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Cell Injury

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Title: Slide 1 Author: LitzenbL Last modified by: HollanLo Created Date: 8/10/2004 2:31:28 PM Document presentation format: On-screen Show Company – PowerPoint PPT presentation

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Title: Cell Injury


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Cell Injury
  • Robert Low MD PhD

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Cell and tissue injury produce human
disease Injury-acute vs chronic
  • sites within cells that are easily injured
  • reversibility of injury and complete recover
  • adaptation to chronic injury
  • cell death-necrosis vs apoptosis
  • Hypoxic injury-starving cells/tissues for oxygen
    problems of too much oxygen and cell damage from
    oxygen radicals

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  • Human disease occurs because of injury to
    cells/tissue

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Cell Injury Damage or alteration of one or
more cellular components
  1. Many types of injury we incur are tissue specific
    because of anatomic relationships and the
    tissue tropism of chemical and infectious agents.
  2. Cell injury perturbs cell physiology the cell
    does not function at full capacity.

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Basic Types of Tissues
  • Epithelium
  • Muscle (skeletal, smooth, cardiac)
  • Nerve (CNS, PNS)
  • Connective (bone, cartilage, soft tissue,
    adventitia, ligaments, blood and lymph, etc)

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  • Most human disease results from injury to
    Epithelium

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Epithelium arises from each of three germ layers
  1. Cells cover external surfaces (skin) line
    internal closed cavities, secretory glands and
    tubes- -GI, respiratory, GU tracts- -that
    communicate with external surfaces
  2. Also includes liver, exocrine pancreas, parotid
    glands, thyroid, parathyroid, epithelium of
    kidney
  3. Also vascular endothelium, mesothelium

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  • Injury to one tissue usually affects the adjacent
    or underlying tissue as well

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Cell Injury Produces
  • Signs- abnormal physical findings
  • Symptoms- complaints experienced
  • by the patient

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Cell Injury Produces (cont)
  1. Morphologic change- A visual change in the cell
    shape or appearance, seen when cells are stained
    and viewed by light microscopy or examined by
    E.M. in the injured tissue or seen grossly
    with the naked eye.

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Outcomes from cell injury depend upon
  1. Type of injury
  2. Severity of the injury
  3. Duration of the damage
  4. Type of cell being injured- Some cell types
    sustain injury better than others some tissues
    (e.g. liver) have a capacity to regenerate.

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Cell Injury Vulnerable Sites
  1. Cell membranes
  2. Mitochondria
  3. Endoplasmic reticulum
  4. Nucleus

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Cell Membrane- why so easily injured
  1. Membrane faces the external environment sustains
    trauma, extracellular oxidants, proteases, etc.
  2. Requires a constant supply of ATP for normal
    function (ion pumps).
  3. Lipid molecules in the membrane are easily
    oxidized and support and oxidative chain reaction
    called lipid peroxidation.

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Consequences of Injury
  1. No long term effects- - the cell damage is
    repaired, the effects of the injury are
    reversible.
  2. The cell adapts to the damaging stimulus.
  3. The cell dies, undergoing necrosis. The damage is
    irreversible.

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Reversible Cell Injury
  • Examples
  • Cell swelling usually accompanies all types of
    injury. Results from an increase in water
    permeability. Reverses once membrane function is
    restored.
  • Increase in extracellular metabolite because of a
    biochemical derangement. Ex. Increase in
    extracellular glycogen in diabetes.

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Reversible Cell Injury (cont)
  • Examples
  • Fatty change in liver. Vacuoles of fat accumulate
    within the liver cell following many types of
    injury alcohol intoxication, chronic illness,
    diabetes mellitus, etc.
  • Due to An increase in entry of free fatty acids.
  • An increase in synthesis of free fatty
    acids.
  • A decrease in fatty acid oxidation.

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Adaptation- the cell responds successfully to
the injurious stimulus
  • Examples
  • Hypertrophy- the cell increases in size. Ex.
    cardiac myocytes of the left ventricle increase
    in size from essential hypertension.
  • Atrophy- the cell decreases in size because of a
    loss of cell substance.

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Causes of Cell Atrophy
  1. Loss of blood supply or innervation
  2. Loss of endocrine factors (ex. TSH)
  3. Decrease in the workload
  4. Aging, chronic illness

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Cell Death
  • Necrosis
  • Apoptosis

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Morphology of Necrosis
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Coagulative Necrosis
  • Dead cell remains a ghost-like remnant of its
    former self-classically seen in an MI.

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Pyknosis
  • Intensely dark staining and shrunken nucleus,
    seen in a necrotic (dead) cell.

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Karyorrhexis
  • Fragmentation of pyknotic nucleus.

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Karyolysis
  • Extensive hydrolysis of the pyknotic nucleus
    with loss of staining. Represents breakdown of
    the denatured chromatin.

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Liquefactive Necrosis
  • The dead cell undergoes extensive autolysis,
    caused by the release of lysosomal hydrolases
    (proteinases, DNases, RNases, lipases, etc.)
  • Seen classically in the spleen and brain
    following infarction.

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Caseous Necrosis
  • Seen in Tuberculosis (mycobacterium
    tuberculosis).
  • Type of necrosis seen within infected tissues
    characterized as soft, friable, whitish-grey
    (resembles the milk protein casein).

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Fat Necrosis
  • Leakage of lipases from dead cells attack
    triglycerides in surrounding fat tissue and
    generate free fatty acids and calcium soaps.
  • These soaps have a chalky-white appearance.
  • Seen in the pancreas following acute
    inflammation.

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Causes of Cell and Tissue Injury
  1. Physical agents
  2. Chemicals and drugs
  3. Infectious pathogens
  4. Immunologic reactions
  5. Genetic mutations
  6. Nutritional imbalances

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Causes of Cell and Tissue Injury (cont)
  • Hypoxia and Ischemia-
  • cell injury resulting from inadequate levels of
    oxygen.
  • Many important causes
  • A. Inadequate blood supply
  • B. Lung disease
  • C. Heart failure
  • D. Shock

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Why So Important?
  • All cells in the body require a continuous
    supply of oxygen in order to produce ATP via
    oxidative phosphorylation in mitochondria.
  • ATP is absolutely critical for life.

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Susceptibility of specific cells to ischemic
injury- -
  • Neurons 3 to 5 min.
  • Cardiac myocytes, hepatocytes, renal epithelium
    30 min. to 2 hr.
  • Cells of soft tissue, skin, skeletal muscle
    many hours

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Hypoxic Injury- changes which are
reversible
  1. Decrease in extracellular ATP levels
  2. Decrease in the Na pump, with cell swelling
  3. Increase in glycolysis, with a decrease in
    intracellular pH
  4. Decrease in protein synthesis

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Hypoxic Injury- changes which are
irreversible
  1. Activation of lysosomal enzymes. (recall that
    lysosomal enzymes are active at low pH, ca. pH
    4-5)
  2. Degradation of DNA and protein.
  3. Influx of calcium. (recall that calcium activates
    many lipases and proteases)

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Hypoxic cells are exposed to damage from oxygen
radicals-
  1. Hypoxic patients are given high levels of oxygen.
    This oxygen is toxic to the cells lining the
    alveolar spaces in the lung because the high 02
    produces oxygen radicals.

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Hypoxic cells are exposed to damage from oxygen
radicals- (cont)
  1. Hypoxic tissues are often infiltrated with PMNs.
    PMNs have enzymes, myleoperoxidases, which
    produce activated oxygen

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Hypoxic cells are exposed to damage from oxygen
radicals- (cont)
  1. Hypoxic tissues are often reperfused once the
    blood supply is restored. Xanthine oxidase,
    produced from proteolysis during hypoxia,
    generates free radicals when the 02 is brought
    back to normal levels.

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GOOD/BAD REACTION
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BAD REACTIONS
H202 H. 0H. (very reactive) FE H202
FE 0H. 0H- H202 02- 0H. 0H-
02
1 2 3
FENTON REACTION
HABER-WEISS REACTION
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GOOD REACTIONS
2 H202 02 2H20 2 0H. 2 GSH 2 H20
GSSG H202 2 GSH 2 H20 GSSG
1 2
GLUTATHIONE PEROXIDASE
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