Biomedical Engineering Reference
In-Depth Information
Furthermore, neutrophil depletion (with a significant reduction in NE
activity) did not protect against smoke induced emphysema while macro-
phage depletion (with normal neutrophil activity) did. These results ques-
tioned the importance of the neutrophil in the pathogenesis of COPD and
suggested that the macrophage was the only effector cell (at least in mice).
However, this view ignored the weight of evidence amassed over the past
three decades favoring the neutrophil and was overly simplistic. It seems
likely that in vivo, a combination of cells and chemoattractants is needed.
Bronchoalveolar lavage fluid from cigarette-exposed mice shows an
acute influx of neutrophils with evidence of both elastin and collagen degra-
dation in a dose dependent manner at 6 and 24 hr. This resolves by 48 hr
and can be reduced by neutrophil depletion or the administration of the ser-
ine proteinase inhibitor
a
1
-AT (177). Other animal models have also found
an early rise in neutrophil number and activity, and a corresponding rise in
matrix breakdown products after exposure to cigarette smoke (114). In these
studies, NE inhibitors reduce TNF-
a
and emphysema by ~30%, but only if
given at the start of exposure. When NE inhibitors are given after 4 months
of exposure, these effects are not seen. The TNF-
a
receptor knock-out mice
are also protected from the acute neutrophil infiltrate and connective tissue
breakdown seen following cigarette smoke exposure in wild-type mice (192).
Therefore, both neutrophils and TNF-
a
appear important.
Cigarette smoke exposed MMP-12 knock-out mice did not display the
early neutrophilic infiltrate or the release of desmosine and hydroxyproline
(matrix breakdown products) that are characteristic of wild-type mice,
although macrophage infiltration did occur (albeit at lower levels). When
MMP-12 knock-out mice underwent intratracheal instillation of normal
macrophages, a neutrophil influx was seen. Use of an MMP inhibitor also pre-
vented a neutrophilic infiltrate and subsequent matrix breakdown (192). Later
studies demonstrated that cigarette smoke induced production of TNF-
a
from
alveolar macrophages in wild-type mice, but not in MMP-12 knock-out mice.
Interestingly, levels of TNF-
a
mRNA were the same in both groups and it was
surmised that MMP-12 processes TNF-
a
after secretion. Thus, it is likely that
MMP-12 is needed to activate TNF-
a
which in turn initiates neutrophil
recruitment, leading to degranulation and tissue damage (Fig. 6).
When interpreting results from in vitro work and animal models, one
must consider that there may be important variations in the pathogenesis of
COPD between cell types and differing species, and indeed, conflicting
results are common. However, it seems likely that neutrophil infiltration
remains at least an early event and appears to be a precursor to the patho-
logical changes seen. Macrophages seem central to neutrophil recruitment,
probably via activation of TNF-
a
, and may be needed to sustain the inflam-
matory process and hence emphysema. The studies have not provided a
means of studying the effects of other complex processes, such as the
recurrent exacerbations in COPD, or the effect of smoking cessation and
