Objectives: This research is to investigate a mechanism of smoking induced atherosclerosis and to assess the impact of smoking reduction strategies on arterial injury. Improving our understanding of smoking induced atherosclerosis will increase our armamentarium against this and non-smoking induced atherosclerosis.
Specific aims : 1) To address the hypothesis that nicotine substitution or buproprion reduces smoking induced thromboxane (TX) formation and consequent endothelial dysfunction. 2) To address the hypothesis that nicotine substitution or buproprion reduces the smoking induced increment in isoprostane generation and inflammatory cytokines. 3) To address the hypothesis that smoking reduction may improve endothelial function even in the absence of smoking cessation. Relationship to health: Smoking is the leading cause of preventable death in America. Smoking costs the United States approximately $1 billion per annum. Reducing the harm of smoking will have a considerable impact on the health and health care costs of the United States. Research design: Healthy endothelium displays a vasodilatory response to vasoactive stimuli, which is blunted or absent in arterial disease. Flow mediated vasodilatation (FMD) can be measured non-invasively by ultrasound and correlates closely with subsequent development of atherosclerosis. Urinary isoprostane measured by gas chromatography / mass spectrometry (GC/MS) provide a specific and sensitive means to measure oxidative stress (OS) in vivo in humans. GC/MS also allows for accurate non-invasive quantification of TX and prostacyclin (PGI2) metabolites in humans. This research will be carried out in healthy age and gender matched human volunteers. Subjects will be studied for 6 months. It will quantify FMD in non- smokers, light and heavy smokers, before and after administration of vitamin C - an antioxidant, and aspirin - an inhibitor of TX and PGI2 synthesis. It will correlate FMD and eicosanoid production, before during and after smoking cessation on nicotine and non-nicotine smoking cessation medications. In addition, this research, in a separate experiment, will study the impact of nicotine and non nicotine assisted smoking reduction strategies on these parameters. Expected findings: We expect to find that smokers have impaired FMD and elevated OS, TX and PGI2 production. We expect that smoking reduction and cessation and the administration of antioxidants and aspirin will improve these parameters towards the levels of healthy volunteers and that the effects will be additive.
| Burke, Anne; Fitzgerald, Garret A (2003) Oxidative stress and smoking-induced vascular injury. Prog Cardiovasc Dis 46:79-90 |
