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and neuropeptides and produce cytokines. In this context, neurogenic inflammation
seems to be less than fully independent of the immune system. Moreover, most cells
expressing receptors for neuropeptides also generate the neuropeptide-degrading
peptidases neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE),
thereby terminating the inflammatory stimulus (see below). Similarly, cells synthe-
sizing receptors for the neurotransmitters acetylcholine and noradrenaline also gen-
erate enzymes that control the effects of these molecules. Thus, a close interaction
between neuromediators, target cell receptors, and neuropeptide-degrading enzymes
is critical for controlling neurogenic and immunological inflammation
[15]
.
Finally, recent findings suggest that classic autonomic neurotransmitters, cyto-
kines as well as neuropeptides, can also be generated by nonneuronal and nonimmune
cells such as keratinocytes, astrocytes, endothelial cells, alveolar cells, and the like.
Interestingly, there is histological evidence of the presence of cytokines, especially
IL-6, within both sensory and autonomic nerves. The release of the pro-inflammatory
cytokines with nervous discharge provides a powerful stimulus for inflammatory
immune cells in the areas affected to amplify immune response, and indicates a fur-
ther linkage between neurogenic and immunological stimulation
[7,16]
. This demon-
strates the complex interaction among tissue, neural, and immune cells in initiation,
amplification, and termination of an inflammatory signal (
Figure 8.1
).
Consequently, as already mentioned, the distinction between neurogenic and
immunological inflammation seems to be limited to the catalysts, because the two
types cross over after the release of mediators. For instance, it seems that chemical
toxins (e.g., cigarette smoke) may stimulate chemosensitive sensory nerve endings,
whereas bacterial material (e.g., LPS) may activate immune cells (especially mac-
rophages), and mechanical injury or ischemia may at first affect local tissue cells
(
Figure 8.1
). However, crossovers will follow.
Furthermore, the clinical appearance of neurogenic and immunological inflamma-
tion is not identical in all cases. In the upper airways and skin, the initial complaint
associated with exposure to chemical irritants is burning or pain, whereas itching is the
initial complaint associated with immune-mediated exposures. It may be that there is
individual variability in the degree to which crossover is clinically manifested
[6,17]
.
Progress has been made in understanding the regulation of neurogenic inflamma-
tion. Recent studies indicate that NEP and ACE play an important role in down-reg-
ulation of neurogenic inflammation. Although ACE is capable of degrading SP, NEP
additionally cleaves the neuropeptides NK-A, NK-B, VIP, PACAP, atrial natriuretic
peptide, and endothelins. Both NEP and ACE have been identified in different tissue
cells (skin, lung, mucosa, CNS, etc.).
In vivo
studies using NEP knockout mice dem-
onstrated a significant increase of plasma extravasation and cutaneous inflammation.
Maximal inflammation occurred 6 hours after challenge in a model of experimen-
tally induced contact dermatitis, which confirms the anti-inflammatory role of NEP
[17,18]
. Similar effects on cutaneous inflammation (contact hypersensitivity) were
observed for ACE. These findings imply that up-regulation of NEP is a potential ther-
apeutic approach to limit the effects of neurogenic inflammation. Down-regulation of
NEP and ACE may result in an uncontrolled stimulation of neuropeptides and lead to
chronic inflammation
[15]
.
