Cell Injury, Cell Death, and Adaptations
Cell damage (also known as cell injury)
is a variety of changes of stress that a cell suffers due to
external as well as internal environmental changes. Amongst other causes, this
can be due to physical, chemical, infectious, biological, nutritional or
immunological factors.
CAUSES
OF CELL INJURY: The
causes of cell injury span a range from gross physical trauma, such as after a
motor vehicle accident, to a single gene defect that results in a nonfunctional
enzyme in a specific metabolic disease. Most injurious stimuli can be grouped
into the following categories.
Hypoxia
and ischemia: Hypoxia, which
refers to oxygen deficiency, and ischemia, which means reduced blood supply, are
among the most common causes of cell injury. Both deprive tissues of oxygen,
and ischemia, in addition, results in a deficiency of essential nutrients and a
buildup of toxic metabolites. The most common cause of hypoxia is ischemia
resulting from an arterial obstruction, but oxygen deficiency also can result
from inadequate oxygenation of the blood, as in a variety of diseases affecting
the lung, or from reduction in the oxygen-carrying capacity of the blood, as
with anemia of any cause, and carbon monoxide
(CO) poisoning.
Toxins: Potentially toxic agents are encountered
daily in the environment; these include air pollutants, insecticides, CO, asbestos,
cigarette smoke, ethanol, and drugs. Many drugs in therapeutic doses can cause
cell or tissue injury in a susceptible patient or in many individuals if used
excessively or inappropriately.
Infectious
agents: All types of
disease-causing pathogens, including viruses, bacteria, fungi, and protozoans,
injure cells.
Immunologic
reactions: Although the immune
system defends the body against pathogenic microbes, immune reactions also can
result in cell and tissue injury. Examples are autoimmune reactions against
one’s own tissues, allergic reactions against environmental substances, and
excessive or chronic immune responses to microbes.
In all of these
situations, immune responses elicit inflammatory reactions, which are often the
cause of damage to cells and tissues.
Genetic
abnormalities Genetic aberrations
can result in pathologic changes as conspicuous as the congenital malformations
associated with Down syndrome or as subtle as the single amino acid substitution
in hemoglobin giving rise to sickle cell anemia. Genetic defects may cause cell
injury as a consequence of deficiency of functional proteins, such as enzymes in
inborn errors of metabolism, or accumulation of damaged DNA or mis folded proteins,
both of which trigger cell death when they are beyond repair.
Nutritional
imbalances Protein–calorie
insufficiency among impoverished populations remains a major cause of cell
injury, and specific vitamin deficiencies are not uncommon even in developed
countries with high standards of living. Ironically, excessive dietary intake
may result in obesity and also is an important underlying factor in many diseases,
such as type 2 diabetes mellitus and atherosclerosis.
Physical
agents Trauma, extremes of
temperature, radiation, electric shock, and sudden changes in atmospheric pressure
all have wide-ranging effects on cells.
Aging Cellular senescence results in a diminished ability
of cells to respond to stress and, eventually, the death of cells and of the
organism.
SEQUENCE
OF EVENTS IN CELL INJURY AND CELL DEATH
Although
various injurious stimuli damage cells through diverse biochemical mechanisms,
all tend to induce a stereotypic sequence of morphologic and structural
alterations in most types of cells.
Reversible Cell Injury
Reversible injury is the stage of cell injury at which the deranged
function and morphology of the injured cells can return to normal if the
damaging stimulus is removed. In reversible injury, cells and intracellular organelles typically become swollen because
they take in water as a
result of the failure of energy-dependent ion pumps in the plasma membrane, leading
to an inability to maintain ionic and
fluid homeostasis. In some forms of injury, degenerated organelles and lipids may accumulate inside the injured cells.
MORPHOLOGY
The two main morphologic correlates of reversible cell injury are
cellular swelling and fatty change.
• Cellular swelling is commonly seen in cell injury associated with
increased permeability of the plasma membrane. It may be difficult to appreciate
with the light microscope, but it is often apparent at the level of the
whole organ.
When it affects many cells in an organ, it causes pallor (as
a result of compression of capillaries), increased turgor, and an increase
in organ weight. Microscopic examination may show small, clear vacuoles
within the cytoplasm; these represent distended and pinched-off segments of the
endoplasmic reticulum (ER). This pattern of nonlethal injury is sometimes
called hydropic change or vacuolar degeneration.
• Fatty change is manifested by the appearance
of triglyceride containing lipid vacuoles in the cytoplasm. It is
principally encountered in organs that are involved in lipid metabolism, such
as the liver.
The cytoplasm of injured cells also may become redder (eosinophilic),
a change that becomes much more pronounced with progression to necrosis.
Other intracellular changes associated with cell injury include
(1) Plasma membrane alterations such as
blebbing (Blebs are protrusions of the cell membrane), blunting, or distortion of
microvilli, and loosening of intercellular attachments.
(2) Mitochondrial changes such as swelling and the appearance of phospholipid-rich
amorphous densities.
(3) Dilation of the ER with detachment of ribosomes and dissociation of polysomes, and
(4) Nuclear
alterations, such as clumping of chromatin. The cytoplasm
may contain so-called “myelin figures,” which are collections of phospholipids resembling myelin sheaths that are derived from damaged cellular membranes.
MECHANISMS
OF CELL INJURY AND
CELL
DEATH
Some
general principles of cell injury should be emphasized.
• The cellular response to
injurious stimuli depends on the type of injury, its duration, and its
severity. Thus, low doses of toxins or a brief
period of ischemia may lead to reversible
cell injury, whereas larger toxin doses or longer ischemic times may result in irreversible injury and cell death.
• The consequences of an
injurious stimulus also depend on the type, status, adaptability, and genetic
makeup of the injured cell. The same injury has vastly different outcomes depending on the cell type. For instance, striated skeletal muscle in the
leg tolerates complete ischemia for 2 to 3 hours without irreversible injury, whereas cardiac muscle dies after only 20
to 30 minutes of ischemia. The nutritional (or hormonal) status also can be important;
understandably, a glycogen-replete
hepatocyte will survive ischemia better than one that has just burned its last glucose molecule.
Genetically
determined diversity in metabolic pathways can contribute to differences in responses to injurious stimuli.
For instance, when exposed
to the same dose of a toxin, individuals who inherit variants in genes encoding cytochrome P-450 may catabolize the toxin at
different rates, leading to different
outcomes. Much effort is now directed toward understanding the role of genetic polymorphisms in responses to drugs and toxins, (a
field of study called pharmacogenomics)
. In fact, genetic variations influence susceptibility to many complex diseases as well as responsiveness to various
therapeutic agents. Using the
genetic makeup of the individual patient to guide therapy is one example of
“precision medicine.”
• Cell injury usually results
from functional and biochemical abnormalities in one or more of a limited
number of essential cellular components (Fig.
2.15).
As
we discuss in more detail later, different external insults and endogenous
perturbations typically affect different cellular organelles and biochemical
pathways.
For instance, deprivation of oxygen and nutrients (as
However, it
should be emphasized that the very same injurious agent may trigger multiple
and overlapping biochemical pathways. Not surprisingly, therefore, it has
proved difficult to prevent cell injury by targeting an individual pathway. As
we discussed in the beginning of this chapter and have alluded to throughout,
there are numerous and diverse causes of cell injury and cell death. Similarly,
there are many biochemical pathways that can initiate the sequence of events
that lead to cell injury and culminate in cell death. Some of these pathways
are recognized to play important roles in human diseases.
In the
following section, we organize our discussion of the mechanisms of cell injury
along its major causes and pathways, and discuss the principal biochemical
alterations in each. For the sake of clarity and simplicity, we emphasize the
unique mechanisms in each pathway, but it is important to point out that any
initiating trigger may activate one or more of these mechanisms, and several
mechanisms may be active simultaneously.
INTRACELLULAR ACCUMULATIONS
Under
some circumstances, cells may accumulate abnormal amounts of various
substances, which may be harmless or may cause varying degrees of injury. The
substance may be located in the cytoplasm, within organelles (typically
lysosomes), or in the nucleus, and it may be synthesized by the affected cells
or it may be produced elsewhere.
The
main pathways of abnormal intracellular accumulations are inadequate removal
and degradation or excessive production of an endogenous substance, or
deposition of an abnormal exogenous material.
Selected
examples of each are described as follows.
Fatty Change. Fatty
change, also called steatosis, refers to any accumulation of
triglycerides (Triglycerides are a type of fat (lipid) found in your blood) within parenchymal cells.
It
is most often seen in the liver, since this is the major organ involved in fat
metabolism, but also may occur in heart, skeletal muscle, kidney, and other
organs.
Steatosis
may be caused by toxins, protein malnutrition, diabetes mellitus, obesity, or
anoxia. Alcohol abuse and diabetes associated with obesity are the most common
causes of fatty change in the liver (fatty liver) in industrialized nations.
Cholesterol and Cholesteryl Esters.
Cellular
cholesterol metabolism is tightly regulated to ensure normal generation of cell
membranes (in which cholesterol is a key component) without significant
intracellular accumulation. However, phagocytic cells may become overloaded
with lipid (triglycerides, cholesterol, and cholesteryl esters) in several
different pathologic processes, mostly characterized by increased intake or
decreased catabolism of lipids. Of these, atherosclerosis is the most
important.
Proteins. Morphologically
visible protein accumulations are less common than lipid accumulations; they
may occur when excesses are presented to the cells or if the cells
synthesize
excessive amounts. In the kidney, for example, trace amounts of albumin
filtered through the glomerulus are normally reabsorbed by pinocytosis in the
proximal convoluted tubules. However, in disorders with heavy protein leakage
across the glomerular filter (e.g., nephrotic syndrome), much more of the
protein is reabsorbed, and vesicles containing this protein accumulate, giving
the histologic appearance of pink, hyaline cytoplasmic droplets. The process is
reversible: if the proteinuria abates, the protein droplets are metabolized and
disappear. Another example is the marked accumulation of newly synthesized
immunoglobulins that may occur in the RER of some plasma cells, forming
rounded, eosinophilic Russell bodies.
Glycogen. Excessive
intracellular deposits of glycogen are associated with abnormalities in the
metabolism of either glucose or glycogen. In poorly controlled diabetes
mellitus, the prime example of abnormal glucose metabolism, glycogen
accumulates in renal tubular epithelium, cardiac myocytes, and β cells of
the islets of Langerhans. Glycogen also accumulates within cells in a group of
related genetic disorders collectively referred to as glycogen storage
diseases, or glycogenoses.
Pigments. Pigments
are colored substances that are either exogenous, coming from outside the body,
such as carbon, or are endogenous, synthesized within the body itself, such as
lipofuscin, melanin, and certain derivatives of hemoglobin.
The
most common exogenous pigment is carbon, a ubiquitous air pollutant of urban life. When inhaled, it is
phagocytosed by alveolar macrophages and transported through lymphatic channels
to the regional tracheobronchial lymph nodes. Aggregates of the pigment blacken
the draining lymph nodes and pulmonary parenchyma (anthracosis).
• Lipofuscin, or “wear-and-tear pigment,” is
an insoluble brownish-yellow granular intracellular material that accumulates
in a variety of tissues (particularly the heart, liver, and brain) with aging
or atrophy. Lipofuscin represents complexes of lipid and protein that are
produced by the free radical–catalyzed peroxidation of polyunsaturated lipids
of subcellular membranes. It is not injurious to the cell but is a marker of
past free radical injury. The brown pigment , when present in large amounts,
imparts an appearance to the tissue that is called brown atrophy.
• Melanin is an endogenous, brown-black
pigment that is synthesized by melanocytes located in the epidermis and acts as
a screen against harmful UV radiation. Although melanocytes are the only source
of melanin, adjacent basal keratinocytes in the skin can accumulate the pigment
(e.g., in freckles), as can dermal macrophages.
• Hemosiderin is a hemoglobin-derived granular
pigment that is golden yellow to brown and accumulates in tissues when there is
a local or systemic excess of iron. Iron is normally stored within cells in
association with the protein apoferritin, forming ferritin micelles.
Hemosiderin pigment represents large aggregates of these
ferritin
micelles, readily visualized by light and electron microscopy; the iron can be
unambiguously identified by the Prussian blue histochemical reaction. Although
hemosiderin accumulation is usually pathologic, small amounts of this pigment
are normal in the mononuclear phagocytes of the bone marrow, spleen, and liver,
where aging red cells are normally degraded. Excessive deposition of
hemosiderin, called hemosiderosis, and more extensive accumulations of iron
seen in hereditary hemochromatosis.
CELLULAR
ADAPTATIONS TO STRESS
Adaptations are
reversible changes in the number, size, phenotype, metabolic activity, or
functions of cells in response to changes in their environment. Physiologic adaptations usually represent responses of cells to
normal stimulation by hormones or endogenous chemical mediators (e.g., the
hormone-induced enlargement of the breast and uterus
during pregnancy), or to the demands of mechanical stress (in the case of bones and muscles). Pathologic adaptations are responses to stress that allow cells to modulate their structure
and function and thus escape injury, but at
the expense of normal function, such as squamous metaplasia of bronchial epithelium in smokers. Physiologic and pathologic adaptations can take several distinct forms, as
described in the following text.
Hypertrophy
Hypertrophy is an increase in the size of cells resulting in an
increase in the size of the organ. In contrast, hyperplasia (discussed next) is an increase in cell number. Stated another way, in pure hypertrophy
there are no new cells, just
bigger cells containing increased amounts of structural proteins and organelles.
Hyperplasia is an adaptive response
in cells capable of replication, whereas hypertrophy occurs when cells have a limited
capacity to divide.
Hypertrophy
and hyperplasia also can occur together, and obviously both result in an
enlarged organ. Hypertrophy can be physiologic or pathologic and is caused either by increased
functional demand or by growth factor or hormonal
stimulation.
•
The massive physiologic enlargement of the uterus during pregnancy occurs as a
consequence of estrogenstimulated smooth muscle hypertrophy and smooth muscle
hyperplasia. In contrast, in response to increased workload the striated muscle
cells in both the skeletal muscle and the heart undergo only hypertrophy because
adult muscle cells have a limited capacity to divide. Therefore, the chiseled
physique of the avid weightlifter stems solely from the hypertrophy of individual
skeletal muscles.
•
An example of pathologic hypertrophy is the cardiac enlargement that occurs
with hypertension or aortic valve disease. The differences between normal,
adapted, and irreversibly injured cells are illustrated by the responses of the
heart to different types of
stress.
Myocardium subjected to a persistently increased workload, as in hypertension
or with a narrowed (stenotic) valve, adapts by undergoing hypertrophy to
generate the required higher contractile force. If, on the other hand, the
myocardium is subjected to reduced blood flow (ischemia) due to an occluded
coronary artery, the muscle cells may undergo injury.
The mechanisms
driving cardiac hypertrophy involve at least two types of signals: mechanical
triggers, such as stretch, and soluble mediators that stimulate cell growth, such
as growth factors and adrenergic hormones. These stimuli turn on signal
transduction pathways that lead to
the induction
of a number of genes, which in turn stimulate synthesis of many cellular
proteins, including growth factors and structural proteins. The result is the
synthesis of more proteins and myofilaments per cell, which increases the force
generated with each contraction, enabling the cell to meet increased work
demands. There may also be a switch of contractile proteins from adult to fetal
or neonatal forms. For example, during muscle hypertrophy, the α-myosin heavy chain is replaced by the fetal β form of the myosin heavy chain, which
produces slower, more energetically economical contraction.
An
adaptation to stress such as hypertrophy can progress to functionally significant
cell injury if the stress is not relieved. Whatever the cause of hypertrophy, a limit is reached
beyond which the enlargement of muscle mass can no
longer compensate for the increased burden. When this happens
in the heart, several degenerative changes occur in the myocardial fibers, of
which the most important are fragmentation and loss of myofibrillar
contractile elements.
Why hypertrophy
progresses to these regressive changes is incompletely understood. There may be
finite limits on the abilities of the vasculature to adequately supply the enlarged
fibers, the mitochondria to supply ATP, or the biosynthetic machinery to
provide sufficient contractile proteins or other cytoskeletal elements. The net
result of these degenerative changes is ventricular dilation and ultimately cardiac
failure.
Hyperplasia
Hyperplasia
is an increase in the number of cells in an organ that stems from increased
proliferation, either of differentiated cells or, in some instances, less
differentiated progenitor cells. As
discussed earlier, hyperplasia takes place if
the tissue contains cell populations capable of replication;
it may occur concurrently with hypertrophy and often in
response to the same stimuli.
Hyperplasia
can be physiologic or pathologic; in both situations, cellular proliferation is
stimulated by growth factors that are produced by a variety of cell types.
• The two types
of physiologic hyperplasia are (1) hormonal hyperplasia, exemplified by the
proliferation of the glandular epithelium of the female breast at puberty and
during pregnancy, and (2) compensatory hyperplasia, in which residual tissue
grows after removal or loss of part of an organ. For example, when part of a
liver is resected, mitotic activity in the remaining cells begins as
early as 12
hours later, eventually restoring the liver to its normal size. The stimuli for
hyperplasia in this setting are polypeptide growth factors produced by
uninjured hepatocytes as well as nonparenchymal cells in the liver. After
restoration of the liver mass, various growth inhibitors turn off cell
proliferation.
• Most forms of
pathologic hyperplasia are caused by excessive hormonal or growth factor
stimulation. For example, after a normal menstrual period there is a burst of
uterine epithelial proliferation that is normally tightly regulated by the
stimulatory effects of pituitary hormones and ovarian estrogen and the
inhibitory effects of progesterone. A disturbance in this balance leading to increased
estrogenic stimulation causes endometrial hyperplasia, which is a common cause
of abnormal menstrual bleeding. Benign prostatic hyperplasia is another common
example of pathologic hyperplasia induced in responses to hormonal stimulation
by androgens. Stimulation by growth factors also is involved in the hyperplasia
that is associated with certain viral infections; for example, papillomaviruses
cause skin warts and mucosal lesions that are composed of masses of hyperplastic
epithelium. Here the growth factors may be encoded by viral genes or by the genes
of the infected host cells. An important point is that in all of these
situations, the hyperplastic process remains controlled; if the signals that initiate it abate, the hyperplasia disappears. It is this responsiveness to normal
regulatory control mechanisms that distinguishes pathologic hyperplasias from
cancer, in which the growth control mechanisms become permanently dysregulated
or ineffective. Nevertheless, in many cases, pathologic hyperplasia constitutes
a fertile soil in which cancers may eventually arise. For example, patients
with hyperplasia of the endometrium are at increased risk of developing
endometrial cancer.
Atrophy
Atrophy
is shrinkage in the size of cells by the loss of cell substance. When a sufficient number of cells are involved, the entire tissue or organ is reduced in size, or atrophic. Although atrophic cells may have diminished function,
they are not dead. Causes of atrophy include a decreased workload (e.g., immobilization of a limb to permit healing of a fracture), loss of innervation, diminished blood supply, inadequate nutrition, loss of endocrine stimulation, and aging (senile atrophy). Although some of these stimuli are physiologic (e.g., the loss of hormone stimulation in menopause) and others are pathologic (e.g., denervation), the fundamental cellular changes are similar. They represent a retreat by the cell to a smaller size at which survival is still possible; a new equilibrium is achieved between cell size and diminished blood supply, nutrition, or trophic stimulation.
Cellular atrophy results from a combination of decreased protein synthesis
and increased protein degradation.
•
Protein synthesis decreases because of reduced metabolic activity.
•
The degradation of cellular proteins occurs mainly by the ubiquitin-proteasome
pathway. Nutrient deficiency and disuse may activate ubiquitin ligases, which
attach multiple copies of the small peptide ubiquitin to cellular proteins and
target them for degradation in proteasomes.
This
pathway is also thought to be responsible for the accelerated proteolysis seen
in a variety of catabolic conditions, including the cachexia associated with cancer.
•
In many situations, atrophy also is associated with autophagy, with resulting
increases in the number of autophagic vacuoles. As discussed previously,
autophagy is the process in which the starved cell eats its own organelles in
an attempt to survive.
Metaplasia
Metaplasia is a change in which one adult cell type (epithelial or
mesenchymal) is replaced by another adult cell type. In this type of cellular
adaptation, a cell type sensitive to a particular stress is replaced by another cell type better able to withstand the adverse
environment. Metaplasia is
thought to arise by the reprogramming of stem cells
to
differentiate along a new pathway rather than a phenotypic change
(transdifferentiation) of already differentiated cells.
Epithelial
metaplasia is exemplified by the change that occurs in the respiratory epithelium
of habitual cigarette smokers, in whom the normal ciliated columnar epithelial cells
of the trachea and bronchi often are replaced by stratified squamous epithelial
cells (Fig.
2.23). The rugged
stratified squamous epithelium may be able to survive the noxious chemicals in
cigarette smoke that the more fragile specialized epithelium would not
tolerate. Although the metaplastic squamous epithelium has survival advantages,
important protective mechanisms are lost, such as mucus secretion and ciliary
clearance of particulate matter. Epithelial metaplasia is therefore a double-edged
sword. Because vitamin A is essential for normal epithelial differentiation, its
deficiency also may induce squamous metaplasia in the respiratory epithelium.
Metaplasia
need not always occur in the direction of columnar to squamous epithelium; in
chronic gastric reflux, the normal stratified squamous epithelium of the lower
esophagus may undergo metaplastic transformation to gastric or intestinal-type columnar
epithelium. Metaplasia also may occur in mesenchymal cells, but in these
situations it is generally a reaction to some pathologic alteration and not an
adaptive response to stress. For example, bone is occasionally formed in soft tissues,
particularly in foci of injury.
The influences that induce metaplastic change in an epithelium, if
persistent, may predispose to malignant transformation. In fact, squamous metaplasia of
the respiratory
epithelium often
coexists with lung cancers composed of malignant squamous cells. It is thought that cigarette smoking initially
causes squamous metaplasia, and
cancers arise later in some of these altered foci.
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