreased ATP
• Phospholipase
• decreased phospholipids
• Endonuclease
• nuclear chromatin damage
• Protease
• disruption of membrane and cytoskeletal
  proteins

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• - Increased anaerobic glycolysis
• glycogen depletion
• lactic acid accumulation
• accumulation of inorganic phosphates
• reduced intracellular pH

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• - Detachment of ribosomes
• reduced protein synthesis
• - Worsening mitochondrial function
• - Increasing membrane permeability
• - Cytoskeleton dispersion
• loss of microvilli
• formation of cell surface blebs

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• Reversible Injury results in
• Swelling of mitochondria, endoplasmic reticulum,
  and entire cells

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• Irreversible Injury
• Mitochondrial changes
• severe vacuolization
• amorphous calcium-rich densities
• Extensive plasma membrane damage
• Prominent swelling of lysosomes
• Massive influx of calcium (on reperfusion)
• Continued loss of cell proteins, coenzymes,
  ribonucleic acids and other metabolites
• Leakage of enzymes measured in serum

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• Injury to lysosomal membranes
• leakage of degradative enzymes
• activation of acid hydrolases due to reduced
  intracellular pH with degradation of cell
  components
• Prominent leakage of cellular enzymes
• Influx of macromolecules from interstitium
• Myelin figures-whorled phospholipid masses

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• FREE RADICAL MEDIATION OF CELL INJURY

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• Free Radical Injury Contributes to
• Chemical and radiation injury
• Oxygen and other gaseous toxicity
• Cellular aging
• Microbial killing by phagocytic cells
• Inflammatory damage
• Tumor destruction by macrophages
• Others

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• Definition Of Free Radicals
• Extremely unstable, highly reactive chemical
  species with a single unpaired electron in an
  outer orbital
• Examples Of Free Radicals
• OH., H., O2.-

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• Source of Free Radicals
• Hydrolysis of water into OH. and H. by ionizing
  radiation
• Redox reactions in normal physiology
• respiration
• intracellular oxidase action
• transition metal reactions
• Metabolism of exogenous chemicals

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• Free Radical Injury Mechanisms
• Lipid peroxidation of membranes
• double bonds in polyunsaturated lipids
• Lesions in DNA
• reactions with thymine with single-strand breaks
• Cross-linking of proteins
• sulfhydryl-mediated protein cross-linking

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• Free Radical Degradation
• Unstable with spontaneous decay
• Decay accelerated by
• superoxide dismutase
• glutathione
• Catalase
• Antioxidants (vitamin E, ceruloplasmin)
• block formation or scavenge

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• CHEMICAL INJURY

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• Can cause
•        Injury to cell membrane and other cell
  structures
•        Block enzyme pathways (e.g cyanide)
•        Coagulate cell proteins
•        Upset concentration gradients and pH
• Direct action or Conversion to reactive toxic
  metabolite

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• RADIATION INJURY

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• Causes
• Immediate cell death
• Interuption of cell replication (cancer cells)
• Mutation (thymidine dimers)
• Non-ionizing radiations can cause thermal injury

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• BIOLOGICAL AGENTS CAUSING INJURY

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• Viral injury
• Direct cytotoxicity
• Indirect cytotoxicity, via the immune system
  (activated killer T cells identify viral proteins
  on the cell surface and kill the cell)
• Bacterial injury
• Mostly due to their metabolic products
  secretions
• Host inflammatory reaction