PaRt II Immune Effector Mechanisms production of distinctive profiles of chemokines by destina- Endothelial damage tion tissues and sites provide rich opportunities for the dif- ferential regulation of activities of different leukocyte popu lations. Indeed, differences in patterns of chemokine-receptor Activation of expression occur within leukocyte populations as well as be Hageman factor tween different ones. Recall that THl and TH2 subsets of TH Activated cells can be distinguished by their different patterns of cyto- kine production. These subsets also display different profiles Prekallikrein cascade of chemokine receptors. TH2 cells express CCR3 and-4, and Thrombin a number of other receptors not expressed by THl cells. On Kallikrein the other hand, THl cells express CCrl, -3, and-5, but most Fibrinopeptides Plasmin TH2 cells do not. fibrin clot Bradykinin Kininogen Fibrin degradatio Other mediators of Inflammation T Vascular permeabilityTVascular Compleme vas In addition to chemokines, a variety of other mediators Pain released by cells of the innate and acquired immune sys- Smooth-muscle chemotaxis tems trigger or enhance specific aspects of the inflammatory contraction platelets, and a variety of leukocytes, including neutrophils, FIGURE 15-10 Tissue damage induces formation of plasma en. monocytes/macrophages, eosinophils, basophils, and phocytes. In addition to these sources, plasma contains four rinolytic system. These mediators cause vascular changes, among interconnected mediator-producing systems: the kinin sys- the earliest signs of inflammation, and various other effects. Plasmin tem, the clotting system, the fibrinolytic system, and the not only degrades fibrin clots but also activates the classical comple- complement system. The first three systems share a common ment pathway. diate, Hageman factor, as illustrated in Figure 1 When tissue damage occurs, these four systems are activated to form a web of interacting systems that generate a number of mediators of inflammatio insoluble fibrin strands crisscross one another to form a clot The Kinin System Is Activated which serves as a barrier to the spread of infection. The clot by Tissue Injury ting system is triggered very rapidly after tissue injury to pre- ding and limit ad of invading The kinin system is an enzymatic cascade that begins when a into the bloodstream. The fibrinopeptides act as inflamma- plasma clotting factor, called Hageman factor, is activated tory mediators, inducing increased vascular permeability following tissue injury. The activated Hageman factor then and neutrophil chemotaxis activates prekallikrein to form kallikrein, which cleaves kininogen to produce bradykinin (see Figure 15-10). This The Fibrinolytic System Yields Plasmin inflammatory mediator is a potent basic peptide that in- Generated Mediators of Inflammation creases vascular permeability, causes vasodilation, induces pain, and induces contraction of smooth muscle. Kallikrein Removal of the fibrin clot from the injured tissue is achieved also acts directly on the complement system by cleaving C5 by the fibrinolytic system. The end product of this pathway into C5a and C5b. The C5a complement component is an is the enzyme plasmin, which is formed by the conversion of anaphylatoxin that induces mast-cell degranulation, result- plasminogen. Plasmin, a potent proteolytic enzyme, breaks ng in the release of a number of inflammatory mediators down fibrin clots into degradation products that are chemo- from the mast cell tactic for neutrophils. Plasmin also contributes to the in flammatory response by activating the classical complement The Clotting System Yields Fibrin-Generated pathway Mediators of Inflammation The Complement System Produces Another enzymatic cascade that is triggered by damage to Anaphylatoxins blood vessels yields large quantities of thrombin. Thrombin acts on soluble fibrinogen in tissue fluid or plasma to pro- Activation of the complement system by both classical and duce insoluble strands of fibrin and fibrinopeptides. The alternative pathways results in the formation of a number ofproduction of distinctive profiles of chemokines by destina￾tion tissues and sites provide rich opportunities for the dif￾ferential regulation of activities of different leukocyte popu￾lations. Indeed, differences in patterns of chemokine-receptor expression occur within leukocyte populations as well as be￾tween different ones. Recall that TH1 and TH2 subsets of TH cells can be distinguished by their different patterns of cyto￾kine production. These subsets also display different profiles of chemokine receptors. TH2 cells express CCR3 and -4, and a number of other receptors not expressed by TH1 cells. On the other hand, TH1 cells express CCR1, -3, and -5, but most TH2 cells do not. Other Mediators of Inflammation In addition to chemokines, a variety of other mediators released by cells of the innate and acquired immune sys￾tems trigger or enhance specific aspects of the inflammatory response. They are released by tissue mast cells, blood platelets, and a variety of leukocytes, including neutrophils, monocytes/macrophages, eosinophils, basophils, and lym￾phocytes. In addition to these sources, plasma contains four interconnected mediator-producing systems: the kinin sys￾tem, the clotting system, the fibrinolytic system, and the complement system. The first three systems share a common intermediate, Hageman factor, as illustrated in Figure 15-10. When tissue damage occurs, these four systems are activated to form a web of interacting systems that generate a number of mediators of inflammation. The Kinin System Is Activated by Tissue Injury The kinin system is an enzymatic cascade that begins when a plasma clotting factor, called Hageman factor, is activated following tissue injury. The activated Hageman factor then activates prekallikrein to form kallikrein, which cleaves kininogen to produce bradykinin (see Figure 15-10). This inflammatory mediator is a potent basic peptide that in￾creases vascular permeability, causes vasodilation, induces pain, and induces contraction of smooth muscle. Kallikrein also acts directly on the complement system by cleaving C5 into C5a and C5b. The C5a complement component is an anaphylatoxin that induces mast-cell degranulation, result￾ing in the release of a number of inflammatory mediators from the mast cell. The Clotting System Yields Fibrin-Generated Mediators of Inflammation Another enzymatic cascade that is triggered by damage to blood vessels yields large quantities of thrombin. Thrombin acts on soluble fibrinogen in tissue fluid or plasma to pro￾duce insoluble strands of fibrin and fibrinopeptides. The insoluble fibrin strands crisscross one another to form a clot, which serves as a barrier to the spread of infection. The clot￾ting system is triggered very rapidly after tissue injury to pre￾vent bleeding and limit the spread of invading pathogens into the bloodstream. The fibrinopeptides act as inflamma￾tory mediators, inducing increased vascular permeability and neutrophil chemotaxis. The Fibrinolytic System Yields Plasmin￾Generated Mediators of Inflammation Removal of the fibrin clot from the injured tissue is achieved by the fibrinolytic system. The end product of this pathway is the enzyme plasmin,which is formed by the conversion of plasminogen. Plasmin, a potent proteolytic enzyme, breaks down fibrin clots into degradation products that are chemo￾tactic for neutrophils. Plasmin also contributes to the in￾flammatory response by activating the classical complement pathway. The Complement System Produces Anaphylatoxins Activation of the complement system by both classical and alternative pathways results in the formation of a number of 348 PART III Immune Effector Mechanisms Bradykinin Kallikrein Kininogen Prekallikrein Activated fibrinolytic system Plasmin Activation of Hageman factor Fibrinopeptides + fibrin clot Fibrin degradation Thrombin Endothelial damage Activated clotting cascade ↑ Vascular permeability Vasodilation Pain Smooth-muscle contraction ↑Vascular permeability Neutrophil chemotaxis Complement activation FIGURE 15-10 Tissue damage induces formation of plasma en￾zyme mediators by the kinin system, the clotting system, and the fib￾rinolytic system. These mediators cause vascular changes, among the earliest signs of inflammation, and various other effects. Plasmin not only degrades fibrin clots but also activates the classical comple￾ment pathway