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Causes Of Cellular Injury

Most important causes of cellular injury are

A. Hypoxia

  1. Most common cause of injuryQ
  2. Lack of oxygen leads to inability of the cell to synthesis sufficient A TP by aerobic respiration.

B. Major causes of hypoxia Ischemia- Most common cause of hypoxia decreased arterial flow or -decreased venous    outflow -

  1. Atherosclerosis                                   
  2. Thrombosis,
  3. Thromboembolism                             
  4. Cardiopulmonary failure,
  5. Decreased oxygen carrying capacity of blood as in anemia.

C. Infections

  1. Viruses, bacteria parasites and fungi
  2. Cause of injury - direct infection cells
  3. Production of toxins                          
  4. Host inflammatory response

D. Immunologic reactions

  1. Hypersensitivity reactions                  
  2. Autoimmune disease

E. Congenital disorders

     Genetic derangements e.g. Tay-Sach disease, sickle cell anaemia

F. Chemical injury

  1. Drugs                                                             
  2. Poisons (cyanide, arsenic, mercury)
  3. Pollution                                                         
  4. Occupational exposure (CCL4, Asbestos)

G. Physical injury

  1. Trauma                                                                       
  2. Burns
  3. Radiation                                                       
  4. Pressure changes

H. Nutritional or vitamin imbalance

  1. Inadequate calorie/protein intake e.g. Marasmus
  2. Excess calorie intake e.g. obesity, atherosclerosis
  3. Vitamin deficiency e.g. Vitamin A deficiency - night blindness
  4. Hypervitaminosis
Cellular Response To Injury
  1. Adaptations e.g. hypertrophy, atrophy etc.
  2. Reversible cell injury seen by Light microscope as Hydropic / Fatty degenerationQ
  3. Irreversible cell injury seen by Light microscope as Necrosis / apoptosisQ
  4. Intracellular accumulations
  5. Pathological calcificationQ
  6. Cellular Aging
Table: Cellular responses to injury
Nature and Severity of Injurious Stimulus Cellular Response
 Altered physiologic stimuli: Cellular adaptations:
 • Increased demand, increased trophic stimulation (e.g. growth factors, hormones) • Hyperplasia, hypertrophy
 • Decreased nutrients, stimulation • Atrophy
 • Chronic irritation (chemical or physical) • Metaplasia
 Reduced oxygen supply; chemical injury; microbial infection Cell injury:
 • Acute and self-limited • Acute reversible injury
 • Progessive and severe (including DNA damage) • Irreversible injury → cell death
• Mild chronic injury • Subcellular alterations in various organelles
 Metabolic alterations, genetic or acquired Intracellular accumulations; calcifications
 Prolonged life span with cumulative sublethal injury Cellular aging

Cellular Response To Injury Depends On
  1. Type of injury                   
  2. Duration of injury              
  3. Severity of injury              
  4. Type of cell injured                                               
  5. Cells metabolic state                      
  6. Cells ability to adapt
Intracellular Systems Vulnerable To Injury
  1. Cell membrane
  2. Production of A TP via Aerobic respiration
  3. Protein synthesis by endoplasmic reticulum & ribosomes
  4. DNA
Important Mechanisms Of Cell Injury
  1. Free Radical Injury
  2. ATP Depletion - Seen In Hypoxic Cell Injury
  3. Influx Of Calcium: Important Mediator Of Cell Injury Especially In Ischemic & Toxic. Q
    Normal Free cytosolic Ca-lowQ conc. Intracellular calcium is sequestered in mitochondria and ER. Ischemia and toxins. This increases cytosolic Ca due to influx of extra cellular Ca and release of Ca from mitochondria and ER.
    Increase cytosolic CaQ  activates wide spectrum of enzymes.
    The various important and vital enzymes activated are –
    1. Proteases Q-protein break down
    2. ATP ases Q- ATP depletion
    3. PhospholipidsQ - cell membrane injury
    4. EndonucleasesQ- DNA damage
  4. Increased Cell Membrane Permeability
    1. This change is effectively noted and Seen in most forms of cell injury
    2. Biochemical mechanisms that contribute to membrane damage
      1. Mitochondrial dysfunction → ↓ phospholipids synthesis
      2. ↑cytosolic Ca2+ associated with ATP depletion
      3. This leads to the activation of phospholipase And this further depletion of phospholipids from
      4. all  membranes
      5. Reactive oxygen species → lipid per oxidation of membranes.
  5. Mitochondrial Dysfunction –
    This is the target for virtually all types of injurious stimuli
  1. Decrease oxidative phosphorylation
  2. Formation of mitochondrial permeability transition (MPT) channels. Q
  3. Release of cytochrome c is a trigger for apoptosis
Mechanism Of Cell Injury: Reversible Cell Injury
  1. Decreased synthesis of A TP by oxidative phosphorylation
  2. Decreased function of Na + Ka+ ATPase membrane pumps
    1. Influx of Na+ and waterQ                             
    2. Efflux of K+Q
    3. Cellular swelling (Hydropic swelling) Q       
    4. Swelling of the endoplasmic reticulum Q
  1. Switch to glycolysis
  1. Depletion of cytoplasmic glycogen               
  2. Increased lactic acid production
  3. decreased intracellular pH                 
  1. Decreased protein synthesis
    Detachment of ribosomes from the rough endoplasmic reticulum
  2. Plasma - membrane blebs and myelin figures may be seen
Fig1: Postulated sequence of events in reversible and irreversible ischemic cell injury.
  1. Mechanism of cell injury: Irreversible cell injury
    1. ​Severe membrane damage
      1. Membrane damage plays a critical role in irreversible injury
      2. Massive influx of calcium
      3. Efflux of intracellular enzymes and proteins into the circulationQ
    2. Marked mitochondrial dysfunction

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