Biology Reference
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large amounts, interact with specific cell receptors and induce the production of
various inflammatory mediators. These mediators include cytokines; products of the
plasma enzyme systems (complement, the coagulation system, kinin, and fibrinolytic
pathways); lipid mediators (prostaglandins and leukotrienes) released from tissue
cells or macrophages; and vasoactive mediators released from mast cells, basophils,
and platelets. These inflammatory mediators control different types of inflammatory
reactions. Fast-acting mediators, such as vasoactive amines and the products of the
kinin system, modulate the immediate response. Later, newly synthesized mediators
such as leukotrienes become involved in the accumulation and activation of other
cells. Though of obvious benefit and even life saving on occasion, inflammation is a
two-edged sword, with undesirable consequences such as systemic shock and circu-
latory collapse, wasting if prolonged, and local tissue injury in many organs
[2,3,29]
.
Therefore, a crucial commitment in immunological inflammation is to convert the
response from the antibacterial, tissue-damaging mode to a mode that promotes tis-
sue repair and epithelial closure. This transformation begins as complement, neutro-
phils, and macrophages kill microbes, and macrophages secrete more serine protease
inhibitor (SLPI), a serine protease inhibitor expressed late after exposure to micro-
bial products or cytokines. SLPI has anti-inflammatory and wound-healing effects.
Furthermore, SLPI binds and synergizes with proepithelin, a cytokine that promotes
epithelial growth and suppresses neutrophil activation, protecting it from proteolytic
conversion into pro-inflammatory epithelins. Furthermore, macrophages ingest apop-
totic neutrophils and degrade their residual stores of elastase. The ingestion of apop-
totic neutrophils induces in macrophages production of the anti-inflammatory and
tissue-repair cytokine TGF-
[3,30-32]
. To control the potentially harmful pro-in-
flammatory response, the immune system releases further anti-inflammatory media-
tors such as IL-10, IL-1 receptor antagonist (ra), and soluble TNF receptors, which
either inhibit the production of (e.g., IL-10), neutralize (e.g., soluble TNF- recep-
tors 1 (p55) and 2 (p75)), or competitively antagonize (IL-1ra) pro-inflammatory
mediators
[31,33,34]
. Interestingly, TNF-, IL-1, and PG by themselves are power-
ful inducers of the compensatory anti-inflammatory response syndrome (CARS).
In addition to the auto-regulatory pathways of the immune cells, the delicate bal-
ance between pro- and anti-inflammatory responses is controlled by brain-dependent
“central” mechanisms. However, in contrast to neurogenic inflammation, where
inflammation is mediated by a spinal reflex, the counter-regulatory inflammatory
reflex involves the brain. Under these circumstances, inflammatory stimuli activate
sensory pathways that relay information to the hypothalamus and brainstem and lead
to activation of a brain-mediated anti-inflammatory response that is fast and subcon-
scious (
Figure 8.1
). This should prevent spillage of inflammatory products into the
circulation. Tracey described the neural control of acute local inflammation as reflex-
ive, directly interconnected, and controllable
[29,35]
.
The inflammation-sensing pathways can activate responses even when the inflam-
matory agents are present in tissues in quantities that are not high enough to reach
the brain through the bloodstream. This type of response involves the expression
of pro-inflammatory cytokines such as IL-1, TNF-, and IL-6 in the periphery.
The mechanisms by which local inflammation can affect brain function have been
