General Pathology

Theme 2: Principles of Cellular Injury

1. Discuss general causes of tissue injury
2. Describe the parenchymal and interstitial effects of tissue injuries

Causes of Tissue Injury

Oxygen deprivation: (hypoxia), which occurs as a result of:
� Ischemia (loss of blood supply)
� Inadequate oxygenation (e.g., cardiorespiratory failure)
� Loss of oxygen-carrying capacity of blood (e.g. anemia, carbon monoxide poisoning)

Free radicals: e.g. oxygen-based free radicals react with membrane lipids.

Enzymes: that lyse cell (lipid peroxidation), leading to membrane damage.
e.g. pancreatic lipases liberated during acute pancreatic inflammation cause necrosis in nearby cells.
e.g. Clostridium perfringens (one of the causes of gas gangrene) produce enzymes that damage plasma membranes and cause necrosis.

Viruses, bacteria and other infectious agents (rickettsiae, fungi and parasites): e.g. cytopathic viruses cause lysis by direct insertion into cell membranes while other viruses cause lysis indirectly bia an immune response to virally determined antigens on surface of infected cells.

Activation of complement system: final compounds of activated complement pathway exert phospholipase-like effect that enzymatically damage plasma membrane.

Physical agents: extremes of heat and cold, trauma, radiation and electric shock.

Chemical agents; e.g. solvents, toxins like alcohol, drugs, heavy metals by interfering with biochemical reactions. Therapeutic drugs (e.g. acetaminophen [Tylenol] may also cause damage)

Genetic derangements such as chromosomal alterations or specific mutations in genes.

Nutritional imbalances, including protein-calorie deficiency and lack of specific vitamins as well as nutritional excesses. Additionally the composition of the deiet can make a significant contribution to disease.

Cell Injury

Cellular swelling dominates the pattern of reversible cellular injury with swelling in the ER and mitochondria.

Cell Death

Irreversible injury is marked by severe mitochondrial vacuolization; extensive damage to plasma membranes; swelling of lyzosomes; and the appearance of large, amorphous densities in mitochondria. Injury to lysosomal membranes leads to leakage of the enzymes into the cytoplasm and, by their activation, to enzymatic digestion of cell and nuclear components.

2 types are recognisible:

1. Necrosis the sum of the morphologic changes that follow cellular death in living tissue or organs. 2 processes that cause the basic morphologic changes of necrosis being (1) denaturation of proteins and; (2) enzymatic digestion of organelles and othe cytosolic components.
   • Necrotic cell is eosinophilic (pink) and glassy and may be vacuolated.
   • Cell membranes are fragmented
   • Nuclear changes in cells include pyknosis (small, dense nucleus), karyolysis (faint, dissolved nucleus), and karyorrhexis (nucleus broken up into many clumps).
   • Autolysis may follow owing to digestion by lysosomal enzymes of the dead cells.
   • Heterolysis is digestion by lysosomal enzymes of immigrant leukocytes.
   • Necrotic cells may attract calcium salts in the form of granular basophilic deposits, referred to as dystrophic calcification (particularly true of necrotic fat cells).
2. Apoptosis
   • Cell shrinkage
   • Chromatin condensation and fragmentation
   • Cellular blebbing and fragmentation into apoptotic bodies
   • Phagocytosis of apoptotic bodies by adjacent healthy cells or macrophages; lack of inflammation

If cell injury is irreversible and serious enough to proceed to necrosis instead of apoptosis, inflammation of the surrounding tissues can occur.

Inflammation

Acute inflammation has 3 major components:

1. Alterations in vascular caliber that lead to an increase in blood flow
2. Structural changes in the microvascular that permit the plasma proteins and leukocytes to leave the circulation to produce an inflammatory exudate
3. Emigration of the leukocytes from te microcirculation and their accumulation in the focus of injury

There are 4 cardinal signs of inflammation:

• Heat (calor)
• Redness (rubor)
• Edema (tumor)
• Pain (dolor)