ABSTRACT
II. Imaging Neovascularization in Asthma 368
III. Imaging Neovascularization after Pulmonary Artery Obstruction 371
IV. Imaging Neovascularization in Lung Cancer 377
V. Concluding Comments and Future Expectations 382
References 382
I. Imaging Neovascularization in the Lung: Challenges for Measurement
Angiogenesis refers to the process by which new blood vessels form to meet new
needs demanded by ischemic tissue. In several pathologic processes, angiogen-
esis arises as a response to specific insults. For instance, when lung tumors
grow beyond the point at which they can be nourished by the existing pulmonary
circulation, the cancerous tissue becomes ischemic and starts signaling a need for
increased perfusion. Without such increased perfusion, tumor growth could not
continue, and this is the motivation for the intensive search for inhibitors of
angiogenesis as a therapy for cancer. In chronic asthma, there is often a slight
thickening of the airway wall, accompanied by increased smooth muscle and
vascularization. These new blood vessels may contribute to the warming or
humidification of inspired air, but their precise role in this disease remains some-
what controversial (1). Angiogenesis in the lung also occurs where there is patho-
logic obstruction of the pulmonary vasculature. In such cases, the bronchial
circulation expands to meet the needs of the ischemic tissue. Although this
process is clearly beneficial in keeping the lung tissue alive, the gas exchange
function of the lung is not corrected. Although hypoxia is often listed as a stimu-
lus for angiogenesis, the fact that angiogenesis readily occurs in the ventilated
lung with obstruction of deoxygenated pulmonary blood flow proves that ische-
mia is the more relevant stimulus. Because these new vessels to ischemic tissue
always originate from the microcirculation, attempts to visualize such vessels
will clearly stress the limits of all imaging modalities. In a recent excellent
review article, the applications and limitations of many of these techniques in
systemic organs are described (2). However, the lung poses unique challenges
because efforts to visualize angiogenesis in this organ are hampered by several
physiological factors. Most significant is the fact that new vessel growth predo-
minantly arises from the systemic circulation that normally perfuses the airways
and thorax. Although changes in pulmonary vessels occasionally appear in
metastases (3), nearly all observations of lung angiogenesis can trace the
origin of new vessels to their arterial sources from either the tracheobronchial
vasculature or intercostal arteries surrounding the lungs. Although in animal
models this neovascularization can develop to as much as 30% of the cardiac
output (4), under normal conditions the bronchial circulation represents ,3% of cardiac output (5). Because of the two distinct vascular systems within the
lungs, the larger and recruitable pulmonary vasculature obscure small angiogenic
alterations of the bronchial vasculature. In vivo imaging of the lungs with bron-
chial arteriograms can provide qualitative information about neovascularization.
However, to confirm new vessel proliferation, investigators have resorted to his-
tologic evaluation of tissue biopsy specimens with quantification of vascular
density. Even this approach has been difficult because unique endothelial
markers distinguishing new angiogenic vessels relative to pulmonary vessels
are not currently apparent, although a few studies have focused on defining endo-
thelial heterogeneity within normal lungs (6,7). Thus, in vivo imaging of neovas-
cularization within the lungs represents a significant challenge requiring further
characterization of vascular phenotype. This chapter is organized around three
different but well-characterized pathophysiologic conditions, for which different
imaging modalities are being used to assess vascular function and angiogenesis:
asthma, pulmonary artery obstruction, and lung cancer.
