Cell damage can occur in many ways.
For purposes of discussion, the ways by which cells are injured have been
grouped into five categories:
•
Injury
from physical agents
•
Radiation
injury
•
Chemical
injury
•
Injury
from biologic agents
•
Injury
from nutritional imbalances
Injury from Physical Agents
Physical agents responsible for
cell and tissue injury include mechanical forces, extremes of temperature, and
electrical forces. They are common causes of injuries due to environmental
exposure, occupational and transportation accidents, and physical violence and
assault.
Mechanical Forces. Injury or trauma due to mechanical forces
occurs as the result of body impact with another object. The body or the mass
can be in motion or, as sometimes happens, both can be in motion at the time of
impact. These types of injuries split and tear tissue, fracture bones, injure
blood vessels, and disrupt blood flow.
Extremes of Temperature. Extremes of heat
and cold cause damage to the cell, its organelles, and
its enzyme systems. Exposure to low-intensity heat (43°C to 46°C), such as occurs
with partial-thickness burns and severe heat stroke, causes cell injury by
inducing vascular injury, accelerating cell metabolism, inactivating
temperature-sensitive enzymes, and disrupting the cell membrane. With more
intense heat, coagulation of blood vessels and tissue proteins occurs. Exposure
to cold increases blood viscosity and induces vasoconstriction by direct action
on blood vessels and through reflex activity of the sympathetic nervous system.
The resultant decrease in blood flow may lead to hypoxic tissue injury,
depending on the degree and duration of cold exposure. Injury from freezing
probably results from a combination of ice crystal formation and
vasoconstriction. The decreased blood flow leads to capillary stasis and
arteriolar and capillary thrombosis. Edema results from increased capillary
permeability.
Electrical Injuries. Electrical injuries can affect the body through
extensive tissue injury and disruption of neural and cardiac impulses. Voltage,
type of current, amperage, pathway of the current, resistance of the tissue,
and interval of exposure determine the effect of electricity on the body.
Alternating current (AC) is usually
more dangerous than direct current (DC) because it causes violent muscle contractions,
preventing the person from releasing the electrical source and sometimes
resulting in fractures and dislocations. In electrical injuries, the body acts
as a conductor of the electrical current. The current enters the body from an
electrical source, such as an
exposed wire, and passes through the body and exits to another conductor, such as the moisture on the ground or a piece of metal the person is
holding. The pathway that a current takes is critical because the electrical
energy disrupts impulses in excitable tissues. Current flow through the brain
may interrupt impulses from respiratory centers in the brain stem, and current
flow through the chest may cause fatal cardiac arrhythmias.
The resistance to the flow of
current in electrical circuits transforms electrical energy into heat. This is
why the elements in electrical heating devices are made of highly resistive
metals. Much of the tissue damage produced by electrical injuries is caused by
heat production in tissues that have the highest electrical resistance. Resistance
to electrical current varies from the greatest to the least in bone, fat,
tendons, skin, muscles, blood, and nerves. The most severe tissue injury
usually occurs at the skin sites where the current enters and leaves the body
(Fig. 5.5). After electricity has penetrated the skin, it passes rapidly
through the body along the lines of least resistance through body fluids and
nerves. Degeneration of vessel walls may occur, and thrombi may form as current
flows along the blood vessels. This can cause extensive muscle and deep tissue
injury. Thick, dry skin is more resistant to the flow of electricity than thin,
wet skin. It is generally believed that the greater the skin resistance, the
greater is the amount of local skin burn, and the less the resistance, the
greater are the deep and systemic effects.
Radiation Injury
Electromagnetic radiation comprises
a wide spectrum of wave-propagated energy, ranging from ionizing gamma rays to
radiofrequency waves (Fig. 5.6). A photon is a particle of radiation energy. Radiation
energy above the ultraviolet (UV) range is called ionizing radiation because
the photons have enough energy to knock electrons off atoms and molecules. Nonionizing
radiation refers to radiation energy at frequencies below those of visible light. UV radiation represents
the portion of the spectrum of
electromagnetic radiation just above the visible range. It contains
increasingly energetic rays that are powerful enough to disrupt intracellular
bonds and cause sunburn.
Ionizing Radiation. Ionizing radiation impacts cells by causing
ionization of molecules and atoms in the cell. This is accomplished by
releasing free radicals that destroy cells and by directly hitting the target
molecules in the cell.16 It can immediately kill cells, interrupt cell replication,
or cause a variety of genetic mutations, which may or may not be lethal. Most
radiation injury is caused by localized irradiation that is used in the
treatment of cancer. Except for unusual circumstances such as the use of
high-dose irradiation that precedes bone marrow transplantation, exposure to
whole-body irradiation is rare.
The injurious effects of ionizing
radiation vary with the dose, dose rate (a single dose can cause greater injury
than divided or fractionated doses), and the differential sensitivity of the
exposed tissue to radiation injury. Because of the effect on deoxyribonucleic
acid (DNA) synthesis and interference with mitosis, rapidly dividing cells of
the bone marrow and intestine are much more vulnerable to radiation injury than
tissues such as bone and skeletal muscle. Over time, occupational and
accidental exposure to ionizing radiation can result in increased risk for the
development of various types of cancers, including skin cancers, leukemia,
osteogenic sarcomas, and lung cancer. This is especially true when the person
is exposed to radiation during childhood.
Many of the clinical manifestations
of radiation injury result from acute cell injury, dose-dependent changes in
the blood vessels that supply the irradiated tissues, and fibrotic tissue
replacement. The cell’s initial response to radiation injury involves swelling,
disruption of the mitochondria and other organelles, alterations in the cell
membrane, and marked changes in the nucleus. The endothelial cells in blood vessels
are particularly sensitive to irradiation. During the immediate postirradiation
period, only vessel dilatation is apparent (e.g., the initial erythema
of the skin after radiation therapy). Later or with higher levels of radiation,
destructive changes occur in small blood vessels such as the capillaries and
venules. Acute small blood vessels
such as the capillaries and venules. Acute reversible necrosis is represented by such disorders as radiation
cystitis, dermatitis, and diarrhea from enteritis. More persistent damage can
be attributed to acute necrosis of tissue cells that are not capable of
regeneration and chronic ischemia. Chronic effects of radiation damage are
characterized by fibrosis and scarring of tissues and organs in the irradiated
area (e.g., interstitial fibrosis of the heart and lungs after
irradiation of the chest). Because the radiation delivered in radiation therapy
inevitably travels through the skin, radiation dermatitis is common. There may
be necrosis of the skin, impaired wound healing, and chronic radiation
dermatitis.
Ultraviolet Radiation. Ultraviolet radiation causes sun-burn and
increases the risk of skin cancers. The degree of risk depends on the type of
UV rays, the intensity of exposure, and the amount of protective melanin
pigment in the skin. Skin damage produced by UV radiation is thought to be
caused by reactive oxygen species (ROS) and by damage to melanin-producing
processes in the skin.18 UV radiation
also damages DNA, resulting in the formation of pyrimidine dimers (i.e., the
insertion of two identical pyrimidine bases into replicating DNA instead of
one). Other forms of DNA damage include the production of single-stranded
breaks and formation of DNA–protein cross-links. Normally errors that occur
during DNA replication are repaired by enzymes that remove the faulty section
of DNA and repair the damage. The importance of DNA repair in protecting
against UV radiation injury is evidenced by the vulnerability of people who
lack the enzymes needed to repair UV-induced DNA damage. In a genetic disorder
called xeroderma pigmentosum, an enzyme needed to repair
sunlight-induced DNA damage is lacking. This autosomal recessive disorder is
characterized by extreme photosensitivity and an increased risk of skin cancer
in sunexposed skin.
Nonionizing Radiation. Nonionizing radiation includes infrared light,
ultrasound, microwaves, and laser energy. Unlike ionizing radiation, which can
directly break chemical bonds, nonionizing radiation exerts its effects by
causing vibration and rotation of atoms and molecules. All of this vibrational and rotational energy is eventually converted to thermal energy. Low-frequency nonionizing
radiation is used widely in radar, television, industrial operations (e.g., heating,
welding, melting of metals, processing of wood and plastic), household
appliances (e.g., microwave ovens), and medical applications (e.g., diathermy).
Isolated cases of skin burns and thermal injury to deeper tissues have occurred
in industrial settings and from improperly used household microwave ovens.
Injury from these sources is mainly thermal and, because of the deep
penetration of the infrared or microwave rays, tends to involve dermal and
subcutaneous tissue injury.
Chemical Injury
Chemicals capable of damaging cells
are everywhere around us. Air and water pollution contains chemicals capable of
tissue injury, as does tobacco smoke and some processed or pre- served foods.
Some of the most damaging chemicals exist in our environment, including gases
such as carbon monoxide, insecticides, and trace metals such as lead.
Chemical agents can injure the cell
membrane and other cell structures, block enzymatic pathways, coagulate cell proteins,
and disrupt the osmotic and ionic balance of the cell. Corrosive substances such
as strong acids and bases destroy cells as the substances come into contact
with the body. Other chemicals may injure cells in the process of metabolism or
elimination. Carbon tetrachloride (CCl4 ), for example, causes little damage until it
is metabolized by liver enzymes to a highly reactive free radical (CCl3 •). Carbon
tetrachloride is extremely toxic
to liver cells.
Drugs. Many drugs alcohol, prescription drugs, over the-counter drugs, and street drugs are capable of directly or indirectly
damaging tissues. Ethyl alcohol can harm the gastric mucosa, liver, developing
fetus, and other organs. Antineoplastic and immunosuppressant drugs can
directly injure cells. Other drugs produce metabolic end products that are
toxic to cells. Acetaminophen, a commonly used over-the-counter analgesic
drug, is detoxified in the liver, where small amounts of the drug are converted
to a highly toxic metabolite. This metabolite is detoxified by a metabolic
pathway that uses a substance (i.e., glutathione) normally present in
the liver. When large amounts of the drug are ingested, this pathway becomes
overwhelmed and toxic metabolites accumulate, causing massive liver necrosis.
Lead Toxicity. Lead is a particularly toxic metal. Small
amounts accumulate to reach toxic levels. There are innumerable sources of lead
in the environment, including flaking paint, lead-contaminated dust and soil,
lead-contaminated root vegetables, lead water pipes or soldered joints, pottery
glazes, newsprint, and toys made in foreign countries. Adults often encounter
lead through occupational exposure. Children are exposed to lead through
ingestion of peeling lead paint, by breathing dust from lead paint, or from
playing in contaminated soil. There has been a decline in blood lead levels
of both adults and children since the
removal of lead from gasoline and
from soldered food cans. High lead blood levels continue to be a problem,
however, particularly among children. In the United States alone, there are
approximately 250,000 children between 1 and 5 years of age who have lead
levels greater than 10 mg/mL. The prevalence of elevated blood lead levels was
higher for children living in more urbanized areas. By race or ethnicity,
non-Hispanic Black children residing in central cities with a population of 1
million or more had the highest proportion of elevated blood lead levels.
Lead is absorbed through the
gastrointestinal tract or the lungs into the blood. A deficiency in calcium,
iron, or zinc increases lead absorption. In children, most lead is absorbed
through the lungs. Although children may have the same or a lower intake of
lead, the absorption in infants and children is greater; thus, they are more
vulnerable to lead toxicity. Lead crosses the placenta, exposing the fetus to
levels of lead that are comparable with those of the mother. Lead is stored in
bone and eliminated by the kidneys. Although the half-life of lead is hours to
days, bone deposits serve as a repository from which blood levels are
maintained. In a sense, bone protects other tissues, but the slow turnover
maintains blood levels for months to years.
The toxicity of lead is related to
its multiple biochemical effects. It has the ability to inactivate enzymes,
compete with calcium for incorporation into bone, and interfere with nerve
transmission and brain development. The major targets of lead toxicity are the
red blood cells, the gastrointestinal tract, the kidneys, and the nervous
system.
Anemia is a cardinal sign of lead
toxicity. Lead competes with the enzymes required for hemoglobin synthesis and
with the membrane-associated enzymes that prevent hemolysis of red blood cells.
The resulting red cells are coarsely stippled and hypochromic, resembling those
seen in iron-deficiency anemia. The life span of the red cell is also decreased.
The gastrointestinal tract is the main source of symptoms in the adult. This is
characterized by “lead colic,” a severe and poorly localized form of acute
abdominal pain. A lead line formed by precipitated lead sulfite may appear
along the gingival margins. The lead line is seldom seen in children. The
kidneys are the major route for excretion of lead. Lead can cause diffuse
kidney damage, eventually leading to renal failure. Even without overt signs of
kidney damage, lead toxicity leads to hypertension.
In the nervous system, lead
toxicity is characterized by demyelination of cerebral and cerebellar white
matter and death of cortical cells. When this occurs in early childhood, it can
affect neurobehavioral development and result in lower IQ levels and poorer
classroom performance. Peripheral demyelinating neuropathy may occur in adults.
The most serious manifestation of lead poisoning is acute encephalopathy. It is
manifested by persistent vomiting, ataxia, seizures, papilledema, impaired
consciousness, and coma. Acute encephalopathy may manifest suddenly, or it may
be preceded by other signs of lead toxicity such as behavioral changes or
abdominal complaints.
Because of the long-term neurobehavioral and cognitive deficits that occur in children with even
moderately elevated lead levels, the Centers for Disease Control and Prevention
have issued recommendations for childhood lead screening.22 A safe blood level
of lead is still uncertain.At one time, 25 mg/dL was considered safe. Surveys
have shown abnormally low IQs in children with lead levels as low as 10 to 15
mg/dL.
Screening for lead toxicity
involves use of capillary blood obtained from a finger stick to measure free
erythro- cyte protoporphyrin (EP). Elevated levels of EP result from the
inhibition by lead of the enzymes required for heme synthesis in red blood
cells. The EP test is useful in detecting high lead levels but usually does not
detect levels below 20 to 25 mg/dL. Thus, capillary screening test values
greater than 10 mg/dL should be confirmed with those from a venous blood
sample. Because the symptoms of lead toxicity usually are vague, diagnosis is
often delayed. Anemia may provide the first clues to the disorder. Laboratory
tests are necessary to establish a diagnosis. Treatment involves removal of the
lead source and, in cases of severe toxicity, administration of a chelating
agent. Asymptomatic children with blood levels of 45 to 69 mg/dL usually are
treated. A public health team should evaluate the source of lead because
meticulous removal is needed.
Mercury Toxicity. Mercury has been used for industrial and
medical purposes for hundreds of years. Mercury is toxic, and the hazards of
mercury-associated occupational and accidental exposures are well known.
Currently mercury and lead are the most
toxic metals. Mercury is toxic in four primary forms: mercury vapor, inorganic
divalent mercury, methyl mercury, and ethyl mercury. Depending on the form of
mercury exposure, toxicity involving the central nervous system and kidney can
occur.
In the case of dental fillings, the
concern involves mercury vapor being released into the mouth. However, the
amount of mercury vapor released from fillings is very small. The main source
of methyl mercury exposure is from consumption of long-lived fish, such as tuna
and swordfish. Fish concentrate mercury from sediment in the water. Only
certain types of fish pose potential risk, however, and types such as salmon
have miniscule amounts or no mercury. Because the developing brain is more
susceptible to mercury-induced damage, it is recommended that young children
and pregnant and nursing women avoid consumption of fish known to contain high
mercury content. Thimerosal is an ethyl mercury–containing preservative that
helps prevent microorganism growth in vaccines. Due to the concern of this
preservative, it is hardly ever used
in the United States.
