2 Cell Injury & Cell Death

• Normal homeostasis refers to the balanced and stable conditions within a cell that are necessary for its proper functioning.
• Cells require a specific environment to maintain their activities, they have various mechanisms in place to maintain homeostasis
• Cellular Injury is an alteration in cell structure or function due to stress or pathologic stimuli; it is the most common response of the cells in almost all types of diseases.
• Cellular injury occurs when a cell’s exposure to injurious agents or stress which exceeds its capability for adaptive response
• Hypoxia & Ischemia are the most common causes of cellular injury
• Hypoxia is the condition where not enough oxygen makes it to the cells and tissue in the body
• Ischemia is when there is a loss of blood supply; most common cause.
• Anything in excess of chemicals and drugs, even an innocuous substance may cause cell adaptation, injury or death.
• Physical agents such as trauma, extremes of heat and cold, sudden changes in atmospheric pressure, radiant energy, electrical energy can also cause cellular injury.
• Microbiologic agents that leads to infections may also cause cellular injury.
• Immunologic reactions may cause cell injury even if the immune system serves in the defense against biologic agents
• Nutritional imbalances

  • Protein-calorie deficiency – most common examples.
  • Avitaminoses – deficiency of vitamins in the body.
  • Over nutrition – important causes of morbidity and mortality.
• Aging causes progressive decline in functions.
• Psychogenic diseases

  • Depression, Schizophrenia – most common.
  • Drug addiction, alcoholism, smoking – results in lung and liver damage, chronic bronchitis, lung cancer.
• Iatrogenic causes are errors due to physician.
• Idiopathic causes are diseases or disorders due to unknown causes
• Four common causes of cell injury:

  1. Hypoxia
  2. Free radicals and activated O2 species
  3. Some chemicals
  4. Viruses
• • Small dose of chemical toxin or short duration of ischemia causes cell injury.
  • Large dose of same chemical persistent ischemia causes cell death.
• Skeletal muscle withstands (resist) hypoxic injury for long time while cardiac muscle suffers irreversible cell injury after 30-60 minutes of continuous ischemia.

  
• Biochemical reactions are common in all form of cell injury.
• Morphologic consequences are biochemical changes caused by cell injury are expressed in the form of morphological alterations
• Loss of energy such as ATP depletion and Oxygen depletion are usually in hypoxic and chemical injuries
• Mitochondrial damage is one of the hallmarks of irreversible cell injury.

  • Mitochondria are important targets of all types of injury, including hypoxia and toxins.
  • Mitochondrial changes are seen as vacuoles in the mitochondria and deposit of amorphous calcium salts in mitochondrial matrix
• Influx of intracellular calcium & Loss of calcium homeostasis

  • Ischemia causes an increase in cytosolic calcium concentration.
  • Increase in calcium activates number of enzymes.
• • ATPase – hastening ATP depletion.
  • Phospholipases – causes membrane damage.
  • Proteases – breakdown both membrane and cytoskeletal proteins.
  • Endonucleases – responsible for DNA and chromatin fragmentation.
• Free radicals are chemicals that have single unpaired electron.
• In ischemic cells, membrane damage may be the result of ATP depletion and calcium-modulated activation of phospholipases
• Usually, cells have mechanisms to repair DNA after damage, however if the damage is too severe the cell triggers a suicide program called apoptosis.
• Reversible cell injury is the stage of cell injury at which the deranged function and morphology of the injured cells can return to normal if the damaging stimulus is removed.
• Cells and intracellular organelles in reversible cell injury typically become swollen because they take in water as a result of the failure of energy-dependent ion pumps in the plasma membrane, leading to an inability to maintain ionic and fluid homeostasis.
• Cellular swelling is commonly seen in cell injury associated with increased permeability of the plasma membrane
• Microscopic examination of cellular swelling may show small, clear vacuoles within the cytoplasm; these represent distended and pinched-off segments of endoplasmic reticulum (ER).
• Fatty change is manifested by the appearance of triglyceride containing lipid vacuoles in the cytoplasm; principally encountered in organs that are involved in lipid metabolism, such as the liver.
• Plasma membrane alterations includes blebbing, blunting, or distortion of microvilli, and loosening of intercellular attachments
• Mitochondrial changes includes swelling and the appearance of phospholipid-rich amorphous densities
• Nuclear alterations includes clumping of chromatin
• Irreversible cell injury is where there is a persistent and excessive exposure; inability to restore mitochondrial function even after resolution of the original injury.
• Cell death may be due to irreversible cell injury
• Necrosis is when an injury is too severe to be repaired and many cellular constituents simply fail or fall apart; always an indication of a pathologic process.
• Apoptosis is the regulated or programmed cell death that serves to eliminate unwanted cells during normal development and to maintain constant cell numbers, so it is not necessarily associated with pathologic cell injury