Biomedical Engineering Reference
In-Depth Information
blockade of chemokine receptors CCR2, CCR5, and CXCR3 protects mice from
experimental colitis [9]. Importantly, MCP-1 has been shown to regulate the balance
between pro- and antiinflammatory cytokines in a murine model of septic shock
[10], which is consistent with a role for macrophages in mediating as well as
resolving inflammation.
In vivo
, local increases in COX-2 gene expression are associated with inflam-
mation and inflammatory diseases [11]. COX-1, which is constitutively expressed,
and COX-2, which is inducibly expressed downstream of inflammatory mediators,
are responsible for prostaglandin H
2
biosynthesis from arachidonic acid. COX prod-
ucts, mainly PGE
2
, modulate the classic signs of inflammation [11].
The traditional proinflammatory cytokines TNF
α
and IL-1 are elevated in inflam-
matory lesions. TNF
is a key mediator in the host's response against bacteria and
other pathogens [12]. Mice deficient for TNF receptor 1 are resistant to lethal doses
of LPS but are severely impaired in their ability to clear
L.
monocytogenes
and easily
succumb to infection [13]. IL-1 induces tissue factor production, thus triggering the
clotting cascade, and induces systemic hormonal effects that induce fever [14]. IL-1
mediates inflammation by recruitment of neutrophils, activation of macrophages,
and stimulation of T and B cell proliferation and differentiation [15]. Other potent
inflammatory mediators include the leukotrienes, which are produced by the
5-lipoxygenase pathway downstream of arachidonic acid production [16].
Treatment for inflammation typically involves the utilization of steroidal com-
pounds, such as hydrocortisone or dexamethasone (or derivatives), or nonsteroidal
antiinflammatory drugs (NSAIDs) [11,17]. Given that TNF
α
is a crucial cytokine
in the establishment and maintenance of inflammation, it was logical to target TNF
as a therapeutic approach for several inflammatory diseases. Infliximab and etaner-
cept, two injectable biologic TNF-blocking drugs, have shown efficacy in rheumatoid
arthritis and Crohn's disease [18], and trials are underway for the use of these drugs
in other inflammatory diseases.
α
2-adrenergic agonists have antiinflammatory effects
based on the fact that neutrophils, monocytes, and macrophages express
β
2-receptors
[19]. Additionally, statin compounds function as antiinflammatory compounds inde-
pendent of their ability to modulate cholesterol levels [20, 21].
β
8.1.2
R
ESOLUTION
OF
I
NFLAMMATION
Except under conditions of chronic inflammation and disease, inflammation
resolves through a series of recently identified mechanisms. For example, evidence
has been presented that COX-2, which has proinflammatory functions related to
the production to prostaglandin PGE
2
, also has antiinflammatory functions (see
Figure 8.3
)
. In these studies, COX 2 expression occurred at 2 hours following
inflammatory stimulus, and this coincided with elevated PGE
2
and a proinflamma-
tory response [22]. COX-2 expression reoccurred at 48 hours, coinciding with
minimal PGE
2
but elevated cyclopentonone prostaglandin 15d-PGJ
2
; 15d-PGJ
2
is
now known to be the endogenous ligand for the nuclear receptor PPAR
[23].
Interestingly, cyclopentonone prostaglandins appear to serve as antiinflammatory
mediators and to promote resolution of inflammation
in vivo
[22]. Thus, 15d-PGJ
2
is proposed to be an antiinflammatory prostaglandin through its ability to signal
γ
