Biomedical Engineering Reference
In-Depth Information
response to monocyte-selective chemokines produced in the lungs. The mon-
ocyte-selective chemokine monocyte chemoattractant protein-1 (MCP-1) is
increased in sputum and BAL of patients with COPD (12,13), with increased
expression in alveolar and small airway macrophages (14).
CXC chemokines also act as monocyte chemoattractants and act via
the low affinity chemokine receptor CXCR2. The concentration of the
CXC chemokine growth-related oncogene-
a
(GRO-
a
, CXCL1), which selec-
tively activates CXCR2, is markedly increased in sputum and BAL of
patients with COPD (12). Monocytes from patients with COPD show a
greater chemotactic response to GRO-
a
than cells from normal smokers
and nonsmokers, but this is not explained by an increase in CXCR2 density
(15). Interestingly, while all monocytes express CCR2, the receptor for
MCP-1, only
30% of monocytes express CXCR2. It is possible that these
CXCR2-expressing monocytes transform into macrophages that behave
differently - e.g., release more inflammatory proteins.
B. Macrophage Proliferation
The increased numbers of macrophages in COPD may be due to increased
recruitment of monocytes from the circulation, but may also be due to
increased proliferation and prolonged survival of macrophages in the lungs.
Macrophages have a very low proliferation rate in the lungs, but there is
some increase in cell proliferation measured by proliferative cell nuclear
antigen (PCNA) in macrophages from smokers compared to normal and
asthmatic macrophages, with approximately 5% of cells staining positive
in smokers compared with only 2% of cells in nonsmokers (16). These small
but significant differences could be important over time as macrophages
have a long survival in lung tissue. Alveolar macrophages also show signs
of increased proliferation in other chronic inflammatory lung diseases (17).
C. Macrophage Survival
Macrophages have a survival time of several months so this is difficult to
measure directly. There is a report of cigarette particulates in alveolar
macrophages over 2 years after cessation of smoking (18). In alveolar
macrophages from smokers, there is markedly increased expression of the
antiapoptotic protein Bcl-X
L
and increased expression of p2l
CIP
=
WAFI
in
the cytoplasm, which is associated with prolonged survival (16). This may
be secondary to oxidative stress which mimics these effects in vitro. This
suggests that macrophages may have a prolonged survival in the lungs of
smokers and patients with COPD. On the other hand, acute exposure of
rodent and human alveolar macrophages to cigarette smoke extract induces
apoptosis, an effect that is also mediated via oxidative stress (19). This
suggests that acute and chronic effects of cigarette smoking on macrophage
survival may differ.
