Inflammation
General Features of Inflammation
Inflammation was identified 2,000 years ago.
Inflammation is an important pathologic process often encountered by dentists and dental hygienists. As an indicator of disease, it has been recognized for centuries. Almost 2,000 years ago, the Roman physician Celsus recognized the warmth, redness, swelling, and pain associated with now is known as "inflammation."
Inflammation is directed at destroying harmful agents and initiating repair.
Warmth, redness, swelling, and pain is caused by a series of cellular and tissue responses to some injurious agent. These responses are directed at destroying the inciting agent or, at least, rendering it harmless. In the process, the reaction often also isolates the agent and prevents spread to other locations. All this activity may cause damage or destruction to normal tissue in the immediate area; the inflammatory process cleans up resulting debris and starts restoring damaged tissues.
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Inflammation is a very common disease process.
Inflammation is a fundamental and common pathologic process. When recognized, it indicates that the body is struggling to deal with some invading agent or damaged tissues. It is a process seen in many disease states -- from splinters to syphilis, from arthritis to AIDS.
Inflammation plays an important role in dental practice.
There are a number of oral diseases in which inflammation is a significant component: periodontal disease, pulpal disease, periapical disease, and oral infections.
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Many agents can initiate inflammation.
There are many agents that can provoke an inflammatory response. The painful redness that follows over-exposure to solar radiation (sunlight), a physical agent, is one common example. As but one example of the inflammation-causing effects of some chemicals, turpentine, a common paint solvent, was used by scientists to provoke inflammation in laboratory animals. The pain and redness so commonly associated with rheumatoid arthritis attest to the relationship of inflammation and hypersensitivity. The pain, swelling, and pus associated with a severe bacterial infection are cardinal signs of inflammation.
Table 1. Some Agents Causing Inflammation
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Inflammation is the immune response in action.
From the examples presented above, it is clear that any substance that can elicit an immune response will elicit an inflammatory response as well. Put another way, immune responses and inflammatory responses are synonymous. When a dental practitioner recognizes the signs and symptoms of inflammation, he/she is witnessing the body's attempt to weaken, destroy, and isolate some injurious agent.
Acute inflammation is quick; chronic inflammation is slow.
There are two fundamental types of inflammation: acute and chronic. A rapid onset, short duration, and profound signs and symptoms characterize acute inflammation. On the other hand, a slow onset, long duration, and less obvious signs and symptoms characterize chronic inflammation. In addition to the two basic forms (acute and chronic), there are two others that appear less commonly: subacute and granulomatous chronic inflammation. Subacute inflammation is an ill-defined form that has some clinical features of acute and some of chronic inflammation. Granulomatous chronic inflammation, as its name signifies, is a special form of chronic inflammation. This type is associated with tuberculosis as well as some other less common diseases.
Table 2. Types of Inflammation
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A series of responses of small blood vessels and some blood and tissue cells to "injurious" agents resulting in weakening, destruction, or isolation of the agent. Cardinal signs of inflammation include redness, swelling, warmth, pain, and loss of function. Fever, leukocytosis, abscesses, and cellulitis may be present.
Acute inflammation is the most studied type of inflammation.
Acute inflammation immediately follows injury by physical, chemical, or biologic agents. The events following injury cause blood vessel changes allowing entrance of certain blood cells into the injured area. As these cells grapple with the agent that provoked their appearance, normal surrounding tissue may be damaged or even killed. The sequence of these vascular, cellular, and tissue events have been known for decades and are straightforward. More recently, however, the unfolding molecular basis for them has resulted in a maze of interacting compounds that has complicated the picture considerably. In the following discussion, microscopic and physiologic events will be emphasized more than chemical and molecular ones.
Acute inflammation unfolds as a predictable series of events.
After entrance of a foreign antigenic agent into the body's connective tissue spaces, a predictable sequence of events invariably ensues. These events occur within minutes. They explain the characteristic redness, warmth, swelling, and pain accompanying acute inflammation.
An initial brief contraction of blood vessels is observed experimentally.
In the laboratory, the first event following tissue injury is a sudden, but short-lived, contraction of small blood vessels in the immediate area. This transient vasoconstriction may be caused by stimulation of nerves in the area. Whatever its cause, it last but a few seconds and has no apparent clinical significance.
1. Blood Vessel Dilation
Dilation of small blood vessels is the first event observed in patients.
In the first minutes, small blood vessels (capillaries and venules) increase their diameter (dilate) allowing more blood to flow into the area. This increased blood flow is fed by dilation of supplying arterioles, a process known as "active hyperemia" (hyper- = increased; -emia = blood). With increased blood flow, increased numbers of blood cells enter the area too.
Dilation of blood vessels makes the injured area appear red and feel warm.
As more blood enters the injured area, it will be redder and warmer than surrounding unaffected areas. To the dental practitioner, then, areas of redness and warmth signify the presence of acute inflammation. Celsus used the terms "rubor" (red) and "calor" (heat) in his descriptions.
2. Increased Blood Vessel Permeability
Fluids (plasma) leak out of the dilated blood vessels into the injured area.
Soon after blood vessel dilation, the blood vessels become leaky allowing the fluid portion of blood (plasma) to escape into surrounding tissues. At first, this leakage is the result of increased local blood pressure forcing a filtrate of plasma out leaving large protein molecules behind, a process known as "transudation." A short time later, changes in blood vessel endothelial cells allow plasma along with its important clotting and immunologic proteins to escape. The increased volume of proteins accumulating in the area of tissue injury further increases the rate of plasma escape by increasing osmotic tension. This rapid exodus of protein-rich plasma is known as "exudation." Transudation, then, is an early short-lived event during which protein-deficient plasma exits blood vessels; in exudation, a later and longer lasting event, protein-rich plasma leaves to accumulate in the area of tissue injury.
Endothelial Cell
Leakage of plasma causes swelling, pain, and loss of function.
As might be expected, increased fluid accumulation in within the area of tissue injury produces visible swelling, or "tumor" as Celsus called it. Increased pressure within the damaged tissue and increased production of acid by-products of the inflammatory reaction causes pain ("dolor") and loss of function ("functio laesa") of the inflamed part.
3. Blood Flow Stagnation
Plasma leakage causes blood flow to become stagnant.
Plasma leakage causes blood cells to become more closely packed (hemoconcentration) causing sluggish flow. In fact, blood flow in the affected area may even stop. When blood flow is normal, "formed elements" normally are found in a cell-rich "axial core" separated from the endothelial lining by a thin cell-free "plasmic zone." The maintenance of the axial core and clear plasmic zone depends on a strong rapid current of blood flow. As blood flow slows during inflammation, the axial core can no longer be maintained allowing blood cells to touch the endothelial lining cells.
Figure 1. Axial Blood Flow
4. Margination
As blood flow slows, some blood cells stick to the blood vessel lining.
As blood flow slows and the axial core collapses, blood cells have the opportunity to contact the surface of endothelial cells lining the vessel wall. Some blood cells ricochet off while others stick to it. In acute inflammation, neutrophils are sticky cells while later in chronic inflammation lymphocytes are the sticky ones. When blood vessels are examined with the LM at this stage of acute inflammation, neutrophils are seen to line up along the interior lining surface, a feature known as "margination" or "pavementing."
5. Emigration
Some sticky cells squeeze out of blood vessels entering the injured area.
Once adherent, WBCs crawl along the lining surface until they find an open junction between endothelial cells. Finding a gap, they squeeze through it only to become trapped between the outer endothelial surface and the underlying basement membrane. The temporarily trapped WBCs crawl along its basement membrane until they find a seam to squeeze through. By such considerable effort, WBCs leave blood vessels to enter the area of tissue injury. This active process is known as "emigration" or, less commonly, "diapedesis."
Emigration
Neutrophils and monocytes are the first to enter the injured area.
Two leukocyte types, neutrophils and monocytes, are the first blood cells to emigrate. Neutrophils are the most common leukocyte; they compose about 65% of the circulating WBCs. These common cells soon dominate the injured area. Neutrophils die out in 48 hours or so as a consequence of self-destruction and increasing acidity of the environment. They are relatively fragile cells with a short life span.
Neutrophil
Monocytes also emigrate early in the inflammatory reaction; however, since they comprise only 5% of the circulating WBCs, their presence in the area of inflammation is obscured for a time by overwhelming numbers of neutrophils. Once monocytes enter the injured tissues they are given a name more indicative of their function -- macrophages. Unlike neutrophils, macrophages have a long life span and have great tolerance to acidic environments. Monocytes outlive neutrophils to become more apparent later.
6. Exudation
The materials accumulating in the injured area destroy the causative agent.
At this point blood plasma, neutrophils, and monocytes/macrophages have accumulated in the area of tissue injury. The term "exudate" refers to these accumulated products. From what you have learned already, the acute inflammatory exudate is composed of protein-rich plasma, of neutrophils, and of monocytes/macrophages.
Antibodies from blood plasma may destroy the causative agent.
Plasma proteins leave blood vessels early in the inflammatory response. Of these, two play a particularly important role. Immunoglobulins, a group of antibodies that have the ability to react with certain antigens by destroying them or by making them vulnerable to action by neutrophils and macrophages.
Formation of a blood clot may wall off the injured area.
The second are blood-clotting proteins. A blood clot is composed of a meshwork of "fibrin" a protein end product of a complex interaction of plasma, tissue, and cell factors. If fibrin is produced in the area of tissue injury, it may prevent spread of the injurious agent.
Table 3. Sequence of Events
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Neutrophils may destroy causative agents.
Neutrophils are capable of engulfing bacteria that have been prepared by antibodies called "opsonins." Prepared microorganisms are brought into the cell by phagocytosis and come to lie in membrane-bound body called phagosomes. Neutrophil lysosomes fuse with phagosomes releasing powerful enzymes, hydrogen peroxide, hypochlorite, and other substances capable of killing bacteria. In the process of encountering millions of bacteria, many neutrophils are killed. When this happens, neutrophil bactericidal agents are released into the surrounding tissue where they can kill more bacteria and some host tissue as well.
Monocytes/Macrophages also may destroy causative agents.
Monocytes/macrophages appear in larger and larger numbers as neutrophils die off. These cells are a key component of what immunologists call "cell based immunity." Macrophages (macro- = large; -phago = eater) are excellent phagocytes and are particularly good at engulfing and processing antigenic substances and presenting altered antigens to other cells (lymphocytes) for ultimate destruction.
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Pathogenesis of Acute Inflammation
Role of the Autonomic Nervous System
Blood vessel dilation can be caused by nerve impulses.
Arterioles are "hard-wired" to the autonomic nervous system. This means that certain nerve impulses cause contraction of smooth muscle in arteriolar walls while others cause smooth muscle relaxation. Autonomic impulses play a role in relaxation of arteriole smooth muscle so that these vessels can dilate.
Role of Chemical Mediators
Many chemical compounds can cause blood vessel dilation.
A host of chemicals have been identified that mediate or otherwise influence a number of inflammatory responses. While some of these "chemical mediators" have been known for years, others were discovered more recently. There are four classes of chemical mediators.
Cell secretions can cause blood vessel dilation and leakage -- histamine & serotonin.
The first are compounds known as "vasoactive amines," histamine and serotonin, both of which are powerful vasodilators. Histamine is found in mast cells while serotonin is found in blood platelets. Beyond its known vasodilator functions, serotonin's role in inflammation is not clear. Much more is known about histamine. It is well known that mast cell granules are histamine-filled secretory vesicles which produce dilation of blood vessels. If a lot of histamine is released all at once, a life-threatening anaphylactic reaction may ensue. In run-of-the-mill inflammatory responses histamine is released in small amounts in the immediate area of tissue injury. It is in these settings that histamine acts to dilate blood vessels.
Blood vessel injury stimulates production of vasodilator chemicals-bradykinin.
The second are a group of proteins constituting the "kinin system." It is the activation of this system that produces another powerful vasodilator known as "bradykinin." Initial activation results from exposure of collagen to blood plasma; such exposure is caused by injury to the endothelial blood vessel linings allowing plasma to contact collagen in underlying basement membranes. Following collagen exposure, a series of reactions starting with activation of factor XII leads, ultimately to formation of bradykinin. It is interesting that blood vessel injury can also lead to blood clot formation by activation of a related system -- the blood-clotting cascade. In sum, following blood vessel injury, bradykinin causes dilation of small blood vessels in the injured area.
Chemicals found in plasma can cause blood vessel dilation-complement.
Third, a series of plasma proteins (C1-C9) are activated by the presence of antigenic agents. These plasma proteins constitute the "complement system" or the "complement cascade." An activated form of at least one of these proteins (C5a) binds on sensitized mast cells causing them to release histamine. Because of the anaphylactic response the release of large amounts of histamine produce, C5aand other related complement proteins are sometimes known as "anaphylatoxins."
Damaged tissue cells stimulate production of vasodilator chemicals-prostaglandins.
Finally, "prostaglandins" produce vasodilatation in the areas of tissue injury. These are substances produced by a series of reactions from the damaged cell membranes and the subsequent release of "Arachidonic acid." Arachidonic acid-derivatives become vasodilator prostaglandins.
Figure 2. Important Chemical Mediators
How "Increased Permeability" Occurs
Leakage of plasma is caused by contraction of blood vessel lining cells.
There are two mechanisms that explain escape of plasma into the surrounding tissues in the early phase of acute inflammation: endothelial cell contraction and endothelial cell injury. The continued presence of histamine, bradykinin, and other chemical mediators cause endothelial cell contraction, an event that opens intercellular junctions allowing early transudation of protein-deficient plasma. If the inflammatory reaction is severe and long-lasting enough, endothelial cell damage (or even death) allows rapid escape of protein-rich plasma. Such injury is caused by chemicals that accumulate in the area of tissue injury and by the activation of certain white blood cells that, in turn, secrete enzymes that in the process of destroying the inciting agent kill endothelial cells.
How "Margination" Occurs
Surface receptors on WBCs and endothelial cells cause their "stickiness."
There are two explanations for adherence of leukocytes (WBCs) to blood vessel walls: 1) changes in WBCs and 2) changes in the endothelial lining cells. In both cases chemical mediators increase the numbers of surface receptors allowing increased adherence. C5aincreases surface receptors on neutrophils. Secretions of lymphocytes and monocytes called "cytokines" increase the surface receptor on endothelial cell surfaces.
Chemotaxis
Attraction of WBCs to injured areas is caused by chemical mediators-chemotaxis.
Apparently neutrophils do not just appear in the injured area; they are enticed by chemical agents. The attraction of WBCs by chemicals has been known for decades; the term "chemotaxis" has been used to identify it. As chemotaxic chemicals appear in the area of tissue injury, neutrophils and monocytes migrate along the path of its increasing concentration. A number of chemotaxic agents have been identified: C5aand certain leukotrienes (a product of arachidonic acid) are but two examples. These agents bind with neutrophil and monocyte/macrophage surface receptors stimulating 1) cell movement and 2) cell activation, secretion, and degranulation.
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Clinical Features of Acute Inflammation
So far we have considered the minute-by-minute developments in the early phases of inflammation. Now it is time to turn to more practical considerations.
Recognizing "cardinal signs" will lead to a diagnosis of acute inflammation.
Acute inflammation is easily recognized by its signs and symptoms. The inflamed area is red, warm, swollen, and painful. The part is so sore that the patient protects losing its function. These features are known as the "cardinal signs" of acute inflammation. Students seem to remember these signs (and symptoms) easier by learning the terms Celsus used two millennia ago: rubor (redness), calor (warmth), tumor (swelling), dolor (pain), and functio laesa (loss of function). Any time a patient presents with a warm, red, painful swelling it is likely that their body is fighting off some bacterial infection.
Swelling
Systemic Features of Acute Inflammation
Systemic features of inflammation may cause a patient to appear sick.
Severe acute inflammatory reactions produce effects far away from the area of tissue injury. Patients with serious bacterial infections are sick. The most important of systemic changes that occur with such infections are fever and elevated white cell counts.
Table 4. Cardinal Signs
| English | Greek/Latin | Caused By |
| Redness | Rubor | Hyperemia |
| Warmth | Calor | Hyperemia |
| Swelling | Tumor | Increased permeability |
| Pain | Dolor | Low pH |
| Loss of function | Functio laesa | Pain, swelling |
Elevation of body temperature is a sign of acute inflammation-fever.
Normal body temperature (as measured orally) is 98.6oF.; in a serious infection, temperature may rise to 103-104o. If an infection is suspected in a dental patient, her/his temperature should be measured and noted in the dental record.
Secretions of inflammatory cells (cytokines) can cause fever.
Fever is caused by secretion of cytokines by cells that appear in the inflammatory reaction (e.g. macrophages). Two common cytokines are interleukin-1 (Il-1) and tumor necrosis factor (TNF). Given that these factors cause fever and are produced by inflammatory cells, it follows that a large number of cells produce large amounts of cytokines resulting in higher fever. There is, then, a direct relationship between the severity of the inflammatory response and fever.
Numbers of circulating WBCs increase in acute inflammation-leukocytosis.
In severe acute inflammatory responses, greater than normal numbers of white cells appear in circulation, a condition known as "leukocytosis" (leuko- = white; -cyt- = cell; -osis = condition of). Normally, white blood cells number about 4,000 to 10,000 in each cubic millimeter of blood. In severe infections, white cell counts may reach 30,000/mm3. The additional cells are produced in bone marrow under the influence of the same cytokines that produce fever.
The presence of immature WBCs suggests a severe infection is present.
Neutrophils are the most prominent cells in acute inflammation. If extraordinary numbers of these cells are needed to fight a severe infection, bone marrow is called upon to release developing neutrophils as soon as possible. As a consequence of this demand, immature neutrophils appear in the blood stream. When performing a blood count in such patients, it is possible to differentiate immature neutrophils from mature ones because the immature nuclei are not segmented, and are horse shoe-shaped. These characteristic nuclear changes have earned immature neutrophils the names "band cells" or "non-segmented neutrophils." The appearance of many immature neutrophils is sometimes designated as a "shift to the left," a reference to a form once used for reporting blood counts. By the way, neutrophils are often known as "polys" or "PMNs."
A differential blood count is a simple way to find changes in blood cells.
It is common practice to count various blood cell types and report the percentages of each when performing a blood count. This procedure is known as a "differential blood count." In a normal individual, neutrophils account for about 65% of the WBCs, lymphocytes 30%, monocytes 5%, eosinophils 1%, and basophils 0.5%. In severe acute inflammatory responses, the percentage of neutrophils (mature and immature forms) may greatly exceed the 65% rate normal for these cells.
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Microscopic Features of Acute Inflammation
Dilated blood vessels and neutrophils are the prominent microscopic features.
Acute inflammation is easily recognized by its LM appearance. As might be expected, dilated congested capillaries are prominent. Neutrophils are also an obvious feature. Therefore, the presence of neutrophils is specific (pathognomic) for a diagnosis of acute inflammation. In addition to dilated/congested blood capillaries/venules and neutrophils, distended tissue spaces suggest the exudation of plasma in the area. Fibrin may be present as well. Monocytes/macrophages are present also, however large concentrations of neutrophils may obscure them.
Table 5. Microscopic Features
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Microscopic Features
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The Exudates of Acute Inflammation
The materials appearing at a site of tissue injury are "exudates."
By common usage, the term "exudate" refers to all the materials that appear at the site of injury in inflammation. An acute inflammatory exudate is composed, then, of plasma, neutrophils, monocytes/macrophages, fibrin, and dead surrounding tissue. However, in some circumstances one component of the exudate is common than another.
Purulent (Suppurative) Exudate
Suppuration is an exudate composed largely of neutrophils and dead tissue.
As mentioned, when an acute inflammatory reaction is severe, large numbers of neutrophils accumulate. As the reaction proceeds, many neutrophils die; some (or much) surrounding normal tissue will die too. Dead and dying neutrophils coupled with dead and dying tissue produce a foul-smelling yellow material known commonly as "pus." A more acceptable designation for this material is "purulent exudate" or "suppurative exudate." Purulent exudates are a common part of dentistry. They may exude from periodontal pockets and from deep infections that have broken through the skin or the oral mucous membrane. They may also occur at the apex of an infected tooth.
Serous Exudate
Watery leakage from a blister is an exudate composed largely of plasma.
In some exudates plasma is the predominate material. Clinically, plasma appears as a clear, amber-colored fluid that has no particular odor; it a "serous exudate." This exudate is found in common blisters. Burns also produce serous exudates. In fact, in large burns the exudation of plasma can be so profound that life threatening fluid loss can result.
Fibrinous Exudate
A white membrane covering a lesion is an exudate composed largely of fibrin.
Occasionally, fibrin is the predominate component of an exudate; if so, it is called a "fibrinous exudate." This usually occurs in the surface of some organ like the heart or lungs; it may also be seen in the pharynx or gingiva. Fibrinous exudates appear as a thick, white, shaggy covering. Sometimes the exudate is so thick that it resembles a membrane. When this happens, the term "pseudomembrane" is used. If diphtheria, a now uncommon bacterial infection affecting the throat, should occur in a child, a pseudomembrane forming in the pharynx may block air passages.
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The Lesions of Acute Inflammation
Abscesses: Confined Acute Inflammatory Lesions
A walled-off collection of pus is an abscess.
An "abscess" is a localized collection of pus. Emigration of neutrophils, along with much tissue destruction, is the hallmark of abscesses. In abscesses the resulting purulent exudate is localized preventing the spread of the infectious agent elsewhere.
Pus-producing bacteria often cause abscesses.
These lesions are commonly produced by a group of microorganisms known as the pyogenic (pus-producing) bacteria. The staphylococci are a group of bacteria possessing pyogenic properties.
Abscesses are treated by antibiotic therapy and drainage.
Treatment of an abscess involves removal of the causative agent (usually a bacterial infection) by antibiotic therapy. It is also necessary to remove the purulent exudate before healing will occur. If unattended, an abscess may drain by extending along anatomic planes until a skin or mucous membrane surface is reached. A practitioner may direct drainage to a favorable site by cutting into the abscess and placing an artificial drain. This procedure is known as "incision and drainage" or an "I&D."
Cellulitis: The Spreading Acute Inflammatory Lesion
Pus that spreads to adjacent areas causes "cellulitis."
If a purulent exudate spreads into surrounding tissues, the resulting lesion is "cellulitis." The purulent exudate and the microorganism that produced it cause the reaction to spread to distant sites.
Cellulitis is a sign of a potentially fatal infection.
These spreading infections are serious life-threatening events. They must be treated by vigorous 1) elimination of the infectious agent (usually with antibiotics) and 2) incision and drainage of the lesion.
Bacteria producing "spreading factors" cause cellulitis.
Cellulitis is usually caused by infection with pyogenic bacteria that produce "spreading factors." The streptococci are notorious in this regard. These factors are bacterial-produced enzymes that dissolve connective tissue ground substance (hyaluronidases) and/or inflammation-produced fibrin (fibrinolysins).
Ulcers: Denuded Acute Inflammatory Lesions
Destruction of overlying epithelium by inflammation produces "ulcers."
Inflammation occurring under an epithelial covering membrane may destroy the overlying epithelial cells. Once the covering epithelium is lost, the underlying connective tissue will be exposed. This lesion is an "ulcer." Ulcers are common lesions encountered in the oral cavity -- canker sores (aphthous stomatitis) are common examples of oral ulcerations.
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An immune reaction to some "mild" but persistent antigen producing a proliferation of lymphocytes and/or plasma cells (B cells). There is usually no pain, redness, swelling, or warmth. Scarring and persistence of etiologic agent is common.
General Features of Chronic Inflammation
Chronic inflammation is longer lasting and less dramatic.
If inflammation is subdued, has a quiet onset, and lasts for days to weeks, the term "chronic inflammation" is used. This type of inflammation is, then, characterized by an insidious onset and long duration. The signs and symptoms of chronic inflammation are not as dramatic as those associated with acute inflammation.
Chronic inflammation may follow acute or start anew.
Sometimes chronic inflammation follows acute inflammation; other times it starts anew (de novo) without going through an acute phase first.
Etiology and Pathogenesis of Chronic Inflammation
Persistent acute inflammation will become chronic.
If an acute inflammatory reaction persists, it will enter a chronic phase. There are two general causes of such persistence: the inability to eliminate or continual reacquisition of the offending agent. These situations are common in dentistry where, for example, an open pulp chamber keeps reintroducing microorganisms into the tissues around the root (periapical tissues). It also may occur when there is continual exposure to some inanimate materials like pollens and dusts.
Low-grade irritants may initiate chronic inflammation.
More often than not, chronic inflammation arises without going through an acute phase first (de novo chronic inflammation). Two examples of this come to mind: persistent infections and autoimmune diseases.
Microorganisms with low virulence may initiate chronic inflammation.
Infection with a microorganism of low virulence that cannot be eliminated easily may result in chronic rather than acute inflammation. Tuberculosis and some dental conditions (to be discussed later) are examples of such infections.
Constant stimulation of the immune system may initiate chronic inflammation.
Sometimes a patient may be "allergic" to her/his own cells. This condition is known as autoimmunity. In these cases, the affected patient's cells serve as a source of constant stimulation of the chronic inflammatory process. Systemic lupus erythematosus and rheumatoid arthritis are autoimmune diseases characterized by chronic inflammation.
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The Cells of Chronic Inflammation
Mononuclear cells are characteristic of chronic inflammation.
In chronic inflammation, macrophages and lymphocytes are the predominant cells; there are few, if any, neutrophils. These, along with most other cells associated with chronic inflammation, have single nuclei. Because of this feature, they are commonly known as "mononuclear cells" or "round cells."
Macrophages
Macrophages are prominent in chronic inflammatory exudates.
Macrophages are monocytes that have entered an area of tissue injury. They can live for months and can thrive in acid environments. For macrophages to carry out their functions they must be stimulated (activated) by chemical mediators. Among the chemical mediators are lymphokines (cytokines secreted by lymphocytes), fibronectin-coated surfaces, and mediators that initiate acute inflammation.
Phagocytosis is the main function of macrophages.
Macrophages are excellent phagocytes. They engulf and process antigens allowing them to be neutralized by other cells (lymphocytes). Activated macrophages can also engulf and kill certain microorganisms. Macrophages also secrete a number of substances that assist in the recruitment of other cells (monokines) and cause tissue destruction (collagenases, elastases, reactive oxygen).
Macrophage
T-Lymphocytes
T-Lymphocytes are the most characteristic cell of chronic inflammation.
Lymphocytes emigrate from blood vessels late in an inflammatory reaction. Because lymphocytes account for about one-third (33%) of the circulating WBCs, they become the predominant cell in chronic inflammation. There are two types of lymphocytes: T and B. T-lymphocytes are produced in the thymus gland and are responsible for cell-based immunity. B-lymphocytes, on the other hand, arise from bone marrow and are responsible for humoral immunity.
T-Lymphocytes must be activated; they also can activate macrophages.
T lymphocytes must be activated before they carry out their functions. Such activation is effected by monokines and, in some cases, directly by antigens. Once activated, lymphocytes can react with certain antigens destroying them or rendering them harmless. They also secrete lymphokines that stimulate macrophages. Thus, macrophages and lymphocytes are interdependent -- the activation of one stimulates the activation of the other.
Lymphocyte
B-Lymphocytes (Plasma Cells)
Plasma cells are activated B-lymphocytes.
Plasma cells are derived from activation of a class of lymphocytes known as "B cells." They do not circulate in the blood stream but are transformed in lymphoid organs or at the site of chronic inflammation. They possess off-center nuclei, abundant basophilic cytoplasms, pale spots near the nuclei (negative Golgi images), and clock-face distribution of nuclear chromatin.
Plasma cells secrete antibodies.
Plasma cells manufacture and secrete antibodies against specific antigens. The antibodies circulating in blood plasma are derived from plasma cells; these circulating antibodies are called "humoral antibodies." A plasma cell produces antibodies against a single antigen. Once a B lymphocyte is activated, it creates a clone of cells capable of producing antibodies against the antigen that stimulated it.
Plasma Cell
Eosinophils
Eosinophils can destroy parasites and certain cells.
Eosinophils are related to neutrophils; both display a segmented nucleus; both are polymorphonuclear leukocytes. Eosinophils comprise about 3% of the circulating WBCs and are recognized by the bright red granules within their cytoplasm. These granules are filled with a substance called "major basic protein" that can destroy some parasites and some cells.
Eosinophils accumulate in certain diseases.
These cells are not seen in all chronic inflammatory reactions. Rather, they appear in parasitic infestations, hypersensitivity reactions, and some autoimmune conditions.
Microscopic Features
Multinucleated Giant Cells
Multinucleated giant cells respond to foreign bodies and certain bacteria.
Huge cells with many nuclei may appear in chronic inflammatory reactions. These cells are formed by the fusion of macrophages and are called "multinucleated giant cells." They are often seen associated with foreign particulate matter (splinters, talc, debris). They may also accompany reactions to certain microorganisms of low virulence (e.g. tuberculosis).
Multinucleated Giant Cells
Fibroblasts and Collagen
Collagen production is a feature of chronic inflammation.
Fibroblasts and the collagen they produce are prominent features of chronic inflammation. In fact, over-exuberant collagen formation may permanently deform inflamed tissues; this circumstance in known as "fibrosis."
Chemical mediators stimulate collagen-producing cells.
Fibroblasts are recruited to enter an area of tissue injury by lymphokines and monokines. Once in the area, they produce collagen. In the inflammatory reaction does not resolve in a reasonable time, the collagen can form scar tissue (fibrosis).
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Microscopic Features of Chronic Inflammation
Lymphocytes and collagen are features of chronic inflammation.
The presence of lymphocytes and collagen are the two constant microscopic features of chronic inflammation. While plasma cells, eosinophils, and giant cells may appear in certain situations, lymphocytes are always present and if the reaction lasts more than a week or two, collagen is always present as well. Dilated blood vessels so characteristic of acute inflammation are usually absent in chronic inflammation.
Table 6. Microscopic Features
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Microscopic Features
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Clinical Features of Chronic Inflammation
The clinical features of chronic inflammation are subdued.
Acute inflammation has dramatic and easily recognized clinical features (e.g. redness, warmth, swelling, pain, loss of function, fever). These signs are absent or greatly suppressed in chronic inflammation.
Complications of Chronic Inflammation
Unlike acute inflammation where the reaction itself may be life threatening (e.g. cellulitis), the adverse effects of chronic inflammation are not so dramatic. Two complications are rather common: fibrosis and persistence.
Table 7. Complications
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Too much collagen production may cause disfiguring scars.
Scarring -- Much tissue can be destroyed during a long-standing chronic inflammatory reaction. This missing tissue is usually replaced by continual production of collagen by fibroblasts. If the inflammatory reaction persists for a long time, collagen build up can be significant. If this occurs, scars may form causing permanent distortion of the tissue and interfere with its function. Also, the presence of scar tissue may hinder regeneration of parenchymal cells.
Chronic inflammation may persist for a long time.
Persistence -- Substances with low antigenic properties may not be eliminated quickly. If these persist, the chronic inflammatory reaction may be continually stimulated. Similarly, reactions to one's own cells (autoimmunity) may also produce long-standing chronic inflammation due to continual cellular destruction and, therefore, the unending supply of antigen.
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Granulomatous Chronic Inflammation
Granulomatous chronic inflammation appears in granulomatous diseases.
Under certain circumstances a chronic inflammatory reaction will acquire features so special that they will narrow a diagnosis to a group of conditions called "granulomatous diseases." These conditions include tuberculosis, syphilis, leprosy, and most fungal (mycotic) infections. The microorganisms producing these granulomatous diseases are low-virulence ones causing persistence of chronic inflammatory reactions.
The granuloma consists of granulation tissue and chronic inflammation.
The lesion of granulomatous chronic inflammation is the "granuloma." It is a little mass of chronic inflammation with a background of new capillaries, new fibroblasts, and new collagen. This reparative tissue is called "granulation tissue." It is the presence of granulation tissue that gives the granuloma its name.
The epithelioid cell is the hallmark of granulomatous chronic inflammation.
When macrophages become activated they acquire special morphologic features. These cells acquire large, round nuclei that remind pathologists of epithelial cell nuclei. It is this feature that gives rise to their designation as "epithelioid cells." Epithelioid cells are diagnostic of granulomatous chronic inflammation.
Granulomatous Chronic Inflammation
Subacute inflammation is ill defined; clinicians use it more than pathologists.
Pathologists do not speak of subacute inflammation often because it is so ill defined that its microscopic appearance cannot be described. However, clinicians sometimes use the term to refer to a clinical situation in which the signs and symptoms displayed by the patient are neither "acute" nor "chronic" they seem to be somewhere in between. In these cases, the reaction is neither "clinically acute" nor "clinically chronic" and, therefore, is "subacute."
