Reversible Cell Injury and Cell Death
The mechanisms of cell injury can produce sublethal and reversible cellular damage or lead to irreversible injury with cell destruction or death (Fig. 5.8). Celldestruction and removal can involve one of two mechanisms:
• Apoptosis, which is designed to remove injured or worn-out cells
• Cell death or necrosis, which occurs in irreversibly damaged cells
Reversible Cell Injury
Reversible cell injury, although impairing cell function, does not result in cell death. Two patterns of reversible cell injury can be observed under the microscope: cellular swelling and fatty change. Cellular swelling occurs with impairment of the energy-dependent Na+/K+–ATPase membrane pump, usually as the result of hypoxic cell injury.
Fatty changes are linked to intracellular accumulation of fat. When fatty changes occur, small vacuoles of fat disperse throughout the cytoplasm. The process is usually more ominous than cellular swelling, and although it is reversible, it usually indicates severe injury. These fatty changes may occur because normal cells are presented with an increased fat load or because injured cells are unable to metabolize the fat properly. In obese people, fatty infiltrates often occur within and between the cells of the liver and heart because of an increased fat load. Pathways for fat metabolism may be impaired during cell injury, and fat may accumulate in the cell as production exceeds use and export. The liver, where most fats are synthesized and metabolized, is particularly susceptible to fatty change, but fatty changes may also occur in the kidney, the heart, and other organs.
Programmed Cell Death
In most normal nontumor cells, the number of cells in tissues is regulated by balancing cell proliferation and cell death. Cell death occurs by necrosis or a form of programmed cell death called apoptosis.
Apoptosis is a highly selective process that eliminates injured and aged cells, thereby controlling tissue regeneration. Cells undergoing apoptosis have characteristic morphologic features as well as biochemical changes. As shown in Figure 5.9, shrinking and condensation of the nucleus and cytoplasm occur. The chromatin aggregates at the nuclear envelope, and DNA fragmentation occurs. Then, the cell becomes fragmented into multiple apoptotic bodies in a manner that maintains the integrity of the plasma membrane and does not initiate inflammation. Changes in the plasma membrane induce phagocytosis of the apoptotic bodies by macrophages and other cells, thereby completing the degradation process.
Apoptosis is thought to be responsible for several normal physiologic processes, including the programmed destruction of cells during embryonic development, hormone-dependent involution of tissues, death of immune cells, cell death by cytotoxic T cells, and cell death in proliferating cell populations. During embryogenesis, in the development of a number of organs such as the heart, which begins as a pulsating tube and is gradually modified to become a four-chambered pump, apoptotic cell death allows for the next stage of organ development. It also separates the webbed fingers and toes of the developing embryo (Fig. 5.10). Apoptotic cell death occurs in the hormone- dependent involution of endometrial cells during the menstrual cycle and in the regression of breast tissue after weaning from breast-feeding. The control of immune cell numbers and destruction of autoreactive T cells in the thymus have been credited to apoptosis. Cytotoxic T cells and natural killer cells are thought to destroy target cells by inducing apoptotic cell death.
Apoptosis is linked to many pathologic processes and diseases. For example, interference with apoptosis is known to be a mechanism that contributes to carcinogenesis. Apoptosis may also be implicated in neurodegenerative disorders such as Alzheimer disease, Parkinson disease, and ALS. However, the exact mechanisms involved in these diseases remain under investigation.
Two basic pathways for apoptosis have been described (Fig. 5.11). These are the extrinsic pathway, which is death receptor dependent, and the intrinsic pathway, which is death receptor independent. The execution phase of both pathways is carried out by proteolytic enzymes called caspases, which are present in the cell as procaspases and are activated by cleavage of an inhibitory portion of their polypeptide chain.
The extrinsic pathway involves the activation of receptors such as tumor necrosis factor (TNF) receptors and the Fas ligand receptor. Fas ligand may be expressed on the surface of certain cells such as cytotoxic T cells, or appear in a soluble form. When Fas ligand binds to its receptor, proteins congregate at the cytoplasmic end of the Fas receptor to form a death-initiating complex. The complex then converts pro- caspase-8 to caspase-8. Caspase-8, in turn, activates a cascade of caspases that execute the process of apoptosis. The end result includes activation of endonucleases that cause fragmentation of DNA and cell death. In addition to TNF and Fas ligand, primary signaling molecules known to activate the extrinsic pathway include TNF-related apoptosis-inducing ligand (TRAIL); the cytokine interleukin-1 (IL-1); and lipopolysaccharide (LPS), the endotoxin found in the outer cell membrane of gram-negative bacteria.
The intrinsic pathway, or mitochondrion-induced pathway, of apoptosis is activated by conditions such as DNA damage, ROS, hypoxia, decreased ATP levels, cellular senescence, and activation of the p protein by DNA damage. It involves the opening of mitochondrial membrane permeability pores with release of cytochrome c from the mitochondria into the cytoplasm. Cytoplasmic cytochrome c activates caspases, including caspase-3. Caspase-3 activation is a common step to both the extrinsic and intrinsic pathways. Furthermore, activation or increased levels of proapoptotic proteins, such as Bid and Bax, after caspase-8 activation in the extrinsic pathway can lead to mitochondrial release of cytochrome c, thereby bridging the two pathways for apoptosis. Many inhibitors of apoptosis within cells are known and thought to contribute to cancer and autoimmune diseases. The therapeutic actions of certain drugs may induce or facilitate apoptosis. Apoptosis continues to be an active area of investigation to better understand and treat a variety of diseases.
Necrosis refers to cell death in an organ or tissue that is still part of a living organism. Necrosis differs from apoptosis since it causes loss of cell membrane integrity and enzymatic breakdown of cell parts and triggers the inflammatory process. In contrast to apoptosis, which functions in removing cells so new cells can replace them, necrosis often interferes with cell replacement and tissue regeneration.
With necrotic cell death, there are marked changes in the appearance of the cytoplasmic contents and the nucleus. These changes often are not visible, even under the microscope, for hours after cell death. The dissolution of the necrotic cell or tissue can follow several paths. The cell can undergo liquefaction (i.e., liquefaction necrosis); it can be transformed to a gray, firm mass (i.e., coagulation necrosis); or it can be converted to a cheesy material by infiltration of fatlike substances (i.e., caseous necrosis). Liquefaction necrosis occurs when some of the cells die but their catalytic enzymes are not destroyed. An example of liquefaction necrosis is the softening of the center of an abscess with discharge of its contents. During coagulation necrosis, acidosis develops and denatures the enzymatic and structural proteins of the cell. This type of necrosis is characteristic of hypoxic injury and is seen in infarcted areas.Infarction (i.e., tissue death) occurs when an artery supplying an organ or part of the body becomes occluded and no other source of blood supply exists. As a rule, the shape of the infarction is conical and corresponds to the distribution of the artery and its branches. An artery may be occluded by an embolus, a thrombus, disease of the arterial wall, or pressure from outside the vessel.
Caseous necrosis is a distinctive form of coagulation necrosis in which the dead cells persist indefinitely. It is most commonly found in the center of tuberculosis granulomas, or tubercles.
Gangrene. The term gangrene is applied when a considerable mass of tissue undergoes necrosis. Gangrene may be classified as dry or moist. In dry gangrene, the part becomes dry and shrinks, the skin wrinkles, and its color changes to dark brown or black. The spread of dry gangrene is slow, and its symptoms are not as marked as those of wet gangrene. The irritation caused by the dead tissue produces a line of inflammatory reaction (i.e., line of demarcation) between the dead tissue of the gangrenous area and the healthy tissue. Dry gangrene usually results from interference with the arterial blood supply to a part without interference with venous return and is a form of coagulation necrosis.
In moist or wet gangrene, the area is cold, swollen, and pulseless. The skin is moist, black, and under tension. Blebs form on the surface, liquefaction occurs, and a foul odor is caused by bacterial action. There is no line of demarcation between the normal and diseased tissues, and the spread of tis- sue damage is rapid. Systemic symptoms are usually severe, and death may occur unless the condition can be arrested. Moist or wet gangrene primarily results from interference with venous return from the part. Bacterial invasion plays an important role in the development of wet gangrene and is responsible for many of its prominent symptoms. Dry gangrene is confined almost exclusively to the extremities, but moist gangrene may affect the internal organs or the extremities. If bacteria invade the necrotic tissue, dry gangrene may be converted to wet gangrene.
Gas gangrene is a special type of gangrene that results from infection of devitalized tissues by one of several Clostridium bacteria, most commonly Clostridium perfringens. These anaerobic and spore-forming organisms are widespread in nature, particularly in soil. Gas gangrene is prone to occur in trauma and compound fractures in which dirt and debris are embedded. Some species have been isolated in the stomach, gallbladder, intestine, vagina, and skin of healthy people. Characteristic of this disorder are the bubbles of hydrogen sulfide gas that form in the muscle. Gas gangrene is a serious and potentially fatal disease. Antibiotics are used to treat the infection and surgical methods are used to remove the infected tissue. Amputation may be required to prevent spreading infection involving a limb. Hyperbaric oxygen therapy has been used, but clinical data supporting its efficacy have not been rigorously assessed.