Biomedical Engineering Reference
In-Depth Information
Hypoxia may elicit proliferation of SMCs in pulmonary arteries by
pathways unrelated to vessel contraction. Indeed, isolated vascular SMCs
in culture proliferate when exposed to hypoxia by mechanisms that are
related to potassium currents and, therefore, independent of the vascular
tone or the presence of other vascular cells (i.e., endothelium) (116).
Furthermore, hypoxia may induce the endothelial synthesis and release of
mediators that are capable to induce proliferation of SMCs such as ET-1
(117) or serotonin (58), and inhibit antiproliferative mediators, such as
NO or prostacyclin (110).
Hypoxia is a major factor involved in the induction of VEGF gene
expression, which may promote pulmonary vascular remodeling in chronic
lung diseases (81,118). Indeed, hypoxia-inducible factor-1 (HIF-1) activates
VEGF gene expression and upregulates VEGF receptor-1 (119,120). Never-
theless, the effect of hypoxia by VEGF-dependent mechanisms is complex
since it might exert opposite effects on cell proliferation. Inhibition of
VEGF receptor-2 causes muscularization of arterioles in nonhypoxic rat
lung (110), an effect attributed to the impairment of the endothelial synth-
esis of NO and prostacyclin by VEGF-dependent mechanisms. On the other
hand, exposure to hypoxia of rats treated with a VEGF receptor-2 inhibitor
results in endothelial cell proliferation and severe pulmonary hypertension
(121).
The role of hypoxia in the pathogenesis of pulmonary vascular
changes in COPD is further puzzled by clinical and histological observations
after hypoxemia correction. In subjects living at high altitudes or in animals
kept in a hypoxic environment, restoration of normal oxygen levels results
in normalization of pulmonary artery pressure and regression of muscular-
ization of pulmonary vessels (122). By contrast, long-term oxygen therapy
does not reverse completely pulmonary hypertension in COPD (123), and
prominent vascular changes persist in subjects who have received this treat-
ment for years (11). In addition, structural abnormalities in pulmonary
arteries can be observed, at least in part, in patients with mild COPD
who do not have hypoxemia and also in smokers with normal lung function
(4,6,62).
Overall, these observations suggest that mechanisms other than
hypoxemia might contribute to pulmonary vascular changes in COPD.
C.
Inflammation
The idea of an inflammatory process as a mechanism of vascular remodeling
arises from studies demonstrating a correlation between the severity of the
inflammatory infiltrate in small airways and the structural abnormalities
of pulmonary muscular arteries (4,8). Recent morphologic studies have
shown an increased number of CD8
รพ
T-lymphocytes infiltrating the adven-
titia of pulmonary muscular arteries in patients with mild-to-moderate
