Neutrophils - Chronic Obstructive Pulmonary Disease - page 153

cells (165), and all of these effects are abrogated by NE inhibitors. Neutro-
phil elastase can also induce apoptosis of epithelial cells (166) and detach-
ment of bronchial epithelial cells from the extracellular matrix (167), and
both PR3 and NE induce detachment and apoptosis of endothelial cells
(168), which have been implicated in the pathogenesis of COPD (169).
The effects of NE on epithelial and endothelial cells and the extracellular
matrix are, therefore, likely to be important in the pathogenesis of COPD.
Recent work has shown that NE activity relates to sputum purulence
(which is due to MPO and can be graded visually) (45). During bacterial
exacerbations of COPD, sputum purulence and hence neutrophil influx
and NE activity increase (45), and therefore it is likely that proteinase-
induced damage also increases. Indirectly, this is supported by the finding
that tissue degradation product release is increased during the episodes
and that the frequency of exacerbations relates to the decline in lung func-
tion (170,171).
Animal studies have also studied the effects of smoke exposure and
proteinases on the lung. Neutrophil elastase knock-out mice are only
partially protected (45%) against the development of emphysema (172).
However, these models are limited, as CG and PR3 persist, and CG has
been shown to cause secretory cell metaplasia (141) and PR3 causes both
emphysema and secretory cell metaplasia (173).
If NE is important in the development of emphysema, it is reasonable
to hypothesize that NE inhibitors may limit or prevent the development of
the disease. Animal models have suggested that both synthetic (146) and
natural NE inhibitors (147,174,175) can limit emphysema when delivered
simultaneously with the elastase insult. Certainly, most animal models have
supported the concept that neutrophil influx is greatest during the early
stages of COPD with macrophage influx, and their metalloproteinases accu-
mulating at a later stage (176,177). However, even when given once disease
is established, NE inhibitors can still limit inflammation and connective
tissue breakdown (114). Such studies clearly have implications for the design
of future preventative strategies for COPD in man.
B. Matrix Metalloproteinases
Neutrophils and macrophages also produce large amount of metalloprotei-
nases (MMPs) and their inhibitors, the tissue inhibitors of metalloprotei-
nases (TIMPs). The MMPs are proteolytic enzymes that are secreted as
proenzymes (activated by other MMPs) and remain bound to cell mem-
branes. The MMPs degrade not only matrix proteins, but also antiprotei-
nases such as a 1 -AT and a 1 -ACT, activate enzymes involved in the
clotting cascade, and interact with cytokines and adhesion molecules,
thus leading to widespread interest in their role in the pathogenesis of
COPD.