MISSION

pression/reduction of MCP-1 and long-lasting changes in the balance between PEDF and VEGF. If confirmed,
analysis of blood MCP-1, PEDF, VEGF, quinones, nicotine, and cotinine, as well as analysis of
urine quinones and cotinine, will serve as biomarkers for risk of progression of AMD. Importantly, results
from this study will be directly applicable to other cardiovascular diseases associated with SHS.
A ROLE FOR CATHEPSIN B IN SECOND HAND TOBACCO SMOKE-RELATED VASCULAR DISEASES
Eunok Im, PhD; University of California, Los Angeles; YCSA 2006
SHS increases the risk of ocular diseases. For instance, the vascularized form of age-related macular
degeneration (AMD), one of the malicious vascular diseases that lead to blindness in the elderly, is tightly
associated with SHS. Therefore, identifying regulators of vessel formation will aid in finding early diagnostic
tools and ways to prevent disease progression. Dr. Im discovered that cathepsin B (a lysosomal cysteine
protease) inhibits angiogenesis by suppressing pro-angiogenic factors (vascular endothelial cell growth factor)
and generating anti-angiogenic factors (endostatin). These findings reveal cathepsin B as modulator of
angiogenesis. The goal of Dr. Im’s project is to fully elucidate the mechanism by which cathepsin B modulates
pro- and anti-angiogenic factors, and apply this information to the development of effective approaches
to control SHS-induced angiogenesis. First, it will determine if cathepsin B inhibits angiogenesis. By
comparison of ocular angiogenesis in cathepsin B null mice and control mice expansion of the understandings
of how cathepsin B affects AMD will occur. Second, assessment of the combination of SHS and loss
of cathepsin B will be conducted. Tests will be performed to show if SHS promotes angiogenesis within
the eye and if the combination of SHS and loss of cathepsin B intensifies angiogenesis. Finally, Dr. Im and
colleagues will investigate how cathepsin B regulates the stability of hypoxia-inducible factor 1 subunit a
(HIF-1a), and the outcome of these studies will substantially advance the understanding of how HIF-1a is
controlled. The molecular dissection of angiogenesis will enable better treatment and control of diseases
arising from SHS.
FAMRI Supported Publications
Rhee SH, Im E, Pothoulakis C. Toll-like receptor 5 engagement modulates tumor development and
growth in a mouse xenograft model of human colon cancer. Gastroenterology 2008;135(2):518-528.
VISION
COMPLETED RESEARCH
INFLAMMATION, SMOKING, AND BLINDNESS FROM OCULAR NEOVASCULARIZATION
Scott W. Cousins, MD; Duke University; CIA 2004
Neovascular acute macular degeneration (AMD), typified by choroidal neovascularization and invasion
of abnormal new blood vessels into the retina, has pathogenic features similar to other cardiovascular diseases,
particularly macrophage infiltration. AMD is caused by exposure to cigarette smoke. Dr. Cousins’
research tested the hypothesis that tobacco smoke-related nicotine acts upon circulating monocytes to
induce partially activated monocytes in the blood. The monocytes are recruited to the eye in areas of
choroidal neovascularization and lead to increasingly severe neovascularization via tumor necrosis factor
alpha (TNF-alpha) production (a potent cytotoxic and angiogenic factor). The relationships between neovascular
AMD, blood cotinine levels, and partial activation of blood monocytes were evaluated in a human
case-control study of passive and active smokers versus non-smokers. If a relationship were confirmed, it
would allow blood monocyte activation status to serve as a biomarker for risk of AMD progression. The
results of this study are also applicable to other cardiovascular diseases caused by exposure to cigarette
smoke. A similar study in mice evaluated the capacity of passive and active cigarette smoke (or nicotine) to
affect bone marrow progenitor cells, causing them to differentiate into activated monocytes after smoking
cessation. Results demonstrated that mice exposed to cigarette smoke suffered more severe pathology in
the bone marrow stem cells than those who were not exposed. Dr. Cousins’ results carry an implication of
particular interest to FAMRI, i.e., that flight attendants and others exposed to SHS may have long-term
changes in bone marrow stem cells predisposing them to vascular diseases, including atherosclerosis and
macular degeneration, long after cessation of the cigarette smoke exposure.
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