Biomedical Engineering Reference
In-Depth Information
confers susceptibility to hypoxic pulmonary hypertension. 5-HT may pro-
mote the development of hypoxic pulmonary hypertension by stimulating
SMC growth (54). In fact, exposure of PASMCs to hypoxia results in a rapid
increase in 5-HTT expression and activity, together with a marked enhance-
ment in the growth-promoting effect of 5-HT (55,56). Increased 5-HTT gene
expression also occurs in remodeled pulmonary arteries from animals devel-
oping pulmonary hypertension related to chronic hypoxia exposure (55).
Several observations support the development of pulmonary hyperten-
sion through 5-HT. The mitogen effect of 5-HT on SMCs is dose-dependently
inhibited by selective inhibitors of 5-HT transport such as paroxetine and
fluoxetine (55-57), but not by the 5-HT2A receptor antagonist ketanserin.
In mice lacking, the 5-HTT gene and exposed to hypoxia for 2 weeks, wall
thickness and the number of muscularized pulmonary arteries were decreased
as compared with wild-type controls (58). These animals also developed less
severe hypoxic pulmonary hypertension than wild-type controls.
The mechanism by which 5-HT exerts its mitogenic effect after being
transported inside SMCs remains speculative. The mitogenic action of 5-
HT is initiated through its binding to a cell surface receptor and transport
into the cell, notably the 5-HT2A type (56,59) where tyrosine phosphoryla-
tion of a GTPase-activating protein appears as a downstream intermediate
in the signaling pathway. The involvement of superoxide anions formation
in association with 5-HT transport could also to play a role in the mitogenic
effects of 5-HT (60).
IV.
INFLAMMATORY CELLS
COPD is defined as an inflammatory disease of the lung in response to inhaled
toxic agents, usually cigarette smoking (61). Accordingly, it is conceivable
that inflammatory cells might contribute to the alterations of pulmonary ves-
sels. Indeed, the extent of pulmonary vascular remodeling correlates with the
severity of the inflammatory cell infiltrate in small airways (4,10). The authors
have shown that patients with COPD have an increased number of inflamma-
tory cells infiltrating the walls of pulmonary vessels (62). The number of
inflammatory cells in the adventitia of pulmonary muscular arteries of patient
with mild-to-moderate COPD was compared with that in nonsmokers and
smokers with normal lung function. There was an increased number of leuko-
cytes in pulmonary arteries of the COPD group as compared with the other
two groups (62). This inflammatory infiltrate was largely constituted by acti-
vated T lymphocytes with a predominance of the CD8
þ
T cell subset (62). The
number of neutrophils, macrophages, and B-lymphocytes was minimal in the
different groups and did not differ among them. The finding of increased
number of CD8
þ
T-lymphocytes in pulmonary arteries of COPD patients
was subsequently corroborated by Saetta et al. (15) and is consistent with a
