Cell injury

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Cell injury

• By
• Dr. Abdelaty Shawky Dr. Gehan Mohamed

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Fatty Change

• Definition abnormal accumulation of
  triglycerides within parenchymal cells.
• Site
• liver, most common site which has a central role
  in fat metabolism.
• it may also occur in heart as in anaemia or
  starvation (anorexia nervosa)
• Other sites skeletal muscle, kidney and other
  organs.

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Causes

1. Toxins (most importantly Alcohol abuse)
2. Diabetes mellitus
3. Protein malnutrition (starvation)
4. Obesity
5. Anoxia

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The significance of fatty change

• Depends on the severity of the accumulation.
• Mild it may have no effect .
• Severe form, fatty change may precede cell
  death, and may be an early lesion in a serious
  liver disease called nonalcoholic steatohepatitis
  

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Is Fatty liver reversible?

• Fatty change is reversible except if some vital
  intracellular process is irreversibly impaired .

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Prognosis of Fatty liver

• In Mild cases 3 will develop cirrhosis
• Moderate to sever inflammation, degeneration in
  hepatocytes, fibrosis (30 develop cirrhosis).

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Other form of accumulation

• Cholesteryl esters
• These give atherosclerotic
• plaques with their characteristic
• yellow color and contribute to
• the pathogenesis of narrowing of
• the blood vessels.
• This is called atherosclerosis

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Accumlation of Exogenous pigment

• Tattooing Indian ink pigments produce effective
  tattoos because they are engulfed by dermal
  macrophages which become immobilized and
  permanently deposited.
• Anthracosis inhalation of carbon dust particles.
  When inhaled, it is phagocytosed by alveolar
  macrophages and transported through lymphatic
  channels to the regional tracheobronchial lymph
  nodes.

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• Anthracosis

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Hemosiderin ( iron)
Accumulation of Endogenous pigments

• is a hemoglobin-derived granular pigment that is
  golden yellow to brown and accumulates in tissues
  when there is a local or systemic excess of iron.
  
• Iron is normally carried by specific transport
  proteins, transferrins. In cells, it is stored in
  association with a protein, apoferritin, to form
  ferritin micelles. Ferritin is a constituent of
  most cell types. When there is a local or
  systemic excess of iron, ferritin forms
  hemosiderin granules.

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Hemosiderosis

• Causes of Hemosiderosis
• Increased absorption of dietary iron
• Impaired utilization of iron
• Hemolytic anemias
• Repeated blood transfusions (the transfused red
  cells constitute an exogenous load of iron).
• Hereditary hemochromatosis with tissue injury
  including liver fibrosis, heart failure, and
  diabetes mellitus
• .

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• Although hemosiderin accumulation is usually
  pathologic, small amounts of this pigment are
  normal.
• Where?
• in the mononuclear phagocytes of the bone marrow,
  spleen, and liver.
• Why?
• there is extensive red cell breakdown.

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Hemosiderosis(systemic overload of iron)

• It is found at first in the mononuclear
  phagocytes of the liver, bone marrow, spleen, and
  lymph nodes and in scattered macrophages
  throughout other organs.
• With progressive accumulation, parenchymal cells
  throughout the body (principally the liver,
  pancreas, heart, and endocrine organs) will be
  affected

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Hemosiderin
HE golden brown pigment Prussian
blue stain blue
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Lipofuscin

• Wear-and-tear pigment" is a brownish-yellow
  granular intracellular material that seen
  normally in a variety of tissues (the heart,
  liver, and brain) as a function of age or
  atrophy.
• Consists of complexes of lipid and protein that
  derive from the free radical-catalyzed
  peroxidation of lipids of subcellular membranes.
• It is not injurious to the cell but is important
  as a marker of past free-radical injury.
• The brown pigment when present in large amounts,
  imparts an appearance to the tissue that is
  called brown atrophy.

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Pathological calcification

• It implies the abnormal deposition of calcium
  salts in tissues rather than bone and teeth.
• It has 2 types
• Dystrophic calcification
• When the deposition occurs in dead or dying
  tissues e.g. areas of necrosis or atherosclerotic
  patches.
• it occurs with normal serum levels of calcium
• Metastatic calcification
• The deposition of calcium salts in normal tissues
  
• It almost always reflects hypercalcemia.

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Irreversible cell injury
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• Mechanism
• Persistent or severe injury (hypoxia) takes the
  cell to the "point of no return" where the injury
  becomes irreversible.
• At this point no intervention can save the cell.
• Two phenomenon characterize irreversible injury
• Mitochondrial damage.
• Damage to the structural integrity of plasma
  membrane.
• Calcium plays a major role in irreversible injury.

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1. Mitochondrial damage

• Marked reduction in ATP production leads to
  mitochondrial damage results in formation of high
  conductance channels (Mitochondrial Permeability
  Transition (MPT) channels) which Release
  cytochrome c into cytosol which is a trigger for
  apoptosis.

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MITOCHONDRIAL DYSFUNCTION or INJURY
?ATP production
H
Cytochrome C
Mitochondrial Permeability Transition (MPT)
Apoptosis
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2. Damage to plasma membrane

• Due to
• Decreased production of membrane phospholipids
  due to mitochondrial dysfunction and decreased
  ATP production.
• Loss of membrane phospholipids due to the action
  of phospholipases.
• Damage to cytoskeleton due to the action of
  proteases.

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Consequences of membrane damage

• Mitochondrial membrane
• Formation of MPT (mitochondrial permeability
  transition channels).
• Release of cytochrome c ? activates apoptosis.
• Plasma membrane
• Loss of osmotic balance.
• Influx of fluids and ions.
• Loss of proteins, enzymes, RNA.
• Lysosomal membrane
• Leakage of lysosomal enzymes and their activation
• RNases, DNases, proteases, phosphatases,
  glucosidases.
• Enzymatic digestion of cell components
• Cell death by necrosis.

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Role of calcium in irreversible cell injury

• Increased cytosolic calcium Leads to
• Enzyme activation
• ATPases Hasten ATP depletion
• Phospholipases cause membrane damage ?
  increased permeability.
• Proteases ? damages membrane and structural
  proteins
• Endonucleases ? damages nuclear chromatin and
  DNA, causing fragmentation (karyorrhexis).
• Increased mitochondrial permeability release of
  cytochrome c (activates apoptosis)

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INJURIOUS AGENT
Ca 2
Ca 2
Increased Cytosolic Ca2
ATPase
Phospholipase
Protease
Endonuclease
Disruption of membrane cytoskeletal Proteins
?ATP
Nuclear Chromatin damage
? Phospholipids
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Morphology of irreversible cell injury
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Light microscopy of irreversible cell injury

• Pyknosis Shrinkage and darkening of the
  nucleus.
• Karyorrhexis fragmentation and breakdown of the
  nucleus, (into "nuclear dust").
• Karyolysis dissolution of the nucleus.

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Nuclear pyknosis
Karyorrhexis
Karyolysis
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Types of cell death

• Necrosis local death of a group of cells within
  the living body.
• Apoptosis genetically controlled programmed
  single cell death.

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Some important terms!

• Autolysis degradation of cell and its
  constituents caused by its own enzymes.
• Heterolysis degradation of cell and its
  constituents by enzymes derived from sources
  extrinsic to the cell (e.g. neutrophils,
  bacteria).
• Putrefaction lysis of dead tissue by bacterial
  enzymes.

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Morphological types of necrosis

• Coagulation necrosis.
• Liquefactive necrosis.
• Caseation necrosis.
• Fat necrosis.
• Traumatic.
• Enzymatic .
• Fibrinoid necrosis.
• Gangrenous necrosis.
• Gummatous necrosis.

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Coagulative necrosis

• Mechanism
• Denaturation and coagulation of structural and
  enzymatic proteins due to intracellular acidosis.
  
• Denaturation of lysosomal enzymes by
  intracellular acidosis prevents autolysis.
• Preserving cell outlines and tissue architecture.

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• Etiology
• ischemia (secondary to atherosclerosis ? thrombus
  formation). The most common cause.
• Heavy metal poisoning (lead).
• Irradiation.
• Organs affected Commonly seen in solid organs
  like Heart, kidney, spleen

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• Infarction
• Refers to a localized area of tissue necrosis
  resulting from loss or reduction in blood supply
  ( ischemic necrosis).
• The dead tissue is called an infarct.
• Coagulative necrosis is the type of necrosis
  associated with infarction except in infarction
  of brain.
• In Brain
• Lack of good structural support.
• Cells rich in lysosomal enzymes result in
  liquefactive necrosis.

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Infarction of the spleen (ischemic coagulative
necrosis)
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Morphology of Coagulation necrosis

• GROSS APPEARANCE
• The necrotic tissue appears firm and dry.
• Cut surface grey white.
• MICROSCOPY
• Loss of the nucleus but preservation of cellular
  shape.
• Increased cytoplasmic eosinophilia.

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Area of necrosis
Area of Necrosis
Preservation of cellular shape.
Increased cytoplasmic eosinophilia
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Good luck