Proteinases in COPD - Chronic Obstructive Pulmonary Disease - page 332

including MMP-7 and fully processed form of MMP-12, are still susceptible
to TIMP inhibition although with a lower Ki. TIMP-2 is secreted complexed
to MMP-2 in fibroblasts. A significant body of work has uncovered complex
mechanisms, whereby TIMP-2, not only inhibits MMP-2, but also is
involved in docking pro-MMP-2 to the cell surface where the enzyme is acti-
vated by MT1-MMP. TIMP-3 is expressed predominantly by epithelial cells
and binds to extracellular matrix.
TIMPs are secreted from many cell types and are abundant in tissues.
Alveolar macrophages secrete both a variety of MMPs as well as TIMP-1
and TIMP-2. Endotoxin induces synthesis of macrophage MMPs and
TIMP-1, but inhibit TIMP-2 production (5). Other cytokines, such as inter-
feron- g , inhibit MMP-1 and MMP-3 expression in macrophages with little
effect on TEVIP-1 (6). Thus, depending on the inflammatory stimulus,
MMPs and TIMPs may be coordinately regulated, perhaps to limit tissue
injury during normal remodeling associated with inflammation, or regula-
tion may be discoordinate, potentially leading to tissue injury.
2. MMPs in COPD
Of the many MMPs, this discussion will focus on those that have elastolytic
or collagenolytic capacity, and are expressed by inflammatory cells or other
cells in the lung and hence might contribute to COPD. Discussed in the next
section are specific MMPs that have been implicated in COPD directly.
Substrates: Elastin is a highly inert substance and there are few protei-
nases that are elastases; these include the gelatinases (MMP-2,MMP-9), matri-
lysin (MMP-7), and macrophage elastase (MMP-12). There are three major
collagenases; interstitial collagenase (MMP-1, a human enzyme not found in
rodents), neutrophil collagenase (MMP-8), and collagenase-3 (MMP-13). In
addition, MMP-2 has been shown to cleave collagen as having membrane type
MMP-1 (MT1-MMP). The collagenases, particularly MMP-1, have a limited
substrate specificity, while MMP-7 and MMP-12, along with the stromelysins
(MMP-3, MMP-10), have the capacity to catalyze the degradation of many
extracellular matrix substrates excluding collagens.
The capacity of MMPs to degrade non-matrix proteins is also becoming
appreciated. For example, most MMPs like the related ADAMs ( a d isintigrin
and m etalloproteinase domain) can cleave and activate latent TNF- a , thereby
regulating inflammation. MMPs (7), particularly MMP-12 (8), degrade and
inactivate a 1 -AT, thus indirectly enhancing the activity of NE. Thus, MMPs
play both direct and indirect roles in matrix-destruction associated with
emphysema, and may indirectly influence cytokine release and angiogenesis
that could influence the development and progression of COPD.
Cellular Expression: Macrophages and neutrophils are the major cell
types associated with COPD, although many other hematopoietic and struc-
tural cells might be involved and produce MMPs.