Biomedical Engineering Reference
In-Depth Information
or no response to corticosteroids (88). The molecular mechanism or this
action is currently unknown, but identification of the cellular target for
resveratrol may lead to the development of a novel class of anti-inflamma-
tory compounds. Resveratrol itself has a very low oral bioavailability; so,
related drugs or a suitable inhaled formulation will need to be developed.
VII. DRUGS ACTING ON STRUCTURAL CELLS
A. Mucoregulators
Mucus hypersecretion is commonly seen in cigarette smokers, but is not
necessarily associated with airflow limitation. In individuals with COPD,
mucus hypersecretion is associated with more rapid decline in FEV
1
and
increased frequency of exacerbations (89). Reducing mucus hypersecretion
may therefore have therapeutic benefit, although suppression of the normal
airway mucus secretion may be detrimental. Mucolytic drugs have been
used for many years to reduce mucus viscosity but these drugs do not appear
to have any clinical value. As discussed in Chapter 5, there are many inflam-
matory products and neural mechanisms that regulate mucus secretion and
therefore there are several targets for the development of mucoregulators.
Several novel approaches to inhibiting mucus hypersecretion are cur-
rently being explored (90). Mucus hypersecretion appears to be largely dri-
ven in COPD by the neutrophil inflammatory response, so that effective
anti-inflammatory treatments would be expected to reduce mucus hyperse-
cretion (90).
Epidermal growth factor (EGF) plays a critical role in airway mucus
secretion from goblet cells and submucosal glands and appears to mediate
the mucus secretory response to several secretagogs, including oxidative
stress, cigarette smoke, and inflammatory cytokines (91). Epidermal growth
factor may also be responsible for the mucus hyperplasia seen in chronic
bronchitis. Small molecule inhibitors of EGF receptor kinase, such as
gefitinib, have now been developed for clinical use.
Another novel approach involves inhibition of calcium-activated
chloride channels (CACC), which are important in mucus secretion from
goblet cells. Activation of human hCLCAl induces mucus secretion and
mucus gene expression and may therefore be a target for inhibition. Small
molecule inhibitors of CACC, such as niflumic acid and MSI 1956, have
been developed (92). Other approaches include inhibition of the neural
mechanisms driving mucus secretion, including tachykinin receptor antago-
nists and potassium channel openers (93).
B.
Fibrosis Inhibition
Transforming growth factor-
b
1 (TGF-
b
1) is highly expressed in airway
epithelium and macrophages of small airways in patients with COPD
