Differential Redox & Electrophilic Toxicities of Modified Tobacco Products

描述（由申请人提供）：香烟烟雾（CS）是分布在焦油和气相之间的反应性化学物质的有毒混合物。这些化合物中的许多通过产生活性氧（ROS）或通过耗尽含巯基的抗氧化剂而直接或间接地具有破坏性。因此，可能发生吸入香烟烟雾对肺上皮细胞组分的不可逆氧化应激诱导的损伤，并且与心血管疾病和慢性阻塞性肺病的发病机制有关。CS诱导的氧化应激也可能导致DNA损伤和不受控制的细胞增殖，从而导致肺癌。 我们的总体目标是表征来自不同卷烟品牌的亲电和/或氧化还原活性共轭酮的毒性作用，这些卷烟品牌被修改为减少危害。共轭酮，如不饱和酮，醛和醌具有毒理学重要性，因为它们促进氧化应激并最终通过共价修饰细胞大分子而导致肺中的细胞损伤。在香烟燃烧产物中检测到这些高活性化学物质的浓度很大，但浓度不同。然而，可燃低风险烟草制品的比较排放数据很少，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气相和焦油相提取物中的亲电和氧化还原活性成分来表征，并且这些化合物的不同毒性将通过无细胞和基于细胞的生物测定中的不同抗氧化反应来反映。 我们将测试我们的假设与以下三个目标：1。改进香烟烟雾中亲电气相羰基化合物和焦油相醌化合物的生成、取样和定量方法。2.评估来自不同类型香烟的香烟烟雾提取物中气相羰基化合物和焦油相醌类化合物的亲电和氧化还原电位。评估来自改性烟草产品的香烟烟雾组分对培养的原代小气道上皮细胞（SAEC）的抗氧化防御机制的差异影响这将是比较香烟类型之间不同CS组分中的亲电和促氧化组分的首批研究之一。将采用最先进的方法来准确地量化这些成分。这项拟议的研究将为标准香烟和所谓的"减害香烟"中亲电和氧化还原活性化合物对抗氧化酶系统的影响提供新的见解。“这项研究还有望指导进一步研究香烟烟雾中亲电羰基化合物和醌类化合物的生物和临床影响。

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.