Biomedical Engineering Reference
In-Depth Information
or anti-inflammatory. They may be activated by several stimuli, including
cigarette smoke, proinflammatory cytokines, endotoxin, and immune
stimuli. Overall, alveolar macrophages from COPD patients show greater
release of inflammatory mediators than cells from normal smokers, which
in turn secrete more than cells from nonsmokers.
A.
Lipid Mediators
Alveolar macrophages have the capacity to generate leukotrienes (LT) and
prostaglandins (PG). In patients with COPD, there is an increase in LTB
4
concentration in sputum and exhaled breath (35-37), but this is likely to
be derived predominantly from neutrophils rather than alveolar macro-
phages. Human alveolar macrophages express cytosolic phospholipase A
2
and release LTB
4
and platelet-activating factor on activation (38). Alveolar
macrophages also secrete PGE
2
and may contribute to the increased PGE
2
in exhaled breath of COPD patients (37). This is likely to be derived from
cyclo-oxygenase-2 (COX-2) which is expressed in macrophages (39). There
is increased COX-2 expression in alveolar macrophages from patients with
COPD compared to normal control subjects (40).
B. Chemokines
Alveolar macrophages have the capacity to release multiple chemokines
leading to the recruitment of several cell types from the circulation, includ-
ing monocytes, neutrophils, and T-lymphocytes.
The best studied chemokine is IL-8 which is released by alveolar
macrophages in response to several stimuli, including cigarette smoke
extract, endotoxin, and IL-1
b
. Hypoxia also releases IL-8 from alveolar
macrophages and this mechanism might be relevant in severe COPD and
exacerbations (41). It is likely that macrophages contribute to the high con-
centrations found in the airways of patients with COPD (42), although neu-
trophils recruited by macrophage-derived neutrophil chemokines may be the
major source. Alveolar macrophages from COPD patients release signifi-
cantly more IL-8 at baseline and after stimulation with IL-1
b
and cigarette
smoke than macrophages from normal smokers and nonsmokers and these
differences are maintained in cell culture, suggesting that external factors are
not responsible for this increased activation (43).
Macrophages also have the capacity to release the chemokines IP-10
(CXCL10), I-TAC (CXCL11) and Mig (CXCL9), which are chemotactic
for CD8
þ
Tcl cells via interaction with the CXCR3 receptor expressed on
these cells (44). Macrophages may therefore play a key role in the recruit-
ment of T-lymphocytes, and particularly CD8
þ
cells, to the lungs. The
release of IFN-g by these cells may further release these chemokines, result-
ing in a chronic inflammatory cycle.
