Differential Redox & Electrophilic Toxicities of Modified Tobacco Products

描述(申请人提供)：香烟烟雾(CS)是一种分布在焦油和气相之间的活性化学物质的有毒混合物。这些化合物中的许多直接或间接地通过产生活性氧物种(ROS)或耗尽含有巯基的抗氧化剂而具有破坏性。因此，吸入香烟烟雾可能会对肺上皮细胞成分造成不可逆转的氧化应激损伤，并与心血管疾病和慢性阻塞性肺疾病的发病机制有关。CS诱导的氧化应激也可能导致DNA损伤和细胞增殖失控，从而可能导致肺癌。我们的总体目标是表征来自不同卷烟品牌的亲电性和/或氧化还原活性的共联酮的毒性效应，这些品牌的卷烟被市场上作为减少危害的改良剂。共轭的酮，如不饱和的？，？-醛和苯醌具有重要的毒理学意义，因为它们促进氧化应激，最终通过共价修饰细胞大分子而导致肺内的细胞损伤。在卷烟燃烧产物中检测到大量但不同浓度的高活性化学物质。然而，可燃、降低风险的烟草产品的比较排放数据很少，而且缺乏烟草行业以外的全面毒性评估。我们的总体假设是，不同类型的香烟可以通过测量CS气体和焦油相提取物中的亲电性和氧化还原活性成分来表征，这些化合物的不同毒性将通过无细胞和基于细胞的生物检测中不同的抗氧化反应来反映。我们将通过以下三个目标来验证我们的假设：1.卷烟烟气中亲电气相酮和焦油相醌的生成、采样和定量的改进方法。2.评估来自不同类型卷烟的卷烟烟雾提取物中气相羰基和焦油相醌的亲电性和氧化还原潜力3.评估来自改良烟草产品的卷烟烟雾成分对培养的原代小气道上皮细胞(SAECs)抗氧化防御机制的不同影响这将是第一次比较不同卷烟类型卷烟不同CS组分中的亲电和促氧化成分的研究之一。将采用尖端方法来准确量化这些成分。这项拟议的研究将提供新的见解，了解标准香烟和所谓的“减害卷烟”中的亲电化合物和氧化还原活性化合物对抗氧化酶系统的影响。这项研究还有望指导进一步研究香烟烟雾中的亲电羰基和苯二酚的生物学和临床影响。

DESCRIPTION (provided by applicant): Cigarette smoke (CS) is a toxic mixture of reactive chemicals distributed between tar and gas phases. Many of these compounds are directly or indirectly destructive by generation of reactive oxygen species (ROS) or by depletion of sulfhydryl-containing antioxidants. As a result, irreversible oxidative stress-induced damage to cellular components of the lung epithelium by inhaled cigarette smoke may occur and has been linked to the pathogenesis of cardiovascular disorders and chronic obstructive pulmonary disease. CS-induced oxidative stress may also cause DNA damage and uncontrolled cell proliferation that could lead to lung cancer. Our overall objective is to characterize the toxic effects of electrophilic and/or redox-active conjugated ketones from different cigarette brands marketed as being modified for harm reduction. Conjugated ketones, such as unsaturated ?,?-aldehydes and quinones are of toxicological importance because they promote oxidative stress and eventually lead to cellular damage in the lung by covalently modifying cellular macromolecules. These highly reactive chemicals are detected in large but variable concentrations in cigarette combustion products. However, comparative emission data for combustible reduced risk tobacco products are rare and a comprehensive toxicity assessment outside of the tobacco industry is lacking. Our overarching hypothesis is that different types of cigarettes can be characterized by measuring the electrophilic and redox active constituents in CS gas- and tar-phase extracts and that the differential toxicity of these compounds will be reflected by different antioxidant responses in cell-free and cell-based bioassays. We will test our hypotheses with the following three aims: 1. Advance methods to generate, sample and quantify electrophilic gas-phase carbonyls and tar-phase quinones in cigarette smoke. 2. Assess the electrophilic and redox potential of gas phase carbonyls and tar phase quinones in cigarette smoke extracts derived from different types of cigarettes 3. Assess the differential effects of cigarette smoke components from modified tobacco products on the antioxidant defense mechanisms of cultivated primary small airway epithelial cells (SAECs) This will be among the first studies to compare electrophilic and pro-oxidative components in different CS fractions between cigarette types. Cutting-edge methods will be adapted to accurately quantify these components. The proposed study will provide new insights into the impact on antioxidant enzyme systems by electrophilic and redox-active compounds in both standard and so-called "harm reduction cigarettes." The study is also expected to guide further research on the biological and clinical impacts of electrophilic carbonyls and quinones in cigarette smoke.