Biomedical Engineering Reference
In-Depth Information
that can account for their beneficial effects in asthma (26), but there are few
mechanistic studies in COPD. Transforming growth factor-
b
(TGF-
b
)
downregulates
b
2
-receptors in human cell lines by inhibiting gene transcrip-
tion (27). Transforming growth factor-
b
inhibits the bronchodilator
response to
b
-agonists in guinea pig trachea in vitro (28), and as there is
increased expression of TGF-
b
in peripheral airways of COPD patients
(29), this may downregulate
b
2-receptor on smooth muscle cells of small air-
ways and impair the bronchodilator response to
b
2-agonists. Corticoster-
oids increase the expression of
b
2
-adrenergic receptors in small airways
(30) and thus might restore the reduction if
b
2
-receptors increase the bronch-
odilator response to
b
2
-agonists.
b
2
-Agonists may also have effects on
glucocorticoid receptors, facilitating their nuclear translocation so that the
anti-inflammatory effect of corticosteroids is enhanced (31,32). It is possible
that this may reduce the resistance to corticosteroids seen in COPD, but
further studies are needed to explore this possibility.
V. MEDIATOR ANTAGONISTS
As discussed in Chapter 11, many mediators are involved in the pathophy-
siology of COPD, although there is much less information about the med-
iators of COPD than the mediators of asthma. An approach to new
therapies in COPD is to antagonize specific mediators or to prevent their
synthesis with enzyme inhibitors. Although this is an easily testable
approach, it is unlikely that blocking a single mediator will control the dis-
ease, as so many mediators are involved and there is considerable redun-
dancy between these mediators. For example, there are several mediators
that may increase neutrophil chemotaxis, including leukotriene B
4
(LTB
4
),
interleukin (IL) -8 and anaphylotoxins, so that blocking a single mediator
may not have a marked effect on neutrophilic inflammation in the lungs.
A.
Leukotriene Inhibitors
Leukotriene B
4
is a potent chemoattractant of neutrophils and is increased in
the sputum and exhaled breath of patients with COPD (33,34). It is probably
derived from alveolar macrophages, as well as neutrophils, and may be syner-
gistic with IL-8. Two subtypes of receptor for LTB
4
have been described;
BLT
1
receptors are expressedmainly on granulocytes andmonocytes, whereas
BLT
2
receptors are expressed on T lymphocytes (35). BLT
1
antagonists, such
as LY29311, have now been developed for the treatment of neutrophilic
inflammation (36). LY293111 and another antagonist SB225002 inhibit the
neutrophil chemotactic activity of sputum from COPD patients, indicating
the potential clinical value of such drugs (37,38). Several selective BLT
1
antagonists are now in development. Leukotriene B
4
is synthesized by 5
0
-
lipoxygenase (5-lLO), of which there are several inhibitors, although there
