Biology Reference
In-Depth Information
recruitment, described above. The contribution of elastolytic MMPs to atheroscle-
rotic plaque formation and rupture has also been investigated. Interestingly, MMP3
and -9 are protective against plaque rupture whereas MMP12 was disease promot-
ing (Johnson et al.
2005
).
Within the lung, the roles of MMP9 (gelatinase B or 92-kDa gelatinase) and
MMP12 (macrophage elastase) appear to be reversed, with MMP12 playing a
substantially greater role at least in mice. The majority of elastolytic properties of
murine alveolar macrophages can be attributed to MMP12. Human alveolar macro-
phages may also be more dependent upon MMP9, and likely MMP7, to degrade
elastin (Filippov et al.
2003
). Nevertheless, MMP12 has consistently been demon-
strated as an essential component of emphysema pathogenesis in both mouse and
man. First described in 1975 (Werb and Gordon
1975
), the subsequent cloning and
generation of null-mutant mice for MMP12 has established this largely macro-
phage-specific elastase as essential for the disruption of basement membrane
structures both in vitro and in vivo (Shipley et al.
1996
). As discussed above,
MMP12
/
mice are completely protected from both the development of airspace
enlargement and macrophage accumulation upon exposure to cigarette smoke
(Hautamaki et al.
1997
). MMP12-mediated degradation of elastic fibers is sufficient
to cause both the structural (loss of elastic recoil) and biological (generation of EFs
and accumulation of macrophages) consequences of elastolysis (Houghton et al.
2006a
,
b
). Expression profiling has demonstrated that MMP12 is the most upregu-
lated gene in human alveolar macrophages (Woodruff et al.
2005
). Most recently,
Hunninghake and colleagues demonstrated that polymorphisms in MMP12 influ-
ence the prevalence of COPD/emphysema in humans (Hunninghake et al.
2009
).
The role of MMP9 in COPD/emphysema is less clear. MMP9 is an elastase, and
is easily identifiable in human emphysematous lungs (Ohnishi et al.
1998
), being
highly expressed by both macrophages and neutrophils. Surprisingly,
MMP9
/
mice are not protected from cigarette smoke-induced airspace enlargement (SDS,
unpublished). They are protected from the occurrence of subepithelial airway
fibrosis within the airways. Thus it is likely that MMP9 is involved in the patho-
genesis of COPD/emphysema, and further studies using bone marrow transfer
protocols may yet tease apart disparate roles for airway epithelial cell-derived
and inflammatory cell-derived MMP9. The major phenotypes of elastase null-
mutant mice are reviewed in Table
9.2
.
9.5.3 Cysteine Proteinases
The cysteine proteinases are a large group of plant and animal endopeptidases with
amino acid homology limited to the active site. The mechanism of catalysis is
similar to that of the serine proteinases, utilizing a catalytic dyad in which a
His residue donates a proton to the sulfhydryl group of the Cys, which functions
as the nucleophile (Wolters and Chapman
2000
). There are 11 human cysteine
cathepsins, which belong to the papain subfamily of cysteine proteinases. These are
