heat and redness in the area. As discussed below, subsequent reduction in blood velocity and concomitant cytokine‐induced and kinin‐induced increased expression of adhesion molecules on the endothelial cells lining the blood vessel promote the binding of circulating leukocytes to the vessel. These events facilitate the attachment and entry of leukocytes into tissues and the recruitment of neutrophils and monocytes to the site of inflammation. Another major change in the local blood vessels is increased vascular permeability. This results from the separation of previously tightly joined endothelial cells lining the blood vessels leading to the exit of fluid and proteins from the blood and their accumulation in the tissue. These events account for the swelling (edema) associated with inflammation, which contributes significantly to the pain, and to the attendant redness and heat associated with the accumulation of cells to the site.
Most of the cells involved in inflammatory responses are phagocytic cells, consisting mainly of the polymorphonuclear leukocytes that accumulate within 30–60 minutes, phagocytize the intruder or damaged tissue, and release their lysosomal enzymes in an attempt to destroy the intruder. If the cause of the inflammatory response persists beyond this point, within 4–6 hours the area harboring the invading microorganism or foreign substance will be infiltrated by macrophages and lymphocytes. The macrophages supplement the phagocytic activity of the polymorphonuclear cells, thus adding to the defense of the area. They also participate in the processing and presentation of antigens expressed by the invading pathogen or foreign substance to T cells, which then generate antigen‐specific responses. Activated T cells synthesize and release a variety of cytokines that proactively stimulate antigen‐specific B cells, thus facilitating antibody production. Within 5–7 days, antibodies produced by these B cells are detectable as serum antibodies and thus become part of the humoral immune defense arsenal.
Localized Inflammatory Responses: Roles of Kinins and the Coagulation Pathway
Activation of the kinins and the coagulation system also contributes to localized inflammatory responses. Once activated, the kinins have several important localized effects on cells and organ systems. Together with the locally released cytokines, they (1) act directly on local smooth muscle and cause muscle contraction; (2) act on axons to block nervous impulses, leading to distal muscle relaxation; and (3) act on vascular endothelial cells, causing them to contract and leading to increase in vascular permeability.
Kinins are very potent nerve stimulators and are the molecules most responsible for pain (and itching) associated with inflammation. They are rapidly inactivated after their activation by proteases, which are generated during these localized responses.
Following kinin‐induced damage to blood vessels, the coagulation pathway is activated. Plasma enzymes are activated in a cascading manner contributing to the inflammatory response by forming a physical barrier with platelets (clot or thrombus) that prevents microorganisms from entering the bloodstream. The simultaneous activation of kinins and the coagulation system during inflammatory responses thus produces inhospitable conditions for invading pathogens as well as new physical barriers to limit their ability to use the circulatory system to gain entry to distal tissues and organs.
The Acute Phase Response
Within minutes after injury, the inflammatory process begins with activation of innate immune cells responding to microbes expressing PAMPs. Activation is stimulated by ligation of PRRs and results in the release of proinflammatory cytokines such as IL‐1, IL‐6, and TNF‐α. These cytokines travel through the blood and stimulate hepatocytes in the liver to secrete acute phase proteins that function as soluble PRRs (Figure 3.10). Other consequences of the acute phase response include increased white blood cell production (neutrophils demarginate first; consequently their numbers increase quickly) and increased synthesis of hydrocortisone and adrenocorticotropic hormone (ACTH). Systemic inflammatory responses also include the induction of fever (discussed below) due to the ability of the hypothalamus to respond to elevated levels of acute phase proteins.
Table 3.2 provides a list of the major acute phase proteins. Among these, C‐reactive protein (CRP) is capable of binding to the membranes of certain microorganisms and activating the complement system (see Chapter 4). This results in lysis of the microorganism, enhanced phagocytosis by phagocytic cells, and several other important host defense functions, as we shall see later. It is noteworthy that acute phase responses are commonly assessed clinically by measuring blood levels of CRP as well as erythrocyte sedimentation rate (ESR). CRP is considered a nonspecific marker of inflammation and is therefore used as a marker to detect or monitor significant inflammation in an individual suspected of having an acute condition such as serious bacterial infections (e.g., sepsis), fungal infections, or pelvic inflammatory disease, just to name a few. Measuring CRP is also useful in monitoring people with chronic inflammatory conditions to detect flare‐ups and/or to determine if treatment is effective. Examples include inflammatory bowel disease, some forms of arthritis, and autoimmune diseases (e.g., systemic lupus erythematosus [SLE]). Increased ESR associated with increased plasma viscosity can also be due to increased concentrations of acute phase proteins and is therefore an indicator of nonspecific inflammation. However, moderately elevated ESR may also occur with anemia and pregnancy (the latter due to increased levels of fibrinogen during pregnancy). A very high ESR may also be due to a marked increase in globulins as a result of severe infection but also myeloma and other lymphoid malignancies.
Figure 3.10. The acute phase response stimulated by cytokines produced by innate immune cells
TABLE 3.2. Acute Phase Proteins
| Protein | Immune system function |
|---|---|
| C‐reactive protein | Binds to phosphocholine expressed on the surface of dead or dying cells and some types of bacteria Opsonin |
| Serum amyloid P component | Opsonin |
| Serum amyloid A | Recruitment of immune cells to inflammatory sites Induction of enzymes that degrade extracellular matrix |
| Complement factors | Opsonization, lysis, and clumping of target cells Chemotaxis |
| Mannan‐binding lectin | Mannan‐binding lectin pathway of complement activation |
| Fibrinogen (α β globulin), prothrombin, factor VIII, von Willebrand factor | Coagulation factors Trapping invading microbes in blood clots Some cause chemotaxis |
| Plasminogen | Degradation of blood clots |
| α2‐Macroglobulin | Inhibitor of coagulation by inhibiting thrombin Inhibitor of fibrinolysis by inhibiting plasmin |
| Ferritin | Binding iron, inhibiting microbe iron uptake |
| Hepcidin |
Stimulates the internalization of ferroportin,
|
