Chapter 3. The Acute Inflammatory Response

Acute inflammation is the early (almost immediate) response of a tissue to injury. It is nonspecific and may be evoked by any injury short of one that is immediately lethal. Acute inflammation may be regarded as the first line of defense against injury and is characterized by changes in the microcirculation: exudation of fluid and emigration of leukocytes from blood vessels to the area of injury. Acute inflammation is typically of short duration, occurring before the immune response becomes established, and it is aimed primarily at removing the injurious agent.

Until the late 18th century, acute inflammation was regarded as a disease. John Hunter (1728–1793, London surgeon and anatomist) was the first to realize that acute inflammation was a response to injury that was generally beneficial to the host: “But if inflammation develops, regardless of the cause, still it is an effort whose purpose is to restore the parts to their natural functions.”

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).

Exudation of Fluid

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).

Cellular Response

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.

Chemotactic Factors

(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).

Phagocytosis

See Figure 3-5.

Recognition

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.

Engulfment

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.

Microbial Killing

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.

1. 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.

2. 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).

3. 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.

4. Immunologic mechanisms such as macrophage-activating factor, a lymphokine released by sensitized T lymphocytes, assist microbial killing by macrophages (Chapter 4: The Immune Response).

5. As the immune response develops, a variety of other microbicidal mechanisms come into effect (Figure 3-6).

The Triple Response

(Figure 3-7)

Sir Thomas Lewis, in a series of elegant and simple experiments in 1927, elucidated the basic factors that mediate acute inflammation. Firmly stroking the forearm with a blunt instrument such as a pencil evokes the triple response: (1) Within 1 minute, a red line appears along the line of the stroke as a result of dilation of arterioles, capillaries, and venules at the site of injury; (2) simultaneously, a red flare develops as a result of vasodilation in the tissue surrounding the injury; and (3) a wheal forms because of exudation of fluid along the line of injury.

Lewis showed that vasodilation in tissue surrounding the injury—the flare, a minor part of the acute inflammatory response—is mediated by a local axon reflex (Figure 3-7). The major components of acute inflammation—the red line and the wheal—were shown to be independent of neural connections in the tissue. Lewis then demonstrated that local injection of histamine (Lewis's “H substance”) produced a reaction equivalent to the red line and wheal. This discovery laid the foundation for understanding the role of chemical mediators in acute inflammation.

Specific Mediators

(Table 3-2)

In the years since Lewis's experiments, it has become apparent that histamine can account for only a small part of the acute inflammatory response. Many other chemical mediators have been discovered, but the exact role of individual mediators in inflamed tissue is unknown; their actions in vivo can only be postulated on the basis of their demonstrated in vitro activity.

Vasoactive Amines

Histamine and serotonin are released from mast cells and platelets and can be identified early in the course of acute inflammation. Histamine is more important than serotonin in humans; it acts mainly on venules that have H1-histamine receptors. Both of these amines cause vasodilation and increased permeability and are probably the main agents responsible for the immediate phase of the acute inflammatory response. Histamine levels decrease rapidly within an hour after the onset of inflammation.

The Kinin System

Bradykinin, the final product of the kinin system, is formed by the action of kallikrein on a precursor plasma protein (high-molecular-weight kininogen). Kallikrein is present in its inactive form prekallikrein in plasma and is activated by activated factor XII (Hageman factor) of the coagulation cascade. Bradykinin causes increased vascular permeability and stimulates pain receptors.

The Coagulation Cascade

Note that the coagulation cascade, leading to production of fibrin, is also initiated by Hageman factor (activated factor XII). The fibrinopeptides that are also formed in the catabolism of fibrin (fibrinolysis) also cause increased vascular permeability and are chemotactic for neutrophils.

The Complement System

(Chapter 4: The Immune Response). C5a and C3a, which are formed in the activation of complement, cause increased vascular permeability by stimulating release of histamine from mast cells. C5a is a powerful chemotactic agent for neutrophils and macrophages. C3b is an important opsonin. C5a activates the lipoxygenase pathway of arachidonic acid metabolism (see below).

Arachidonic Acid Metabolites

Arachidonic acid is a 20-carbon unsaturated fatty acid found in phospholipids in the cell membranes of neutrophils, mast cells, monocytes, and other cells. Release of arachidonic acid by phospholipases initiates a series of complex reactions that culminate in the production of prostaglandins, leukotrienes, and other mediators of inflammation (Figure 3-8).

Neutrophil Factors

Proteases and toxic oxygen-based free radicals generated by the neutrophil are believed to cause endothelial damage leading to increased vascular permeability.

Other Mediators and Inhibitors

Numerous other chemical mediators of acute inflammation have been described that are ignored here because they play either a minor or a dubious role. Negative feedback (inhibition) of inflammation also occurs but is not well understood; possible inhibitory factors include C1 esterase inhibitor (inhibits the complement cascade) and α1-antitrypsin (inhibits proteases).

Acute inflammation may be accompanied by systemic features in addition to the local cardinal signs described earlier.

Fever

Fever may result following the entry of pyrogens and prostaglandins into the circulation at the site of inflammation. These act upon the brain stem to reset body temperature.

Changes in the Peripheral White Blood Cell Count

(Figure 3-9)

The total number of neutrophils in the peripheral blood is increased (neutrophil leukocytosis); initially, this is due to accelerated release of neutrophils from bone marrow. Later, neutrophil production in the marrow is increased. Peripheral blood neutrophils tend to be the less mature forms, and they frequently contain large cytoplasmic granules (toxic granulation). The term shift to the left signifies this change (see Figure 3-9 and Chapter 26: Blood: III. the White Blood Cells). Viral infections tend to produce neutropenia (decreased number of neutrophils in the blood) and lymphocytosis (excess of normal lymphocytes in the blood). Acute inflammation resulting from viral infection therefore represents an exception in that the microcirculatory changes and fluid exudation are accompanied by a lymphocytic rather than a neutrophil response.

Changes in Plasma Protein Levels

The levels of certain plasma proteins typically increase when acute inflammation is present. These acute phase reactants include C-reactive protein, α1-antitrypsin, fibrinogen, haptoglobin, and ceruloplasmin. Increased levels of these substances in turn lead to an increased erythrocyte sedimentation rate, a simple and useful (though nonspecific) clue to the presence of inflammation.

The preceding description of acute inflammation is that of the classic, most frequently occurring form. It is important to recognize variations from this common type because they provide clues to the causative agent (Table 3-4).

The acute inflammatory response is aimed at neutralizing or inactivating the agent causing the injury. There are several possible outcomes:

1. Resolution: In uncomplicated acute inflammation, tissue returns to normal in a process of resolution (Chapter 6: Healing & Repair), in which the exudate and cellular debris are liquefied and removed by macrophages and lymphatic flow.

2. Repair: When tissue necrosis has occurred before the agent is neutralized, repair ensues, and dead cells are either replaced by regeneration or repaired by scar formation (Chapter 6: Healing & Repair).

3. Suppuration: In virulent bacterial infections, exaggerated emigration of neutrophils with liquefactive necrosis occurs (suppurative inflammation). The liquefied mass of necrotic tissue and neutrophils is called pus. When an area of suppuration becomes walled off, an abscess results (Figure 3-10).

4. Chronic inflammation: When the noxious agent is not neutralized by the acute inflammatory response, the body mounts an immune response (Chapter 4: The Immune Response), which leads to chronic inflammation (Chapter 5: Chronic Inflammation).

(Table 3-5)

Local cardinal signs of inflammation permit diagnosis of acute inflammation when the process involves surface structures—skin, conjunctiva, mouth, etc. Acute inflammation in internal organs such as the lung and kidney may first manifest with systemic changes such as fever and alterations in the blood (white cell count, proteins, etc). More rarely, it is necessary to examine a fluid exudate or tissue sample (biopsy) to establish the presence of acute inflammation.