Inflammation, immunity, and repair are the body’s responses to injury. Inflammation allows the human body to eliminate tissue injured by trauma or infection, to contain injuries, and to begin the process of healing. This chapter begins with a description of the inflammatory response, tissue regeneration, and repair, and continues with a description of oral lesions that occur in response to injury. Many of these lesions are quite common and are likely to be encountered when the dental hygienist examines the hard and soft tissues of the oral cavity. Lesions that occur as a result of destruction through activity of the immune responses are described in Chapter 3. Lesions that occur as a result of infection are included in Chapter 4.
Injury is the result of an alteration in the environment that causes tissue damage. Severe injury may result in necrosis, the pathologic death of one or more cells or a portion of tissue or an organ that results from irreversible damage to cells. Less severe injury may result in reversible cellular responses such as hyperplasia, hypertrophy, and atrophy, which are described later in this chapter. Injury to oral tissues may have different causes. These include physical injury, chemical injury, infection, and nutritional toxicities and deficiencies. Physical injury can affect teeth, soft tissue, and bone. Chemical injury can occur from the application of caustic substances to oral tissues. Microorganisms can cause injury by invading orofacial tissues. causing infections. Nutritional deficiencies can render oral tissues more susceptible to injury from other sources, and overdoses of some nutrients can cause tissue damage.
The body has a number of innate defenses to protect against injury. These are inborn defenses that are present from birth. Intact skin or mucosa acts as a physical barrier to injury. Cilia and mucus in the respiratory system serve as a mechanical defense system. Stomach acid kills most of the microorganisms that are taken into the body through the mouth. The flushing action of tears, saliva, urine, and diarrhea also removes foreign substances. Components of saliva and tears have antimicrobial activity. The resident microflora on skin and mucosa prevents colonization by pathogenic bacteria. The process of inflammation and its white blood cells that are brought to the area of injury are innate or inborn responses to injury.
Inflammation is a nonspecific response to injury and occurs in the same manner, regardless of the nature of the injury. The extent and duration of the injury determine the extent and duration of the inflammatory response. The inflammatory response may be local and limited to the area of injury, or it may become systemic if the injury is extensive. Inflammation of a specific tissue is denoted by the suffix –itis combined with the name of the tissue, such as in tonsillitis, pulpitis, and gingivitis.
The inflammatory response may be acute or chronic. If the injury is minimal and brief and its source is removed from the tissue, it is considered acute and the duration of the acute inflammatory response is short, lasting only a few days. The tissue may return to its original state (regeneration), or repair of the tissue may begin immediately. If injury to the tissue continues and the inflammatory response is longer lasting, it is referred to as chronic inflammation. Thus, chronic inflammation may last weeks, months, or even indefinitely. The inflammatory response is a dynamic process, continually changing in response to injury and repair.
Thus transitional stages exist during which the response is changing from one type of inflammation to the next and from an innate inflammatory response to an immune response (see Chapter 3). In addition, an acute inflammatory response may be superimposed over a chronic inflammatory response. On occasion, an overwhelming inflammatory response may lead to further injury. Repair of the tissue occurs only if the persistent source of injury is removed.
Current research is demonstrating that chronic inflammation is a major component of the pathogenesis of common disorders such as atherosclerosis, insulin resistance, colon cancer, and Alzheimer’s disease.
Microscopic events occur within the injured tissues during both acute and chronic inflammation. These events cause changes that can be observed clinically. The local clinical changes at the site of injury are called the classic (cardinal) signs of inflammation: redness, heat, swelling, pain, and loss of normal tissue function (Table 2-1). In addition, systemic signs of inflammation may be present when the response is more extensive; these signs are discussed later in this chapter.
|CLINICAL FEATURE||ASSOCIATED MICROSCOPIC EVENTS|
|Localized Signs of Inflammation|
|Redness (erythema) and heat||Hyperemia resulting from dilation of the microcirculation|
|Swelling||Permeability of the microcirculation leads to exudate formation in the tissues|
|Pain||Pressure on nerves by exudate formation and release of biochemical mediators|
|Loss of normal tissue function||Events associated with swelling and pain|
|Systemic Signs of Inflammation|
|Fever||Production of pyrogens affects the hypothalamus, which influences body temperature|
|Leukocytosis||An increase in the number of white blood cells circulating in the blood|
|Lymphadenopathy||Hyperplasia and hypertrophy of lymphocytes|
|Elevated C-reactive protein||A protein produced in the liver and elevated in the circulating blood when inflammation is present somewhere in the body|
The microscopic events of inflammation involve the small blood vessels or microcirculation. These include arterioles, capillaries, and venules in the area of injury as well as red blood cells, white blood cells, and chemicals in the body called biochemical mediators (Figure 2-1). Normally, blood, and the cells it contains, flows through the microcirculation. Exchange of oxygen and nutrients needed for the health of the surrounding tissue occurs as plasma fluid passes between the endothelium lining the vessel walls of the arterioles and capillaries. Plasma is the fluid component of blood in which the blood cells are suspended; it is composed mainly of water and proteins. Normally most of the plasma that leaves the microcirculation reenters the circulation through the venules. The lymphatic vessels carry away any excess plasma that does not reenter the blood vessels.
The first microscopic event of the inflammatory response is a brief, immediate reflex constriction of the microcirculation in the area of the injury. This is followed, within seconds, by a dilation of the same small blood vessels. Dilation is an increase in the diameter of the vessels and is caused by biochemical mediators that are released at the time of the injury. Dilation of the microcirculation results in increased blood flow through the vessels. The increased blood flow that fills the capillary beds in the injured tissue is called hyperemia. Hyperemia is responsible for two clinical signs of inflammation: erythema and heat. Erythema, or redness, is easily visible in most inflamed orofacial tissues. However, local temperature changes may be more difficult to recognize.
While hyperemia is occurring, the permeability of the vessels of the microcirculation also increases; the blood vessels become “leaky.” The endothelial cells contract and spaces form between the cells. As a result, plasma fluid with a low protein content that contains no cells passes between the endothelial cells and enters the tissue. This fluid is called a transudate and is the same type of fluid that normally moves from the microcirculation to the tissues to supply oxygen and nutrients. The loss of fluid within the microcirculation leads to increased blood viscosity. The blood becomes thicker and cannot flow as easily. This eventually results in decreased flow through the microcirculation. As the blood flow slows down, the red blood cells begin to pile up in the center of the blood vessels, and the white blood cells are displaced to the periphery of the blood vessels. This movement of the white blood cells to the periphery is called margination. The white blood cells are now in position to adhere themselves to the inner walls of the injured blood vessels, which have become “sticky” because of specific factors on the surfaces of the cells. This lining of the walls by white blood cells is called pavementing (Figure 2-2).
After pavementing the vessel walls, the white blood cells begin to escape from the blood vessels, along with more fluid, and enter the injured tissue. This process by which the white blood cells escape from the blood vessels is called emigration. Emigration occurs as a result of opening of the cellular junctions of the endothelial cells lining the blood vessels; these cells contract in size in response to biochemical mediators. As the white blood cells (primarily neutrophils) emigrate through the blood vessel walls and surrounding basement membrane, they further increase the permeability of the microcirculation and allow larger molecules and other cells to escape. The fluid that now flows into the injured tissues is called an exudate. This fluid contains cells and a higher concentration of protein molecules than in a transudate. The presence of transudate and exudate in the injured tissue helps to dilute injurious agents that may be present and carries injurious agents through the lymphatic vessels to the lymph nodes, where an immune response is stimulated (Chapter 3).
As transudate escapes into the tissue, excess fluid collects in the fibrous connective tissue at the site. This excess fluid in the interstitial space is called edema and results in localized enlargement or swelling of the tissue, another clinical sign of inflammation (Figure 2-3). If the swollen tissue area is injured further, exudate may flow out of the tissue as either a thin, clear fluid (serous exudate) or as a thick, white-to-yellow pus that contains tissue debris and many white blood cells (purulent exudate). An abscess is a collection of purulent exudate that has accumulated in a cavity formed by the tissue.
The formation of exudate may be so excessive that it interferes with repair of the tissue. The injured tissue may allow the excess exudate to drain by formation of a drainage passage that bores through the tissue, allowing drainage to the outside. This channel through the tissue is called a fistula or fistulous tract; it is formed at the expense of healthy, functioning tissue in the area that is lost as the tissue undergoes necrosis (Figure 2-4). In some cases, excessive exudate in damaged tissue must be drained mechanically by making an incision in the surface of the swollen area and, often, by placing a drainage tube in the site of the incision (Figure 2-5). This procedure of incision and drainage may be accompanied by the administration of an antibiotic and medication to reduce inflammation.
Exudate formation also results in another clinical sign of inflammation, pain, as the exudate presses on sensory nerves in the area. Some biochemical mediators present in inflamed tissue can add to the pain level. The swelling and pain in tissue resulting from the inflammatory process may then cause a loss of normal tissue function, another clinical sign of inflammation.
This directed movement of white blood cells toward the site of the injury is called chemotaxis; biochemical mediators that enhance this directed movement are chemotactic factors. Emigration and chemotaxis of white blood cells to the area of injury allow these cells to be mobilized in the defense against the injury.
At first these cells try to wall off the site of the injury from the surrounding healthy tissue. Later, in the injured tissue, the white blood cells also try to remove foreign substances from the site by ingesting and then digesting them, thus undergoing phagocytosis (Figure 2-6). The foreign substances may include pathogenic microorganisms or tissue debris. The presence of these substances interferes with the repair process; therefore they must be removed for the inflammation to resolve and any necessary tissue repair to proceed.
Emigration of white blood cells (leukocytes) from the blood vessels into the site of injury and subsequent chemotaxis and phagocytosis are important components of the process of inflammation. Two types of white blood cells are initially involved in the inflammatory response: (1) neutrophils and (2) monocytes circulating in the blood, which become macrophages in tissue. Neutrophils are also called polymorphonuclear leukocytes because they are the most prevalent of the white blood cells that contain a multilobed nucleus. However, this term also includes other white blood cells; therefore neutrophil is a more specific name for this cell. Other cells within the blood and tissue, such as lymphocytes and plasma cells, eosinophils, and mast cells, participate in both inflammatory and immune responses. The immune response and the involvement of these cells are discussed in Chapter 3.
The neutrophil is the first type of white blood cell to arrive at the site of injury and is the most common inflammatory cell present during acute inflammation (Figure 2-8). The second type of white blood cell to arrive at the site of injury within the tissue is the macrophage. This cell, when circulating in the blood, was called a monocyte. When it leaves the microcirculation and enters the tissue it becomes a macrophage. As inflammation continues, the number of neutrophils decreases. If the injury persists and chronic inflammation occurs, macrophages, lymphocytes, and plasma cells replace the neutrophils and become the most prevalent white blood cells present in the tissue (Figure 2-9).
As discussed, the neutrophil is the first type of white blood cell recruited into the area of injury in response to chemotactic factors. The main function of the neutrophil is phagocytosis of substances such as pathogenic microorganisms and tissue debris. Microscopically, neutrophils possess a multilobed nucleus, which is why they are called polymorphonuclear leukocytes, and a granular cytoplasm that contains lysosomal enzymes (Figure 2-10). Lysosomal enzymes contained within vacuoles in the cell cytoplasm destroy substances after the cell has engulfed them. Removal of these substances from the site of injury is necessary to allow the process of repair. Neutrophils die shortly after phagocytosis; as a result, lysosomal enzymes and other damaging cellular substances that were meant only for intracellular destruction of foreign substances are released from the cells. This can cause further tissue damage to the site when large numbers of neutrophils die.
Normally, neutrophils constitute 60 to 70 percent of the entire white blood cell population. Like all white blood cells, neutrophils are derived from stem cells in the bone marrow (Figure 2-11). Stem cells are undifferentiated cells in the spongy tissue that is found in the center of certain long and flat bones, such as the bones of the pelvis and sternum. Neutrophils are produced throughout life and are mobile cells.
The monocyte is the second type of white blood cell to emigrate from the blood vessels into the injured tissue, where it becomes a macrophage. Like neutrophils, monocytes are derived from stem cells in the bone marrow (see Figure 2-11). As a macrophage, it responds to chemotactic factors, is capable of phagocytosis, is mobile, and has lysosomal enzymes in its cytoplasm that assist in the destruction of foreign substances within the cell.
The macrophage is larger than its monocytic precursor. It constitutes 3 to 8 percent of the entire white blood cell population. Microscopically, it has a single round nucleus and does not have granular cytoplasm (Figure 2-12). The macrophage has a somewhat longer life span than the neutrophil. In addition to its role in phagocytosis during inflammation, the macrophage is also an important cell in the immune response (see Chapter 3).
From the earlier discussion, it can be seen that chemical agents called biochemical or inflammatory mediators cause many of the events involved in the inflammatory response. Biochemical mediators are essential to the inflammatory response and can start or amplify the response. During the response, basic mediators of inflammation can recruit other mediators and immune mechanisms, thus escalating the overall process. Some biochemical mediators are circulating in blood, some come from endothelial cells, some from white blood cells, and some from platelets; others are produced by certain pathogenic microorganisms as they injure the tissue.
Three systems of plasma proteins circulating in the blood may be activated during inflammation, becoming biochemical mediators of inflammation: (1) the kinin system, (2) the clotting mechanism, and (3) the complement system. The activation of each of these plasma protein systems involves a sequential cascade of events. These systems are interrelated; interaction among the systems takes place during their activation, among their products, and within their various actions.
The kinin system biochemically mediates inflammation by causing increased dilation of the blood vessels at the site of injury and increasing the permeability of local blood vessels. This system is rapidly activated both by substances present in plasma and by those present in injured tissue. However, its role is limited to the early phases of inflammation. Components of the kinin system also induce pain. The primary kinin is bradykinin.
The clotting mechanism functions primarily in the clotting of blood, which helps stop bleeding at the site of injury. The clotting mechanism forms a fibrinous meshwork at the site of injury that protects adjacent tissues and keeps foreign substances corralled at the site. It also biochemically mediates inflammation because certain of its products that are activated when tissue is injured cause local vascular dilation and permeability by also activating the kinin system. Later it will be shown that the clotting mechanism is also important in tissue repair, because it forms a future framework for the repair process.
The complement system is composed of a series of plasma proteins that are activated in a cascading fashion, with one protein activating the next in the series. Components of the complement system function during both inflammation and immunity. Complement components can cause mast cells to release granules from their cytoplasm that contain the biochemical mediator histamine and other mediators into the surrounding tissue. Mast cells are active during certain inflammatory reactions. They are normally located in large numbers in the loose connective tissue of the skin and mucosa. When histamine is released from mast cells it causes an increase in vascular permeability and vasodilation (see Figure 2-1). Other components of the complement system can cause cell death by creating holes in the cell membrane (cytolysis). Complement proteins can also attach to the surface of bacteria, stimulating white blood cells to phagocytize them, a process called opsonization.
In addition to the biochemical mediators derived from circulating blood that have been described already, others can be involved during inflammation. These include prostaglandins, released white blood cell lysosomal enzymes and endotoxins, and lysosomal enzymes from pathogenic microorganisms. Prostaglandins are derived from cell membranes. They function in biochemically mediating the inflammatory response by causing increased vascular dilation and permeability, erythema, and pain, as well as changes in connective tissue. The lysosomal enzymes that are released from the granules within white blood cells act as chemotactic factors and can also cause damage to connective tissue and to the clot that has formed at the site of injury.
Endotoxin and lysosomal enzymes released by pathogenic microorganisms may also serve as biochemical mediators. Endotoxin, produced from the cell walls of gram-negative bacteria, can serve as a chemotactic factor, activate complement, and function as an antigen and damage bone tissue. The lysosomal enzymes released from pathogenic microorganisms during infection are similar in chemical composition and action to those released by white blood cells.
Cell products from lymphocytes, such as cytokines, can also affect the inflammatory response. These are described in Chapter 3, as they participate in the immune response.
In addition to the local features of inflammation, four major systemic signs may also occur: (1) fever, (2) an increase in the number of white blood cells (leukocytosis), (3) enlargement of lymph nodes (lymphadenopathy), and (4) elevated C-reactive protein (see Table 2-1).
Body temperature is controlled by a regulatory center in the brain called the hypothalamic thermoregulatory center. Fever is a body temperature higher than the normal level of 98.6° F (37° C) and is associated with a systemic inflammatory response. White blood cells and pathogenic microorganisms produce fever-producing substances known as pyrogens. Pyrogens produce fever by increasing the synthesis and release of prostaglandins in the hypothalamus. Measuring body temperature with a thermometer is helpful in assessing whether a systemic inflammatory response is present.
The function of this increased body temperature by a fever is not clear. A moderately high fever may be helpful in combating some infections because increased temperature slows the growth of many pathogenic microorganisms. However, the body cannot tolerate excessively high fever for very long, and such fever could prove fatal. Drugs can be given to reduce high fever by reducing inflammation.
Leukocytosis is an increase in the number of white blood cells circulating in blood. The normal level is 4,000 to 10,000/mm3. During a systemic inflammatory response, particularly a response to infection, leukocytosis occurs and the numbers increase to 10,000 to 30,000/mm3. This increase primarily involves neutrophils. This increase in the number of circulating white blood cells, by increasing their formation and releasing immature forms from the bone marrow into the blood, is considered “a shift to the left.” Leukocytosis occurs in response to biochemical mediators and is an attempt to provide more cells for phagocytosis.
A complete blood count is a laboratory blood test that can be used to evaluate a patient for infection or a blood disorder. It includes a “differential” white blood cell count. This measures the proportion of each white blood cell type. It can be useful in distinguishing a viral infection from a bacterial infection. In a viral infection there is characteristically an increase in lymphocytes whereas in a bacterial infection there is an increase in neutrophils,. In addition, in an allergic reaction there may be an increase in eosinophils. These results provide a useful tool for evaluating patients but do not indicate the particular cause or site of inflammation within the body.
During the inflammatory process the lymph nodes enlarge. This enlargement of the lymph nodes is referred to as lymphadenopathy (Figure 2-13). The enlarged lymph node or nodes, if located superficially, can be palpated as a mass or masses in the area of inflammation and possibly along the associated lymphatic drainage route (Figure 2-14). When palpated, the involved node feels firmer and larger than usual and may also be tender. Deeper lymph nodes may also be enlarged, but these cannot be palpated during an examination.
Lymphadenopathy results from changes in the lymphocytes that reside in the lymph node. Lymphocytes are white blood cells that mature in lymphoid tissue. They are the main white blood cells of the immune response. Lymphocytes travel from the lymph node to the tissues through the circulation where they are involved in the immune response. The role and maturation of lymphocytes is described in detail in Chapter 3. The changes in the lymphocytes cause the change in size of the lymph nodes. These changes include an increase in the number of cells (hyperplasia), resulting from increased cell division, and an enlargement of individual cells (hypertrophy), resulting from cellular maturation. These changes in the lymphocyte population usually occur during chronic inflammation. The lymphoid tissue in Waldeyer’s ring (the palatine, lingual, and pharyngeal tonsillar tissue) may also undergo these changes.
C-reactive protein is a protein produced in the liver; it plays an important role in interacting with the complement system as well as in the clotting mechanism. Measurement of C-reactive protein is a diagnostic test associated with inflammation. Normally, low levels of C-reactive protein circulate in the blood. Elevated C-reactive protein levels are present during episodes of acute inflammation or infection and may continue at high levels with chronic inflammation. A concentration greater than 10 mg/L is usually considered high for C-reactive protein; most infections and episodes of inflammation result in C-reactive protein levels at 100 mg/L. These high levels drop to more normal levels when inflammation subsides.
The C-reactive protein level can be used to help assess conditions such as rheumatoid arthritis and systemic lupus erythematosus and to determine whether a medication that has been taken is effective. It may be used to monitor tissue healing and as an early detection system for possible infections in patients who have had surgery, organ transplants, or severe burns. A chronically elevated C-reactive protein level is associated with an increased risk for cardiovascular disease, and researchers are exploring its role as a marker of periodontal disease activity. A high-sensitivity C-reactive protein (hs-CRP) assay is now available. However, it is important to note that higher levels of C-reactive protein are a nonspecific marker of inflammation levels for the entire body.
Chronic inflammation results from injuries that persist, often for weeks or months, even indefinitely. In addition to neutrophils and monocytes, other white blood cells are involved, as is the proliferation of fibroblasts. The cells involved in chronic inflammation include macrophages, lymphocytes, and plasma cells. Repair takes place at the same time that chronic inflammation proceeds, but it cannot be completed until the source of the injury is removed.
Granulomatous inflammation is a distinctive form of chronic inflammation. It is characterized by the formation of granulomas, which are microscopic groupings of macrophages usually surrounded by lymphocytes and occasional plasma cells. The macrophages within the granuloma become larger as they group together with their multiple nuclei and become multinucleated giant cells. Foreign substances in tissue and certain infections such as tuberculosis tend to stimulate the formation of granulomas. The body is unable to destroy the offending substances and tries to enclose them in these masses of inflammatory cells.
Antiinflammatory drugs block or suppress the inflammatory response, preventing or reducing the clinical signs of inflammation and adverse reactions to the injury. Diseases and conditions such as asthma, arthritis, organ transplantation, and surgical trauma are treated with steroidal or nonsteroidal antiinflammatory agents. Prednisone is an example of a steroidal antiinflammatory drug. These agents exert their analgesic effects by inhibiting the synthesis of prostaglandin. Examples of nonsteroidal antiinflammatory drugs (NSAIDs) include acetylsalicylic acid (aspirin) and ibuprofen. Nonsteroidal antiinflammatory agents also exert their analgesic effects by inhibiting the synthesis of prostaglandin, which if not inhibited could have served as a biochemical mediator of inflammation. Another group of drugs, antihistamines, reduces the effects of the biochemical mediator histamine that is released in allergic responses.
Medications that are traditionally used to treat cancer such as methotrexate, sulfasalazine, leflunomide, cyclophosphamide, and mycophenolate are now being used to treat inflammatory diseases because they suppress the inflammatory response. The doses are significantly lower, and the risk of side effects tends to be considerably less than when prescribed in higher doses to treat cancer.
The cells in a tissue or organ may respond to injury by undergoing an adaptive response such as hyperplasia, hypertrophy, or atrophy. Hyperplasia is defined as an increase in the number of cells in a tissue or organ, with a consequent increase in size of the tissue or organ, in response to conditions that cause cellular stress. Pathologic hyperplasia frequently occurs in oral tissues. In the oral cavity an increase in the number of epithelial cells and an increased thickness of the epithelium commonly occur in response to chronic injury (Figure 2-15). Normally, as surface epithelial cells are lost, division of deeper basal epithelial cells increases to replace the lost cells. With hyperplasia, the production of new cells exceeds the original number of cells lost; thus the epithelium becomes thickened, and the tissue appears paler or whiter.
When the injury subsides the proliferation ceases. With time, the epithelium usually returns to its normal size, and the color of the tissue returns to normal. However, in some cases, the hyperplastic tissue persists even after the irritation is discontinued. Deeper hyperplasia of fibrous connective tissue may also occur in response to chronic injury and is common in the oral cavity. Oral lesions caused by epithelial and fibrous hyperplasia are described later in this chapter.
Hypertrophy is a response to cellular stress that is defined as an increase in the size of a tissue or organ because of an increase in the size of individual cells, not the number. For example, hypertrophy occurs in the smooth muscles of the uterus and the mammary glands in response to pregnancy, in cardiac muscle in response to long-standing high blood pressure, and in skeletal muscle in response to increased exercise. Hyperplasia and hypertrophy are often present together as a tissue or organ responds to the injury. Lymphadenopathy is an example in which both the size and number of cells increase.
In contrast to hyperplasia and hypertrophy, atrophy is the decrease in size and function of a cell, tissue, organ, or the whole body in response to certain conditions of cellular stress. Atrophied cells are capable of increasing to their normal size after the stress is removed. Atrophy can be present in the muscular wasting that occurs in some chronic diseases that do not allow mobility and thus function of the body (“use it or lose it”). It can also happen with changes in cellular growth, malnutrition, ischemia (disruption of blood supply), or hormonal changes.
With resolution of the inflammatory response, the injured tissue undergoes healing as either regeneration or repair. When tissue damage has been slight, the inflamed area may return completely to its normal structure and function. This is called regeneration. Regeneration is the most favorable resolution of acute inflammation and involves complete removal of all cells, by-products, and inflammatory exudate that entered the tissue during inflammation and return of the microcirculation to its preinflammatory state.
In contrast, the process of repair takes place when complete return of the tissue to normal is not possible because the damage has been too great. Some tissue types such as epithelium, fibrous connective tissue, and bone have the ability to undergo repair. Other tissue types such as enamel do not.
Repair is the final defense mechanism of the body in its attempt to restore injured tissue to its original state. During the repair process cells and tissues that have undergone necrosis are replaced with live cells and new tissue components. However, the repair process cannot be completed until the source of injury is removed or the injurious agents are destroyed. Repair is not always a perfect process. Functioning cells and tissue components are often replaced by nonfunctioning scar tissue. Research studies are currently investigating ways to enhance the repair process.
After an injury occurs microscopic events occur in both the epithelium and connective tissue (Figure 2-16). These events are different for each of these tissue types, but occur almost simultaneously and are dependent on each other for optimal healing. If the source of the injury is removed, the repair process for both types of tissues is usually completed within 2 weeks. The repair process is slightly different in the oral cavity than in skin because mucosal tissues are moist and a scab does not form. There are three phases to the repair process that occur during these 2 weeks: (1) inflammation, (2) proliferation, and (3) maturation.
Immediately after the injury, a clot forms as blood flows into the injured tissue. The clot is produced in the area of injury as a result of activation of the clotting mechanism. The clot consists of a meshwork structure composed of locally produced fibrin, aggregated red blood cells, and platelets. Platelets are cellular fragments found in the blood and are extremely important in the formation of a clot. There are 250,000 to 400,000 platelets/ml3 within the blood. The number of platelets is measured within the panel of the complete blood count (CBC). Hereditary factors, drugs, extensive injury, or certain diseases may affect red blood cells, platelets, and other factors involved in the formation of the clot and thus prevent or delay tissue repair.
The day after the injury, acute inflammation is taking place in the area of future repair. Neutrophils emigrate from the microcirculation into the injured tissue, and phagocytosis of foreign substances and necrotic tissue with its dead cells occurs as part of the inflammatory response.
Within 2 days of the injury, monocytes begin to emigrate from the microcirculation into the injured area as macrophages. Macrophages continue phagocytosis in a manner similar to that of the neutrophils. Neutrophils are reduced in number as the chronic inflammatory process proceeds. Fibroblasts proliferate within the injured connective tissue in response to biochemical mediators from macrophages. Fibroblasts become the most important cells during healing as they begin to produce and secrete new collagen fibers, using the fibrinous meshwork of the clot as a scaffold. This process is called fibroplasia.
Because an ample blood supply is necessary to sustain new tissue growth, the microcirculation begins to establish itself in the immature connective tissue (type 1 collagen). Macrophages, while removing tissue debris by phagocytosis and promoting fibroblast levels, also secrete growth factors to stimulate the growth of new blood vessels. This process is called angiogenesis.
The initial connective tissue formed is called granulation tissue. It is an immature tissue, with many more capillaries and fibroblasts than the usual connective tissue so that it clinically appears a vivid pink or red. It consists of immature collagen (type 1 collagen) that is laid down in a haphazard disorganized fashion. In some cases, the growth of this tissue is excessive (exuberant) and may interfere with the repair process until it is removed surgically.
If the surface epithelium has been destroyed by the injury, the epithelial cells create a new surface tissue at the same time that granulation tissue forms in the injured connective tissue. The epithelial cells from the borders of the healing injured area lose their cellular junctions and become mobile. They then divide and migrate across the injured tissue, using the fibrinous meshwork of the clot as a guide to form a new surface layer. This process is called epithelialization.
In addition to serving as a guide for migrating epithelial cells and as a scaffold for forming connective tissue, the fibrinous meshwork of the clot serves to protect these two newly formed deeper tissue types from further injury. Thus it is important for the clot to remain in place during this healing time to allow optimal repair in the tissues. In some injuries, dressings placed over the clot may prove beneficial to the healing process (e.g., periodontal pack).
At the end of 2 days, lymphocytes and plasma cells begin to emigrate from the surrounding blood vessels into the injured area as chronic inflammation and an immune response begin. The macrophages already present in the area now assist the lymphocytes in the immune response occurring at the site of injury.
If the source of the injury has been completely removed, the inflammatory and immune responses in the tissue are completed 1 week after the injury. The fibrinous meshwork of the clot is digested by tissue enzymes and sloughs off, and the initial repair of the tissue is completed. Clinically the surface of the repaired injury remains redder than normal because of the thinness of the new surface epithelium and the increased vascularity of the new underlying connective tissue. The immature type of collagen fibers found in granulation tissue is still present and remains fragile and at risk of reinjury. During this time fibroblasts differentiate into myofibroblasts, cells that are similar to smooth muscle cells, and the tissue in the site begins to contract. This contracting peaks 5 to 15 days after the injury and continues until the site is completely reepithelialized.
Two weeks after the injury, the initial granulation tissue and its fibers have been remodeled, giving the tissue its full strength. This matured fibrous connective tissue is now called scar tissue; it clinically appears whiter or paler at the surface of the repaired injury because of the increased number of collagen fibers and decreased vascularity. A stronger type of collagen (type 3 collagen) has replaced the immature collagen (type 1 collagen) and the collagen overall becomes more organized.
The amount of scar tissue remaining after an injury depends on many factors such as heredity, the strength and flexibility needed in the tissue, the tissue type involved, and the type of repair that has occurred. The oral mucosa is less prone to scar formation than skin. There are three types of repair that can occur: (1) healing by primary intention, (2) healing by secondary intention, and (3) healing by tertiary intention.