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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, preventing release of iron bound by ferritin within intestinal enterocytes and macrophages
Ceruloplasmin	Oxidizes iron, facilitating for ferritin, inhibiting microbe iron uptake
Haptoglobin	Binds hemoglobin, inhibiting microbe iron uptake
Orosomucoid (α1‐acid glycoprotein)	Steroid carrier
α 1‐Antitrypsin, α(α) 1‐antichymotrypsin	Serpin, downregulates inflammation

Figure 3.11 illustrates the importance of adhesion molecules in this process. The expression of L‐selectin by leukocytes and P‐ and E‐selectin by activated endothelial cells is mostly responsible for the tethering and rolling of leukocytes on the luminal endothelial blood surface. Selectins interact with glycosylated ligands expressed by the interacting cells. Leukocyte activation and firm adhesion to the endothelium are then rapidly induced by the engagement of leukocyte chemotactic receptors by chemotactic factors immobilized on glycosaminoglycans or heparin sulfates present in the milieu. Chemotactic factors include PAMPs such as formylated peptides, complement proteins (e.g., C5a and C3a), lipids, and chemokines such as IL‐8.