Biomedical Engineering Reference
In-Depth Information
(29,94). It is a potent inducer of fibrosis, partly via the release of the potent
fibrogenic mediator connective tissue growth factor, and may be important
in inducing the fibrosis and narrowing of peripheral airways (obstructive
bronchiolitis) in COPD. Transforming growth factor-
b
1 also activates
MMP-9, which then further activates TGF-
b
1, thus providing a link
between small airway fibrosis and emphysema in COPD. MMP-9 may med-
iate proteolysis of TGF-
b
-binding protein (LTBP1), and this may be a
mechanism for physiological release of TGF-
b
1 (95). Inhibition of TGF-
b
1
signaling may therefore be a useful therapeutic strategy in COPD. Small
molecule antagonists which inhibit TGF-
b
receptor kinase or TGF-
b
-
activated pathways are now in development (96,97), although the long-term
safety of such drugs might be a problem, particularly as TGF-
b
affects tissue
repair and is a potent anti-inflammatory mediator.
Proteinase-activated receptor-2 (PAR-2) expression is widespread in
the airways, and expression is increased in the central airways of smokers
and nonsmokers (98). Proteinase-activated receptor-2 may be involved in
MMP-9 release from airway epithelial cells and proliferation of fibroblasts
(99,100). However, a potential drawback for strategies to antagonize
PAR-2 is that activation of epithelial PAR-2 causes bronchoprotection in
the airways (101).
C. Antiproteases
As discussed in Chapters 13 and 14, there is compelling evidence for an
imbalance between proteases that digest elastin (and other structural
proteins) and antiproteases that protect against this. This suggests that
either inhibiting these proteolytic enzymes or increasing endogenous anti-
proteases may be beneficial and theoretically should prevent the progression
of airflow obstruction in COPD. Considerable progress has been made in
identifying the enzymes involved in elastolytic activity in emphysema and
in characterizing the endogenous antiproteases that counteract this activity
(102). The fact that there are so many proteinases implicated in COPD
might mean that blocking a single enzyme may not have a major effect.
One approach is to give endogenous antiproteases (
a
1
-antitrypsin,
secretory leukoprotease inhibitor, elafin, tissue inhibitors of MMP) either
in recombinant form or by viral vector gene delivery (103,104). These
approaches are unlikely to be cost effective, as large amounts of protein have
to be delivered and gene therapy is unlikely to provide sufficient protein.
A more promising approach is to develop small molecule inhibitors of
proteases, particularly those that have elastolytic activity (105). Small mole-
cule inhibitors, such as ONO-5046 and FR901277, have been developed
which have high potency (106). These drugs inhibit neutrophil elastase-
induced lung injury in experimental animals, whether given by inhalation
or systemically and also inhibit the other serine proteinases released from
