Biomedical Engineering Reference
In-Depth Information
results in a conformational change, which results in the disruption of a salt
bridge between Phe83 and Asp237. As a consequence of this, the N-terminal
region of MMP-3 moves and an interaction is set up with Met66 of TIMP-1.
B. MMP:TIMP Ratios in Lung Disease
The balance between MMPs and TIMPs is essential for the prevention of
tissue breakdown and inappropriate remodeling of tissue by excess MMP
activity. Studies in mice that are null for specific MMP or TIMP genes have
shed some light on changes that can occur in the lung due to alterations in
MMP or TIMP levels. Mice deficient in MMP-12 (metalloelastase) do not
develop emphysema following long-term exposure to cigarette smoke com-
pared with wild-type controls (82). Likewise, TIMP-3 null mice exhibit
enlarged airspaces at 2 weeks of age, increased collagen turnover, and live
only half as long as wild-type mice, indicating that loss of TIMP activity dis-
turbs the MMP
=
TIMP balance with resulting increased MMP activity and
subsequent lung destruction (83). Increased release of MMP-9 and TIMP-1
by smokers compared with nonsmokers has been observed in AM superna-
tants (84). In a follow-up study, greater amounts of MMP-9 were released
from the AMs from patients with COPD compared with healthy smokers
and nonsmokers. In contrast, nonsmoker AMs released greater amounts
of TIMP-1 compared with AMs from healthy smokers and patients with
COPD (85). Type II pneumocytes exhibit increased MMP-1 expression in
patients with emphysema, but is absent from the parenchyma of normal
control subjects (86). Polymorphisms have been identified in the TIMP-2
gene, which occur with greater frequency in patients with COPD compared
with controls, and it has been speculated that these polymorphisms may lead
to decreased expression or mRNA stability of TIMP-2 and predispose to
development of COPD (26). Increased MMP-9:TIMP-1 ratios have been
observed in acute asthma, although TIMP-1 levels exceed MMP-9 in
chronic stable asthma patients (87,88). Therefore, early membrane degen-
eration caused by MMP-9 in asthma may be followed at a later stage by
impaired tissue repair and increased extracellular matrix deposition due to
increased TIMP-1 levels.
C. Other Functions of TIMPs
Tissue inhibitors of metalloproteases possess activities that are independent
of their MMP-inhibitory activities. The TIMP-1 and -2 have been found to
have mitogenic effects on a number of cell lines, although overexpression of
these inhibitors causes reduced tumor cell growth (89). The TIMP-1 has also
been shown to increase MMP-1 production by fibroblasts (90). The TIMP-3
induces apoptosis of human colon carcinoma cells and melanoma cells pos-
sibly by stabilizing TNF-
a
receptors perhaps via reduced receptor shedding
(91). The proapoptotic effect of TIMP-3 is in contrast to TIMP-1 and -2,
