Biomedical Engineering Reference
In-Depth Information
Recently, alterations in the BMP signaling pathway have been identi-
fied in secondary forms of pulmonary hypertension (thromboembolic, scler-
oderma, mitral valve disease) (103). In these patients, Du et al. (103)
reported upregulation of angiopoietin-1 in SMCs of small pulmonary
arteries and increased phosphorylation of its receptor (TIE2) in endothelial
cells, as well as nearly complete downregulation of the BMP receptor type
1A (BMPR1 A) in endothelium. Endothelial cell culture studies demon-
strated that angiopoietin-1 downregulates BMPR1A gene product (103).
These findings emphasize that inactivation of the BMP receptor complex,
either by a mutation or by downregulation of its steady-state levels, is criti-
cal for the pathogenesis of pulmonary hypertension, not only in the primary
(idiopathic) form of the disease but also when it is associated with other
disease conditions.
To what extent alterations in the TGF
=
BMP signaling pathway are
important in the pathogenesis of pulmonary vascular abnormalities occur-
ring in COPD is currently unsettled. Yet, considering the significant obser-
vations made in the idiopathic form and other secondary forms of
pulmonary hypertension this pathway deserves to be explored in COPD.
2.
Serotonin Transporter
Human 5-HTT gene transcription is modulated by a common polymorph-
ism in its upstream regulatory region. The short variant (S) of this poly-
morphism reduces the transcriptional efficiency of the 5-HTT gene
promoter, resulting in decreased 5-HTT expression and 5-HT uptake
(104). Eddahibi et al. (105) have shown that patients with pulmonary hyper-
tension are frequently homozygote for the long (L) variant of the 5-HTT
gene promoter, exhibiting higher platelet uptake of 5-HT, as well as greater
expression of 5-HTT mRNA and immunoreactivity in lung tissue than
controls. Indeed, pulmonary artery SMCs from patients with PPH with
the LL polymorphism are more proliferative in response to 5-HT than
SMCs from patients with PPH who do not carry the polymorphism (105).
Recent studies conducted in COPD have shown that in patients carry-
ing the LL genotype, pulmonary hypertension is more severe than in
patients with the LS or SS genotype (106). Compared with control subjects,
platelet 5-HTT protein is increased in COPD patients in proportion to the
level of hypoxemia, and strong 5-HTT immunostaining has been observed
in remodeled pulmonary arteries from COPD patients. Accordingly, 5-
HTT gene polymorphism seems to modulate the severity of pulmonary
hypertension in hypoxemic patients with COPD.
B. Hypoxia
During decades, pulmonary hypertension associated with COPD has been
considered to have a hypoxic origin. Indeed, in the current classification
