Other complement regulatory proteins proteolytically cleave active complement components. For instance, Factor H is a plasma protein that serves as a cofactor for the proteolysis of the C3 convertase; its deficiency results in excessive complement activation. Mutations in Factor H are associated with a kidney disease called the hemolytic uremic syndrome (Chapter 14), as well as increased permeability of retinal vessels in wet macular degeneration of the eye.
The complement system contributes to disease in several ways. The activation of complement by antibodies or antigen–antibody complexes deposited on host cells and tissues is an important mechanism of cell and tissue injury (Chapter 5). Inherited deficiencies of complement proteins cause increased susceptibility to infections, and, as mentioned earlier, deficiencies of regulatory proteins cause a variety of disorders.
Other Mediators of Inflammation
PAF is a phospholipid-derived mediator that was discovered as a factor that caused platelet aggregation, but it is now known to have multiple inflammatory effects. A variety of cell types, including platelets themselves, basophils, mast cells, neutrophils, macrophages, and endothelial cells, can elaborate PAF. In addition to platelet aggregation, PAF causes vasoconstriction and bronchoconstriction, and at low concentrations it induces vasodilation and increased vascular permeability. Despite these documented actions, trials of PAF antagonists in various inflammatory conditions have been disappointing.
Products of Coagulation
Studies performed more than 50 years ago suggested that inhibiting coagulation reduced the inflammatory reaction to some microbes, leading to the idea that coagulation and inflammation are linked processes. This concept was supported by the discovery of protease-activated receptors (PARs), which are activated by thrombin (the protease that cleaves fibrinogen to produce a fibrin clot). PARs are expressed on leukocytes, suggesting a role in inflammation, but their clearest role is in platelets, in which thrombin activation of a PAR known as the thrombin receptor is a potent trigger of platelet aggregation during the process of clot formation (Chapter 4). In fact, it is difficult to dissociate clotting and inflammation, because virtually all forms of tissue injury that lead to clotting also induce inflammation, and inflammation causes changes in endothelial cells that increase the likelihood of abnormal clotting (thrombosis, described in Chapter 4). Whether the products of coagulation, per se, have a significant role in stimulating inflammation is still not established.
Kinins are vasoactive peptides derived from plasma proteins, called kininogens, by the action of specific proteases called kallikreins. The enzyme kallikrein cleaves a plasma glycoprotein precursor, high-molecular-weight kininogen, to produce bradykinin. Bradykinin increases vascular permeability and causes contraction of smooth muscle, dilation of blood vessels, and pain when injected into the skin. These effects are similar to those of histamine. The action of bradykinin is short-lived, because it is quickly inactivated by an enzyme called kininase. Bradykinin has been implicated as a mediator in some forms of allergic reaction, such as anaphylaxis.
Neuropeptides are secreted by sensory nerves and various leukocytes, and may play a role in the initiation and regulation of inflammatory responses. These small peptides, including substance P and neurokinin A, are produced in the central and peripheral nervous systems. Nerve fibers containing substance P are prominent in the lung and gastrointestinal tract. Substance P has many biologic functions, including the transmission of pain signals, regulation of blood pressure, stimulation of hormone secretion by endocrine cells, and in increasing vascular permeability.