Therapeutic Implications and Future Developments - Chronic Obstructive Pulmonary Disease - page 502

critical MMP-9. Nuclear factor- k B is activated in macrophages and
epithelial cells of COPD patients, particularly during exacerbations
(68,69). There are several possible approaches to inhibition of NF- k B,
including gene transfer of the inhibitor of NF- k B(I k B), inhibitors of I k B
kinases (IKK), NF- k B-inducing kinase (NIK), and I k B ubiquitin ligase,
which regulate the activity of NF- k B, and the development of drugs that
inhibit the degradation of I k B (70). The most promising approach may be
the inhibition of IKK-2 by small molecule inhibitors, several of which are
now in development (71). A small molecule IKK-2 inhibitor suppresses
the release of inflammatory cytokines and chemokines from alveolar macro-
phages (72) and might be effective in COPD, as alveolar macrophages are
resistant to the anti-inflammatory actions of corticosteroids (10). One
concern about long-term inhibition of NF- k B is that effective inhibitors
may result in immune suppression and impair host defenses, as mice that
lack NF- k B genes succumb to septicemia. However, there are alternative
pathways of NF- k B activation via kinases other than IKK that might be
more important in inflammatory disease (73,74).
C. p38 MAP Kinase Inhibitors
Mitogen-activated protein kinases play a key role in chronic inflammation,
and several complex enzyme cascades have now been defined (75). One of
these, the p38 MAP kinase pathway is activated by cellular stress and reg-
ulates the expression of inflammatory cytokines, including IL-8, TNF- a ,
and MMPs (76). Small molecule inhibitors of p38 MAP kinase, such as
SB 203580, SB 239063, and RWJ 67657, have been developed and these
drugs have a broad range of anti-inflammatory effects (76,77). SB 239063
reduces neutrophil infiltration after inhaled endotoxin and the concentra-
tions of IL-6 and MMP-9 in bronchoalveolar lavage fluid of rats, indicating
its potential as an anti-inflammatory agent in COPD (78). It is likely that
such a broad-spectrum anti-inflammatory drug will have some toxicity,
but inhalation may be a feasible therapeutic approach. Several p38 inhibi-
tors are now in clinical development and some are in Phase II trials for other
inflammatory indications.
D. Phosphoinositide 3-Kinase Inhibitors
Phosphoinositide 3-kinases (PI-3Ks) are a family of enzymes that lead to the
generation of lipid second messengers that regulate a number of cellular
events. A particular isoform, PI-3K g , is involved in neutrophil recruitment
and activation. Knock-out of the PI-3K g gene results in inhibition of
neutrophil migration and activation, as well as impaired T-lymphocyte
and macrophage function (79). This suggests that selective PI-3K g inhibitors
may have relevant anti-inflammatory activity in COPD and small molecule
inhibitors of PI-3K g and PI-3K d are in development (80).