Biomedical Engineering Reference
In-Depth Information
A. Cytokines
Cytokines are mediators of short-range signals between cells, and they
control growth, differentiation, effector function, and survival of cells.
Cytokines comprise of families of molecules including interleukins, lympho-
kines, monokines, growth factors, interferons, and chemokines. Two of the
most important proadhesive cytokines in COPD are tumor necrosis factor
a
(TNF-
a
) and interleukin-1
b
(IL-1
b
).
1. Tumor Necrosis Factor
a
Tumor necrosis factor
a
is mainly produced by activated macrophages
[although it can be produced by activated T cells (19), mitogen stimulated
B cells (20), natural killer cells (21), and airway epithelial cells (22)]. It is nor-
mally synthesized as a 26-kDa precursor (pro-TNF-
a
), which is stored in a
membrane-bound form. With the appropriate stimuli [e.g., bacterial lipopo-
lysaccharide (LPS)], the precursor is converted to TNF-
a
, a 17 kDa biologi-
cally active form. Pro-TNF-
a
is converted to active TNF-
a
by a membrane-
bound metalloproteinase called TNF-
a
converting enzyme (TACE) (23)
although other matrix metalloproteinases (MMPs) also have a greater or
lesser degree of TNF-
a
converting potential (23). In vitro metalloproteinase
12 (MMP-12) has been shown to release active TNF-
a
from a synthetic pro-
form, and animal models suggest that (at least in mice) active TNF-
a
release
from macrophages, after acute smoke exposure, is dependent upon both
TACE and MMP-12 (24). Tumor necrosis factor
a
upregulates the expres-
sion of adhesion molecules on neutrophils and endothelial cells, but is not
chemotactic for neutrophils.
Animal models utilizing acute smoke exposure have suggested that
macrophages (as well as their metalloproteinases) are needed for the produc-
tion of TNF-
a
which in turn is required for neutrophil recruitment into
the lungs, activation of endothelial cells, adherence to endothelium, and
migration of neutrophils.
Recently, there has been much interest in polymorphisms of the
TNF-
a
gene in the pathogenesis of COPD, especially TNF-308, the biallelic
polymorphism located in the first intron of the lymphotoxin-
a
gene and
exons 1 and 6 of the TNF receptor 1 and 2 genes. These polymorphisms
have been associated with enhanced TNF transcription and therefore
production of greater concentrations of TNF-
a
than controls (25) following
activation. An Irish study has suggested that homozygosity of the 308 poly-
morphism is associated with more severe airflow obstruction and a worse
prognosis in COPD (26), and the same polymorphism correlates with extent
of emphysema on high resolution CT scan in a Japanese cohort (27). How-
ever, an Italian study of 63 Caucasian patients with COPD found no
increase in prevalence of TNF-308 and TNF receptor gene 1 or 2 compared
with healthy controls (28). This discrepancy may reflect ethnic variations in
