Biomedical Engineering Reference
In-Depth Information
tion of wild-type (MMP-12
þ
=
þ
) mice to long-term cigarette smoke exposure
led to inflammatory cell recruitment followed by alveolar space enlargement
similar to the pathologic defect in humans. However, mice deficient in
macrophage elastase (MMP-12
=
) were protected from development of
emphysema despite long-term smoke-exposure (22). Surprisingly, MMP-
12
=
mice also failed to recruit monocytes into their lungs in response to
cigarette smoke. Because MMP-12 and most other MMPs are only
expressed upon differentiation of monocytes to macrophages, it appeared
unlikely that monocytes require MMP-12 for transvascular migration.
The working hypothesis is that cigarette smoke induces constitutive
macrophages, which are present in lungs of MMP-12
=
mice, to produce
MMP-12 that in turn cleaves elastin thereby generating fragments chemo-
tactic for monocytes (Fig. 2). This positive feedback loop perpetuates
macrophage accumulation and lung destruction. The concept that proteoly-
tically generated elastin fragments mediate monocyte chemotaxis is not ori-
ginal. Independent studies by Senior et al. (25,26) as well as Hunninghake
et al. (27) from the early 1980s demonstrated that elastase-generated elastin
fragments were chemotactic for monocytes and fibroblasts. Gene targeting
is merely reinforcing this as a major in vivo mechanism of macrophage accu-
mulation in a chronic inflammatory condition. Whether human emphysema
is also dependent on this single MMP is of course uncertain. At the very
least, this study demonstrates a critical role of macrophages in the develop-
ment of emphysema and unmasks a proteinase-dependent mechanism
of
inflammatory cell
recruitment
that may have broader biological
implications.
Figure 2
Potential role of elastin fragments in monocyte recruitment in COPD.
Cigarette smoke induces constitutive macrophages to produce macrohage elastase
(MME or MMP-12) that in turn cleaves elastin thereby generating fragments chemo-
tactic for peripheral blood monocytes.
