|
 |
 |
 |
 |
|
|
|
|
|
|
A study of the inflammatory response to injury should place many of the concepts discussed in previous sections of this syllabus in an orderly perspective. As the primary host defense mechanism against all forms of injury, the inflammatory reaction will be encountered on a continuous basis throughout the study of clinical medicine and surgery.
The student should be able to define, spell and use the following terms as they relate to inflammation and injury.
Inflammation can best be defined as the vascular and cellular response of living tissue to injury. However, the reaction of blood vessels is its identifying feature. The inflammatory process serves to destroy, dilute or wall-off the injurious agent as well as the tissue cells that may have been destroyed. In other words, a complex series of events are initiated which, as far as possible, heal and reconstitute the damaged tissue. Repair is the process by which lost or destroyed cells are replaced by vital cells. Sometimes, repair is accomplished by regeneration of native parenchymal cells, but more often it occurs by fibroblastic scar formation. On the whole, inflammation and repair are beneficial to the host. In their absence, infections would go unchecked, burns would not heal, and wounds would remain festering open sores. However, under certain circumstances, inflammation and repair may become aberrant and harmful.
As discussed in section 1 of this syllabus, inflammation has a rich and ancient history that is intimately linked to the history of wars and the resulting wounds and infections.
(The interested students should review the "Historical Aspect of Pathology" as discussed in section 1 of this syllabus).
As the discussion of inflammation unfolds, the student should be reminded of the following pertinent points:
Traditionally, inflammation has been divided into acute and chronic forms, depending on its duration (subacute is an intermediate form).
Acute inflammation is one of relative short duration, lasting for a few minutes, several hours, or one to two days. It is characterized by the exudation of fluids and plasma proteins (inflammatory edema) and by the emigration of leukocytes (predominantly neutrophils). In general, the acute inflammatory response is basically the same regardless of the location or nature of the injurious agent.
Subacute inflammation usually is characterized by a decline in the vascular contribution (edema and hyperemia) and often by a change in the character of infiltrating leukocytes. although neutrophilic may be prominent at the inflammatory site, the infiltrate becomes mixed with mononuclear cells (lymphocytes, macrophages and maybe plasma cells) in reasonable numbers. It represents an intermediate time frame that can vary from a few days to a few weeks depending on the nature of the inciting stimulus.
Chronic inflammation is less uniform than acute inflammation. It is generally of longer duration and is associated with the presence of lymphocytes, macrophages and the proliferation of small blood vessels and fibroblasts. However, many factors may modify the course and histologic appearance of chronic inflammation (which will become apparent later in this section).
In the following discussions, the acute inflammatory response is considered first, the the chronic response, and finally, repair. However, the student should remember that these phases of the inflammatory response occur together (even though they are discussed separately). For example, repair actually begins soon after the inflammatory process is initiated.
The events in the acute inflammatory reaction are conveniently divided into:
Hemodynamic changes or changes in vascular flow and caliber begin very early after injury, but develop at varying rates, depending on the severity of the injury. These changes consist of an integrated chain of events activated by chemical mediators, but perhaps transiently initiated by neurogenic mechanisms.
8.6.1.1 Transient Vasoconstriction of Arterioles
Vasoconstriction of arterioles occurs immediately following injury. However, this is an inconstant finding. With mild forms of injury, it disappears within three to five seconds. With more severe injury, it may remain for several minutes. The mechanism of this vasoconstriction is unknown, but is probably neurogenic or adrenergic in origin.
8.6.1.2 Vasodilatation of Arterioles resulting in Increased Blood Flow
Vasodilatation is a constant and fundamental event in the inflammatory process. Initially, it involves arterioles which result in opening of new capillaries and venular beds in the area. Subsequent to vasodilatation, there is increased blood flow to the affected areas (this is the hallmark of the early hemodynamic changes in acute inflammation).
Remember, active hyperemia is the first stage of inflammation.
Vasodilatation is induced in part by an axon reflex arc which occurs immediately after tissue injury. Following stimulation of sensory nerve endings at the site of injury, a nerve impulse passes centrally along the axon to its division and then peripherally to the arteriole supplying the injured area. Synaptic vesicles within the adrenergic synapse liberate adrenalin which dilates the peripheral arterioles resulting in increased blood flow to the affected area. The vasomotor nerves are not necessary to the development of dilation or any other aspect of the inflammatory response. Chemical mediators are of more importance in causing vasodilation and are of greater significance in altering vascular permeability.
8.6.1.3 Retardation of Blood Flow
Slowing of the blood flow to the injured area is brought about by increased permeability of the microvasculature (to be discussed later). The slowing and/or stasis of blood disrupts the laminar flow pattern of the blood and results in the displacement of the cellular elements to the periphery of the microvessels. The leukocytes appear to fall out of the central column of flow and assume positions in contact with the endothelium. When numerous cells adhere to and virtually line the endothelium, the process is referred to as pavementing. These marginated leukocytes stick to the vascular endothelium and eventually migrate through the vascular wall into the extravascular space by a process called emigration which is an active process since leukocytes are motile.
Remember, erythrocytes have no power of movement and their passages through the vascular wall is passive or via diapedesis.
Immediately after an injury, there is arteriolar dilatation which may be preceded by a transient vasoconstriction. Pre-capillary sphincters open which leads to increased blood flow in previously functioning capillaries as well as opening of inactive capillary beds. Also, the postcapillary venules dilate and fill with the rapidly flowing blood. Thus, the microvasculature at the site of injury becomes hyperemic (active hyperemia). The hyperemia is followed by slowing of blood (which may progress to stasis). Concomitant with the development of hyperemia, the venules and capillaries become abnormally permeable, resulting in the escape of fluid. Thus, the viscosity of blood is increased leading to increased frictional resistance to flow. Subsequently, the outflow from the injured site is impeded which contributes to the stasis of blood (there is increased hydrostatic pressure in venules and capillaries). Along with the slowing and/or stasis of blood, the laminar flow pattern is disrupted and cellular elements are displaced to the periphery of microvessels (margination). Soon after margination becomes evident, leukocytes escape from their vascular confinement (via emigration) and appear in the perivascular tissue.
Increased vascular permeability with the escape of plasma fluid (including plasma proteins) and leukocytes is known as exudation. This is a major and constant feature of all acute inflammatory reactions.
By employing special techniques, three general patterns of increased permeability responses can be recognized. These patterns are dependent on the severity of various types of injury and include
Immediate-Transient Permeability Response: begins immediately after mild injury, reaches it peak by 5 to 10 minutes and phase out within 15 to 30 minutes. The response is elicited by histamine and histamine-like chemical mediators. The venules are the site of increased permeability and leakage (the capillaries are not affected). Vascular leakage result from contraction of endothelial cells which leads to the formation of intercellular gaps.
Intermediate-Prolonged Permeability Response: begins immediately after injury, is sustained at a high peak for several hours and continues for one to several days until the damaged vessels are thrombosed or repaired. The response is encountered with severe injury (usually associated with necrosis of endothelial cells). Increased permeability and vascular leakage occur at all levels of the microcirculation, including venules, capillaries and arterioles. The mechanism for increased permeability appear to be "direct damage" to the vascular endothelium.
Delayed-Prolonged Permeability Response: occurs after a period of delay (latent period of 6-12 hours) and lasts for several hours or days (the duration of the latent period and the time of peak permeability vary with the form of injury). This response occurs after mild to moderate thermal injury, or x-ray or ultraviolet irradiation, with certain bacterial toxins and in delayed hypersensitivity reaction. It is believed that the delayed leakage is largely due to direct injury to the endothelium by the injurious agent. However, electron microscopy studies show the leakage to occur between endothelial cells, somewhat similar to that produced by histamine, but there is no endothelial cell contraction. Why intercellular gaps form with this type of direct injury and why the leakage is delayed is unknown. Increased permeability and leakage occur in both venules and capillaries.
Leukocytic exudation refers to the massing of leukocytes, principally neutrophils and monocytes (macrophages), in sites of inflammation. The phagocytic leukocytes engulf and destroy or, at least, weaken foreign invaders.
The sequence of events by which leukocytes aggregate and act at the inflammatory site can be considered under the following headings:
Margination or the peripheral orientation of leukocytes in the slow-moving bloodstream was mentioned in the discussion of "hemodynamic changes." Basically, slowing or stagnation of blood disrupts the normal laminar pattern of flow and cellular elements fall out of the central column to assume positions in contact with the endothelium. Subsequently, leukocytes adhere to the endothelial wall (pavementing). This displacement of leukocytes toward the periphery of the bloodstream is apparently governed by the laws of physics.
Emigration refers to the process by which motile leukocytes escape from the blood vessel lumen into the perivascular tissues (neutrophils, basophils, monocytes and lymphocytes all use the same pathway).
It is now apparent that the route of leukocytic emigration along intercellular junctions is the same as that described for vascular leakage of fluids and proteins. However, leukocytic emigration and increased vascular permeability are two separate phenomena that may or may not occur concurrently.
In addition to leukocytes, erythrocytes may also leave blood vessels and enter the perivascular tissues (especially in severe injuries). These cells are non-motile and are passively pushed through the vessel walls by increased hydrostatic pressure. Erythrocytes are not active components of the inflammatory process.
The cell type found in the inflammatory response varies with the duration of the lesion and with the type of injurious agent. Neutrophils predominate in most types of acute inflammatory reactions for the first 6 to 24 hours. After this time, monocytes are most prominent. However, there are many exceptions to this pattern (i.e., in viral infections, lymphocytes predominate during the acute stages. In some hypersensitivity reactions, eosinophils may be the main cell type).
Chemotaxis may be defined as the unidirectional migration of leukocytes toward an attractant. Thus, leukocytes are drawn to the site of injury by chemotactic influences which may be exogenous or endogenous. All granulocytes, monocytes and, to a lesser extent, lymphocytes respond to such chemoattractants.
Neutrophils are attracted primarily by two chemotactic agents:
Recent evidence suggest that neutrophils respond to chemotactic influences by converting an inert cytoplasmic precursor (proesterase I) to the active enzyme "serine esterase" upon exposure to the chemotactic factor(s). Activation of serine esterase makes it possible for neutrophils to move toward the attractant.
Monocytes are attracted by chemotactic factors which include:
Eosinophil chemotactic substances include
Phagocytosis refers to the engulfment of foreign particulate matter by phagocytic cells, particularly by neutrophils and macrophages. Once particulate matter is engulfed, the phagocytic cells release powerful enzymes which kills or degrades. Phagocytosis involves three distinct but interrelated steps:
Recognition of foreign particulate matter by leukocytes is the initial step. Once a foreign particulate matter is recognized, it becomes attached to the surface of the leukocytes. Most organisms are not attached to leukocytes (recognized) until they are coated with serum factors called opsonins. IgG and the opsonic fragment of C3 (generated by activation of complement by immune or non-immune mechanisms) are well characterized opsonins.
Engulfment occurs once the phagocyte recognizes a foreign particle. Extensions of the cytoplasm (pseudopods) flow around the particle to be engulfed. Eventually, the particle is completely surrounded by the cytoplasmic membrane (phagosome). Subsequently, the limiting membrane of the phagosome fuses with the limiting membrane of the enzyme-rich lysosomal granule of leukocytes, resulting in discharge of the granule's content into the phagolysosome.
(1) increased oxygen consumption,
(2) glycogenolysis,
(3) increased glucose oxidation via the hexose-monphosphate shunt and (4) hydrogen peroxide production.
Killing and/or Degradation is the ultimate step in the process of phagocytosis. There are a number of antimicrobial mechanisms or degradative enzymes to account for these events, at least in neutrophils. The two categories of bactericidal mechanisms recognized in neutrophils are:
Oxygen-dependent Bactericidal Mechanisms are initiated by a burst of oxidative activity during phagocytosis. This results from activation of a plasma membrane linked oxidase that converts oxygen (O2) to hydrogen peroxide (H2O2). It is now believed that various toxic byproducts of such oxygen are the killers of ingested bacteria. The toxic products that have been most widely studied are hydrogen peroxide and superoxide ions.
Hydrogen-Peroxide-Myeloperoxidase-Halide System is effective in killing bacteria, fungi, viruses and mycoplasma. During phagocytosis, reduced pyridine nucleotide oxidase is activated, resulting in the liberation of hydrogen peroxide within the phagolysosome. This hydrogen peroxide in the presence of myeloperoxidase (an enzyme found in lysosomes of neutrophils) and a halide ion (such as chloride, iodide or bromide) is effective in killing phagocytized organisms.
Superoxide anion is a free radical generated during the conversion of oxygen to hydrogen peroxide in the phagosomes. There is evidence that this reactive radical alone is toxic to microorganisms.
Oxygen-Independent Bactericidal Mechanisms include the following:
At this point in the discussion of the acute inflammatory process, the chemical mediators (histamine, etc.) eluded to earlier should be considered in more detail. The student should be reminded that the inflammatory response is precipitated by injury, but it is mediated by chemicals derived from plasma, cells or damaged tissue.
The chemical mediators of inflammation are usually present within the body in an inactive form that is activated by injury. In general, the mediators dilate vessels, alter permeability and attract leukocytes into the following groups:
is contained within and released from granules of mast cells (also released from basophils and platelets). It induces dilatation of arterioles and increased permeability of venules and capillaries. Histamine exerts its effect almost exclusively in early inflammatory responses. Its action is relatively brief and occurs primarily during the intermediate-transient response induced by mild injury. There are a number of agents that act to release histamine from mast cells, these include
Has actions similar to those of histamine in some species (rodents). It is also released from mast cell granules.
Are polypeptides in circulating blood that arise from alpha 2-globulin. Lysis of cells in the injured area (especially leukocytes) releases enzymes which generate kinins. Once generated, the kinins sustain and enhance the early transitory vascular alterations begun by histamine (arteriolar vasodilatation and increased capillary permeability). In addition, kinins are potent mediators of pain and smooth muscle contraction (arterioles and venules). The formation of the vasoactive bradykinin occurs as outlined below:
 |
Is a self-assembling, extracellular system of serum enzymes that occur in body fluids in association with membranes. The complement sequence is activated by antigen-antibody complexes and by some other large molecules. The components of the system that have biologic activity in inflammation are as follows:
Are 20-carbon chain unsaturated fatty acids that exert enhancing or depressant effects on numerous biological processes (including inflammation). The inflammatory stimuli induce prostaglandin synthesis and release. In inflammation, prostaglandins contribute to the genesis of vasodilatation, increased permeability, fever and pain.
Of neutrophils (cationic proteins, acid proteases, neutral proteases) have numerous and profound effects on the inflammatory process. They may serve to increase vascular permeability and chemotaxis.
Are referred to as lymphokines and they are produced by the sensitized T-lymphocytes associated with cell-mediated immunity. The lymphokines induce a variety of activities, including chemotaxis of macrophages, neutrophils and basophils as well as inhibition of macrophage migration.
At this point, it is appropriate to consider the various cell types that participate in the inflammatory reaction. All of these cells play fairly distinctive roles in inflammatory reaction. All of these cells play fairly distinctive roles in inflammation and enter into the inflammatory response in a definite, though overlapping, sequence. Therefore, for convenience, those cells associated with acute and/or chronic reactions are discussed. In the following brief discussion, an attempt is made to summarize the morphologic appearance and origin of inflammatory cells, as well as the conditions under which these cells are encountered and their functions.
Morphology: Neutrophils are 10-12 microns in diameter and have nuclei which are band-shaped or have three to five lobes. In tissue sections, the nuclei usually stain intensely with hematoxylin. The cytoplasm is irregular and may not be seen with H & E. If observable, the cytoplasm tends to be eosinophilic. In blood smears, the cytoplasm of neutrophils contains granules which are lavender. These granules (which are not usually apparent in tissue sections), correspond to the lysosomes and they are rich in proteolytic enzymes. Neutrophils are actively motile and phagocytic.
Origin:
Neutrophils originate from myeloid tissue of the bone marrow. They are attracted to injured areas by chemotactic substances and do not reproduce at the inflamed sites.
Conditions Encountered:
Neutrophils constitute the "first line of cellular defense" against invading organisms and particulate material. They are the first to gather in acute inflammation. Neutrophils are seen in response to pyogenic organisms and are the principal constituent of pus. Remember, the number of neutrophils in the circulation increases greatly in the early stages of inflammation.
Function:
All of the neutrophil's characteristic cell activities participate in the inflammatory response. These include
- (1) phagocytosis,
- (2) production of proteolytic and lipolytic enzymes to digest bacteria, dead cells, etc.,
- (3) they may produce substances which neutralize the toxic products of bacteria and
- (4) they may act as an energy source for other cells (there is evidence that neutrophils shed their cytoplasm which is then transferred to "mononuclear cells" as an energy source).
Morphology:
The eosinophil is 10-15 microns in diameter. In tissue sections, it has a nucleus which is usually bilobed and does not stain as intensely as the nucleus of the neutrophil. The cytoplasmic granules are larger and more eosinophilic than those of neutrophils. The eosinophil of the horse has the largest granules among domestic animals. This cell is motile, phagocytic and attracted by chemotactic substances.
Origin:
The eosinophil originates in the myeloid tissue of bone marrow and does no reproduce at the site of inflammation.
Conditions Encountered:
The eosinophil may appear early and/or late in inflammation. It is most prominent in conditions where there is no immune response (hay fever and asthma in man, parasitic conditions, etc.). The eosinophil is especially prominent in
- (1) the secondary invasion of parasites in a tissue,
- (2) in the brain of pigs with salt poisoning and
- (3) in so-called eosinophilic myositis of cattle.
Function:
The true functions of the eosinophil are unknown. Their biologic activities resembles, to some degree, those of neutrophils. They are motile, respond to chemotactic agents and are also phagocytic (although to a much lesser degree than are neutrophils). In hypersensitivity reactions, it has been suggested that eosinophils serve to degrade chemical mediators (especially histamine) and terminate the allergic reactions (i.e., eosinophil granules contain histinase). The phagocytic function may be of importance, especially the phagocytosis of antigen-antibody complexes. Another possible function is the production of fibrinolysin.
Morphology: In blood smears, the basophil is 10-12 microns in diameter and contains blue granules (with Giemsa or Wright stain). The cell is slowly motile and not phagocytic. Basophils are present in blood in very small numbers and they are seldom seen as a prominent part of the inflammatory reaction. Morphologically, basophils have large lobulated nuclei and their granules contain heparin and histamine but no acid hydrolases. There remains no convincing evidence that the mature circulating basophil represents a precursor of mature tissue mast cells.
Mast cells are granular connective tissue cells found throughout the connective tissues in virtually every organ, principally in perivascular sites. They have mononuclear nuclei, are slightly larger, and have somewhat more abundant cytoplasm than the basophil. Their granules contain heparin, histamine and other proteolytic enzymes. In some animals they also are rich in serotonin.
Function:
The true functions of basophils are unknown. However, both basophils and mast cells release pharmacologically active compounds (heparin/histamine) in response to antigen-antibody complexes (as well as trauma and drugs). The immunoglobulin IgE binds selectively to the surfaces of mast cells and basophils and interaction of this antibody with specific antigens trigger degranulation and the release of histamines and other mediators. Mast cells are intimately involved in the pathogenesis of acute inflammation since it is their release of histamine which triggers many of the manifestations arising from smooth muscle contraction and edema formation.
Morphology:
The mature lymphocyte is 7 10 12 microns in diameter, but larger lymphocytes may range up to 16 microns or more in diameter. The nucleus is round to somewhat oval and the nuclear membrane is thinner than that of the other inflammatory cells. Heavy chromatin granules are present within the nucleus and these often tend to be marginated just under the nuclear membrane. Their nucleoli usually are masked by the heavy clumps of chromatin. In tissue sections, the cytoplasm, if visible, consists of a narrow rim which may or may not completely surround the nucleus. The cytoplasm is homogeneous, pale blue and may contain a few azurophilic granules. Larger lymphocytes have more cytoplasm. Lymphocytes are slightly ameboid, but they are not phagocytic.
Origin:
Lymphocytes originate in lymphoid tissue, such as lymph nodes, spleen and thymus, and are carried to the site of inflammation by the blood. In addition, some lymphocytes are produced in bone marrow and there is some reproduction at the site of inflammation. Circulating small lymphocytes represent at least two different functional populations of lymphoid cells (however, they cannot be distinguished structurally). These thymic-derived lymphocytes (T-lymphocytes) and bone marrow-derived lymphocytes (B-lymphocytes) are differentiated on the basis of life-span, their response to mitosis-inducing drugs and the reactivity of their cell membranes in immunologic reactions. B-lymphocytes represent the precursors of plasma cells which form antibody. Following contact with an appropriate antigen, these lymphocytes become transformed into large "blast" cells (plasmablasts). The T-lymphocytes are associated with cell-mediated reactions involving the direct interaction of small lymphocytes and foreign proteins. The immunologic reaction is represented in tissues as lymphocytic "exudate" (lymphocytic perivascular cuffing). The small T-lymphocyte may transform into large lymphocytes (activated T-lymphocytes that act by secreting lymphotoxins and lymphokines).
Conditions Encountered:
Lymphocytes appear late in inflammation. The arbitrary time of 48 to 72 hours is usually given as the time of appearance. They are seen as a prominent part of long-standing inflammatory reactions. Viral infections, particularly those of the central nervous system, are often associated with lymphocytes. In the brain and spinal cord, lymphocytes tend to accumulate around blood vessels (perivascular cuffing). The number of lymphocytes is under the control of endocrine secretions from the pituitary and adrenal cortex. Some of the glucocorticoids cause a decrease in the circulating lymphocytes and eosinophils. They also have an anti-inflammatory effect by decreasing the accumulation of lymphocytes and other inflammatory cells in the tissue.
Function:
It is generally agreed that lymphocytes function primarily in the immune response (including both the humoral and cell-mediated immunity). The T-lymphocytes form the major portion of circulating lymphocytes. They have the capability of recirculating from lymphoid tissue to the thoracic duct, to the circulating blood and back to lymphoid tissue. These cells are involved in cell-mediated immunity. The B-lymphocytes are found in the blood, but do not recirculate. They are found in lymphoid tissues and are responsible for antibody synthesis (along with plasma cells). Other less well-defined functions have also been attributed to lymphocytes.
Morphology:
The plasma cell is about 12 to 15 microns in its greatest diameter. The nucleus is similar to that of lymphocytes, although the arrangement of the chromatin tends to resemble more nearly the typical "cartwheel" of "clock-face" (with the large chromatin mass in the center of the nucleus surrounded by other masses just beneath the nuclear membrane). The nucleus is usually eccentrically located in the cell. The cytoplasm is more abundant than in lymphocytes and tends to be more basophilic. There is usually a clear space or halo near the nucleus which corresponds to the Golgi complex. The plasma cell is said to be slightly ameboid and slightly phagocytic.
Origin:
Plasma cells originate from lymphocytes. Under an appropriate antigenic stimulus, small lymphocytes (B-cells) transform into larger "blast" cells which, in turn, develop into plasma cells. Once the plasma cell is formed, there is no evidence of reproduction.
Function:
Plasma cells are committed to antibody production. Following excretion of globulin, most lyse and die.
Morphology:
Macrophages vary in size (from 12 to 20 microns or more in diameter). The nucleus is round to oval and the nuclear membrane is relatively thin. There are fine to medium chromatin granules in the nucleus. One to two nucleoli can usually be seen. There is abundant homogeneous, eosinophilic cytoplasm. Macrophages may "bunch" together and resemble epithelium, thus the term "epithelioid cells." The macrophage is actively ameboid and actively phagocytic.
Origin:
There is evidence that macrophages originate from blood monocytes. Monocytes emigrate from the blood into the inflammatory lesions and immediately transform into macrophages. Even though some macrophages may originate from lymphocytes, the majority of those that accumulate in inflammation are derived from blood monocytes.
Remember, macrophages have the capability of reproducing at the site of inflammation. Macrophages found in various body sites are referred to by the following terms:
- a.Histiocytes - connective tissue macrophages
- b.Kupffer cells - liver macrophages
- c.Inflammatory macrophages - macrophages in inflammatory lesions
- d.Microglial cells - nervous system macrophages
- e.Fixed and free macrophages - macrophages in spleen and lymph nodes
- f.Pleural and peritoneal macrophages - macrophages in serous cavities
- g.Alveolar macrophages - lung macrophages
Monocytes and macrophages belong to the reticuloendothelial system or the mononuclear-phagocytic system.
Conditions Encountered: In inflammatory processes, macrophages appear in large numbers late (48 to 72 hours). Actually, they enter an inflammatory lesion simultaneously with neutrophils. However, they do not appear in large numbers in the early stages of acute inflammation because:
- (1) they are not as aggressively ameboid as neutrophils,
- (2) their number in circulating blood (monocytes) are much lower than neutrophils and
- (3) their reproduction is stimulated at a much slower rate. In general, macrophages are most prominent in subacute to chronic reactions.
Function:
The primary function of macrophages is phagocytosis and they are termed the "second line of cellular defense." They are also capable of pinocytosis of soluble molecules. Thus, the function of macrophages in the inflammatory process include the following:
- a.Phagocytosis and digestion of invading organisms or foreign particles.
- b.Release potent enzymes that may degrade connective tissue.
- c.Release chemotactic and permeability factors that may prolong inflammation.
- d.Release substances responsible for leukocytosis and fever (prostaglandins, endogenous pyrogens).
- e.Release factors that aid in wound healing.
- f.Secrete proteins that are important in defense mechanisms (lysozymes, interferon).
- gServe to process antigens in cell-mediated immune reactions.
Inflammatory giant cells are multinucleated cells that result from the fusion of monocytes and/or macrophages. However, giant cells may form by mitotic division of the nuclei without division of the cytoplasm. In giant cells, the nuclei may be clustered in the center of the cell or arranged in a "ring" fashion around the periphery. The finding of giant cells in lesions usually suggest the possibility of diseases involving fungi, mycobacteria or some foreign body (they are associated with large amounts of indigestible material).
The exudates associated with inflammatory reactions vary in their fluid, plasma protein and cell content. In general, the nature of the exudate is dictated by the severity of the reaction and its specific cause. (Please refer to pages 184-190 of your textbook).
Serous exudation is characterized by the outpouring of a low-protein fluid. (This is so-called inflammatory edema and the protein content is higher than that of non-inflammatory edema). A serous exudate is composed primarily of a slightly cloudy fluid. Its presence usually indicates mild injury. However, this type of exudate is seen in the early stages of most acute inflammatory reactions. Microscopically, serous exudation appears as a homogeneous, slightly eosinophilic material. It functions to dilute the irritant and to bring antibodies into the inflamed area. The skin blister that results from a burn is a simple example of a serous exudate. Serous exudation along with hyperemia represents the "first" stage of pneumonia.
Fibrinous exudation is characterized by the presence of fibrin as the major constituent. It occurs in the more severe inflammations which permit the escape of large fibrinogen molecules from the blood vessels (a fibrinous exudation is indicative of severe vascular damage). Fibrinous exudation occurs chiefly on mucous and serous membranes, including the alveolar surfaces of the lungs. Masses of fibrin on an epithelial surface are referred to as follows:
Microscopically, fibrin appears as fine threads or filaments. These threads may fuse to form a solid eosinophilic mass. Neutrophils are usually present. Grossly, fibrin appears as thin strands or layers of white to yellowish elastic-like material.
Fibrinous exudate serves to help localize bacteria and to act as a scaffold or framework for repair processes. In serous cavities, the strands of fibrin connecting the parietal and visceral layers are called fibrinous adhesions. If during the repair process the fibrinous adhesions are replaced by connective tissue, they are called fibrous adhesions.
A suppurative or purulent exudation is characterized by the presence of pus (neutrophils mixed with cellular debris).
(1) presence of neutrophils that release proteolytic enzymes,
(2) necrosis of some type and
(3) liquefaction.
Suppurative exudation is usually caused by pyogenic or pus-forming bacteria (Corynebacterium pyogenes, Pseudomonas aeruginosa, etc.). The following are some terms applied to different forms of suppurative reactions:
Hemorrhagic exudation occurs whenever some form of severe injury causes rupture of vessels or diapedesis of erythrocytes.
The gross and microscopic appearances are similar to those of hemorrhage except that fibrin or excessive numbers of leukocytes usually accompany the erythrocytes.
A catarrhal exudate is characterized by excessive mucin
Catarrhal exudation is limited to mucous membranes since it is secreted by goblet cells. Grossly, catarrhal exudate appears as a clear or cloudy tenacious fluid on the mucosal surfaces. The increased mucin serves to protect damaged mucosal surfaces.
In summary, serous, fibrinous, purulent, hemorrhagic and catarrhal exudation are associated with acute inflammatory processes. Although the various types of exudative reactions were described separately, mixed patterns develop in many inflammations (serofibrinous, fibrinopurulent, etc.). Also, the exudation may begin as a serous response in any single inflammatory reaction and, with extension and increasing severity of the reaction, it may become predominantly fibrinous and ultimately change into a suppurative exudate. The acute exudates may change to chronic forms in which connective tissue is a prominent feature.
In addition to the five exudative inflammations listed above, some inflammations are recognized by the presence of numerous lymphocytes (lymphocytic exudation). Such lymphocytic accumulations are usually associated with viral infections in the central nervous system and visceral organs (perivascular cuffing). So-called lymphocytic exudate is observed on microscopic examination only.
The local clinical signs of acute inflammation are heat, redness, swelling, pain and loss of function. The heat and redness result from dilation of the microcirculation and increased blood flow into the injured area. Swelling is produced largely by the escape of fluid, plasma proteins and cells from the blood into the perivascular tissue. The origin of pain is somewhat obscure, but the best evidence suggests that overt pain can be induced by the prostaglandins as well as bradykinin. Also, pain may be caused by increased tissue pressure due to the inflammatory exudate.
To this point, the acute inflammatory response as well as inflammatory cells and exudates associated with acute and prolonged responses have been discusses.
Clinically, chronic inflammation may occur in three ways:
Microscopically, chronic inflammation is characterized by:
Infiltration by macrophages is a particularly important component of chronic inflammation. As discussed earlier in this section, monocytes begin to emigrate rather early in acute inflammation and, within 48 to 72 hours, they constitute the predominate cell type. Remember, when the monocyte reaches the extravascular tissue it undergoes transformation into a macrophage. Macrophages may persist for prolonged periods of time in inflamed areas. Other types of cells found in chronic inflammation are plasma cells, lymphocytes and eosinophils.
Plasma cells produce antibody in response to antigens in the inflamed area. Lymphocytes play a role in antibody production and in cell-mediated immunologic reactions. However, they occur in non-immunologic inflammation. Eosinophils are characteristic of immunologic reactions mediated by IgE and in parasitic infections. However, they may be associated with inflammation for obscure reasons. The student should be reminded of the following pertinent points.
The mechanisms that lead to fibroblastic and vascular proliferation (the other two characteristic features of chronic inflammation) are obscure. However, factors derived from activated macrophages have been implicated in both fibroblast and new vessel growth. Regardless of the mechanism, continued fibroblast proliferation results in increased deposition of collagen. Therefore, chronic inflammation is often followed by considerable scarring with resultant deformities.
Granulomatous T a distinctive pattern of chronic inflammation evoked by certain etiologic agents (fungi, mycobacteria, some foreign bodies, etc.). Granulomas consist of collections of modified macrophages (epithelioid cells) usually surrounded by a rim of lymphocytes.
However, the reason for their transformation into this peculiar cell type is poorly understood. In general, epithelioid cells and granulomas are associated with materials that macrophage lysosomes cannot adequately process. The initial phagocytosis of such substances is followed by "digestive failure," and death of the macrophages. Subsequently, more blood monocytes emigrate to the location, transform into macrophages, and rephagocytize the substance and its associated cellular debris. New populations of macrophages collect in progressively enlarging foci called granulomas. Although the material may not be destroyed, granulomas provide an effective means of localizing it and allowing other inflammatory and immunologic mechanisms to act for longer periods of time. The presence of Langhan's or foreign body giant cells (formed from the coalescent and fusion of macrophages) is another feature of granulomas. Also, fibroblasts, lymphocytes, plasma cells and, at times, neutrophils can be seen in granulomas. However, the presence of the characteristic cell ("epithelioid cell") is required for the diagnosis of granulomatous inflammation.
Two factors appear to determine the formation of granulomas:
Systemic manifestations may be evoked by acute or chronic inflammation. Fever and leukocytosis are two of the most prominent systemic manifestations, especially when the inflammation is associated with bacteremia.
8.13.1 .FEVER:
The cause of fever has not been completely elucidated. However, evidence suggests that endogenous pyrogens and prostaglandins play dominant roles in fever production.
NOTE:Normal body temperature is maintained by hypothalmic regulation of the production and dissipation of heat.
Endogenous pyrogens are basic proteins of low molecular weight which act on the thermoregulatory centers in the hypothalamus, leading to elevation of the "thermostat" and the development of fever. Endogenous pyrogens exist in an inactive form in monocytes, macrophages, neutrophils and possibly eosinophils. They are activated and released by phagocytosis, endotoxin, viruses, bacteria, fungi, immune complexes, lymphocyte products, etc. Aspirin, a common antipyretic substance, antagonizes the action of endogenous pyrogens within the hypothalamus. Prostaglandins are also involved in fever production. However, the exact mechanism has not been elucidated.
The following sequence of events are believed to account for the pathogenesis of fever:
Endogenous pyrogens are produced by phagocytic leukocytes in response to infections, toxins, immunologic reactions, etc. These pyogens are released into the bloodstream where they interact with receptors on or near the thermosensitive neurons in the thermoregulatory center of the anterior hypothalamus. Either through the local action of endogenous pyrogens or through the local production of prostaglandins, information is transmitted from the anterior hypothalamus through the posterior hypothalamus to the vasomotor centers, resulting in sympathetic nerve stimulation, vasoconstriction of skin vessels, decrease in heat dissipation and fever.
8.13.2 LEUKOCYTOSIS:
Leukocytosis or an increased number of leukocytes in the circulating blood is a common feature of the inflammatory reaction (especially those induced by bacterial agents).
"Under normal conditions, the number of leukocytes in the circulating bloodstream ranges from 4,000 to 12,000 per cubic millimeter, depending on the species of animal. In most animals, neutrophils constitute approximately 60 to 75% of the total number of leukocytes (however, in a few species (cattle, sheep) neutrophils comprise only 40-50% of the total leukocytes)."
In inflammation, the leukocyte count usually increases to 12,000 - 20,000, but sometimes may reach extraordinary high levels of 40,000 - 100,000. These extreme elevations are referred to as Leukemoid reactions since they are similar to the leukocyte counts obtained in cases of leukemia. The leukocytosis of acute inflammation is usually due to an absolute increase in the number of neutrophils. The leukocytosis apparently initially occurs because of accelerated release of cells from the bone marrow reserve pool (there is often a rise in the number of more immature neutrophils in the blood - shift to the left). However, prolonged infections stimulate proliferation of precursors in the bone marrow. Mediators for the accelerated release from the bone marrow or the proliferation of precursors have not been well elucidated. However, C3 fraction of complement augments neutrophil release.
Remember, certain systemic inflammatory states decrease the number of circulating leukocytes (leukopenia). These include viral infections, rickettsial infections, certain protozoan infections and maelevations are referred to as Leukemoid reactions since they are similar to the leukocyte counts obtained in cases of leukemia. The leukocytosis of acute inflammation is usually due to an absolute increase in the number of neutrophils. The leukocytosis apparently initially occurs because of accelerated release of cells from the bone marrow reserve pool (there is often a rise in the number of more immature neutrophils in the blood - shift to the left). However, prolonged infections stimulate proliferation of precursors in the bone marrow. Mediators for the accelerated release from the bone marrow or the proliferation of precursors have not been well elucidated. However, C3 fraction of complement augments neutrophil release.
Remember, certain systemic inflammatory states decrease the number of circulating leukocytes (leukopenia). These include viral infections, rickettsial infections, certain protozoan infections and many infections which overwhelm the animal defense system.
The discussion of systemic manifestations of inflammation climaxes the basic description of the acute and chronic inflammatory processes. Even though the basic inflammatory changes were described sequentially and may occur in this order in the fully evolved reaction to injury, all of the phenomena usually occur more or less concurrently in a seemingly chaotic but remarkably organized manner.
|
After completing this section, each student should be in a position to provide appropriate answers for the following questions.
|
