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
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.
