John P. Richie - US grants

No abstract provided

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Abstract Toxicity and negative health effects of tobacco smoking results from the inhalation of a complex mixture of over 7000 chemicals including many toxicants and carcinogens included on the FDA list of Harmful and Potentially Harmful Constituents (HPHCs). Oxidants are a major class of toxicant abundant in tobacco smoke and are thought to play a critical role in the development of tobacco related diseases including COPD, CVD and cancer through the generation of oxidative stress/damage and inflammation. However, the specific oxidants most responsible remain unclear. While several oxidants are included on the HPHC list (eg. carbonyls), one of the most reactive, damaging and abundant classes, free radicals, are not represented. Recently we found that delivery of radicals varied greatly (>12-fold) across cigarette brands, was substantially impacted by product design (e.g. tobacco variety) and smoking behaviors and was high in other popular combustible products including little filtered cigars. Radical delivery was also highly correlated with other oxidants including carbonyls (eg. acrolein). Based upon these findings, we propose that tobacco-derived oxidants, including free radicals, represent an important target for developing regulatory strategies aimed at reducing the harm from combustible tobacco use. This approach is strongly supported by our preliminary findings that levels of oxidative stress biomarkers are significantly reduced in smokers who switch from high to low oxidant cigarettes. The objectives of this project are to identify specific oxidants responsible for the generation of tobacco related harm and determine the impact of oxidant reduction on tobacco-related toxicity endpoints. To this end, we propose 3 specific aims. In Aim 1, we will determine the levels and identity of free radicals and other oxidants delivered by different combustible tobacco products/brands using advanced electron paramagnetic resonance (EPR) spectroscopy and liquid chromatography-tandem mass spectrometry (LC- MS/MS) methodologies. In Aim 2 we conduct exposure studies in a relevant mouse model to determine the impact of tobacco smoke oxidants on lung damage and inflammation; comparing effects of high vs. low oxidant brands and tobacco varieties. In Aim 3, we will conduct mouse exposure studies to determine the impact of charcoal filtration of cigarette smoke on oxidant-induced lung damage in the mouse. Overall, these studies will significantly contribute to the field of tobacco regulatory science by focusing on the toxicological importance of oxidant exposure. These data will be of particular value to the FDA for the development of regulatory policies aimed at reducing harm imposed by tobacco usage.

Abstract Cigarette smoke is a major source of reactive oxidants, including free radicals and aldehydes, which are playing critical roles in the development and progression of most tobacco-caused diseases including lung cancer. With the rapidly growing popularity of electronic cigarettes (EC), there is growing concern about potential harm associated with their use. Using state-of-the-art high resolution analytical methods to detect and measure oxidants, we have demonstrated that EC aerosols contain significant levels of highly reactive free radicals and aldehydes. While these oxidants were detected in all types of EC tested, their levels varied substantially by EC product design, flavor additives, and usage behaviors. Based on these studies and the known importance of oxidative stress/damage and inflammation in lung carcinogenesis, our proposal focuses on the potential impact of EC-derived free radicals and aldehydes in mechanisms involved in lung cancer development. Specifically, we hypothesize that exposure to oxidants from EC use will lead to oxidative stress/damage and inflammation in the lung resulting in increased susceptibility to cancer. We will utilize a translational approach to test this hypothesis by first, in the laboratory, identifying the chemical identity and potential for harm for the major free radicals produced by EC (Aim 1), secondly conducting controlled exposure studies in a relevant mouse model on the impact of EC-aerosols on specific lung cancer-related endpoints and lung tumor development (Aim 2), and thirdly, conduct secondary analyses of samples generated from an NIDA-funded EC clinical trial to examine the impact of long-term switching from conventional cigarettes to ECs on relevant oxidative stress/damage and inflammatory biomarkers (Aim 3). In Aim 1, we utilize advanced electron paramagnetic resonance (EPR) spectroscopy techniques and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodologies to identify major radical species in representative EC devices (including the NIDA developed standardized EC, SREC). Aim 2 will consist of multiple short-term exposure studies in the A/J mouse, both in naïve animals and those pre-exposed to cigarette smoke, and will also test the specific impact of flavorants, radicals and aldehydes on systemic and tissue specific biomarkers of oxidative stress/damage, inflammation and lung-cancer related pathways. Additionally, we will determine and compare the impact of EC aerosol and cigarette smoke exposure on lung tumorigenesis in an NNK-induced A/J mouse model. In Aim 3, the impact of switching from conventional cigarettes to EC on biomarkers of oxidative stress/damage and inflammation in healthy adult smokers will be determined. Our research approach is innovative based upon its novel focus on EC-derived free radicals, use of innovative methods and biomarkers, and its integrative translational design. With the completion of these studies, we hope to provide much needed information regarding the potential lung-cancer related harm associated with free radical and oxidant exposure from tobacco products which can be used for the development of regulatory policies aimed at EC products/usage.

Abstract Cigarette smoke (CS) is a major source of reactive oxidants. Oxidative stress and damage resulting from exposure to oxidants such as free radicals and aldehydes play critical roles in the development and progression of most tobacco-caused diseases, including cancer and chronic obstructive pulmonary disease (COPD). Using state-of-the-art high resolution analytical methods to detect and measure oxidants, we have demonstrated that electronic cigarettes (EC) aerosols contain highly reactive free radicals and aldehydes; albeit at levels which are typically 10- to 1000-fold lower than in cigarette smoke. We found that free radicals were produced in all generations of EC products currently on the market, but that levels vary significantly by EC product design and usage behaviors. Based on these studies and the known importance of oxidative stress/damage in pulmonary diseases, our proposal focuses on toxicities caused by exposure to EC-derived free radicals and aldehydes and their role in the development of COPD. Specifically, we hypothesize that 1) EC aerosol exposure will be associated with negative long-term pulmonary health effects, albeit to a lesser extent than combustible cigarette smoke exposure, and 2) switching from combustible cigarettes to EC will lead to reductions in oxidant exposures and, thus, improved prognosis in COPD. In this proposal, we will utilize a highly translational approach, conducting long-term in vivo exposure studies in a CS-induced COPD mouse model and a pilot clinical intervention study of switching to EC in mild-moderate COPD smokers. The specific objectives are to quantitate absolute levels of EC or CS oxidants at the point of exposure in the animal model and to determine the relative impact of these oxidants through the examination of lung function (primary endpoint). Pulmonary biomarkers of oxidative stress and inflammation will also be examined. The specific aims have been designed to allow for a thorough evaluation of the long term health consequences of EC use in naïve and CS exposed mice comparing effects of high vs. low oxidant products, and the impact of selective filtration of oxidant-induced lung damage in the mouse (Aim 1); impact of switching from cigarette smoke exposure to EC aerosols to mimic switching in humans (Aim 2); and translatability of laboratory findings in smokers with mild-moderate COPD (Aim 3). Overall, these studies will significantly contribute to the field of tobacco regulatory science by focusing on the toxicological importance of oxidant exposure from specific EC devices. These data will be of particular value to the FDA for the development of regulatory policies aimed at reducing harm imposed by tobacco products.