Causes of cell injury: Hypoxia (decreased oxygen), ischemia (decreased blood flow), physical and chemical agents, trauma, infectious agents, radiation and toxins, metabolic abnormalities (genetic or acquired), immune dysfunction (hypersensitivity reactions and autoimmune disease), aging, and nutritional imbalances.

Important points regarding cell injury

• Hypoxia and ischemia are two common sources of cellular injury. Of the two, ischemia is much more damaging because it involves hypoxia plus a lack of other nutrients and an accumulation of toxic cellular metabolites.
• When does injury occur? This varies from cell to cell. It depends upon the type, duration, and severity of injury, and the type, adaptability, and makeup of the affected cell.
• Cellular injury may or may not result in the death of the cell. Four cellular systems are especially vulnerable to cellular injury, and include:

  1. DNA

  2. Cell membranes

  3. Protein generation

  4. Adenosine triphosphate (ATP) production

• Although some of the causes of cellular injury have specific mechanisms, the mechanism of cellular injury due to many substances is not understood.

Mechanisms of cellular injury

1. Hypoxia: In general, decreased oxygen results in decreased production of ATP. ATP is normally required by the Na/K+ pump and Ca2+ pump. When ATP levels decrease, these pumps fail and sodium (along with water, which follows sodium) enters the cell, causing swelling. Also, calcium enters the cell, which activates endonucleases, proteases, phospholipases, and DNAses, which damage the cell. Cells switch to anaerobic respiration to produce ATP, which results in accumulation of lactic acid. The accumulation of lactic acid decreases the cellular pH. Decreased pH causes disaggregation of ribosomes from endoplasmic reticulum.

2. Generation of oxygen-derived free radicals by a stressing agent

Basic description of free radical: A free radical is a molecule with an unpaired electron in the outer orbit. Another term for oxygen-derived free radicals is reactive oxygen species.

How free radicals are generated: Free radicals are generated by normal physiologic reduction-oxidation reactions, ultraviolet light, x-rays and ionizing radiation, and transitive metals. Also, metabolism of exogenous chemicals, such as carbon tetrachloride, induces formation of reactive oxygen species.

Damage by free radicals: Lipid peroxidation (damages cell membranes), DNA fragmentation, and protein cross-linking (e.g., sulfhydryl groups), which results in increased degradation and decreased activity.

Methods to prevent formation of reactive oxygen species

• Catalase, which degrades hydrogen peroxide.
• Superoxide dismutase, which converts superoxide to hydrogen peroxide.
• Glutathione, which catalyzes breakdown of hydroxyl radicals.
• Vitamins A, C, and E, which have an antioxidant effect.

3. Chemical injury: Some chemicals are directly toxic to the cells, and others require conversion to a toxic metabolite. For example, ethylene glycol (antifreeze) is not toxic, but its metabolite, oxalic acid, is. In contrast, cyanide directly inactivates cytochrome oxidase, which impairs the formation of ATP.

4. Increased mitochondrial cytosolic calcium: Increased mitochondrial cytosolic calcium leads to lipid peroxidation and formation of mitochondrial permeability transition (a nonselective pore that dissipates the proton gradient). Also, increased mitochondrial cytosolic calcium causes release of cytochrome c, which in turn activates apoptosis.

Two types of cellular injury

• Reversible cellular injury: As described above in the discussion of mechanisms of cellular injury, the decreased production of ATP causes sodium to enter the cell, bringing water and causing cellular and organelle swelling. The conversion from aerobic to anaerobic respiration decreases the pH of the cell. These changes are all reversible. If ATP is once again produced by the cell, the Na/K+ ratio and pH will be corrected.
• Irreversible cellular injury: This type of injury occurs with damage to plasma or lysosomal membranes, loss of DNA, or loss of mitochondria. In these cases, the damage cannot be reversed. The two most important factors determining irreversible damage are membrane disturbances and the inability to reverse mitochondrial dysfunction.

Light microscope morphologic changes of cellular injury

• Reversible injury: Cellular swelling and fatty change.
• Irreversible injury: Nuclear karyolysis (loss of basophilia), pyknosis (shrinkage of nucleus), and karyorrhexis (fragmentation of nucleus).

Electron microscope morphologic changes of cellular injury

• Reversible injury: Cellular blebs and small mitochondrial densities.
• Irreversible injury: Ruptured lysosomes, myelin figures (which indicate phospholipid precipitation), lysis of endoplasmic reticulum, and large calcium rich mitochondrial densities.