When an injury is severe enough that the cell can no longer adapt, the cell develops reversible and/or irreversible changes. These changes may progress to necrosis, apoptosis, and ultimately cell death.
Cell injury can result from many different causes, acting at both gross and microscopic levels.
Hypoxia: Inadequate oxygenation of tissue. In hypoxia, tissues either can’t utilize oxygen or they don’t receive enough oxygen. Hypoxia may be due to hypoxemia (reduced PaO2 from low inspired oxygen concentration, hypoventilation, V/Q defects, shunts, diffusion defects and circulatory shock), anemia, CO poisoning, methemoglobinemia, cyanide poisoning and shock. It results in reduced ATP formation by the mitochondria.
Physical injury: Physical trauma, extremes of temperatures, electric shock, barometric pressure changes, etc. can all cause cellular injury (e.g., frostbite in extreme cold weather).
Chemical injury: Adverse and toxic effects of drugs and poisons (e.g., carbon tetrachloride, strong acids and alkalis), and heavy metals (e.g., lead, arsenic, mercury) are part of a long and ever-increasing list of chemical agents that cause cell injury and cell death.
Infectious agents: All types of pathogenic microbes, including viruses, bacteria, fungi, rickettsia, parasites and prions, can cause cell injury.
Immune reactions: Failure of immune regulation may result in host tissue damage due to immune reactions. Injury may also occur from autoimmunity and complement mediated damage (e.g., Grave’s disease, Goodpasture’s syndrome, paroxysmal nocturnal hemoglobinuria).
Nutritional imbalances: Both nutritional deficiencies and nutritional excess can cause cell injury, ranging from kwashiorkor, marasmus, and anemia to obesity and metabolic syndrome.
Genetic defects: Genetic mutations lead to various disorders such as cystic fibrosis, sickle cell anemia, and Marfan’s syndrome. Most of them are inherited.
Cell injury produces multiple defects in cellular function.
Depletion of ATP: This is seen in hypoxic and chemical cell injuries. Injury may impair oxidative phosphorylation in the mitochondria and glycolysis, leading to reduced ATP production.
ATP depletion leads to several downstream effects:
Increased intracellular Ca++ activates enzymes such as ATPases, phospholipases, proteases and endonucleases, and increases mitochondrial membrane permeability, which can lead to apoptosis.
ATP depletion also interferes with ribosomal protein synthesis, causing detachment of ribosomes from the RER and dissociation of polysomes. Protein misfolding occurs.
Mitochondrial damage: Damage to the mitochondrial membrane may be reversible early on, but it becomes irreversible if the injury persists or is severe. Membrane damage causes mitochondrial swelling and loss of the mitochondrial proton motive force, so ATP production by oxidative phosphorylation stops. Cyt c is released from the mitochondria, initiating apoptosis.
Influx of Ca++ into the cell: Most intracellular Ca++ is sequestered in the endoplasmic reticulum and mitochondria. Ischemia and toxins can cause release of Ca++ from intracellular stores, leading to activation of lytic enzymes.
Free radical injury: Free radicals are reactive oxygen species with a single unpaired electron in their outer orbit. Free radical-mediated injury is seen in radiation and chemical induced injury, ischemia-reperfusion injury and aging.
Free radicals are generated from several sources:
Free radicals damage cells through multiple mechanisms:
Stepwise reduction of O2 to H2O
The body uses several mechanisms to counteract and neutralize free radicals:
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