Processes involved in cell injury30
Cell injury may be reversible (sublethal) or irreversible (lethal). Reversible injury may require cellular adaptation but the cell survives. Irreversible injury leads to death of the cell. When cell death occurs in the living body, the term necrosis is used. At the cellular level, there are many processes that can lead to necrosis. In most cases, the process can be classified as one or other of two main mechanisms: apoptosis and oncosis. In contrast, autolysis is used to imply cell death that has not occurred in a living body.
4.1. Processes involved in cell injury
Causes of cell injury
The causes of both reversible and irreversible cell injury are similar. Many of those listed below may result initially in reversible injury, from which the cell can recover if allowed time to repair itself. However, if the injury is of sufficient severity, the cell reaches a ‘point of no return’ and irreversible injury culminating in cell death will occur.
Possible causes of cell injury include:
• hypoxia (lack of oxygen), e.g. myocardial ischaemia (reduced blood flow to, and therefore oxygenation of, the heart) as a result of narrowing of the coronary arteries
• immunological mechanisms, e.g. thyroid damage caused by autoantibodies (antibodies produced by the body against its own tissues)
• infection by microorganisms, e.g. bacterial, viral, fungal infections (such as tuberculous infection of the lung or damage to respiratory mucosa by influenza virus)
• genetic abnormalities, e.g. Duchenne’s muscular dystrophy or sickle cell disease
• physical agents, e.g. radiation (such as sunburn due to UV light damage to the skin), trauma, heat, cold
• chemicals, e.g. damage to liver cells by alcohol.
Mechanisms of cell injury
The structure and metabolic functions of the cell are interdependent. Therefore, although an injurious agent may target a particular aspect of cell structure or function, this will rapidly lead to wide-ranging secondary effects. Recognised mechanisms of cell injury include:
• cell membrane damage
• complement-mediated lysis via the membrane attack complex (MAC)
• bacterial toxins
• free radicals
• mitochondrial damage leading to inadequate aerobic respiration
• hypoxia
• cyanide poisoning
• ribosomal damage leading to altered protein synthesis
• alcohol in liver cells
• antibiotics in bacterial cells
• nuclear damage
• viruses
• radiation
• free radicals.
Free radicals and cell membrane damage
Free radicals are highly reactive atoms or molecules which have an unpaired electron in an outer orbit. They can be produced in cells by a variety of processes, including normal metabolic oxidation reactions and drug metabolism. Radiation and many organic poisons induce free radicals. Most clinically important free radicals are derived from oxygen, e.g. superoxide and hydroxyl ions. Free radicals can injure cells by generating chain reactions, producing further free radicals, which cause cell membrane damage by cross-linking of proteins and by critical alterations of lipids.
Ion transporter function and intracellular calcium
Raised intracellular calcium can have a number of effects. It may initiate the caspase cascade (see below) causing apoptosis. It can also activate proteases and phospholipases, causing further damage to cell cytoskeleton and membranes and thus contribute to necrosis.
Consequences of cell injury
The consequences of cell injury depend on both the characteristics of the injured cell and the injurious agent.
Cell features
Certain features of cells make them more vulnerable to serious sequelae of cell injury. Specialised cells that are enzyme rich or have special organelles within the cytoplasm may be more vulnerable. The presence of specialised proteins within a cell may make it prone to certain types of injurious agent.
Cell state
Cells that have an inadequate supply of oxygen, hormones or growth factors or lack of essential nutrients may be more prone to injury.
Regenerative ability
The potential of a cell population to enter the cell cycle and divide is important in the response of tissues to injury. Damaged areas in tissues made of cells which can divide may be restored to normal, while populations of permanent cells will be incapable of regeneration.
Injury features
In addition, the character of the injury will also affect the severity of the damage.
Type of injury
The injury may be ischaemic, toxic, traumatic, etc. Some cells will be more susceptible to particular injurious agents than others. For example, hypoxia has a greater effect on heart muscle cells than connective tissue cells.
Intensity
The greater the intensity, the greater the probability of damage. For example, a bone can withstand a bending force up to a certain level, but if the force exceeds the strength of the bone then the bone will break. Likewise, a cell may survive partial hypoxia but not complete lack of oxygen (anoxia).
Exposure time
The length of time of exposure to a toxin or reduced oxygen concentration will affect the chance of a cell surviving the insult. Even relatively resistant cells will be damaged if the duration of exposure is prolonged.
Reversible cell injury
Within limits, cells can accommodate derangements in their metabolism through compensatory mechanisms. However, they may show morphological changes. Under the light microscope, cellular swelling and fatty change are associated with reversible cell injury. Cellular swelling, also known as ballooning or hydropic degeneration, is due to osmotic swelling of cells as they accumulate an excess of small molecules and ions in their cytoplasm. Fatty change is seen when the injured cell cannot process lipids normally and results in the accumulation of fat globules in the cytoplasm (discussed further in Ch. 13).
The ultrastructural changes associated with reversible cell injury can be seen under the electron microscope and include:
• distortion of microvilli and blebbing of the plasma membrane
• cytoplasmic vacuolation
• swelling of mitochondria and endoplasmic reticulum
• clumping of nuclear chromatin.
Irreversible cell injury
Irreversible injury implies that the cell cannot survive and will die by one of the mechanisms discussed in the next section. If the damage is not too severe, death is likely to occur by apoptosis via the intrinsic pathway, but more severe damage causes death by oncosis.
When does reversible injury become irreversible? The exact ‘point of no return’ is difficult to identify, although massive caspase activation and loss of mitochondrial transmembrane potential are among those that have been proposed. Irreversible injury is associated with an influx of calcium and the release of calcium sequestered in endoplasmic reticulum, which activates enzymes that further degrade the constituents of the cell.
The morphological changes of irreversible cell injury take time to develop. It may be 8–12 hours before the appearance of abnormalities that are recognisable at the light microscopic or macroscopic level.
4.2. Cell death
Autolysis
The term ‘autolysis’ has been used in different ways, but pathologists use it to describe the changes that occur in cells after death of an organism or after surgical removal. When an organism dies, the cells are degraded by the post-mortem release of digestive enzymes from lysosomes as the cell membranes break down. A similar process occurs when tissue is removed from the organism. Cells and tissues showing these changes are autolytic. Prompt preservation of tissues in a fixative such as formalin prevents autolysis after surgical removal.
Apoptosis
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