1. Cell Structure and Function | Handbook of Pathophysiology

Authors: Corwin, Elizabeth J.

Title: Handbook of Pathophysiology, 3rd Edition

> Table of Contents > Unit I - Fundamental Mechanisms of Health and Disease > Chapter 1 - Cell Structure and Function

Chapter 1

Cell Structure and Function

The cell is the building block of each living organism. Each cell is a self-contained system that undergoes the functions of energy production and usage, respiration, reproduction, and excretion. Cells join together to form tissues, tissues join to form organs, and organs form body systems. To understand how the organs and systems of the body work, one must first understand the cell. This understanding requires an investigation of the individual structures that make up the cell and of the separate function each structure carries out to serve the whole.

Physiologic Concepts

Cell Structure

A cell is made up of internal structures separated from each other by semipermeable membranes. These internal structures are bound together inside one cell membrane to form a single unit. Although cells differ as to their function in the body, all cells contain the same internal structures (Fig. 1-1). The inside of each cell can be divided into two main compartments: the cytoplasm and the nucleus. All internal structures reside in the cytoplasm or the nucleus.

Cytoplasm

The cytoplasm includes everything inside the cell but outside the nucleus. The mitochondria are the energy sources of the cell, and the endoplasmic reticulum and ribosomes are cytoplasmic structures (organelles) necessary

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for protein synthesis. The Golgi apparatus is a complex of membranes and vesicles responsible for the secretion of proteins synthesized on the ribosomes. Intracellular lysosomes are vesicles that contain potent digestive enzymes. The internal skeleton, called the cytoskeleton, consists of microtubules and microfilaments. The cytoskeleton supports the cell from the inside and allows for the movement of substances inside the cell. The cytoskeleton also supports the movement of projections on the outside of cells, such as the hair-like projections called cilia. The microtubules play an important role in chromosome separation during cell division and assist in maintaining structural integrity.

Figure 1-1. The general structure of the cell with its organelles. (From

Bullock, B.A., & Henze, R.L. [2000]. Focus on pathophysiology. Philadelphia: Lippincott Williams & Wilkins.

)

The Nucleus

The nucleus of the cell is a large, membrane-bound organelle that contains deoxyribonucleic acid (DNA), the genetic material of the cell. To protect itself from breakage, the DNA is folded up inside the nucleus. Proteins responsible for folding and protecting the DNA are called histones. Histones and DNA are found in a part of the nucleus called the nucleolus. DNA replication, cell division, and DNA transcription occur inside the nucleolus.

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Cell Membrane

A cell membrane encircles each cell. The cell membrane is a semipermeable barrier composed of a floating bilayer of phospholipids, with interspersed, freely moving, protein molecules. The protein molecules extend totally or partially through the membrane.

Phospholipid Bilayer

The phospholipid molecules consist of a polar (charged) phosphate molecule joined with a nonpolar fat or lipid extension. The polar head, containing the phosphate, points inside or outside the cell, where it interacts with other polar molecules, including water. The nonpolar extension makes up the body of the membrane layer itself (Fig. 1-2). Because there are two layers of lipid in the membrane, it is called a lipid bilayer. Diffusion through the lipid bilayer is limited to lipid-soluble substances. For non-lipid substances to enter the cell, they must take advantage of the interspersed integral proteins.

Integral Proteins

Proteins that extend completely through the membrane are called integral proteins. Integral proteins are usually glycosylated (glucose bound) or are bound by lipids on the extracellular side (Fig. 1-3). These protein-carbohydrate or protein-lipid complexes often act as receptor molecules for protein hormones, or function in ways that allow cells to communicate with each other. Integral proteins may also act as channels in the membrane to provide pores for the movement of small ions into the cell, or as carriers for polar substances too large to move through the pores. Some integral proteins are membrane-bound enzymes needed to catalyze reactions. Misfolding or mutations in integral proteins may contribute to

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disease. For example, one neurodegenerative disease that may be caused by misfolding of an integral membrane protein is Alzheimer's disease. In this case, the integral proteins known as presenilins may carry mutations that affect their functioning. The presenilins directly or indirectly control the processing of another protein, beta amyloid; abnormal processing of beta amyloid is believed to play a role in the development of Alzheimer's disease.

Figure 1-2. A schematic diagram of the cell membrane showing the lipid bilayer and integral proteins.

Figure 1-3. Cell membrane. The right end is intact, but the left end has been split along the plane of the lipid tails.

Movement Through the Membrane

Lipid-soluble substances, such as oxygen, carbon dioxide, alcohol, and urea, move across the lipid bilayer by simple diffusion. Other substances that are not lipid soluble, such as most small ions, glucose, amino acids, and proteins, move between the extracellular fluid and the intracellular compartments through pores provided by the integral proteins or through carrier-mediated transport systems. Carrier-mediated transport also originates in the integral proteins. The extracellular fluid consists of the fluid between the cells, called the interstitial fluid, and the blood. The fluid inside the cell is called the intracellular fluid.

Simple Diffusion Through the Cell Membrane

Simple diffusion through the cell membrane occurs through random movement of molecules. This process does not require energy, but can result in the movement of a substance across a membrane. However, the substance cannot accumulate in higher concentration on one side of the

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membrane compared to the other. Therefore, a substance that is permeable across the cell membrane will diffuse into or out of the cell until its concentration is equal on both sides (Fig. 1-4).

Figure 1-4. Simple diffusion across a membrane. Permeable substances randomly diffuse from an area of high concentration to an area of low concentration (A) until the concentrations are equal (B).

Osmosis

The diffusion of water into the cell is called osmosis. Osmosis occurs continually between intracellular and extracellular compartments, as water moves down its concentration gradient (i.e., from high concentration to low). The drive for water to move in one direction or the other is described as the osmotic pressure. The osmotic pressure of a solution depends on the number of particles or ions present in the water solution. The more ions that are present in the solution, the less the water concentration and the greater the osmotic pressure (i.e., the pressure for water to diffuse into the solution).

A cell also has osmotic pressure. A dehydrated cell has high osmotic pressure: low water concentration and high particle concentration. Water

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would diffuse into this cell if possible. An overhydrated cell has low osmotic pressure: high water concentration and low particle concentration. Water would diffuse out of this cell if possible.

Simple Diffusion Through Protein Pores

Small ions, such as hydrogen, sodium, potassium, and calcium, are too electrically charged to diffuse through the lipid membrane of the cell. Instead, small ions diffuse through the pores provided by the integral proteins. These protein channels are usually selective about which ions they allow to pass. Selectivity is based on the shape and size of the channel and the electrical nature of the ion.

Many protein channels are gated; they can be open or closed to an ion. Whether the gate is open or closed usually depends on the electrical potential across the gate (i.e., the voltage-gated sodium channel), or on binding to the gate by a ligand that causes it to open or close. An example of ligand gating is when acetylcholine binds to proteins on the neuromuscular junction, thereby opening gates to many small molecules, especially sodium and, to a lesser extent, calcium ions. Like all types of simple diffusion, diffusion through a gate continues until the concentrations on either side of the membrane are equal or the gate is shut. Several human diseases are related to dysfunction of transmembrane protein channels. Cystic fibrosis is the best known human disease caused by a defective transmembrane protein that results in abnormal ion movement through a pore.

Mediated Transport

For many substances like glucose and amino acids, simple diffusion is impossible. These molecules are too charged to pass through the lipid portion of the membrane or too large to pass through a pore. Instead, these substances, called substrates, are transported across the membrane with the assistance of a carrier. This type of movement is called mediated transport and may require energy derived from the splitting of adenosine triphosphate (ATP) (see Energy Production later).

Active transport is mediated transport that requires energy (Fig. 1-5A). With active transport, energy is used by the cell to maintain a substance at higher concentration on one side of the membrane than the other. Examples of substances moved by active transport include sodium, potassium, calcium, and the amino acids. Each of these substances is actively transported, with the assistance of a carrier, in one direction against a concentration gradient. It then moves down its concentration gradient by simple diffusion in the opposite direction.

Facilitated diffusion is mediated transport that does not require energy (Fig. 1-5B). Facilitated diffusion is similar to simple diffusion in that no energy is used by the cell to transport a substance; therefore, the substance cannot be transported against its concentration gradient. Facilitated diffusion differs from simple diffusion in that, with facilitated diffusion, a molecule that is limited in its ability to cross the cell membrane on its own is

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assisted (facilitated) by a carrier and so can cross the membrane. Glucose moves into most cells by facilitated diffusion.

Figure 1-5. Transport of a substrate using a carrier. Active transport (A) requires energy to provide a final difference in concentration; facilitated diffusion (B) transports substrates without requiring energy, but cannot concentrate a substance. Simple diffusion continues at some level in all carrier-mediated systems.

Characteristics of Carriers

Active transport and facilitated diffusion require carriers. All carriers are affected by the properties of specificity, saturation, and competition.

Specificity of carriers means that only certain substrates will be transported by any one carrier. The carrier and its specific substrate appear to fit together like a lock and a key.

Saturation of carriers means that at a certain concentration of substrate, all carriers will be filled and transport will level off. Additional substrate will not increase transport across the membrane.

Competition of carriers occurs when there is more than one substrate transported by the same carrier. The multiple substrates compete with each other for the limited number of carrier sites available. Many drugs, naturally occurring and synthetic, compete with endogenous hormones and neurotransmitters for various carrier molecules.

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Endocytosis

When large substances cannot enter the cell by diffusion or mediated transport, endocytosis (engulfment) of the substance by the cell membrane occurs. Pinocytosis is the engulfment of macromolecules, such as protein, by vesicles. Phagocytosis is the engulfment of dead cells or bacteria. Both processes require energy. Only cells of the immune system (i.e., macrophages and neutrophils) perform phagocytosis.

Energy Production

Cells are required to produce energy for their own use. Cells do this by extracting the energy contained in the chemical bonds of food molecules by combining the food molecules with oxygen inside the mitochondria of the cell. The food molecules used are glucose from carbohydrate metabolism, amino acids from protein metabolism, and fatty acids and glycerol from fat metabolism.

The process whereby the food molecules are combined with oxygen, leading to the production of energy, is called oxidative phosphorylation. This process requires several enzymes, working in sequential fashion in the mitochondria. The net result is the synthesis of the energy-rich molecule adenosine triphosphate (ATP). ATP is composed of the nitrogen base adenosine, the sugar ribose, and three phosphate molecules bound together. The last two phosphates are joined by a high-energy bond, which when split releases approximately 7 kcal/mole of usable energy for the cell.

Oxidative Phosphorylation of Glucose

Although the oxidative phosphorylation of glucose occurs in the mitochondria, an initial step in the handling of glucose must occur before oxidative phosphorylation is initiated. This step is called glycolysis and occurs in the cytoplasm outside the mitochondria. Glycolysis is anaerobic, meaning it occurs without requiring oxygen. During glycolysis, cytoplasmic enzymes convert glucose into pyruvic acid. This process requires two molecules of ATP and produces four molecules of ATP: a result of two net molecules. In times of oxygen deprivation, glycolysis plays a limited but important role in supplying the cell with ATP (see Anaerobic Glycolysis section).

If oxygen is present (aerobic), the molecules of pyruvic acid move into the mitochondria where they enter the citric acid cycle, also called the Krebs cycle, and are converted by enzymes present there into a compound called acetyl coenzyme A (acetyl CoA). This process produces two more ATP molecules. Acetyl CoA is then enzymatically converted to carbon dioxide and hydrogen. The carbon dioxide diffuses out of the mitochondria and out of the cell, where it is picked up by the blood supplying that cell. It is then carried to the lungs and exhaled from the body. The hydrogen atoms remaining in the mitochondria begin the process of oxidative phosphorylation, during which they are combined with molecules of oxygen through an elaborate electron transport chain present in the mitochondrial

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membrane. The result of this process is to produce a tremendous amount of energy in the form of 36 ATP molecules. From the metabolism of one molecule of glucose, therefore, a total of 38 net ATP molecules are formed (36 from oxidative phosphorylation and 2 from glycolysis).

Oxidative Phosphorylation of Fatty Acids and Glycerol

The cell also uses free fatty acids and glycerol in oxidative phosphorylation to produce ATP. Glycerol is a three-carbon carbohydrate, which undergoes glycolysis in the cytoplasm and enters the Krebs cycle as acetyl CoA. Free fatty acids diffuse directly into the mitochondria where they are acted on by enzymes and transformed into acetyl CoA. This acetyl CoA also enters the Krebs cycle. The breakdown of one molecule of fat results in 463 molecules of ATP. Fat has a five times greater weight per mole than glucose. Thus, gram for gram, the metabolism of fat provides about three times as much ATP as glucose metabolism. Therefore, fat is a more efficient form of energy storage than carbohydrate.

Oxidative Phosphorylation of Amino Acids

Amino acids enter the mitochondria after removal of the nitrogen molecule (deamination). After deamination, amino acids enter the Krebs cycle at various points. Some, such as alanine, enter as pyruvic acid; others enter as later intermediates. Where the amino acids enter the Krebs cycle determines how many hydrogen atoms they add to the electron transfer chain and thus how many ATP molecules are synthesized.

Anaerobic Glycolysis

If oxygen is unavailable, the pyruvic acid produced by glycolysis does not enter the Krebs cycle, but combines with hydrogen in the cytoplasm to form lactic acid. Although the two molecules of ATP produced in the breakdown of one molecule of glucose to pyruvic acid are available to keep the cell alive, this is a wasteful use of glucose because it results in the loss of the other 36 molecules of ATP that would have been produced had pyruvic acid entered the Krebs cycle. This process can only continue a short while before glucose is depleted.

The lactic acid produced by anaerobic glycolysis diffuses out of the cell and into the bloodstream. This can create a decrease in plasma pH (an increase in plasma acidity). With the return of oxygen, lactic acid will be reconverted to pyruvic acid, primarily in the liver, and the Krebs cycle will resume.

Energy Usage

ATP formed in the mitochondria moves into the cytoplasm by a combination of simple and facilitated diffusion. When needed by the cell, ATP can be broken down rapidly into adenosine diphosphate (ADP) by enzymatic

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splitting of the bond between the last two phosphates. This results in the release of energy, which is used by the cell to perform its duties of solute transport, protein synthesis, reproduction, and movement.

Although it is through ATP synthesis and breakdown that energy is transferred in the cell, very little ATP is stored in the cell. Instead, energy is stored in the form of substrates for ATP as carbohydrates, fats, proteins, and their metabolic products. The other essential component for ATP production, oxygen, is continually delivered to all cells by combined efforts of the cardiovascular and respiratory systems.

The Sodium-Potassium Pump

An important example of active transport is the pumping of sodium and potassium across cell membranes. This transport depends on an integral carrier protein known as the sodium-potassium pump. Associated with the pump is an enzyme that splits ATP and provides the energy needed for the pump to function. This enzyme is known as the sodium-potassium ATPase. The sodium-potassium pump transports sodium ions out of and potassium ions into the cell. This transport causes greater sodium concentration in the extracellular fluid (142 mEq/L) compared to the intracellular fluid (14 mEq/L), and greater potassium concentration in the intracellular fluid (140 mEq/L) compared to the extracellular fluid (4 mEq/L). The sodium-potassium pump carries three sodium molecules out of the cell for every two potassium molecules it carries in.

The Effects of Pumping Sodium and Potassium

Because sodium and potassium are cations (carrying a positive charge), the transport of three sodium ions out of the cell and only two potassium ions into the cell creates an electrical gradient across the cell membrane. It is this electrical membrane potential that allows nerve and muscle function and action potentials to occur (see Chapter 8).

The sodium-potassium pump also is essential in controlling cell volume. The presence of intracellular proteins and other organic substances that cannot cross the cell membrane increases intracellular osmotic pressure and creates a tendency for water to diffuse into the cell. This diffusion of water, if unlimited, would cause the cell to swell and eventually burst. However, with the active transport of three sodium ions out of the cell, the osmotic pressure inside the cell is reduced and the diffusion of water into the cell is contained.

Coupled Transport

Many substances are transported coupled to the active transport of sodium. These substances include glucose, amino acids, hydrogen ions, and calcium. The energy required for the transport of these other substances is indirectly supplied through the splitting of ATP by the sodium-potassium ATPase. This type of transport is called secondary active transport.

Figure 1-6. Cotransport (A) and countertransport (B) across the cell membrane.

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Coupled transport can be in the same direction as sodium transport (cotransport) or it may occur in the direction opposite that of sodium transport (countertransport) (Fig. 1-6). Both types of transport depend on the diffusion of sodium down its concentration gradient, which in turn depends on the active transport of sodium by the sodium-potassium pump. In cotransport, sodium attaches to a carrier that assists it in moving down its concentration gradient, from outside the cell to inside; the other substance attaches to the same carrier, also on the outside of the cell, and as sodium is moved into the cell, the coupled substance moves with it. In countertransport, the coupled substance binds to the sodium carrier on the inside of the cell membrane with sodium on the outside. Therefore, when sodium is delivered to the inside of the cell, the other substance is delivered to the outside.

Calcium Transport

Calcium can move by simple diffusion through the cell membrane, be transported by coupled transport with sodium, or be moved by primary active transport through a calcium pump. There are two known calcium pumps. One is part of an integral protein present in the cell membrane, which moves calcium out of the cell. The other is an intracellular pump, which pumps calcium out of the cytoplasm into intracellular compartments such as the sarcoplasmic reticulum. This results in sequestering calcium inside the cell. Both pumps keep free intracellular calcium

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concentration low. The calcium pumps serve as ATPases, which derive energy needed to pump the calcium against its concentration gradient by the splitting of ATP.

Cellular Genetics

In humans, the genetic material of each cell is contained in 23 pairs of chromosomes (1 pair from each parent) for a total of 46 chromosomes. Each cell of the body has the same 46 chromosomes. Of the 23 pairs of chromosomes, 22 are the same in both sexes. The 23rd pair of chromosomes consists of the sex chromosomes, the X or the Y. In humans, the female has two X chromosomes and the male has one X and one Y.

DNA

Each chromosome is composed of hundreds of thousands of molecules of DNA. DNA is made up of phosphoric acid, a sugar molecule called deoxyribose, and one of four possible nitrogen bases: adenine, guanine, cytosine, or thymine. DNA molecules line up in the cell in the form of a double helix (Fig. 1-7), in which the phosphoric acid and the deoxyribose sugar form the backbone of the helix. The base pairs from two molecules of DNA lie between the two strands of the helix, opposing each other. Adenine always bonds across the helix with thymine, and cytosine always bonds with guanine. The bonds are loose, so that the helixes can separate when cell division occurs or when protein synthesis is initiated.

Cellular Reproduction

Many cells of the body reproduce and make copies of themselves throughout an organism's lifetime. To reproduce, a cell has to replicate its genetic material and then split in two. Replication and division of a cell occurs during the cell cycle (see Chapter 2).

Replication

To replicate, the DNA double helix uncoils and each strand of DNA serves as a template for a new strand. In the formation of a new strand of DNA, each adenine will only bind with a thymine and each cytosine will only pair with guanine. Therefore, only one strand, acting as a mirror-image template for the other, is needed to replicate the entire double helix.

Replication of the chromosome pairs and the DNA occurs in the nucleus of the cell. Various enzymes participate in DNA replication, which results in each chromosome being exactly copied or duplicated. The duplication is checked and double-checked by several proofreading enzymes to ensure no mistakes are made. If a mistake is identified, proofreading or other enzymes remove the error and correct it, or the cell may initiate its own death in a process called apoptosis. If a mistake is not repaired, and the cell does not undergo apoptosis, a mutation in the DNA will exist.

Figure 1-7. The DNA double helix.

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Cell Division

Once duplicated, the chromosome pairs pull apart and the original cell splits into two cells. Each new cell contains the entire genetic information in 23 pairs of chromosomes. The process whereby a cell divides to produce two identical daughter cells is called mitosis. Briefly, the steps involved include activation of a maturation promoting factor, condensation of chromosomes, disappearance of the nucleolus and the nuclear membrane, formation of a spindle structure, movement of the chromosomes to the equatorial plate, and finally, segregation and formation of two daughter nuclei, each surrounded by a separate cytoplasm. Mitotic division is achieved by coordinating chromosomal, centrosomal, and cytoplasmic cycles.

Meiosis, another type of cell division, occurs in the reproductive cells, the egg and sperm. Meiosis involves two cell divisions resulting in a total of

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four daughter cells produced, each containing 23 single chromosomes rather than 23 pairs. Meiosis and mitosis are described in Chapter 2.

Control of Cellular Replication and Division

Some cells, such as liver, bone marrow, and gut cells, undergo replication and mitosis frequently. Other cells, such as nerve and cardiac muscle cells, do not replicate or divide except during fetal development or in the neonatal period. Growth factors, hormones, and other cell products turn cell division on or off and determine whether and how frequently a cell will replicate and divide. These factors may affect the replication and division of the cell that produces them, or they may circulate and affect a different cell. Physical factors such as crowding can also influence cell division.

Protein Synthesis

Protein synthesis is ongoing in all cells. Protein synthesis occurs when sections of DNA are turned on, which causes the cell to begin making a certain protein. Although each cell contains identical DNA on the 46 chromosomes, some cells have different sections of DNA turned on at a given time compared to other cells. Sections of DNA that turn on and off in different cells are called genes. There are approximately 20,000 to 40,000 genes in the human body distributed among the 46 chromosomes. Each gene contains 90 to 3,000 DNA molecules. Each gene codes for a particular protein or enzyme. Turning on or off different genes causes a cell to make different proteins compared to other cells.

Although genes controlling protein synthesis are in the nucleus, proteins are made in the cytoplasm on specialized structures called ribosomes. The message from the activated gene in the nucleus must be carried to the ribosomes. This is accomplished by making a copy of the gene in the nucleus and transporting the copy to the ribosomes, where it is then translated into a protein.

Transcription of DNA Into Messenger RNA

To transcribe or make a copy of a gene, the area of the double helix on the chromosome where that gene is contained must unravel. Once unraveled, a special enzyme, called an RNA polymerase, attaches to a certain section at the start of the gene, called the promoter or controlling sequence. When the RNA polymerase attaches to this site, the gene is copied as a mirror image, in a manner similar to that described for DNA replication. The new copy is not another piece of DNA, but is a similar molecule called ribonucleic acid (RNA). RNA, like DNA, contains phosphoric acid, but unlike DNA, it contains the sugar ribose instead of deoxyribose and the base uracil instead of thymine. When the gene is copied as RNA, each cytosine base in the gene becomes a guanine in the copy, each guanine becomes a cytosine, each thymine becomes an adenine, and each adenine becomes a uracil. The entire gene is transcribed by this procedure. After the gene is copied, the

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RNA polymerase will reach a special sequence on the DNA (called the termination sequence) and the process will stop. The RNA copy is then released from the gene and moves into the cytoplasm. The RNA copy that carries the DNA message out of the nucleus is called the messenger RNA (mRNA). The mRNA then moves through the cytoplasm to the ribosomes.

Adenine, guanine, cytosine, and uracil are carried as mRNA to the ribosomes in groups of three, called triplets or codons. Each triplet codes for one amino acid. There are 20 amino acids used in the human body that combine in various ways to make up all the proteins of the body. The long strand of mRNA triplets can be snipped at any point before the molecule leaves the nucleus, allowing different proteins to be made from one original gene.

Transfer RNA

Before the ribosomes make the protein from the mRNA template, another type of RNA, called transfer RNA (tRNA), binds to the mRNA by connecting mirror-image bases (called anticodons) to each triplet of mRNA bases. At the opposite end of the anticodon is the amino acid coded for by those three bases. There are at least 20 types of tRNA, each one carrying a certain amino acid on one end and the anticodon for that amino acid on the other end.

The Translation of Messenger RNA into Protein

When the mRNA has found its matching tRNA, both molecules bind onto the ribosome, which is composed partly of a third type of RNA ribosomal RNA. The amino acid carried by the tRNA is added to a chain of amino acids growing on the ribosome until the ribosome is signaled to stop adding to the chain by a special codon known as a stop codon. The protein is then complete and is freed from the ribosome. This process is called translation.

The processes of transcription and translation are shown in Figure 1-8.

Control of Protein Synthesis

Regulatory proteins block or activate the promoter section of each gene in the cell, determining which genes will be turned on, transcribed into mRNA, and made into a protein. If a regulatory protein blocks the promoter region of a gene, protein synthesis will not occur from that gene. If a regulatory protein binds to or near the promoter area in such a way that it makes the area accessible to the RNA polymerase, it will activate the gene's transcription into mRNA. This type of protein would be considered a transcription factor or enhancer; if, on the other hand, a regulatory protein blocked the promoter area of a gene so that it was not transcribed into mRNA, the regulator protein would be a repressor.

Production and activation of regulatory proteins appear to be linked to other genes responding to feedback signals, chemical cues, and hormones such as thyroid hormone and growth hormone. These signals result in the

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production of proteins with repressor or activator functions. Other factors that alter the function of the histones responsible for folding and exposing different portions of the DNA may also affect DNA transcription. Methylation (adding a CH₃ complex) or acetylation of the histones associated with a gene, or methylation of the promoter region of a particular gene, may block that gene from being transcribed. This blocking of transcription results in silencing that gene and is an example of epigenetics, a term coined to describe reversible changes in the genetic material that lead to changes in gene expression.

Figure 1-8. Transcription (copying) of DNA into mRNA occurs in the nucleus. The mRNA moves into the cytoplasm and attaches to the ribosome. On the ribosomes, the matching anticodon is carried on one end of tRNA and the corresponding amino acid on the other end. The amino acid chain grows as the ribosome moves along the mRNA.

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Cell Types

Epithelial Cells

The tissue that lines most internal and external structures of the body is made up of epithelial cells. These cells are packed together, providing support for overlying structures. Epithelial tissue also acts as a protective barrier and a medium for absorption and secretion. Examples of epithelial tissue include the skin (epidermis), the covering on all internal organs and tubules, the microvilli of the intestine, and the cilia lining the respiratory passageways. Glandular cells that secrete substances into ducts (exocrine glands) or into the bloodstream (endocrine glands) are made of epithelial tissue. Sensory organs also contain epithelial cells. Epithelial layers are usually one to two cells thick.

Connective Tissue Cells

Connective tissue is represented by many different cell types, including fibroblasts, adipose (fat) cells, mast cells, blood cells, and cells of the blood-forming organs.

Connective tissue holds different tissues together by the accumulation of protein and gel-like substances secreted from the fibroblasts into the spaces surrounding the cells. Protein substances secreted include collagen, a thick, white fiber that acts to provide structural support; elastin, a stretchy protein that allows tissues to give when stretched; and reticular fibers, thin flexible strands that allow organs to accommodate increases in volume. Tissue gel consists primarily of hyaluronic acid, which intersperses throughout the interstitial spaces to retain water and provide support and protection.

Adipose tissue and endothelial cells provide nourishment and support for the fibroblasts. Mast cells contain granules filled with histamine and other vasoactive substances. Mast cell degranulation is an important step in initiating an inflammatory reaction.

Hematopoietic tissue is considered connective tissue. Hematopoietic tissue includes bone marrow, blood cells, and lymphatic tissue. The basement membrane found along the interface between connective tissue and an adjacent tissue is also considered a connective tissue layer. This membrane bonds, supports, and allows for tissue repair.

Muscle Cells

Muscle cells are highly differentiated (specialized) cells that have the ability to contract and cause movement or increased tension. Groups of muscle cells form one of three types of muscle tissue: skeletal, smooth, or cardiac.

Muscle cells are composed of the proteins actin and myosin. Cross-bridges located between the actin and myosin connect and swing when stimulated in the proper sequence (see Chapter 10). This causes the

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muscle as a whole to contract and do work or produce tension. All types of muscle require an increase in intracellular calcium to contract. Different muscles may use different sources of calcium and thus have slightly different methods of contraction stimulation.

Skeletal muscle is attached to bones by tendons. When stimulated by motor neuron impulses, skeletal muscle voluntarily contracts. Skeletal muscle uses calcium released from intracellular compartments to initiate contraction. Mature skeletal muscle does not undergo further cell division. Skeletal muscle may even be considered a paracrine endocrine organ because it secretes cytokines such as interleukin-8 (IL-8), a peptide that induces angiogenesis (new capillary formation).

Cardiac muscle, found in the heart, contracts spontaneously because of an intrinsic ability to depolarize and fire action potentials. Cardiac muscle is innervated by the nerves of the autonomic nervous system: the sympathetic and parasympathetic nerves. These inputs can increase or decrease the inherent rate or strength of cardiac contraction. Cardiac contraction involves calcium entry into the muscle cell from the extracellular fluid and from an intracellular compartment, the sarcoplasmic reticulum. During embryogenesis, cardiac muscle cells become highly differentiated and do not undergo further cell division. Cardiac muscle is also an endocrine organ in that it secretes the hormone atrial natriuretic peptide (ANP) that acts on the kidney to participate in the control of blood volume.

Smooth muscle is found throughout the body, including the vascular system, the genitourinary tract, and all the parts of the gut. Its function is often considered involuntary. Smooth muscle is innervated by the autonomic nervous system, which can increase or decrease the rate of contraction. When stretched, smooth muscle responds with an increase in contraction. Smooth muscle relies primarily on calcium entry from the extracellular fluid to initiate contraction. Mature smooth muscle cells can undergo cell division.

Stem Cells

In general, as body cells become differentiated (specialized), they become less able to reproduce and thus eventually die. Stem cells are undifferentiated (non-specialized) cells that have the ability to reproduce indefinitely and act as progenitors of other, specialized body cells. As specialized cells die, they can be replaced by new cells arising from local stem cells. Stem cells may come from adult sources (intestinal stem cells, hematopoietic stem cells and epidermal stem cells) or may be derived from human embryos. Human embryo derived stem cells in particular are highly undifferentiated and have the potential to differentiate into approximately 200 different tissues of the body.

Both adult stem cells and embryonic stem cells may provide therapies for some currently untreatable diseases. For example, one application of stem cell therapy currently under investigation is to repair an infarcted heart. This involves transplanting stem cells into the infarcted area of the

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heart in order to increase or preserve the number of cardiac muscle cells, improve vascular supply, and improve the contractile function of the injured myocardium.

Obstacles to using stem cells include a potential for tumorigenicity, immunological rejection of transplanted cells, and the risk of transmitting an infection. The harvesting of embryonic stem cells is of ethical concern for some and is an obstacle to their use in the United States at this time.

Pathophysiologic Concepts

Cells are continually exposed to changing conditions and potentially damaging stimuli. If these changes and stimuli are minor or brief, the cell adapts to them. Cellular adaptations include atrophy, hypertrophy, hyperplasia, and metaplasia. Dysplasia is an abnormal response, reflecting atypical hyperplasia. More prolonged or intense stimuli can cause cell injury or death.

Atrophy

Atrophy is a decrease in the size of a cell or tissue. Atrophy can be an adaptive response that occurs when there is a decrease in the workload of a cell or tissue. With decreased work, the oxygen and nutrient requirements of a cell decrease. This causes most of the intracellular structures, including the mitochondria, the endoplasmic reticulum, the intracellular vesicles, and the contractile proteins, to shrink.

Atrophy can occur as a result of disuse, for instance, as seen in the muscles of an individual who is immobilized or in a weightless (zero gravity) state. Atrophy also can occur as a result of decreased hormonal or neural stimulation of a cell or tissue, which is seen in the breasts of women after menopause or in skeletal muscle after spinal cord transection. Atrophy of fat and muscle occurs in response to a nutritional deficiency and is seen in malnourished or starving people. Atrophy also may occur as a result of insufficient blood supply to cells, which cuts off vital nutrient and oxygen supply.

Hypertrophy

Hypertrophy is the increase in the size of a cell or tissue. Hypertrophy is an adaptive response that occurs when there is an increase in the workload of a cell. The cell's demand for oxygen and nutrients increases, causing growth of most intracellular structures, including the mitochondria, the endoplasmic reticulum, intracellular vesicles, and the contractile proteins. Protein synthesis increases.

Hypertrophy is primarily seen in cells that cannot adapt to increased work by increasing their numbers through mitosis. Examples of cells that cannot undergo mitosis but experience hypertrophy are cardiac and skeletal

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muscle cells. Smooth muscle may undergo hypertrophy and hyperplasia. There are three main types of hypertrophy: physiologic, pathologic, and compensatory.

Physiologic hypertrophy occurs as a result of a healthy increase in the workload of a cell (i.e., increased muscle bulk through exercise).

Pathologic hypertrophy occurs in response to a disease state, for example, hypertrophy of the left ventricle in response to longstanding hypertension and an increase in the workload of the heart.

Compensatory hypertrophy occurs when cells grow to take over the role of other cells that have died. For example, the loss of one kidney causes the cells of the remaining kidney to undergo hypertrophy, resulting in a substantial increase in the size of the remaining kidney.

Hyperplasia

Hyperplasia is the increase in cell number occurring in an organ as a result of increased mitosis. Hyperplasia is seen in cells stimulated by an increased workload, by hormonal signals, or by signals produced locally in response to a decrease in tissue crowding. It can only occur in cells that undergo mitosis, such as liver, kidney, and connective tissue cells. Hyperplasia may be physiologic, pathologic, or may occur as compensation for tissue loss or injury.

Physiologic hyperplasia occurs monthly in uterine endometrial cells during the follicular stage of the menstrual cycle.

Pathophysiologic hyperplasia can occur with excessive hormonal stimulation, which is seen in acromegaly, a connective tissue disease characterized by growth hormone excess.

Compensatory hyperplasia occurs when cells of a tissue reproduce to make up for a previous decrease in cells. An example of compensatory hyperplasia is that which occurs in liver cells after surgical removal of sections of liver tissue. The compensation is striking in its rapidity.

Metaplasia

Metaplasia is the change in a cell from one subtype to another. It usually occurs in response to some continual irritation or injury that results in chronic inflammation of the tissue. By undergoing metaplasia, cells that are better able to withstand chronic irritation and inflammation replace the original tissue. Although metaplastic cells are not cancer cells, the irritants that caused the initial change may be carcinogenic, and metaplasia is a sign of significant cellular irritation.

The most common example of metaplasia is the change in the cells of the respiratory passages from ciliated columnar epithelial cells to stratified squamous epithelial cells in response to years of cigarette smoking. The ciliated cells, essential for the removal of dirt, microorganisms, and toxins in the respiratory passages, are easily injured by cigarette smoke. Stratified epithelial cells are better able to survive smoke damage. Unfortunately,

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they do not assume the vital protective role of ciliated cells. Squamous cell carcinoma is the most common type of lung cancer in the United States.

Dysplasia

Dysplasia is a derangement in cell growth that results in cells that differ in shape, size, and appearance from their predecessors. Dysplasia appears to occur in cells exposed to chronic irritation and inflammation. Although this cell change is not cancerous, dysplasia indicates a dangerous situation and the possibility that a cancerous condition may occur.

The most common sites of dysplasia are the respiratory tract (especially the squamous cells present as a result of metaplasia) and the cervix. Cervical dysplasia usually results from infection of the cells with the human papilloma virus (HPV). Dysplasia is usually rated on a scale to reflect its degree, from minor to severe.

Cell Injury

Cell injury occurs when a cell can no longer adapt to stimuli. This can occur if the stimuli are too long in duration or too severe in nature. Whether a cell recovers from an injury or dies depends on the cell and on the extent and type of injury.

Hypoxia (oxygen deprivation), microorganism infection, temperature extremes, physical trauma, radiation, and free radical exposure cause cell injury. When a cell is injured, it may demonstrate alterations in shape, size, protein synthesis, genetic makeup, and transport properties.

Cell Death

There are two main categories of cell death. The first category is necrotic cell death, which occurs when injurious stimuli to a cell are too intense or prolonged. Necrotic cell death is characterized by cell swelling and rupture of internal organelles, most obviously the mitochondria, and by marked stimulation of the inflammatory response. The second category of cell death is apoptosis, which is programmed cell death, a process in which an orderly sequence of molecular steps occurs, leading to cellular disintegration. Apoptosis is not characterized by swelling or inflammation, but rather the dying cell shrinks on itself and then is engulfed by neighboring cells. Apoptosis is responsible for keeping cell numbers relatively constant and is a mechanism by which unwanted cells, aged cells, dangerous cells, or cells carrying a mistake in DNA transcription can be eliminated. It is an active process, in which the cell itself participates, and draws its name from a Greek word referring to a dropping off, as in petals off a flower.

Thymidine phosphorylase (TP), a platelet-derived endothelial cell growth factor, has been discovered to protect cells from undergoing apoptosis by stimulating nucleoside metabolism and angiogenesis. The use of drugs that specifically target TP has been recommended to

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improve the effects of conventional chemotherapy by enhancing apoptosis of mutated cells.

Causes of Necrotic Cell Death

Common causes of necrotic cell death include prolonged hypoxia, infection leading to the production of toxins and free radicals, and disruption in membrane integrity, the ultimate result of which is cellular bursting. Typically, the immune and inflammatory responses often stimulated by necrosis lead to further injury and death of neighboring cells. Necrotic cell death can be widespread in the body without causing death of the individual.

Causes of Apoptosis

Programmed cell death begins during embryogenesis and continues throughout the lifetime of an organism. Stimuli that initiate apoptosis include hormonal cues, antigen stimulation, immune peptides, and membrane signals that identify aging or mutated cells. Viral infection of a cell will often turn on apoptosis, ultimately leading to the death of the virus and the host cell. This is one way living organisms have evolved to fight viral infection. Certain viruses (e.g., the Epstein-Barr virus responsible for mononucleosis) have in turn evolved to produce specialized proteins that deactivate the apoptosis response. Deficiencies in apoptosis have been implicated in the development of cancer and in neurodegenerative diseases of unknown origin, including Alzheimer's disease and amyotrophic lateral sclerosis (Lou Gehrig's disease). Antigen-stimulated apoptosis of immune cells (T and B cells) is essential for the development and maintenance of immune self-tolerance.

Results of Cell Death

Dead cells liquefy or coagulate and are removed from the area or isolated from the rest of the tissue by immune cells in the process of phagocytosis. If mitosis is possible and the area of necrosis is not too large, new cells of the same type fill in the empty space. Scar tissue will form in the vacated space if cell division is impossible or if the area of necrosis is extensive.

Gangrene refers to the death of a large mass of cells. Gangrene may be classified as dry or wet. Dry gangrene spreads slowly with few symptoms and is frequently seen in the extremities, often as a result of prolonged hypoxia. Wet gangrene is a rapidly spreading area of dead tissue, often of internal organs, and is associated with bacterial invasion of the dead tissue. It exudes a strong odor and is usually accompanied by systemic manifestations. Wet gangrene may develop from dry gangrene. Gas gangrene is a special type of gangrene that occurs in response to an infection of the tissue by a type of anaerobic bacteria called clostridium. It is seen most often after significant trauma. Gas gangrene rapidly spreads to neighboring tissue as the bacteria release deadly toxins that kill neighboring

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cells. Muscle cells are especially susceptible and release characteristic hydrogen sulfide gas when affected. This type of gangrene may prove fatal.

Wound Repair

Destroyed or injured tissues must be repaired by regeneration of the cells or the formation of scar tissue. The goal of both types of repair is to fill in the areas of damage in order to return structural integrity to the tissue.

Tissue regeneration and scar formation begin with inflammatory reactions (see Chapter 5). Platelets control bleeding and white blood cells digest and remove dead tissue in the area. Growth factors and immune peptides (cytokines) (see Chapter 3) are released that draw healing cells to the area. Other factors are produced to stimulate mitosis or scar tissue formation.

Types of Wound Repair

Tissues that heal cleanly and quickly are said to heal by primary intention. Large wounds that heal slowly and with a great deal of scar tissue heal by secondary intention.

Delayed Healing and Repair

Tissue repair can be delayed if the host is compromised in any way by malnutrition, systemic disease, or a poorly functioning immune system. Healing can also be poor or delayed if there is reduced blood flow to the injured tissue or if an infection develops.

eriatric Consideration

The elderly may have delayed healing caused by reduced blood flow and tissue oxygenation caused by systemic diseases such as diabetes mellitus or atherosclerosis. Immune function also appears to be reduced in the elderly, and nutrition may be poor.

Conditions of Disease or Injury

Hypoxia

Hypoxia is the decreased concentration of oxygen in the tissues. The concentration of oxygen in the tissues reflects the concentration of oxygen in the blood, which depends on the amount of oxygen brought in by the lungs and the amount carried in the blood, either dissolved or bound to hemoglobin. Decreased oxygen in the blood is called hypoxemia.

Although a small amount of oxygen is carried in a dissolved state in the blood, most oxygen is carried bound to an iron-based protein called hemoglobin, present in the red blood cell. Cells and tissues become

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hypoxic when there is inadequate intake of oxygen by the respiratory system, inadequate delivery of oxygen by the cardiovascular system, or a lack of hemoglobin.

Oxygen is required by the mitochondria for oxidative phosphorylation and the production of ATP. Without oxygen, this process cannot occur. Although some ATP will be produced through anaerobic glycolysis, this is an inefficient source of ATP and cannot support the cellular energy requirements if there is a prolonged period of hypoxia.

Consequences of Hypoxia

When cells are deprived of ATP, they can no longer maintain cellular functions, including the transport of sodium and potassium through the sodium-potassium pump. Without sodium-potassium pumping, cells begin to accumulate sodium as it diffuses into the cell down its concentration and electrical gradients. The electrical potential across the membrane begins to decrease as intracellular sodium, a positive ion, accumulates. Osmotic pressure inside the cell increases, drawing water into the cell. Ischemic cells (those deprived of oxygen or blood supply) begin to swell, resulting in dilation of the endoplasmic reticulum, decreased mitochondrial function, and increased permeability of intracellular membranes.

Another consequence of hypoxia is the production of lactic acid, which occurs during anaerobic glycolysis. Increased lactic acid causes cellular and blood pH levels to decrease. Decreased intracellular pH (increased acidity) causes damage to the nuclear structures, the cellular membranes, and the microfilaments. An alteration in pH can also affect the electrical potential across the membrane.

The effects of hypoxia are reversible if oxygen is returned within a certain period of time, the amount of which varies and depends on the tissue. However, cell swelling can lead to bursting of lysosomal vesicles, release of their enzymes, and lysis (bursting) of the cell. Cell death is marked by higher than normal levels of intracellular enzymes in the general circulation.

Causes of Hypoxia

Causes of hypoxia include respiratory diseases and anything that affects blood flow, such as myocardial infarct, hemorrhagic shock, blood clots, various poisons, and some toxins released from microorganisms.

Cyanide poisoning occurs as a result of the chemical reaction between cyanide and the final substrate in the electron transport chain. Without this final step, oxidative phosphorylation ceases and ATP is not produced in the mitochondria. Cyanide is present in the seeds of many fruits such as apricots and some apple seeds. Laetrile, an unproven therapy for cancer, is made from the pits of apricots and contains enough cyanide to be fatal.

Carbon monoxide poisoning occurs when carbon monoxide is inhaled and binds to oxygen sites on the hemoglobin molecule. The affinity of hemoglobin for carbon monoxide is 300 times greater than that for oxygen.

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Therefore, exposure to carbon monoxide decreases the binding and transport of oxygen in the blood, causing cellular and tissue hypoxia. Carbon monoxide is a product of cigarette smoke, some heating systems, and automobile exhaust.

Lead poisoning can occur from ingesting lead-based paint. Although lead affects many organ systems, including the brain, it also is known to inhibit hemoglobin synthesis and thus causes hypoxia. Large doses of lead also cause red blood cell lysis with resultant severe hypoxia.

ediatric Consideration

Children are at an increased risk of suffering lead poisoning because lead is absorbed more rapidly through their intestine and they are attracted to lead's sweet taste in paint. Children are also closer to and more frequently sitting on the ground where lead tends to accumulate in soil and dust. Pediatric lead exposure may lead to learning disabilities and behavioral problems.

Clinical Manifestations

Decreased cell functioning. If the source of hypoxia is respiratory failure or myocardial infarct, all tissues will be affected. Cell death may occur.
Increased heart rate.
Increased respiratory rate.
Muscle weakness.
Decreased level of consciousness.
Cyanide poisoning: a choking sensation with accelerated respirations, then gasping.
Carbon monoxide poisoning: accelerated respirations followed by ringing in the ears, drowsiness, and confusion. Respirations quickly cease and unconsciousness develops.
Lead poisoning: abdominal cramping, hyperactivity, anorexia, lead line on gums, and muscle cramps.

Complications

Altered consciousness progressing to coma and death if prolonged cerebral (brain) hypoxia occurs.
Organ failure, including adult respiratory distress syndrome, cardiac failure, or kidney failure, may occur if hypoxia is prolonged.

Treatment

Increase oxygen in inspired air through a mask or mechanical ventilation.
For cyanide poisoning, nitrates and sodium thiosulfate therapy.
For carbon monoxide poisoning, hyperbaric (high pressure) oxygen treatments.

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For lead poisoning, emetics to induce vomiting if acute poisoning.
For chronic conditions, various chelating agents (to take the lead out of the circulation).

Temperature Extremes

Too hot or too cold temperatures may injure or kill cells. Exposure to very high temperatures can cause burn injuries, which directly kill cells or indirectly injure or kill cells by causing coagulation of blood vessels or the breakdown of cell membranes (see Chapter 4). Exposure to very cold temperatures injures cells in two ways. First, cold exposure causes constriction of the blood vessels that deliver nutrients and oxygen to the extremities. This constriction occurs as the body attempts to preserve its core (central) temperature, initially at the expense of the fingers, toes, ears, and nose. Decreased blood flow causes cellular and tissue ischemia. Sluggish blood flow also increases the risk of clot formation, which further blocks tissue oxygenation. The second effect of exposure to very cold temperature is the formation of ice crystals in the cells. These crystals directly damage the cells and can lead to cell lysis (bursting). Prolonged exposure to the cold can lead to hypothermia.

Clinical Manifestations of Cold Exposure and Hypothermia

Numbness or tingling of the skin or extremities.
Pale or blue skin that is cool to the touch.
Shivering early on, then lack of shivering as condition worsens.
Decreased level of consciousness, drowsiness, and confusion.

Complications

Blood clotting, characterized by pain and a decrease in pulse downstream from the clot. If blood flow is inadequate for an extended time, gangrene may result.
Frostbite.
Ventricular dysrhythmia.

Treatment

Transport immediately to a hospital for active re-warming. Any individual who appears dead who may have suffered hypothermia needs to be evaluated at a medical facility and re-warmed to 32 C before being confirmed dead.
During transport to a clinical facility, wet clothing should be removed and the patient covered with blankets. Active re-warming is discouraged until the patient reaches the treatment facility. Warm humidified air or oxygen may be administered during transport.
For a blood clot, drugs to dissolve the clot may be necessary.

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For gangrene, antibiotics and possible amputation are required.
Cardiopulmonary resuscitation may be necessary if the patient is in ventricular fibrillation.

Radiation Injury

Radiation is the transmission of energy through the emission of rays or waves. Radiation energy may be in the visible range of light, or it may be higher or lower energy than visible light. High-energy radiation (including ultraviolet radiation) is called ionizing radiation because it has the capability of knocking electrons off atoms or molecules, thereby ionizing them. Low-energy radiation is called non-ionizing radiation because it cannot displace electrons off atoms or molecules.

Effects of Ionizing Radiation

Ionizing radiation may injure or kill cells directly by destroying the cell membrane and causing intracellular swelling and cell lysis. As cells are killed or injured, the inflammatory response is stimulated, causing capillary leakiness, interstitial edema, white blood cell accumulation, and tissue scarring. Ionizing radiation may also act indirectly on cells by damaging the bonds between the base pairs of the DNA molecules, leading to mistakes in DNA replication or transcription. These mistakes may be repaired; if not, damage may cause programmed cell death or subsequent cancer as a result of the loss of genetic control over cell division.

Ionizing radiation also can cause the production of free radicals, either directly or as a result of cell injury and inflammation. A free radical is a highly reactive atom or molecule with an unpaired electron. The free radical seeks out reactions whereby it may gain back an electron. Sequential reactions may occur, where a series of free radicals are produced. Once produced, a free radical can engage in an energy-rich collision with another molecule, destroying intramolecular bonds. This may ultimately damage the cell membrane, the endoplasmic reticulum, or the DNA of a susceptible cell. It is thought that DNA errors resulting from free radical damage may be involved in the development of some cancers. It is also hypothesized that the free radical production that occurs during the normal metabolism of lipids may damage the endothelial cells lining the blood vessels, leading to atherosclerosis.

Free radicals also accumulate in response to infectious agents and hypoxia. For example, during a period of reduced blood flow, lack of oxygen causes cellular injury or death. If blood flow is restored, free radical production is stimulated by the white blood cells that swarm to the area as part of the inflammatory response; this accumulation of free radicals leads to serious reperfusion injury and a worsening of tissue damage. Free radicals also are produced as a result of exposure to cigarette smoke and are present in many pesticides.

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Normally, cells have in place mechanisms to eradicate free radicals or to minimize their effects. Vitamins E, C, and beta-carotene are known as free radical scavengers and are believed to protect cells against the damaging effects of free radicals.

Cells Susceptible to Ionizing Radiation

Cells most susceptible to damage by ionizing radiation are cells that undergo frequent divisions, including cells of the gastrointestinal (GI) tract, the integument (skin and hair), and the blood-forming cells of the bone marrow.

Ionizing radiation is emitted by the sun, in x-rays, and in substances undergoing radioactive decay, including substances found in the soil and rocks and those produced by nuclear weapons and reactors. Ionizing radiation is also emitted by substances used in medical diagnosis and treatment.

Effects of Non-Ionizing Radiation

Non-ionizing radiation includes microwave and ultrasound radiation. The energy of this radiation is too low to break DNA bonds or damage the cell membrane, but may increase the temperature of a system, causing alterations in transport functions. Non-ionizing radiation does not appear to cause health hazards, but research in this area is ongoing.

Clinical Manifestations of Ionizing Radiation

Skin redness or breakdown.
With high doses, vomiting and nausea caused by GI damage.
Anemia if the bone marrow is destroyed.
Cancer may develop years after the exposure as a result of the production of chromosomal breaks, deletions, or translocations.

Treatment

Damage caused by low doses will be repaired by the cells and does not require treatment.
Cancers should be treated with radiation therapy, chemotherapy, immunotherapy, or surgery.

ediatric Consideration

Fetal cells rapidly undergo cellular replication and division and are highly susceptible to the damaging effects of ionizing radiation. Infants and young children also experience periods of rapid cellular growth and proliferation and are at risk of genetic damage from ionizing radiation. Studies suggest that there are no apparent health risks to fetuses exposed to non-ionizing radiation (i.e., when a pregnant woman uses an electric blanket or video display terminal), at least in moderation.

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Injury Caused by Microorganisms

Microorganisms infectious to humans include bacteria, viruses, mycoplasmas, rickettsiae, chlamydiae, fungi, and protozoa. Some of these organisms infect humans through direct access, such as inhalation, whereas others infect through transmission by an intermediate vector, such as from an insect bite.

Cells of the body may be destroyed directly by the microorganism or by a toxin released from the microorganism, or may be indirectly injured as a result of the immune and inflammatory reactions stimulated in response to the microorganism (see Chapter 4). In addition, as described earlier, infection of a cell by a microorganism may so destabilize the cell that it undergoes apoptosis.

Bacteria

Bacteria are free-living, one-celled organisms that reproduce on their own, but use animal hosts for nutrient access. Bacteria contain no nuclei. They consist of cytoplasm surrounded by a rigid cell wall made out of a specific substance called peptidoglycan. Inside the cytoplasm is the genetic material, both DNA and RNA, and the intracellular structures needed for energy metabolism. Bacteria reproduce asexually by DNA replication and simple cell division. Some bacteria synthesize a capsule that surrounds the cell wall, making it less susceptible to the host's immune system. Other bacteria secrete proteins that reduce their susceptibility to standard antibiotics. Bacteria can be aerobic or anaerobic. Bacteria often release toxins specifically damaging to the host.

Laboratories frequently classify bacteria as gram-positive or gram-negative. Gram-positive bacteria release toxins (exotoxins) that damage host cells. Gram-negative bacteria contain in their cell walls proteins that stimulate the inflammatory response (endotoxins). They may also secrete exotoxins. Gram-positive bacteria stain purple with a standard laboratory dye. Gram-negative bacteria stain red with a second laboratory dye.

Examples of human disease caused by bacteria include staphylococcal and streptococcal infections, gonorrhea, syphilis, cholera, plague, salmonellosis, shigellosis, typhoid fever, Legionnaire's disease, diphtheria, Haemophilus influenzae infection, pertussis, tetanus, and Lyme disease. In a subset of especially difficult-to-treat bacteria are the mycobacteria. These microorganisms cause tuberculosis and leprosy. Studies have shown that human susceptibility to some bacterial infections, including those caused by Mycobacterium and Salmonella, is genetically controlled. Other superimposing variables that influence bacterial infectivity include host nutritional status, co-infections, exposure to environmental microbes, and previous vaccinations.

Viruses

Viruses, unlike bacteria, require a host to reproduce. A virus consists of a single strand of DNA or RNA that is contained within a protein coat called

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a capsid. Viruses must bind to the host cell membrane, enter the cell, and then move into the host cell nucleus to reproduce. Once inside the nucleus, viral DNA can become incorporated into the host cell DNA, thus ensuring that viral genes will be passed to each daughter cell during mitosis. Once in the DNA, the virus begins to take over the functions of the cell. RNA viruses also begin to control cell function after their translation into proteins.

Examples of human disease caused by viruses include encephalitis, yellow fever, German measles, rubella, mumps, poliomyelitis, hepatitis, and many viral respiratory infections. Certain types of viruses can enter the host DNA and remain latent for years, producing infections occasionally or not at all. Viruses that remain latent include all those of the herpes family, including the herpes viruses responsible for varicella (chickenpox), zoster (shingles), cytomegalovirus, mononucleosis, and the herpes simplex viruses 1 and 2, which produce oral cold sores and genital herpes.

Retroviruses

A unique type of virus is the retrovirus. These viruses are RNA viruses that can incorporate into the host DNA as a result of the action of the enzyme reverse transcriptase that changes the viral RNA into DNA. Retroviruses carry reverse transcriptase as part of their structure.

Examples of human disease caused by retroviruses include acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV), and a form of leukemia, HTLV-I. Retroviruses also may remain dormant for long periods of time.

Mycoplasmas

Mycoplasmas are unicellular microorganisms similar in action to bacteria except much smaller and without the peptidoglycan cell wall. Because many antibiotics (e.g., the penicillins) act by destroying the peptidoglycan cell wall, mycoplasmas are insensitive to these antibiotics.

Examples of human disease caused by mycoplasmas include mycoplasma pneumonia, upper respiratory tract infections, and some genital infections.

Rickettsiae

Rickettsiae require a host to asexually reproduce. They contain RNA and DNA inside a rigid peptidoglycan cell wall. Rickettsiae are transmitted to humans through the bite of the flea, tick, or louse. Examples of human disease caused by rickettsiae include typhus and Rocky Mountain spotted fever.

Chlamydiae

Chlamydiae are unicellular organisms that reproduce asexually inside a host cell. They transmit directly to humans and undergo cycles of replication.

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Human diseases caused by chlamydiae include a sexually transmitted urogenital infection and pneumonia.

Fungi

Fungi include yeast and molds. Fungi contain a nucleus and are surrounded by a rigid cell wall. Fungi usually do not cause disease in healthy humans, and some fungi are considered normal human flora. Most fungal infections are superficial, but some may be deep, causing infection of vital organs and tissues.

Superficial fungal infections in humans include oral (thrush) and vaginal candidiasis (yeast infections) and infections of the skin such as ringworm (tinea corporis), athlete's foot (tinea pedis), and jock itch. Onychomycosis refers to fungal infection of the toenails and fingernails.

Deep fungal infections are common in individuals who are immunocompromised. These infections are considered to be opportunistic (produced by organisms that only proliferate if the immune response is poor). Deep, opportunistic fungal infections in humans include the respiratory infections histoplasmosis and coccidioidomycosis, which are common in individuals with AIDS. Systemic and brain fungal infections may also occur.

Parasites

The term parasite refers to protozoa, helminths, and arthropods.

Protozoans are unicellular organisms capable of causing infections. Infection is passed directly between individuals through contaminated food or water, or through an insect vector. Examples of human disease caused by protozoans include malaria and the intestinal disease giardiasis.

Helminths are worms that require a host to sexually reproduce. Transmission to humans occurs through ingestion or penetration of the skin. Examples of human disease caused by helminths include roundworm (nematodes) and tapeworm (cestodes). Helminths are a significant problem in developing countries.

Arthropods are ticks and mosquitoes that act as vectors to carry diseases to humans. Examples of human disease carried by arthropods include bubonic plague (caused by a bacillus) and typhus (caused by a rickettsia). Other arthropods infect and damage body surfaces by their bite or burrowing. Arthropods that infect body surfaces include lice, scabies, chiggers, and fleas.

Clinical Manifestations

Clinical manifestations of infection depend on the specific agent involved, the site of the infection, and the initial state of health of the host.

Infection by bacteria, viruses, and mycoplasmas often results in:

Regional lymph node enlargement
Fever (usually low-grade with a viral infection)

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Body aches
Skin rash or eruption, especially with viral infections
Site-specific responses, such as pharyngitis, cough, otitis media

Infection by chlamydia often results in:

Urethritis (inflammation of the urethra) in males
Cervicitis (inflammation of the cervix), often with a mucopurulent discharge and itching or burning during urination

Infection by rickettsia often results in:

Skin rash
Fever and chills
Headache
Myalgia (muscle aches)
Thrombus formation in any organ

Infection by fungi often results in:

Itching and redness of skin or scalp with superficial infections
Discoloration and thickening with superficial nail infections
Creamy white vaginal discharge with a yeast infection
White plaques on inside of mouth with oral thrush
Signs of pneumonia with deep infections or in an immunocompromised host

Infection with parasites often results in:

Diarrhea with intestinal parasites
Fever with malaria
Itching and rash with skin infections

Treatment

Bacteria and mycoplasmas are treated with antibiotics, preferably after culturing the infection to determine what the infecting microorganism is and to what antibiotic it is sensitive.
Certain viral infections may be treated with antiviral agents. Other viral infections usually are left to resolve on their own, with care taken that a subsequent bacterial infection does not infect the original site or elsewhere.
Rickettsiae are usually treated with the antibiotic tetracycline.
Fungi are treated with topical antifungals, such as nystatin for superficial skin infections and amphotericin B for systemic infections. Oral antifungals are available for treating nail infections, which previously were resistant to treatment. These new therapies, including terbinafine and itraconazole, have a high cure rate, even with sporadic dosing regimens. Pentamidine is used for Pneumocystis carinii.
Parasitic infections of the gastrointestinal (GI) tract are treated with specific agents, including metronidazole (Flagyl) for giardiasis. Malaria
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is treated with various antimalarial drugs. Prophylactic (preventative) therapy is recommended for individuals traveling to areas where malaria is common. Plague is treated with various antibiotics, including tetracycline. Skin infections are treated with various topical agents.

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