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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 increased blood flow, thereby causing 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.