Smoking increases the risks of vascular disease, cancer, and pulmonary dysfunction. Xenobiotic substances in cigarette smoke and tars induce both cancer and atherosclerosis in humans and animals. This proposal aims to define new pathways by which tobacco smoke contributes to cardiovascular disease. In the previous grant period, benzo(a)pyrene (BP), a polycyclic aromatic hydrocarbon procarcinogen present in cigarette smoke, was shown to induce the enzyme cyclooxygenase-2 (COX-2) in human vascular cells by a transcriptional mechanism. Moreover, vascular tissues from smokers were shown to contain detectible DNA adducts of benzo{a]pyrene. COX-2, up regulated in inflammation and cancer, is increased in atherosclerotic lesions. We predict that tobacco smoke mediates additional pathways besides that demonstrated for BP to up regulate COX-2 and other early response genes that promote progression of atherosclerosis. Specifically, our preliminary data indicate that unfractionated tobacco smoke strongly potentiates the action of inflammatory cytokines to increase COX-2 and other key genes that contribute to atherogenesis. BP itself potentiates the capacity of cytokines to activate COX-2 expression. These novel findings of interactions between tobacco smoke components and natural cellular mediators indicate that the tissue toxicities of smoking should be strongly increased in the setting of inflammation. The major aim of this continuing grant proposal is to study the synergy between BP and cytokines, and between tobacco smoke and cytokines, in activation of genes such as COX-2 in vascular cells, tissues and animal models. Such synergy offers a new approach in understanding the noxious effects of smoking on health. Characterizing tobacco smoke/cytokine effects in vascular endothelial and smooth muscle cells will permit new preventive strategies. To this end, modulation of effects of tobacco/cytokine synergy on gene activation by peroxisome proliferator ligands and by COX-2 inhibitors will be studied both in cells and in animal models as potential means to counteract the damaging effects of smoking on the arterial wall.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL055627-05A1
Application #
6472350
Study Section
Pathology A Study Section (PTHA)
Program Officer
Srinivas, Pothur R
Project Start
1997-08-01
Project End
2006-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
5
Fiscal Year
2002
Total Cost
$336,915
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
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