Biomedical Engineering Reference
In-Depth Information
Over 24 mammalian MMPs have been described, and although they
are primarily grouped according to the proteins they degrade, most can
degrade all extracellular substrates. Matrix metalloproteinases are inhibited
by
a
2
-macroglobulin, as well as the four TIMPs described to date (178). The
main MMPs secreted by neutrophils are MMP-9 (gelatinase B), which
degrades collagen, elastin, and gelatine, and MMP-8 (neutrophil collage-
nase), which degrades collagen types I-III. Only MMP-9 has been studied
in COPD.
Although there are increased levels of MMP-9 in lung tissue, BALF,
and plasma taken from patients with COPD (179,180), levels are negatively
correlated with airflow obstruction and relate to the number of sputum neu-
trophils (181,182). MMP-9 not only acts as a proteinase, but may also mod-
ify cellular functions by regulating cytokines and matrix-bound growth
factors and therefore may have a role in lung remodeling after inflammatory
insult (183,184). MMP-9 knock-out mice did not show reduced neutrophil
recruitment or degranulation after exposure to LPS (113). In fact, in one
study, MMP-9 knock-out mice displayed greater neutrophil influx, perhaps
because MMP-9 can degrade neutrophil chemoattractants (160). Smoke-
exposed guinea pigs displayed a reduction in the severity of emphysema
and MMP-9 activity in BALF after the introduction of a broad spectrum
MMP inhibitor, but this may have been because of inhibition of other
metalloproteinases (185). Genetic polymorphisms of MMP-9 have been
identified, which cause enhanced protein expression, and in a Japanese
study, polymorphism-1562C
=
T has been associated with an increased risk
of smoking induced emphysema (186), but this has not been replicated in
other communities (187).
It is likely that the serine proteinases and MMPs act synergistically in
lung disease. Neutrophil elastase degrades TIMPs (188), facilitating MMP
activity, and can activate several MMPs including MMP-9 (189), whereas
MMP-12 inactivates
a
1
-AT, thereby enhancing NE activity (190). However,
the interactions are complex and in mouse models, MMP-9 also degrades
some neutrophil chemoattractants, which would reduce PMN recruitment
and hence NE release (160). The majority of animal ''knock-out'' models
of emphysema support a multifaceted pathogenic process in the disease,
as inhibition of serine, cysteine, or MMPs all show partial protection from
the development of emphysema (114,161).
The noticeable exception is MMP-12. The MMP-12 knock-out mice
exposed to cigarette smoke do not develop emphysema, although macro-
phage recruitment to the lungs is normal in response to monocyte chemoat-
tractant protein-1 (191). In a similar study, neutrophil numbers increased in
the first month following smoke exposure, but breakdown of connective
tissue and the development of emphysema occurred later and related to a
subsequent increase in macrophages (176).
