Leukocyte Migration and Inflammation CHAPTER 15 349 complement split products that serve as important media- cells produce PGD2 Prostaglandins have diverse physiological tors of inflammation(see Chapter 13). Binding of the ana- effects, including increased vascular permeability, increased phylatoxins(C3a, C4a, and C5a) to receptors on the mem- vascular dilation, and induction of neutrophil chemotaxis. brane of tissue mast cells induces degranulation with release The thromboxanes cause platelet aggregation and constriction of histamine and other pharmacologically active mediators. of blood vessels These mediators induce smooth-muscle contraction and Arachidonic acid is also metabolized by the lipoxygenase increase vascular permeability. C3a, C5a, and C5b67 act pathway to yield the four leukotrienes: LTB4, LTC4, LTD4, and together to induce monocytes and neutrophils to adhere to LtE4. Three of these(LtC4, LTD4, and LTE4)together make vascular endothelial cells, extravasate through the endothe- up what was formerly called slow-reacting substance of ana- lial lining of the capillary, and migrate toward the site of phylaxis(SRS-A); these mediators induce smooth-muscle complement activation in the tissues. Activation of the com contraction LTB4 is a potent chemoattractant of neutrophils plement system thus results in influxes of fluid that carry The leukotrienes are produced by a variety of cells, including antibody and phagocytic cells to the site of antigen entry oocytes, macrophages, and mast cells Some Lipids Act as Inflammatory Some Cytokines Are Important mediators Inflammatory Mediators Following membrane perturbations, phospholipids in the A number of cytokines play a significant role in the develop membrane of several cell types(e.g, macrophages, monocytes, ment of an acute or chronic inflammatory response. IL-1 neutrophils, and mast cells) are degraded into arachidonic IL-6, TNF-a, IL-12, and many chemokines exhibit redundant acid and lyso-platelet-activating factor(Figure 15-11). The and pleiotropic effects that together contribute to the inflam- latter is subsequently converted into platelet-activating factor matory response. Some of the effects mediated by IL-1, IL-6, (PAF), which causes platelet activation and has many inflam- and TNF-c are listed in Table 15-3. In addition, IFN-y con- matory effects, including eosinophil chemotaxis and the acti- tributes to the inflammatory response, acting later in the acute ation and degranulation of neutrophils and eosinophils response and contributing in a major way to chronic inflam- Metabolism of arachidonic acid by the cyclooxygenase mation by attracting and activating macrophages. IL-12 in- pathway produces prostaglandins and thromboxanes. Dif- duces the differentiation of the proinflammatory THl subset. ferent prostaglandins are produced by different cells: mono- The role of several of these inflammatory cytokines in the cytes and macrophages produce large quantities of PGE2 and development of acute and chronic inflammation will be PGF2; neutrophils produce moderate amounts of PGE2 mast described more fully in the next section Membrane phospholipids Arachidonic LySo-PAF acid Cyclooxygenase pathways Lipoxygenase pathway Prostaglandin Leukotriene a4 Thromboxane Prostaglandins Leukotriene Leukotriene PAF Vascular permeability SRS-A Neutrophil Platelet aggregation Vascular dilation Bronchial smooth chemotaxis anemotaxis Other effects Neutrophil chemotaxismuscle contraction Neutrophil activation Other effects GURE 15-11 The breakdown of membrane phospholipids generates important mediators of inflammation, including thromboxane, prostaglandins, leukotrienes, and platelet-activating factor(P/complement split products that serve as important media￾tors of inflammation (see Chapter 13). Binding of the ana￾phylatoxins (C3a, C4a, and C5a) to receptors on the mem￾brane of tissue mast cells induces degranulation with release of histamine and other pharmacologically active mediators. These mediators induce smooth-muscle contraction and increase vascular permeability. C3a, C5a, and C5b67 act together to induce monocytes and neutrophils to adhere to vascular endothelial cells, extravasate through the endothe￾lial lining of the capillary, and migrate toward the site of complement activation in the tissues. Activation of the com￾plement system thus results in influxes of fluid that carry antibody and phagocytic cells to the site of antigen entry. Some Lipids Act as Inflammatory Mediators Following membrane perturbations, phospholipids in the membrane of several cell types (e.g., macrophages, monocytes, neutrophils, and mast cells) are degraded into arachidonic acid and lyso–platelet-activating factor (Figure 15-11). The latter is subsequently converted into platelet-activating factor (PAF), which causes platelet activation and has many inflam￾matory effects, including eosinophil chemotaxis and the acti￾vation and degranulation of neutrophils and eosinophils. Metabolism of arachidonic acid by the cyclooxygenase pathway produces prostaglandins and thromboxanes. Dif￾ferent prostaglandins are produced by different cells: mono￾cytes and macrophages produce large quantities of PGE2 and PGF2; neutrophils produce moderate amounts of PGE2; mast cells produce PGD2. Prostaglandins have diverse physiological effects, including increased vascular permeability, increased vascular dilation, and induction of neutrophil chemotaxis. The thromboxanes cause platelet aggregation and constriction of blood vessels. Arachidonic acid is also metabolized by the lipoxygenase pathway to yield the four leukotrienes:LTB4, LTC4, LTD4, and LTE4. Three of these (LTC4, LTD4, and LTE4) together make up what was formerly called slow-reacting substance of ana￾phylaxis (SRS-A); these mediators induce smooth-muscle contraction. LTB4 is a potent chemoattractant of neutrophils. The leukotrienes are produced by a variety of cells, including monocytes, macrophages, and mast cells. Some Cytokines Are Important Inflammatory Mediators A number of cytokines play a significant role in the develop￾ment of an acute or chronic inflammatory response. IL-1, IL-6, TNF-, IL-12, and many chemokines exhibit redundant and pleiotropic effects that together contribute to the inflam￾matory response. Some of the effects mediated by IL-1, IL-6, and TNF- are listed in Table 15-3. In addition, IFN- con￾tributes to the inflammatory response, acting later in the acute response and contributing in a major way to chronic inflam￾mation by attracting and activating macrophages. IL-12 in￾duces the differentiation of the proinflammatory TH1 subset. The role of several of these inflammatory cytokines in the development of acute and chronic inflammation will be described more fully in the next section. Leukocyte Migration and Inflammation CHAPTER 15 349 Arachidonic acid Prostaglandin G2 Leukotriene A4 Cyclooxygenase pathways Lipoxygenase pathway Lyso-PAF Membrane phospholipids Phospholipase Thromboxane Prostaglandins Leukotrienes C4, D4, E4 Leukotriene B4 PAF ↑ Vascular permeability Vascular dilation Neutrophil chemotaxis Other effects Vasoconstriction Platelet aggregation Other effects SRS-A Bronchial smooth￾muscle contraction Neutrophil chemotaxis Platelet aggregation Eosinophil chemotaxis Neutrophil activation FIGURE 15-11 The breakdown of membrane phospholipids generates important mediators of inflammation, including thromboxane, prostaglandins, leukotrienes, and platelet-activating factor (PAF).