Biomedical Engineering Reference
In-Depth Information
complement factors, are believed to play an important role in the accumula-
tion of neutrophils in lung that is seen in COPD (113). In addition, VDBP
can be converted to a potent macrophage-activating factor (114). Thus,
besides its vitamin D binding function, VDBP could have important influ-
ences on the intensity of the inflammatory reaction in the lung in response
to cigarette smoke.
There are three major isoforms of this protein termed 1S, 1F, and 2,
and these isoforms are due to two common substitutions in exon 11 of
the VDBP gene (115). Individuals who had one or two copies of allele 2 were
shown to be protected against COPD (116,117). In addition, Horne et al.
(116) demonstrated that 1F homozygous individuals had a significantly
increased risk of developing COPD. This association was confirmed in a
Japanese population (118). In contrast, no association of this genotype with
lung function level and accelerated decline of lung function was found
(58,119).
Schellenberg et al. (117) examined whether the associations of VDBP
isoforms with COPD could be due to the effect of VDBP on neutrophil
chemotaxis. However, there were no significant differences between the three
VDBP isoforms in their ability to enhance chemotaxis of neutrophils to C5a.
It remains possible that the mechanism for the association with COPD is
related to the activation of macrophages at sites of inflammation. However,
no investigators have examined the influence of these genetic variants on the
ability of the protein to act as a macrophage-activating factor.
Tumor Necrosis Factor
a
:
Tumor necrosis factor
a
(TNF
a
) and
tumar necrosis factor
b
(TNF
b
) (lymphotoxin) are proinflammatory cyto-
kines that have many effects of relevance to the pathogenesis of COPD, e.g.,
neutrophil release from the bone marrow and neutrophil activation. A
recent in vitro study suggested that metalloproteases mediate cigarette
smoke-induced inflammation via the release of TNF
a
from macrophages
(120). Elevated TNF
a
was found in BAL fluid, bronchial biopsy specimens,
and induced sputum of patients with COPD (121).
The TNF
a
and TNF
b
genes contain several polymorphisms including
aG
!
A transition in the TNF
a
gene promoter (TNF
a
G-308A) and an
A
!
G transition in the first intron of the TNF
b
gene (TNF
b
A252G). These
polymorphisms have been shown to be associated with the level of TNF
a
and TNF
b
production in vitro (122). In addition, the TNF
a
-308A allele
has been associated with several diseases including cerebral malaria (123)
and asthma (124,125). An association of the TNF
a
-308A allele with COPD
was found in a Taiwanese population (126). The patients were selected on
the basis of the presence of chronic bronchitis and airflow limitation
(FEV
1
<
80% predicted and FEV
1
=
FVC
<
69%). The prevalence of the
TNF
a
-308A allele was considerably increased in the patients compared
with the controls, yielding an OR of 11.1 for chronic bronchitis.
