PATHOLOGY Lecture 1 Cell injury and cell death Causes of

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PATHOLOGY Lecture 1 Cell injury and cell death
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Causes of cell injury

• hypoxia oxygen deprivation
• physical agents (temperature extremes, pressure,
  electric shock, radiation)
• chemical agents drugs
• infectious agents (viruses, bacteria, fungi,
  parasites)
• immunologic reactions (defense, anaphylactic
  reactions, autoimmune diseases)
• genetic disorders
• nutritional imbalances

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Cell injury and necrosis

• The type, duration and severity of injury
  dictate the cellular response, but the type,
  state and adaptability of the injured cell
  determine the final outcome of cell injury.
• Most vulnerable cellular components/functions
  are
• cell membranes (and mechanisms keeping their
  integrity)
• aerobic respiration
• protein synthesis
• genetic apparatus
• An injury to one of the cellular systems has
  wide-ranging secondary effects on all or some of
  the other cellular systems.
• The morphologic changes lag after biochemical
  events.

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Biochemical mechanisms accompanying necrosis

• The biochemical events important for necrosis
  are
• 1) ATP depletionsources of ATP are oxidative
  phosphorylation (aerobic respiration, O2 is
  reduced to H2O) and gycolysis, affected by
  ischemic or toxic injury
• Oxidative stressoxygen free radicals and oxygen
  derived free radicals
• .

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Biochemical mechanisms accompanying necrosis

• The biochemical events important for necrosis
  are
• 1) ATP depletionsources of ATP are oxidative
  phosphorylation (aerobic respiration, O2 is
  reduced to H2O) and gycolysis, affected by
  ischemic or toxic injury
• Oxidative stressoxygen free radicals and oxygen
  derived free radicals
• Disturbance of Ca homeostasis
• Changes in membrane permeability
• ..

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Biochemical mechanisms accompanying necrosis

• The biochemical events important for necrosis
  are
• 1) ATP depletionsources of ATP are oxidative
  phosphorylation (aerobic respiration, O2 is
  reduced to H2O) and gycolysis, affected by
  ischemic or toxic injury
• Oxidative stressoxygen free radicals and oxygen
  derived free radicals
• Disturbance of Ca homeostasis
• Changes in membrane permeability
• Mitochondrial damage

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Common forms of cell injury causing necrosis

• Ischemic and hypoxic injury first attacks
  aerobic respiration
• Reversible ischemic and hypoxic injury causes
• Cell membrane Na K pump (ATP dependent) no
  longer works adequately leading to swelling
• Energy metabolism changes (anaerobic glycolysis
  in absence of glucose supply)
• Ribosomes disassociate from ER and polysomes
• functional consequences with clinical
  significance (i.e. heart stops)

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Common forms of cell injury causing necrosis

• Ischemic and hypoxic injury
• Irreversible ischemic and hypoxic injury causes
• Mitochondrial dysfunction
• Loss of membrane phospholipids
• Cytoskeletal abnormalities
• Reactive oxygen species
• Lipid breakdown products
• Loss of intracellular amino acids (gycine)

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Common forms of cell injury causing necrosis

• Ischemic and hypoxic injury
• Free radical induced injury
• Due to absorption of radiant energy (UV, X-rays)
• Enzymatic metabolism of drugs (CCl4)
• Changes in normal metabolic reduction-oxydation
  reactions
• Transition metals
• Nitric oxide
• Free radicals cause
• Membrane lipid peroxidation
• Oxidative modification of proteins
• DNA lesions

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Common forms of cell injury causing necrosis

• Ischemic and hypoxic injury
• Free radical induced injury
• Chemical injury
• Direct (i.e. mercury binds sulfhydryl groups of
  proteins in cell membrane, cyanide blocks
  oxidative phosphorylation)
• Indirectchemical is converted to toxic
  metabolites, most often reactive free radicals
  (i.e. P-450 oxydases in SER convert Tylenol into
  a metabolite that has to be detoxified by
  interaction with glutathione)

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Morphology of reversible cell injury and cell
death by necrosis

• Reversible cell injury injury
• Cellular swelling
• Hydropic change (vacuolar degeneration)
• Ultrastructural changes (plasma membrane
  alterationsblebbing, blunting, microvili loss
  swelling of mitochondria and ER nuclear
  alterationsdisaggregation of granular and
  fibrillar elements)
• Necrosisearly alterations resulting from
  enzymatic digestion of the cell and denaturation
  of proteins
• Increased eosinophilia
• Nuclear changeseither karyolysis, pyknosis or
  karyorrhesis

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Apoptosis programmed cell death

• Apoptosis occurs
• During development (embryogenesis as well as
  hormonally regulated tissue/organ involution
• In tissues maintaining cell number/populations
  homeostasis
• During maturation of immune cellsdefense against
  immune reactions
• Removal of damaged cells following injurious
  stimuli (radiation, drugs, viral diseases, as
  well as pathologic atrophy)
• During ageing

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Morphology of cell death by necrosis and apoptosis

• Necrosisearly alterations resulting from
  enzymatic digestion of the cell and denaturation
  of proteins
• Increased eosinophilia
• Nuclear changeseither karyolysis, pyknosis or
  karyorrhesis
• Apoptosis
• Cell shrinkage
• Chromatin condensation
• Cytoplasmic blebs and apoptotic bodies
• Phagocytosis of apoptotic bodies by adjacent cells

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Biochemical features of apoptosis

• Protein cleavage
• caspases
• Protein cross-liking
• Transglutaminase
• DNA degradation
• 50-300 kilobase fragments
• oligonucleosomes
• Phagocytic recognition

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Subcellular responses to cell injury

• Lysosomal catabolism
• Heterophagy
• Autophagy
• Hypertrophy of smooth endoplasmic reticulum (SER)
• Mitochondrial alterations
• Cytoskeletal abnormalities
• Thin filaments (actin miosincell movement)
• Microtubules
• Intermediate filaments (intracellular scaffold)

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