Biomedical Engineering Reference
In-Depth Information
these effects (58). Substance P stimulates secretion from human airways in
vitro and this effect is mediated via NK
1
-receptors (59). In porcine airways
tachykinins elicit submucosal gland section via NK
1
receptors in gland cells,
but also via NK
3
receptors on cholinergic nerve terminal (60).
V. CHEMOKINES
Over 50 different chemokines are now recognized and they activate up to 20
different surface receptors (61). Chemokine receptors belong to the 7 trans-
membrane receptor superfamily of G-protein-coupled receptors and this
makes it possible to find small molecule inhibitors, which have not yet been
possible for classical cytokine receptors (62). Some chemokines appear to be
selective for single chemokine receptors, whereas others are promiscuous
and mediate the effects of several related chemokines. Four different
families of chemokines are now differentiated, based on differences in the
position of critical cysteine residues; CC, CXC, C, and CX
3
C chemokines
are recognized. Each chemokine molecule binds to a single or several recep-
tors expressed on target inflammatory cells, resulting in the activation of
signal transduction pathways that then result in chemotaxis or other cellular
activities that include proliferation, differentiation, and survival. Chemo-
kines appear to act in sequence in determining the final inflammatory
response and so inhibitors may be more or less effective depending on the
kinetics of the response (63).
Chemokines play a critical role in orchestrating inflammatory and
immune responses by regulating the trafficking of inflammatory and
immune cells to target organs (64). Several chemokines are involved in the
recruitment of inflammatory cells in COPD (65). There is considerable
interest in identifying chemokines in COPD as small molecule chemokine
receptor inhibitors are now in development for COPD (66,67).
A.
Interleukin-8
The CXC chemokine IL-8 (CXCL8) is a potent chemoattractant of neutro-
phils and it is not surprising that it has been implicated in COPD. The IL-8
levels are markedly increased in induced sputum of patients with COPD and
correlate with the increased proportion of neutrophils (68,69). The concen-
trations of IL-8 are even more elevated in patients with emphysema due to
a
l-antitrypisn deficiency (70). The concentrations of IL-8 in induced sputum
are further increased during acute exacerbations, which presumably contri-
bute to the increased numbers of neutrophils and the increased purulence of
the sputum (24,71,72). There is a correlation between IL-8 concentrations
and the bacterial colony count in sputum, indicating that bacterial infection
may induce neutrophilic inflammation, at least in part, via induction of IL-8
release in the airways (73,74). The IL-8 is also increased in BAL fluid of
