Page 66 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

52 C H A P T E R 2 Inflammation and Repair
system, inducing the activation of thrombin, fibrinopep-
tides, and factor X, all with inflammatory properties; (3) the
fibrinolytic system, producing plasmin and inactivating
thrombin; and (4) the complement system, producing the
anaphylatoxins C3a and C5a. These are described below.
• Kinin system activation leads ultimately to the formation
of bradykinin from its circulating precursor, high-
molecular-weight kininogen (HMWK) (Fig. 2–19). Like
histamine, bradykinin causes increased vascular perme-
ability, arteriolar dilation, and bronchial smooth muscle
contraction. It also causes pain when injected into the
skin. The actions of bradykinin are short-lived because
it is rapidly degraded by kininases present in plasma
and tissues. Of note, kallikrein, an intermediate in the
kinin cascade with chemotactic activity, also is a potent
activator of Hageman factor and thus constitutes another
link between the kinin and clotting systems.
• In the clotting system (Chapter 3), the proteolytic cascade
leads to activation of thrombin, which then cleaves cir-
culating soluble fibrinogen to generate an insoluble
fibrin clot. Factor Xa, an intermediate in the clotting
cascade, causes increased vascular permeability and
leukocyte emigration. Thrombin participates in inflam-
mation by binding to protease-activated receptors that
are expressed on platelets, endothelial cells, and many
other cell types. Binding of thrombin to these receptors
on endothelial cells leads to their activation and
enhanced leukocyte adhesion. In addition, thrombin
generates fibrinopeptides (during fibrinogen cleavage)
that increase vascular permeability and are chemotactic
for leukocytes. Thrombin also cleaves C5 to generate
C5a, thus linking coagulation with complement
activation.
• As a rule, whenever clotting is initiated (e.g., by acti-
vated Hageman factor), the fibrinolytic system is also acti-
vated concurrently. This mechanism serves to limit
clotting by cleaving fibrin, thereby solubilizing the fibrin
clot (Chapter 3). Plasminogen activator (released from
endothelium, leukocytes, and other tissues) and kalli-
krein cleave plasminogen, a plasma protein bound up in
the evolving fibrin clot. The resulting product, plasmin,
is a multifunctional protease that cleaves fibrin and is
therefore important in lysing clots. However, fibrinoly-
sis also participates in multiple steps in the vascular
phenomena of inflammation. For example, fibrin degra-
dation products increase vascular permeability, and
plasmin cleaves the C3 complement protein, resulting in
production of C3a and vasodilation and increased vas-
cular permeability. Plasmin can also activate Hageman
factor, thereby amplifying the entire set of responses.
As is evident from the preceding discussion, many mole-
cules are involved in different aspects of the inflammatory
reaction, and these molecules often interact with, amplify,
and antagonize one another. From this almost bewildering
potpourri of chemical mediators, it is possible to identify
the major contributors to various components of acute
inflammation (Table 2–7). The relative contributions of
individual mediators to inflammatory reactions to different
stimuli have yet to be fully elucidated. Such knowledge
would have obvious therapeutic implications since it might
allow one to “custom design” antagonists for various
inflammatory diseases.
Table 2–7 Role of Mediators in Different Reactions of Inflammation
Inflammatory Mediators
Component
Vasodilation Prostaglandins
Nitric oxide
Histamine
Increased vascular Histamine and serotonin
permeability C3a and C5a (by liberating vasoactive
amines from mast cells, other cells)
Bradykinin
Leukotrienes C4, D4, E4
PAF
Substance P
Chemotaxis, leukocyte TNF, IL-1
recruitment and activation Chemokines
C3a, C5a
Leukotriene B4
Bacterial products (e.g., N-formyl
methyl peptides)
Fever IL-1, TNF
Prostaglandins
Pain Prostaglandins
Bradykinin
Tissue damage Lysosomal enzymes of leukocytes
Reactive oxygen species
Nitric oxide
IL-1, interleukin-1; PAF, platelet-activating factor; TNF, tumor necrosis factor.
S U M M A RY
Plasma Protein–Derived Mediators of Inflammation
• Complement proteins: Activation of the complement
system by microbes or antibodies leads to the generation
of multiple breakdown products, which are responsible
for leukocyte chemotaxis, opsonization and phagocytosis
of microbes and other particles, and cell killing.
• Coagulation proteins: Activated factor XII triggers the
clotting, kinin, and complement cascades and activates the
fibrinolytic system.
• Kinins: Produced by proteolytic cleavage of precursors,
this group mediates vascular reaction and pain.
Anti-inflammatory Mechanisms
Inflammatory reactions subside because many of the medi-
ators are short-lived and are destroyed by degradative
enzymes. In addition, there are several mechanisms that
counteract inflammatory mediators and function to limit or
terminate the inflammatory response. Some of these, such
as lipoxins, and complement regulatory proteins, have
been mentioned earlier. Activated macrophages and other
cells secrete a cytokine, IL-10, whose major function is to
down-regulate the responses of activated macrophages,
thus providing a negative feedback loop. In a rare inherited
disease in which IL-10 receptors are mutated, affected
patients develop severe colitis in infancy. Other anti-
inflammatory cytokines include TGF-β, which is also a
mediator of fibrosis in tissue repair after inflammation.
Cells also express a number of intracellular proteins, such
as tyrosine phosphatases, that inhibit pro-inflammatory