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290 Part IV: Molecular and Cellular Hematology Chapter 19: The Inflammatory Response 291

IgA aggregates, endotoxin, cobra venom factor, and polysaccharide PROTEINASE-ACTIVATED RECEPTORS
moieties found on some bacterial and fungal cell walls. The third path- Proteinase-activated receptors (PARs) define an important general
way, the “mannan-binding” lectin (MBL) pathway, is activated when mechanism that links several seemingly disparate regulatory systems
MBL binds to a microorganism coated with certain carbohydrate moi- involved in inflammation. PARs subsume a G-protein–coupled recep-
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eties (e.g., mannans). Upon binding, MBL activates MBL-associated tor subfamily defined by a common activation mechanism. Individual
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serine proteases (e.g., MASP-1, MASP-2) which function in a manner PARs include an N-terminal extracellular domain, seven transmem-
analogous to C1r and C1s of the classical pathway. MBL recognizes brane helices connected by three intracellular and three extracellular
carbohydrate moieties infrequently present in mammalian hosts, thus loops, and linkage to cytosolic G-protein–mediated signal transduction
constituting a system for recognizing foreign particulates. As such, the pathways. PARs are activated when extracellular proteinases cleave the
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alternative and MBL pathways are considered to be part of the innate N-terminal extracellular domain at a specific site which results in the
6
system of host defense. The classical pathway is initiated by the fixation creation of a “tethered ligand.” The tethered ligand is the residual, now
of C1 (C1qr s ) by the Fc portion of surface-bound IgG or IgM immu- unmasked N-terminal portion of the PAR; it interacts with the nearby
2 2
noglobulins. Activated C1 (C1qr s ) cleaves C2 and C4, which leads to nontruncated extracellular PAR domain and activates the receptor. The
2 2
the formation of the “classical pathway” C3 convertase, C4b2a. Activa- PAR family possesses of four members: PAR , PAR , PAR , and PAR .
tion of the alternative pathway results in the formation of an “alternative The extracellular domain of each PAR possesses several potential cleav-
2
3
4
1
pathway” C3 convertase following direct cleavage of C3 and subsequent age sites. For example, the canonical PAR tethered ligand sequence cre-
2+
interactions of C3b with factors B and D in the presence of Mg . The ated after cleavage by thrombin is the amino acid sequence, SFLLRN.
1
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resulting complex, C3bBb, is stabilized by properdin, leading to the A wide variety of proteinases that are pivotal in inflammation, throm-
stable C3 convertase, C3bBbP. C3 convertases generated via any of bosis, hemostasis, and wound healing (as well as in development and
the three pathways efficiently cleave C3 to form C3a and C3b. cancer progression) can activate PARs. PAR , PAR , and PAR are sus-
These enzymatic reactions exhibit high activity levels, thus serving ceptible to cleavage by thrombin. Other coagulation system-related pro-
1
3
4
to dramatically amplify the cascade. C3b can bind to either the classical teinases, such as factor Xa, activated protein C, plasmin, and kallikreins
or alternative pathway C3 convertase to form a C5 convertase, which can also activate PAR . Likewise, PAR can also be activated by matrix
cleaves C5 into C5a and C5b. C5a is released into the fluid phase, like metalloproteinase-1, neutrophil elastase, and neutrophil proteinase-3.
1
1
C3a, whereas C5b combines first with C6 and then C7 to form C5b- Various proteinases cleave the N-terminal extracellular domain of
7, which, in turn, binds with C8 and multiple C9 molecules to form PARs at different, yet specific, sites. Examples of PAR activation rele-
C5b-9, the membrane attack complex. In addition to the cell-activating vant to inflammation include thrombin-induced CCL2 expression in
and cytolytic activities of C5b-9, individual complement cleavage prod- osteoblasts and PAR and PAR activation in animal models of arthritis.
ucts and complexes mediate a variety of specific and potent proinflamma- A goal of rational therapeutic design is to target crosstalk interactions
2
4
tory activities. These functions, combined with the rapid amplification using paired drugs or bifunctional agents. Although no PAR-targeting
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in numbers of complement-derived mediators, emphasize the vital role compounds have yet come into clinical use, this is a promising area. 47
of complement in acute inflammation. The most important activation
products of complement appear to be C5a, a major chemotactic factor,
and the anaphylatoxins (C3a, C4a, C5a), of which C3a is the most abun- CHRONIC INFLAMMATION AND REPAIR
dant. C5b-9 is a major cytotoxic product, provided that this complex is
assembled on the surface of a susceptible cell (e.g., bacterium). The chronic inflammatory response and repair processes are, like the
A series of soluble and cell membrane-associated complement acute inflammatory response, highly regulated. By definition, “chronic”
proteins play important roles in the regulation of the complement cas- inflammation connotes a process that lasts at least several days and
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cade. The pivotal regulator of the proximal arm of classical pathway is more often, weeks to months, sometimes years. Chronic inflammation
C1 esterase inhibitor (C1E-INH), a serine protease inhibitor that cova- is characterized by the recruitment of mononuclear cells including lym-
lently bonds to the activated esterase subunits of the C1qrs complex thus phocytes, monocytes and plasma cells, as well as by the proliferation of
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preventing activation of the downstream zymogen cascade. Defects new capillaries (angiogenesis) and increases in the deposition of extra-
in C1E-INH, from genetic defects or those acquired (e.g., neutralizing cellular matrix. Replacement of damaged tissue by new small blood ves-
antibodies against C1E-INH), can result in angioedema. Angioedema sels and extracellular matrix constitutes a fundamental aspect of chronic
can manifest in a variety of ways including as life-threatening laryngeal inflammation and, simultaneously, is an integral part of wound healing
soft tissue swelling. and repair. The recruitment of this wide variety of cell types is achieved
by complex interactions among cytokines, chemokines and indigenous
cells. Great advances in understanding of angiogenesis and extracellular
COAGULATION SYSTEM matrix molecule metabolism have been made in recent years.
The coagulation system is reviewed in detail in Chaps. 113, 114, and Chronic inflammation can be caused by persistent infections with
116. The interrelationships among the coagulation system and several a wide variety of microorganisms (e.g., Treponema pallidum, Myco-
inflammatory mediator systems are important in the context of host bacterium tuberculosis). In contrast to highly virulent organisms that
defense and the pathophysiology of septic shock. Activation of the clot- trigger acute pyogenic infections (e.g., Streptococcus pneumoniae, Hae-
4
ting cascade results in the generation of fibrinopeptides which increase mophilus influenzae), organisms that induce chronic inflammation
vascular permeability and are chemotactic for leukocytes. Thrombin typically exhibit relatively low intrinsic toxicity, are poorly cleared and
and tissue factor induce endothelial expression of P-selectin, resulting may provoke a delayed-type hypersensitivity reaction. Chronic inflam-
in increased neutrophil adhesion. In addition, plasmin is responsible mation is also triggered by long-term exposure to insoluble exogenous
12
for the activation of Hageman factor, which then can activate the kinin particles (e.g., carbon dust, silica). The initiation of other chronic
2
system and can cleave C3 into its active components. It can also gen- inflammatory processes such as atherosclerosis and autoimmune dis-
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erate “fibrin-split” or “fibrin-degradation” products. The induction of eases (e.g., rheumatoid arthritis, systemic lupus erythematosus) is less-
tissue factor in endothelial cells exposed to TNF-α and IL-1β further well understood, but it is clear that a variety of environmental factors
links the coagulation system to the inflammatory response. (e.g., diet in atherosclerosis) and genetic factors (e.g., human leukocyte

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