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et al.
1988
), but notably not nonelastolytic bacterial collagenase. Damiano later
demonstrated the presence of NE on elastic fibers in human emphysematous lungs
using immuno-EM (Damiano et al.
1986
). Subsequent discovery of MMPs with
elastolytic properties (see below) has placed NE within the proper context, one of a
number of proteinases functioning in concert to degrade lung elastic fibers during
the course of chronic cigarette smoke-exposure (Shapiro
2005
).
The contributions of CG and PR3 to elastic fiber degradation in vivo are
considerably less well characterized than those of NE. NE-mediated elastolysis
has been implicated in several disease states including emphysema, acute lung
injury, acute respiratory distress syndrome, and bullous pemphigoid (Liu et al.
2000
; Lee and Downey
2001a
,
b
; Lee and Downey 2001). It is likely that CG
potentiates the elastolytic capabilities of NE, although even this minor role for CG
has been called into question (Boudier et al.
1981
; Reilly et al.
1984
). PR3 is a more
potent elastase than CG. However, with the exception of intratracheal PR3-induced
experimental emphysema, specific elastolytic roles for PR3 are lacking.
9.5.2 Matrix Metalloproteinases
Mammalian-derived elastolytic metalloproteinases are limited to the matrix metallo-
proteinases (MMPs), a member of the metzincin superfamily of enzymes. Taken
together, this family of 23 (in humans) enzymes is capable of processing all compo-
nents of the ECM (Table
9.1
), many of which are essential for tissue development,
remodeling, and repair (Sternlicht and Werb
2001
). When expressed aberrantly, the
MMPs contribute to myriad disease states including cancer (Overall and Kleifeld
2006
), arthritis, pulmonary emphysema, abdominal aortic aneurysm formation, bul-
lous pemphigoid, and atherosclerosis (Hautamaki et al.
1997
)(Pyoetal.
2000
)(Liu
et al.
1998
). MMPs are endopeptidases that share similar structural features including
a prodomain, a Zn-containing catalytic domain, and in most cases, a hemopexin-like
carboxy-terminal domain (excluding MMP7, -23, and -28). Some MMPs contain
additional domains including a gelatin-binding domain (MMP2 and -9), transmem-
brane domain (MMP14, -15, -16, and -24), or a GPI-anchor domain (MMP17 and -25).
MMPs are typically secreted as inactive proenzymes, or zymogens. The inactive
state is maintained by the coordination of the Zn ion with an unpaired cysteine
sulfhydryl group within the propeptide domain. The activation of MMPs usually
occurs in the extracellular space upon the cleavage of the propeptide by other
activated MMPs or serine proteinases, releasing the zinc ion, the coordination of
which is essential for catalysis. There are exceptions to this simple schema, however.
The activation of MMP2, for example, is a complex process involving secretion of
pro-MMP2 and subsequent binding to tissue inhibitor of metalloproteinase-2 (TIMP2).
This surface-bound MMP2, which is resistant to processing by the serine protei-
nases, is then activated by MMP14 (Strongin et al.
1995
).
As is the case for serine proteinases, Alpha-2 macroglobulin functions as a major
serum inhibitor of the MMPs. Specific inhibition of the MMPs is accomplished by
