Biomedical Engineering Reference
In-Depth Information
patients with COPD and correlates with numbers of neutrophils (75,76).
The concentrations of IL-8 are significantly higher in smokers with emphy-
sema than in matched smokers without airflow limitation, whereas the
concentrations of other CXC chemokines in BAL do not appear to
discriminate between these groups (77).
The cellular source of IL-8 in COPD is not completely certain. Airway
epithelial cells secrete IL-8 in response to several stimuli, including TNF-
a
and cigarette smoke extract (78-80). The IL-8 protein and mRNA are
increased in bronchiolar epithelial cells of patients with COPD (81) and
there is increased basal release of IL-8 from airway epithelial cells of patients
with COPD (82,83). Alveolar macrophages also secrete IL-8 in response to
the same stimuli and cells derived from patients with COPD secrete more
IL-8 than those from normal smokers who in turn secrete more than macro-
phages from normal nonsmokers (84). Neutrophils themselves also release
IL-8, and attract more neutrophils, so that a self-perpetuating inflammatory
state may be established (85). The secretion of IL-8 is regulated transcrip-
tionally by several transcription factors, amongst which NF-
k
B is predomi-
nant. NF-
k
B is activated in alveolar macrophages of patients with COPD
and is further activated during exacerbations (86,87).
Neutralization of IL-8 with a blocking antibody significantly reduces
the neutrophil chemotactic activity of sputum from patients with COPD
(20,24). The reduction in neutrophil chemotactic activity is only of the order
of
30%, however, indicating that other neutrophil chemotactic factors are
also involved and that blocking IL-8 alone may be insufficient as a therapeu-
tic strategy to reduce neutrophil inflammation in the respiratory tract.
The IL-8 acts via two receptors: CXCRl, which is a low affinity recep-
tor that is specific for IL-8, and CXCR2, which has high affinity and is
shared by other CXC chemokines (Fig. 3). It is likely that CXCR2 mediates
the chemotactic response of neutrophils and monocytes to IL-8, whereas
CXCRl may mediate the effects of IL-8 on release of mediators and
proteases. There is a marked up-regulation of CXCR2 in airway epithelial
cells during acute exacerbations of COPD and this is correlated with the
increased numbers of neutrophils in the airway (88).
B. Other CXC Chemokines
Growth-related oncogene-
a
(GRO-
a
, CXCL1) is another CXC chemokine
that is likely to be involved in COPD. The GRO-
a
activates neutrophils,
monocytes, basophils, and T lymphocytes via CXCR2 (89) (Fig. 4). The
concentrations of GRO-
a
markedly elevated in induced sputum and BAL
of patients with COPD compared to normal smokers and nonsmokers
(90) (Fig. 5). The GRO-
a
selectively activates CXCR2 and is chemotactic
for neutrophils and monocytes. There is an increase in the monocytes
chemotactic response to GRO-
a
in COPD patients and this may be related
