DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

960 face of environmental pathogens and injury; in some
situations and diseases, the inflammatory response may
be exaggerated and sustained without apparent benefit
and even with severe adverse consequences. No matter
what the initiating stimulus, the classic inflammatory
symptoms include calor (warmth), dolor (pain), rubor
(redness), and tumor (swelling). The inflammatory
response is characterized mechanistically by a transient
local vasodilation and increased capillary permeability,
infiltration of leukocytes and phagocytic cells, and tissue
degeneration and fibrosis.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Many molecules are involved in the promotion and resolution
of the inflammatory process (Nathan, 2002). Histamine was one
of the first identified mediators of the inflammatory process.
Although several H 1
histamine receptor antagonists are available,
they are useful only for the treatment of vascular events in the early
transient phase of inflammation (see Chapter 32). Bradykinin and
5-hydroxytryptamine (serotonin, 5-HT) also may play a role, but
their antagonists ameliorate only certain types of inflammatory
response (see Chapter 32). Leukotrienes (LTs) exert pro-inflammatory
actions and LT-receptor antagonists (montelukast and zafirlukast)
and have been approved for the treatment of asthma (see
Chapters 33 and 36). Another lipid autacoid, platelet-activating factor
(PAF), has been implicated as an important mediator of inflammation;
however, inhibitors of PAF synthesis and PAF-receptor
antagonists have proven disappointing in the treatment of inflammation
(see Chapter 33).
Prostanoid biosynthesis is significantly increased
in inflamed tissue. Inhibitors of the COXs, which
depress prostanoid formation, are effective and widely
used anti-inflammatory agents, highlighting the general
role of prostanoids as pro-inflammatory mediators. The
rapid induction of COX-2 in inflamed tissue and infiltrating
cells provided a rationale for the development
of selective COX-2 inhibitors for treatment of inflammation
(see Chapter 33). Although COX-2 is the major
source of pro-inflammatory prostanoids, COX-1 also
contributes (McAdam et al., 2000). Both COX
isozymes are expressed in circulating inflammatory
cells ex vivo, and COX-1 accounts for ~10-15% of the
PG formation induced by lipopolysaccharide in volunteers.
Impaired inflammatory responses have been
reported in both COX-1- and COX-2-deficient mouse
models, although they diverge in time course and intensity
(Langenbach et al., 1999; Ballou et al., 2000; Yu
et al., 2005). Human data are compatible with the concept
that COX-1-derived products play a dominant role
in the initial phase of an acute inflammatory response,
while COX-2 is upregulated within several hours.
Prostaglandin E 2
(PGE 2
) and prostacyclin (PGI 2
)
are the primary prostanoids that mediate inflammation.
They increase local blood flow, vascular permeability,
and leukocyte infiltration through activation of their
respective receptors, EP 2
and IP (see Table 33–1 and
Figure 33–4). PGD 2
, a major product of mast cells, contributes
to inflammation in allergic responses, particularly
in the lung. Activation of its DP 1
receptor
increases perfusion and vascular permeability and promotes
T H
2 cell differentiation. PGD 2
also can activate
mature T H
2 cells and eosinophils via its DP 2
receptor
(Pettipher et al., 2007). DP 2
antagonists may prove useful
in the treatment of airway inflammation.
Activation of endothelial cells plays a key role in
“targeting” circulating cells to inflammatory sites. Cell
adhesion occurs by recognition of cell-surface glycoproteins
and carbohydrates on circulating cells due to
the augmented expression of adhesion molecules on
resident cells. Thus, endothelial activation results in
leukocyte adhesion as the leukocytes recognize newly
expressed L- and P-selectin; other important interactions
include those of endothelial-expressed E-selectin
with sialylated Lewis X and other glycoproteins on the
leukocyte surface and endothelial intercellular adhesion
molecule (ICAM)-1 with leukocyte integrins.
The recruitment of inflammatory cells to sites of
injury also involves the concerted interactions of several
types of soluble mediators. These include the complement
factor C5a, PAF, and the eicosanoid LTB 4
(see
Chapter 33). All can act as chemotactic agonists.
Several cytokines also play essential roles in orchestrating
the inflammatory process, especially tumor necrosis
factor (TNF) (Dempsey et al., 2003) and
interleukin-1 (IL-1) (O’Neill, 2008). They are secreted
by monocytes, macrophages, adipocytes, and other
cells. Working in concert with each other and various
cytokines and growth factors (such as IL-6, IL-8, and
granulocyte-macrophage colony-stimulating factor
[GM-CSF]; see Chapters 32, 33, and 35), they induce
gene expression and protein synthesis—including
expression of COX-2, adhesion molecules, and acutephase
proteins—in a variety of cells to mediate and promote
inflammation.
TNF is composed of two closely related proteins: mature
TNF (TNF-α) and lymphotoxin (TNF-β), both of which are recognized
by the TNF receptors, a 75-kd type 1 receptor and a 55-kd type 2
receptor (Dempsey et al., 2003). TNF-α blockers (see Chapter 35)
are used to treat inflammatory conditions, including rheumatoid
arthritis, juvenile idiopathic arthritis, psoriasis and psoriatic arthritis,
ankylosing spondylitis, and Crohn’s disease. TNF-α blockers fall
into the category of disease-modifying anti-rheumatic drugs
(DMARDs) because they reduce the disease activity of rheumatoid
arthritis and retard the progression of arthritic tissue destruction.
NSAIDs generally are not considered DMARDs.