particles, such as bacteria. It is a critical protective mechanism of the immune system. Many microorganisms release substances that attract phagocytic cells. Phagocytosis may be enhanced by a variety of factors that make the foreign particle an easier target. These factors, collectively referred to as opsonins (the Greek word meaning “prepare food for”), consist of antibodies and various serum components of complement (see Chapter 4). After ingestion, the foreign particle is entrapped in a phagocytic vacuole (phagosome), which fuses with lysosomes, forming the phagolysosome. The latter releases its powerful enzymes, which digest the particle.
Phagocytes can also damage invading pathogens through the generation of toxic products in a process known as the respiratory burst. Production of these toxic metabolites is induced during phagocytosis of pathogens such as bacteria and catalyzed by a set of interrelated enzyme pathways. The most important of these are nitric oxide (inducible nitric oxidase synthase), hydrogen peroxide and superoxide anion (phagocyte NADPH oxidase), and hypochlorous acid (myeloperoxidase), each of which is toxic to bacteria. These microbicidal products can also damage host cells. Fortunately, a series of protective enzymes produced by phagocytes controls the action of these products so that their microbicidal activity is primarily limited to the phagolysosome (i.e., fused phagosomes and lysosomes; see Figure 3.8), thereby focusing their toxicity on ingested pathogens. These protective enzymes include catalase, which degrades hydrogen peroxide, and superoxide dismutase, which converts the superoxide anion into hydrogen peroxide and oxygen. The absence of, or an abnormality in, any one of the respiratory burst components from phagocytic cells results in a form of immunodeficiency that predisposes individuals to repeated infections (see Chapter 16).
Figure 3.8. Endocytosis and phagocytosis by phagocytes.
THE INFLAMMATORY RESPONSE
A major hallmark of the innate immune response is inflammation, of which two types are recognized. Acute inflammation is a short‐term inflammatory response to an insult to the body. If the cause of the inflammation is not resolved, however, it can lead to chronic inflammation, which is associated with major tissue destruction and fibrosis. Chronic inflammation is ongoing inflammation which can be caused by foreign bodies, persistent infection (e.g., tuberculosis), and autoimmune diseases (e.g., rheumatoid arthritis). In these cases, the inflammatory response continues and can be only temporarily modified by the administration of antiinflammatory agents, such as aspirin, ibuprofen, cortisone, and biopharmaceutical therapies that target cytokines involved in inflammation (e.g., tumor necrosis factor, interleukin‐17). These therapies act on several of the metabolic pathways involved in the elaboration and activation of the pharmacological mediators of inflammation. However, they do not affect the root cause of the inflammation, so when they are withdrawn, the symptoms may return.
As a physiological process, inflammation is typically initiated by tissue damage caused by endogenous factors (such as tissue necrosis or bone fracture) and by exogenous factors. The latter includes various types of damage, such as mechanical injury (e.g., cuts), physical injury (e.g., burns), chemical injury (e.g., exposure to corrosive chemicals), immunological injury (e.g., hypersensitivity reactions; see Chapters 13–15) and biological injury (e.g., infections caused by pathogenic microorganisms; see Chapter 19). Indeed, infection can be thought of as pathogen‐induced injury when considering inflammatory responses, since the innate immune cells called into play and the inflammatory responses that manifest are essentially identical, regardless of the cause of injury. While perhaps paradoxical in light of the discomfort associated with certain types of inflammatory responses (e.g., hypersensitivity to poison ivy), inflammation is a normal immunological process designed to restore immune homeostasis by bringing the injured tissue back to its normal state.
As noted above, inflammation does not have to be initiated by pathogens that cause infection, but can also be caused by tissue injuries. Such injuries cause release of damaged cellular contents at local sites even in the absence of breaks in physical barriers that would allow pathogens to enter. The inflammatory reaction triggers mobilization of phagocytic cells and other innate immune cells to the damaged area to clear cellular debris and to set the stage for wound repair, as discussed in later in this chapter Such mobilization is, in part, the result of transendothelial migration of leukocytes, as discussed below. This happens when damaged cells release their contents into the local environment which initiates release of potent inflammatory mediators from mast cells in and around the area. Inflammatory mediators include histamine, leukotrienes, and prostaglandins. Histamine increases the diameter of local blood vessels (vasodilation), causing an increase in blood flow. Histamine also increases the permeability of local capillaries, causing plasma to leak out and form interstitial fluid causing the swelling associated with inflammation.
Transendothelial Migration of Leukocytes
Immediately following tissue injury, a phenomenon known as transendothelial migration, or diapedesis, occurs. It involves damage‐associated molecular patterns (DAMPs) which are released at the tissue injury site, promoting release of H2O2 from wounded epithelial cells. DAMPs are molecules released by stressed cells undergoing necrosis that act as endogenous danger signals to promote and exacerbate the inflammatory response. DAMPs also trigger release of a family of chemotactic cytokines called chemokines (e.g., IL‐8), other cytokines (IL‐1, tumor necrosis factor [TNF]‐α), and leukotrienes from surrounding tissue cells (e.g., macrophages) to further recruit neutrophils. Early‐arriving neutrophils are then activated to both directly and indirectly promote further secretion of these chemokines and leukotrienes to amplify the recruitment of additional neutrophils from the circulation. The locally produced chemokines and cytokines induce increased expression of endothelial cell adhesion molecules (ECAMs) and ligands on leukocytes to which ECAMs bind. Together, the increased vascular permeability, leukocyte endothelial adherence and rolling result in transendothelial migration(extravasation) of these cells from the blood to local tissue where the inciting inflammatory microbe (e.g., bacteria entering the skin due to a wound) is located (Figure 3.9). Leukocyte extravasation is a process that undergoes the following sequential steps: tethering, rolling, activation, adhesion, crawling, and transmigration, with each step relying on the function of a defined set of molecules.
Figure 3.9. Leukocyte adhesion to endothelium leads to their adhesion, activation, and extravasation from the blood to tissue where they are needed to help destroy (phagocytize) pathogens such as bacteria that initiate this response
Collectively, these events manifest the triad of clinical signs of inflammation: pain, redness, and heat. These can be explained by increased blood flow, elevated cellular metabolism, vasodilation, release of soluble mediators, extravasation of fluids that move from the blood vessels to surrounding tissue, and cellular influx. Pain is caused by increased vascular diameter, which leads to
