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Causes of Cell Injury

Causes of Cell Injury
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.
Electrical burn of the skin. The victim was electrocuted after attempting to stop a fall from a ladder by grasping a high-voltage line.

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.

Spectrum of electromagnetic radiation.

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 tis- sue 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.