Cell injury and cell responses

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Cell injury and cell responses

• Dr. Temur Ahsan Khan

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Cell injury and cell responses

• Cells and tissues undergo a number of responses
  according to intensity and duration of
  pathological conditions and injuries
• Cellular adaptations-----hypertrophy, atrophy,
  hyperplasia, metaplasia etc
• Regressive changes (degeneration)----swelling
  (hydropic degeneration) and steatosis (fatty
  Change)
• Cell death (necrosis) and apoptosis (programmed
  cell death)

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Types of necrosis

1. Coagulative
2. Liquefactive or lytic
3. Caseous
4. Fat necrosis

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Causes of cell injury

• Same as general causes of disease.
• A very common cause of cell injury is hypoxia and
  anoxia (ischemia)
• Combination of hypoxia /anoxia are
• Anoxic anoxia---inadequate oxygen in the presence
  of circulation for example in anaemia, pneumonia,
  liver necrosis, congestion etc.
• Ischemic anoxia---due to decrease or stoppage of
  arterial blood flow as in embolism, thrombism and
  infarction.
• Cytoxic anoxia---there is interference with O2
  utilization as seen in cyanide poisoning.

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Sensitivity to anoxia

• Sensitivity to anoxia varies in different
  tissues, for example following loss of blood
  supply neurons die within 3-5 minutes,
  myocardium, hepatocytes and several epithelial
  cells between 30 minutes to two hours and
  fibroblasts, epidermis and skeletal muscles
  survive for several hours.

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Sites of cell injury

1. Plasma membranes---cause leakage
2. Mitochondria---depletion of ATP
3. Synthesis of proteins in rough endoplasmic
   reticulum is stopped.
4. Preservation of integrity of genetic apparatus is
   compromised.

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Common biochemical mechanisms of cell injury(1)

• ATP depletion
• (a) All energy requiring functions stop, H2O, Na
  and Ca2 go inside the cell and K comes out.
• (b) Energy is derived through anaerobic
  glycolysis which causes accumulation of lactic
  acid and lowering of pH.

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Common biochemical mechanisms of cell injury(2)

• 2.Generation of oxygen derived free radicals
• Supereoxide anion, hydroxyl radical, hydrogen
  peroxide, nitric oxide, carbon tetrachloride.
• Volatile and tissue destructive.
• Important mechanism in radiation injury, killing
  of bacteria by leucocytes etc.
• Generated during metabolism of oxygen and
  mitochondrial electron transport.

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Common biochemical mechanisms of cell injury(3)

• Free radicals oxidize proteins, membranes,
  genetic material and unsaturated fatty acids-
  peroxidation of fatautocatalysis
• Antioxidants superoxide dismutase, hydrogen
  peroxide, catalase, glutathione peroxidase,
  selenium and vitamin E
• Oxidative stress imbalance between free radical
  generation and their removal / inactivation.

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Common biochemical mechanisms of cell injury(4)

• 3. Loss of calcium homeostasis accumulation of
  calcium in cytosol has the following serious
  consequences and eventually causes cell death
• (a) uncoupling of gap junctions, isolation and
  dissociation of injured cells
• (b) depolymerization of cytoskeleton i.e.
  micrifilaments and microtubules. Cytoskeleton
  disappears from the periphery of the cell. The
  cell cannot perform its function of movement,
  phagocytosis and secretion and it looses shape
  (become rounded)
• (c) activation of endogenous phospholipases which
  cause breakdown of cell membranes.

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Common biochemical mechanisms of cell injury(5)

• 4. defects in membrane permeability
• Caused directly by bacterial toxins, viral
  proteins, complement components and cytoxic
  lymphocytes etc.
• Caused indirectly by loss of ATP and enzymes
  activated by Ca2 like phospholipases

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Common biochemical mechanisms of cell injury(6)

• 5. mitochondrial damage
• Several mechanisms
• Increased cytosolic Ca2 and oxidative stress
• Formation of high conductance channels

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Leaking of proteins and enzymes from injured cell

• As the injured cell die, proteins and other large
  molecules present in the cell escape into the
  interstitium and then into the blood circulation.
• Necrosis in the following tissues releases
  specific enzymes into the blood and these can be
  assayed to determine the extent of damage
• Heart---creatine kinase (CK)
• Skeletal muscle---asparatate aminotransferase
  (AST) and CK isoform
• Liver ---alanine aminotransferase (ALT) and AST
• Pancreas---pancreatic specific lipase.

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Sequence of events in ischemic injury
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• General Pathology (PATH 303)
  Lecture 4
• Common Biochemical Mechanisms of Cell
  Injury (Contd.)

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• 1. Mechanisms of injury caused by free radicals
• Lipid peroxidation of plasma and cell membranes
• Attack double bond in unsaturated fatty acids
• Autocatalytic chain reaction
• Cross-linking of proteins
• Inactivate sulphydryl enzymes
• Form disulphide bonds
• DNA fragmentation
• React on thymine in DNA
• Cause mutation and fragmentation

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• 2. Loss of calcium homeostasis
• Increase in cytosolic Ca
• Influx from outside
• Release from mitochondria
• Activates phospholipase, protease, ATPase,
  endonuclease
• Depolymerization of cytoskeleton
• Inhibits cell movement
• Inhibits phagocytosis
• Inhibits secretion

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• 3. Defects in membrane permeability
• Directly damaged by
• Bacterial toxins
• Viral proteins
• Complement component
• Cytotoxic lymphocytes etc.
• Indirectly damaged by
• Loss of ATP synthesis
• Activation of phospholipase by Ca

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• 4. Mitochondrial damage
• Irreparable damage to mitochondria causes cell
  death.
• By increased cytosolic Ca, oxidative stress,
  breakdown of phospholipids.
• Formation of high conductive channels
• Leakage of proteins and cytochrome C

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• 5. Lysosomes, heterophagy and autophagy
• Primary lysosomes contain hydrolytic enzymes
• Fuse with phagosomes to produce phagolysosomes
  and cause break down of ingested material
• Heterophagy --- endocytosis of particulate matter
  from outside e.g. bacteria --- pinocytosis
  uptake of soluble macromolecules.
• Autophagy Removal of damaged or senescent
  organelles by autophagic vacuoles formed from
  RER.
• Fuse to form autophagolysosomes.

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• 6. Cellular swelling
• Disturbance of cellular metabolism leads to
  cellular swelling.
• Causes Toxins, temperature, metabolic diseases,
  poisons, hypoxia
• Gross appearance Organ enlarged, increased
  weight, edges become rounded, cut surface bulges,
  capsule retracts.
• Microscopic appearance Seen in cells of liver,
  kidney, cardiac and skeletal muscles. Cells are
  larger in size. Cytoplasm stains darker and
  appears granular.
• Significance Reversible caused by mild injury---
  disappears when the cause is removed.

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• 7. Hydropic degeneration
• Similar to but more severe than acute cellular
  swelling. Water enters the cells and dilutes
  cytoplasm. Protease clears the cytoplasm.
• Causes Mechanical (rubbing) injuries, thermal
  injuries, chemical agents infectious agents -
  some neoplasm.
• Grossly Blisters are circumscribed, raised area,
  fluctuating, filled with fluid
• Microscopic Water accumulates in endoplasmic
  reticulum forming clear vacuoles, ballooning
  degeneration - Fuse and rupture to form bullae
  and vesicles.
• Significance If uncomplicated, it heals quickly
  without scar formation.
• Secondary infections cause abscessation.