Biomedical Engineering Reference
In-Depth Information
in the 3
0
untranslated region of the
a
1
-AT gene that has been associated with
COPD in some populations (66,67), but not others (58,68,69). In vitro, this
polymorphism was associated with decreased binding of a transcription fact-
or and decreased gene expression (70). The most likely transcription factor
is nuclear factor of interleukin (IL)-6, which is activated by IL-6 and subse-
quently increases the expression of
a
1
-AT (71). Thus, the 3
0
mutation could
affect the acute phase response leading to reduced
a
1
-AT synthesis in
response to inflammation. However, in contrast to the in vitro data, the 3
0
polymorphism was not associated with a reduced
a
1
-AT acute phase
response in patients undergoing open-heart surgery (72) or in patients who
had cystic fibrosis (CF) (73).
Therefore, the role of the 3
0
polymorphism in the pathogenesis of
COPD remains to be determined.
Another polymorphism in the 3
0
region of the
a
1
-AT gene has
been associated with COPD (74). The polymorphism was associated with
normal
a
1
-AT levels and was found in eight out of 70 COPD patients but
in none of 52 controls. There have been no follow-up studies to confirm this
association.
Other Antiprotease Genes:
The association of airflow limitation with
genetic defects in the
a
1
-AT gene also led to a search for genetic variants of
other antiproteases that may be involved in protection against lung destruc-
tion,
a
1
-Antichymotrypsin (
a
1
-ACT) is another serine protease inhibitor
synthesized in the liver and alveolar macrophages and airway epithelia. Sev-
eral functional single nucleotide polymorphisms have been identified. The
Leu
55
!
Pro mutation leads to a defective
a
1
-ACT protein and was associated
with COPD (75). Another polymorphism causes the Pro
229
!
Ala substitu-
tion and
a
1
-ACT serum deficiency and may predispose subjects to COPD
(75,76). Other investigators have found no association of these polymorph-
isms with COPD or related phenotypes (69,77).
a
2
-Macroglobulin is a broad-
spectrum protease inhibitor that is also synthesized in hepatocytes and in
alveolar macrophages. Several polymorphisms of the
a
2-miacroglobulin
gene have been described (78). However, all of these polymorphisms in other
antiproteases are rare and the evidence that they contribute to susceptibility
to COPD is weak.
Matrix Metalloproteinase Genes:
Matrix metalloproteinases (MMPs)
are a structurally and functionally related family of proteolytic enzymes that
play an essential role in tissue remodeling and repair associated with devel-
opment and inflammation (79). Several studies in animals and humans have
provided evidence that MMPl (interstitial collagenase), MMP12 (human
macrophage elastase), and MMP9 (gelatinase B) are important in airway
inflammation and the development of emphysema. In 1992, D'Armiento
et al. (80) demonstrated that transgenic mice, over-expressing human MMPl
in their lungs, developed morphologic changes strikingly similar to human
