Saturday 28 January 2006
Causes of cell injury
- mechanical trauma
- extremes of temperature (burns and deep cold)
- sudden changes in atmospheric pressure
- electric shock
chemical agents and drugs
Cell injury results when cells are stressed so severely that they are no longer able to adapt or when cells are exposed to inherently damaging agents. Injury may progress through a reversible stage and culminate in cellular death.
These alterations may be divided into the following stages:
Reversible cell injury
Initially, injury is manifested as functional and morphologic changes that are reversible if the damaging stimulus is removed. The hallmarks of reversible injury are reduced oxidative phosphorylation, adenosine triphosphate (ATP) depletion, and cellular swelling caused by changes in ion concentrations and water influx.
Irreversible injury and cell death
With continuing damage, the injury becomes irreversible, at which time the cell cannot recover. In ischemic tissues such as the myocardium, certain structural changes (e.g., amorphous densities in mitochondria, indicative of severe mitochondrial damage) and functional changes (e.g., loss of membrane permeability) are indicative of cells that have suffered irreversible injury.
Irreversibly injured cells invariably undergo morphologic changes that are recognized as cell death. There are two types of cell death, necrosis and apoptosis, which differ in their morphology, mechanisms, and roles in disease and physiology.
When damage to membranes is severe, lysosomal enzymes enter the cytoplasm and digest the cell, and cellular contents leak out, resulting in necrosis.
Some noxious stimuli, especially those that damage DNA, induce another type of death, apoptosis, which is characterized by nuclear dissolution without complete loss of membrane integrity.
Whereas necrosis is always a pathologic process, apoptosis serves many normal functions and is not necessarily associated with cell injury. Necrosis and apoptosis are distinct but there may be some overlaps and common mechanisms between these two pathways.
The biochemical mechanisms responsible for cell injury are complex. There are, however, a number of principles that are relevant to most forms of cell injury:
The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity. Thus, small doses of a chemical toxin or brief periods of ischemia may induce reversible injury, whereas large doses of the same toxin or more prolonged ischemia might result either in instantaneous cell death or in slow, irreversible injury leading in time to cell death.
The consequences of cell injury depend on the type, state, and adaptability of the injured cell. The cell’s nutritional and hormonal status and its metabolic needs are important in its response to injury. How vulnerable is a cell, for example, to loss of blood supply and hypoxia? The striated muscle cell in the leg can be placed entirely at rest when it is deprived of its blood supply; not so the striated muscle of the heart.
Exposure of two individuals to identical concentrations of a toxin, such as carbon tetrachloride, may produce no effect in one and cell death in the other. This may be due to genetic variations affecting the amount and activity of hepatic enzymes that convert carbon tetrachloride to toxic byproducts. With the complete mapping of the human genome, there is great interest in identifying genetic polymorphisms that affect the cell’s response to injurious agents.
Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components (Fig. 1-10). The most important targets of injurious stimuli are: (1) aerobic respiration involving mitochondrial oxidative phosphorylation and production of ATP; (2) the integrity of cell membranes, on which the ionic and osmotic homeostasis of the cell and its organelles depends; (3) protein synthesis; (4) the cytoskeleton; and (5) the integrity of the genetic apparatus of the cell.
Consequences of cell injury
Irreversible Cell Injury
The earliest changes associated with various forms of cell injury are decreased generation of ATP, loss of cell membrane integrity, defects in protein synthesis, cytoskeletal damage, and DNA damage.
Within limits, the cell can compensate for these derangements and, if the injurious stimulus abates, will return to normalcy.
Persistent or excessive injury, however, causes cells to pass the threshold into irreversible injury. This is associated with extensive damage to all cellular membranes, swelling of lysosomes, and vacuolization of mitochondria with reduced capacity to generate ATP.
Extracellular calcium enters the cell and intracellular calcium stores are released, resulting in the activation of enzymes that can catabolize membranes, proteins, ATP, and nucleic acids.
Following this, there is continued loss of proteins, essential coenzymes, and ribonucleic acids from the hyperpermeable plasma membrane, with cells leaking metabolites vital for the reconstitution of ATP and further depleting intracellular high-energy phosphates.
The molecular mechanisms connecting most forms of cell injury to ultimate cell death have proved elusive, for several reasons.
First, there are clearly many ways to injure a cell, not all of them invariably fatal.
Second, the numerous macromolecules, enzymes, and organelles within the cell are so closely interdependent that it is difficult to distinguish a primary injury from secondary (and not necessarily relevant) ripple effects.
Third, the "point of no return," at which irreversible damage has occurred, is still largely undetermined; thus, we have no precise cut-off point to establish cause and effect.
Finally, there is probably no single common final pathway by which cells die. It is, therefore, difficult to define the stage beyond which the cell is irretrievably doomed to destruction.
And when does the cell actually die? Two phenomena consistently characterize irreversibility.
The first is the inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) even after resolution of the original injury. The second is the development of profound disturbances in membrane function. As mentioned earlier, injury to the lysosomal membranes results in leakage of their enzymes into the cytoplasm; the acid hydrolases are activated in the reduced intracellular pH of the ischemic cell and degrade cytoplasmic and nuclear components. This dissolution of the injured cell is characteristic of necrosis, one of the recognized patterns of cell death. There is also widespread leakage of potentially destructive cellular enzymes into the extracellular space, with damage to adjacent tissues and a host response (Chapter 2). Whatever the mechanism(s) of membrane damage, the end result is a massive leak of intracellular materials and a massive influx of calcium, with the consequences described above.
It is worth noting that leakage of intracellular proteins across the degraded cell membrane into the peripheral circulation provides a means of detecting tissue-specific cellular injury and death using blood serum samples.
Cardiac muscle, for example, contains a specific isoform of the enzyme creatine kinase and of the contractile protein troponin; liver (and specifically bile duct epithelium) contains a temperature-resistant isoform of the enzyme alkaline phosphatase; and hepatocytes contain transaminases. Irreversible injury and cell death in these tissues are consequently reflected in increased levels of such proteins in the blood.