++
The morphologic and functional changes in acute inflammation were described in the late nineteenth century by Cohnheim, who demonstrated the vascular changes of injury in the vessels of a frog tongue. The two main components of the acute inflammatory response are the microcirculatory response and the cellular response.
+++
Microcirculatory Response
+++
Vasodilation and Stasis
++
The first change in the microcirculation is a transient and insignificant vasoconstriction, which is then followed by marked, active dilation of arterioles, capillaries, and venules. This vasodilation causes an initial marked increase in blood in the area (hyperemia) (Figures 3-2 and 3-3). Subsequently, as fluid is lost into the exudate (see below), stasis may supervene, with very sluggish blood flow.
++
++
+++
Increased Permeability
++
The permeability of capillaries and venules is a function of the intercellular junctions between vascular endothelial cells. These pores normally permit the passage of small molecules (MW < 40,000). Pinocytosis permits selective transfer of larger molecules across the capillary into the interstitium. In normal capillaries, fluid passes out of the microcirculation and into tissues under the influence of capillary hydrostatic pressure—and returns because of plasma colloid osmotic pressure (Chapter 2: Abnormalities of Interstitial Tissues). Normally, fluid that passes out of the microcirculation is an ultrafiltrate of plasma (Table 3-1).
++
++
In acute inflammation, there is an immediate (but reversible) marked increase in the permeability of venules and capillaries due to active contraction of actin filaments in endothelial cells. The effect is separation of intercellular junctions from one another (widening of the pores). Direct damage to the endothelial cells by the noxious agent may also contribute. Increased amounts of fluid and high-molecular-weight proteins are able to pass through these abnormally permeable vessels (see Exudation of Fluid, below).
++
Increase in permeability in acute inflammation occurs in several phases, principally an immediate phase and a sustained or delayed phase. These permeability changes are effected by various chemical mediators (Table 3-2).
++
++
The passage of a large amount of fluid from the circulation into the interstitial tissue produces swelling (inflammatory edema; Chapter 2: Abnormalities of Interstitial Tissues), one of the major features of acute inflammation. Increased passage of fluid out of the microcirculation because of increased vascular permeability is termed exudation. The composition of an exudate approaches that of plasma (Table 3-1); it is rich in plasma proteins, including immunoglobulins, complement, and fibrinogen, because the abnormally permeable endothelium no longer prevents passage of these large molecules. Fibrinogen in an acute inflammatory exudate is rapidly converted to fibrin by tissue thromboplastins. Fibrin can be recognized microscopically in an exudate as pink strands or clumps (Figure 3-4). Grossly, fibrin is most easily seen on an acutely inflamed serosal surface that changes from its normal shiny appearance to a rough, yellowish bread and butter-like surface, covered by fibrin and coagulated proteins.
++
++
Exudation should be distinguished from transudation (Table 3-1). Transudation denotes increased passage of fluid into tissues through vessels of normal permeability. The force that causes outward passage of fluid from the microcirculation into the tissues is either increased hydrostatic pressure or decreased plasma colloid osmotic pressure. A transudate has a composition similar to that of an ultrafiltrate of plasma. In clinical practice, identification of edema fluid as a transudate or an exudate is of considerable diagnostic value because it provides clues to the cause of the disorder, eg, examination of peritoneal (ascites) fluid (Table 3-3).
++
++
Exudation helps combat the offending agent (1) by diluting it; (2) by causing increased lymphatic flow; and (3) by flooding the area with plasma, which contains numerous defensive proteins such as immunoglobulins and complement. The increased lymphatic drainage conveys noxious agents to the draining lymph nodes, thereby facilitating a protective immune response (Chapter 4: The Immune Response). Occasionally, with virulent organisms, the lymphatics may inadvertently promote spread and may actually themselves become inflamed (lymphangitis), together with the lymph nodes (lymphadenitis; Chapter 28: The Lymphoid System: I. Structure & Function; Infections & Reactive Proliferations).
+++
Types of Cells Involved
++
Acute inflammation is characterized by the active emigration of inflammatory cells from the blood into the area of injury. Neutrophils (polymorphonuclear leukocytes) (Figure 3-4) dominate the early phase (first 24 hours). After the first 24–48 hours, phagocytic cells of the macrophage (reticuloendothelial) system—and immunologically active cells such as lymphocytes and plasma cells—enter the area. Neutrophils remain predominant for several days, however.
+++
Margination of Neutrophils
++
In a normal blood vessel, the cellular elements of blood are confined to a central axial stream, which is separated from the endothelial surface by a zone of plasma (Figure 3-2A). This separation is dependent on normal blood flow, which creates physical forces that tend to keep the heaviest cellular particles in the center of the vessel.
++
As the rate of blood flow in the dilated vessels decreases in acute inflammation, the orderly flow of blood is disturbed. Erythrocytes form heavy aggregates (rouleaux) in a phenomenon termed sludging (Figure 3-2B).
++
As a result, leukocytes move to the periphery in contact with the endothelium (margination), to which many then adhere (pavementing) (Figures 3-2B and 3-3). Pavementing is a normal process that is much exaggerated in inflammation as a result of increased expression of various cell adhesion molecules (CAMs) on both leukocytes and endothelial cells. For example, expression of beta 2 integrins (the CD11-CD18 complex), which include leukocyte function antigen-1 (LFA-1), is enhanced by the action of such chemotactic factors as C5a (complement anaphylatoxin; Chapter 4: The Immune Response) and leukotriene LTB4. The complementary CAMs on endothelial cells are similarly up-regulated by the actions of interleukin-1 (IL-1) and tumor necrosis factor (TNF) (tumor necrosis factor, which is not confined to tumors); these include intercellular adhesion molecule (ICAM) 1, ICAM 2, and endothelian leukocyte adhesion molecule (ELAM)-1 (endothelial leukocyte adhesion molecule). Leukocyte adhesion molecule (LAM)-1, which promotes the passage of lymphocytes across high endothelial vesicles into lymph nodes (Chapter 4: The Immune Response), also plays a role in neutrophil and lymphocyte emigration in inflammation.
+++
Emigration of Neutrophils
++
The adherent neutrophils actively leave post capillary venules through intercellular junctions (Figures 3-2 and 3-3) and pass through the basement membrane to reach the interstitial space (emigration). Penetration through the wall takes 2–10 minutes; in interstitial tissue, neutrophils move at a rate of up to 20 μm/min.
++
(Table 3-2.) The active emigration of neutrophils and the direction in which they move are governed by chemotactic factors. Complement factors C3a and C5a (collectively known as anaphylatoxin) are potent chemotactic agents for neutrophils and macrophages, as is leukotriene LTB4. Interaction between neutrophil surface receptors and these chemotaxins increases neutrophil motility (via an influx of Ca2+ ions, which stimulates contraction of actin) and promotes degranulation. Various cytokines (Chapter 4: The Immune Response) play an increasing role as the immune response develops.
++
Erythrocytes enter an inflamed area passively—in contrast to the active process of leukocyte emigration. Red blood cells are pushed out of the vessel by hydrostatic pressure through the widened intercellular junctions behind emigrating leukocytes (diapedesis). In severe injuries associated with disruption of the microcirculation, large numbers of erythrocytes enter the inflamed area (hemorrhagic inflammation).
++
++
++
The first step in phagocytosis is recognition of the injurious agent by the phagocytic cell, either directly (as occurs with large, inert particles) or after the agent has been coated with immunoglobulin or complement factor 3b (C3b) (opsonization). The coating agents are opsonins. Op sonin-mediated phagocytosis is the mechanism operating in the immune phagocytosis of microorganisms. Both IgG and C3b are effective opsonins. Immunoglobulin that is specifically reactive with antigens on the injurious agent (specific antibody) is the most effective opsonin. C3b is generated locally by activation of the complement cascade. Early in acute inflammation—before the immune response has developed—nonimmune factors dominate, but as immunity develops, they are superseded by the more efficient immune phagocytosis.
++
Once recognized by a neutrophil or macrophage, a foreign particle is engulfed by the phagocytic cell to form a membrane-bound vacuole called a phagosome, which fuses with lysosomes to form a phagolysosome.
++
When the offending agent is a microorganism, it must be killed before degradation can occur. The same factors that are instrumental in cell injury (Figure 1-3) are also effective in killing microorganisms.
++
The hydrogen peroxide (H2O2)-myeloperoxidase-halide system is the most important microbicidal mechanism in neutrophils whose cytoplasmic granules contain myeloperoxidase. Superoxide ions are formed by the action of an oxidase in the plasma membrane. Superoxide is spontaneously transformed to microbicidal H2O2 in the lysosome. In addition, myeloperoxidase, in combination with a halide ion (usually chloride), greatly potentiates the microbicidal effect of H2O2, probably by forming highly toxic ions such as HOCl.
Toxic oxygen-based radicals, eg, superoxide (O2−, hydroxyl [OH•], and singlet oxygen, are produced in all phagocytic cells. Microbial killing resulting from the action of these oxygen-based radicals may be direct or may be mediated by ferric ions. Reaction of superoxide with ferric ion results in the formation of ferrous ion, which reacts with hydrogen peroxide to form hydroxyl radicals. Hydroxyl radicals react with bacterial cell wall phospholipids, causing loss of bacterial cell membrane integrity (lipid peroxidation).
Other bactericidal agents released by neutrophil granules include hydrolases, proteases (cathepsin G), lactoferrin, and lysozyme. Lysozyme was first discovered in tears by Alexander Fleming, who called it “tear antiseptic.” It acts by attacking muramic acid linkages in bacterial cell walls.
Immunologic mechanisms such as macrophage-activating factor, a lymphokine released by sensitized T lymphocytes, assist microbial killing by macrophages (Chapter 4: The Immune Response).
As the immune response develops, a variety of other microbicidal mechanisms come into effect (Figure 3-6).
++