Page 65 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster
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The complement-derived factors that are produced along Chemical Mediators and Regulators of Inflammation 51
the way contribute to a variety of phenomena in acute
inflammation: • A protein called C1 inhibitor blocks activation of C1, and
its inherited deficiency causes a disease called heredi-
• Vascular effects. C3a and C5a increase vascular permea- tary angioedema, in which excessive production of
bility and cause vasodilation by inducing mast cells to kinins secondary to complement activation results in
release histamine. These complement products are also edema in multiple tissues, including the larynx.
called anaphylatoxins because their actions mimic those
of mast cells, which are the main cellular effectors of the • Another protein called decay-accelerating factor (DAF)
severe allergic reaction called anaphylaxis (Chapter 4). normally limits the formation of C3 and C5 convertases.
C5a also activates the lipoxygenase pathway of AA In a disease called paroxysmal nocturnal hemoglobinuria,
metabolism in neutrophils and macrophages, causing there is an acquired deficiency of DAF that results in
release of more inflammatory mediators. complement-mediated lysis of red cells (which are more
sensitive to lysis than most nucleated cells) (Chapter 11).
• Leukocyte activation, adhesion, and chemotaxis. C5a, and to
lesser extent, C3a and C4a, activate leukocytes, increas- • Factor H is a plasma protein that also limits convertase
ing their adhesion to endothelium, and is a potent che- formation; its deficiency is associated with a kidney
motactic agent for neutrophils, monocytes, eosinophils, disease called the hemolytic uremic syndrome (Chapter
and basophils. 13), as well as spontaneous vascular permeability in
macular degeneration of the eye.
• Phagocytosis. When fixed to a microbial surface, C3b and
its inactive proteolytic product iC3b act as opsonins, Even in the presence of regulatory proteins, inappropriate
augmenting phagocytosis by neutrophils and macro- or excessive complement activation (e.g., in antibody-
phages, which express receptors for these complement mediated diseases) can overwhelm the regulatory mecha-
products. nisms; this is why complement activation is responsible for
serious tissue injury in a variety of immunologic disorders
• The MAC, which is made up of multiple copies of the (Chapter 4).
final component C9, kills some bacteria (especially thin- Coagulation and Kinin Systems
walled Neisseria) by creating pores that disrupt osmotic Some of the molecules activated during blood clotting are
balance. capable of triggering multiple aspects of the inflammatory
response. Hageman factor (also known as factor XII of the
The activation of complement is tightly controlled by cell- intrinsic coagulation cascade) (Fig. 2–19) is a protein synthe-
associated and circulating regulatory proteins. The presence of sized by the liver that circulates in an inactive form until it
these inhibitors in host cell membranes protects normal encounters collagen, basement membrane, or activated
cells from inappropriate damage during protective reac- platelets (e.g., at a site of endothelial injury). Activated
tions against microbes. Inherited deficiencies of these Hageman factor (factor XIIa) initiates four systems that
regulatory proteins lead to spontaneous complement may contribute to the inflammatory response: (1) the kinin
activation: system, producing vasoactive kinins; (2) the clotting
Cofactor: XII Factor XII (Hageman factor)
HMWK Collagen, basement membrane,
activated platelets
XIIa Factor XIIa
Kinin Kallikrein Prekallikrein Clotting factors Clotting
cascade cascade
HMWK Bradykinin Thrombin
Plasminogen Plasmin Fibrin Fibrinogen
Fibrinolytic Fibrin-split products
system
C3 C3a
Complement
cascade
C5 C5a
Figure 2–19 Interrelationships among the four plasma mediator systems triggered by activation of factor XII (Hageman factor). See text for details.
