Biomedical Engineering Reference
In-Depth Information
Table 4
Antioxidant and Anti-inflammatory Therapeutic Interventions in COPD
Antioxidant compounds
Thiol compounds-N-acetyl-l-cysteine, N-acystelyn (NAL)
Inducers of glutathione biosynthesis
Spin traps
SOD and glutathione peroxidase mimetics
Anti-inflammatory
=
signal transduction inhibitors
p38 kinase inhibitor
NF-
k
B inhibitors
HDAC inducers
Better glucocorticoids
deformability, so preventing neutrophil sequestration or the migration of
neutrophils, either by interfering with the adhesion molecules necessary
for migration, or preventing the release of inflammatory mediators, such
as IL-8 or Ieukotriene B
4
, which result in neutrophil migration. It should
also be possible to use agents to prevent the release of oxygen radicals from
activated leukocytes or to quench those oxidants once they are formed, by
enhancing the antioxidant screen in the lungs. Preliminary studies of a phos-
phodiesterase 4 inhibitor (PDE4) have shown some therapeutic benefit in
patients with COPD (106). The mechanism by which such drugs act is by
decreasing the neutrophil activation. In particular, the release of ROS by
neutrophils may be decreased, since increasing cAMP blocks the assembly
of NADPH oxidase.
B.
Spin Traps and Antioxidant Enzyme Mimetics
The other approach would be to use specific spin traps such as
a
-phenyl-N-
tert-butyl nitrone to react directly with reactive oxygen and reactive nitrogen
species at the site of inflammation (107). The therapeutic purposes of this
drug are currently in clinical development. Inhibitors that have a double
action, such as the inhibition of lipid peroxidation and quenching radicals,
could be developed. In a recent study by Smith et al. (108) have showed that
intratracheal instillation of a catalytic antioxidant, manganese (III) meso-
tetrakis (N,N
0
-diethyl-l,3-imidazolium-2-yl) porphyrin (AEOL 10150 and
AEOL 10113) inhibited the cigarette smoke-induced inflammatory res-
ponse (decreased number of neutrophils and macrophages) in rats after 2
days or 8 weeks (6 hr
=
day, 3 day
=
week) exposure (108). These compounds
also mimic ECSOD and catalase scavenging both lipid peroxides and perox-
ynitrite, and have been shown to be effective in a number of animal models
of lung disease. It has been shown that SOD mimetic M40419 blocked the
development of emphysema and significantly reduced lung markers of oxi-
dative stress in an animal model (108). Animal studies have shown that
