Biomedical Engineering Reference
In-Depth Information
VI. PROTEASES
Alveolar macrophages secrete several elastolytic enzymes, including MMP-
2, MMP-9, MMP-12, cathepsins K, L, and S, and neutrophil elastase taken
up from neutrophils (66,67). Alveolar macrophages from patients with
COPD have a greater elastolytic activity at baseline than those from normal
smokers and this is further increased by exposure to cigarette smoke
(47,67,68). Macrophages demonstrate this difference even when maintained
in culture for 3 days and therefore appear to be intrinsically different from
the macrophages of normal smokers and nonsmoking normal control sub-
jects (67). The predominant elastolytic enzyme secreted by alveolar macro-
phages in COPD patients appears to be MMP-9 (68,69). MMP-9 is also
strongly expressed in emphysematous lung at sites of macrophage accumu-
lation (70). MMP-12 (macrophage metalloelastase) appears to play an
important role in cigarette smoke-induced emphysema in mice and appears
to be necessary for release of activated TNF-
a
from alveolar macrophages
(71). This then leads to increased expression of E-selectin and neutrophil
accumulation in the lungs. The role of MMP-12 in human macrophages is
less well defined as there is less evidence for its expression in human alveolar
macrophages (69,72).
Macrophages also release cysteine proteases, but their role in COPD
has not been evaluated. A cysteine protease inhibitor E-64 significantly
reduces the elastolytic activity of alveolar macrophages from COPD
patients, although this component is less marked and less sustained than
MMP-9 secretion (67). Cathepsins K, L, and S have been identified in asso-
ciation with human macrophages (66,73-75).
VII. RESPONSES TO DRUGS
There have been relatively few studies reporting the effects of drugs on
human alveolar macrophages, particularly in cells derived from COPD
patients. Yet, this is important information if these cells play such a critical
role in orchestrating the chronic inflammatory process in COPD.
A. Corticosteroids
Corticosteroids are ineffective in suppressing inflammation, including cyto-
kines, chemokines, and proteases, in patients with COPD (76-78). In vitro,
the release of IL-8, TNF-
a
, and MMP-9 from macrophages taken from nor-
mal subjects and normal smokers is inhibited by corticosteroids, whereas
corticosteroids are ineffective in macrophages from patients with COPD
(43). Curiously, this does not apply to GM-CSF which does not appear
to have increased secretion in COPD and is suppressed by corticosteroids,
