Differential Redox & Electrophilic Toxicities of Modified Tobacco Products

微分氧化还原

基本信息

批准号：
8445036
负责人：
Norbert Staimer
金额：
$ 15.83万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8445036
关键词：
Accounting Acids Acrolein Activity Cycles Aldehydes Antioxidants Benzoquinones Binding Biological Biological Assay Breathing Cardiovascular Diseases Catalytic Domain Cell Proliferation Cells Cellular Stress Response Cessation of life Chemicals Chronic Obstructive Airway Disease Cigarette Clinical Computers Cysteine DNA Damage Data Defense Mechanisms Disulfides Dithiothreitol Endoplasmic Reticulum Enzymes Epithelial Cells Epithelium Gases Generations Genes Goals Harm Reduction Health Inflammatory Ketones Knowledge Lead Link Lung Mainstreaming Malignant neoplasm of lung Manufacturer Name Marketing Measures Mediating Metals Methods Monitor NF-kappa B Nicotine Oxidation-Reduction Oxidative Stress Particle Size Pathogenesis Phase Phosphorylation Production Property Proteins Protons Quinones Reaction Time Reactive Oxygen Species Reference Standards Regimen Repressor Molecules Research Resolution Risk Sampling Scanning Selenocysteine Sentinel Smoke Smoking Stress System Tars Testing Time Tobacco Tobacco Industry Toxic effect Toxicity Tests United States base cigarette smoke-induced cigarette smoking cigarette smoking comparative cytokine endoplasmic reticulum stress glutathione peroxidase high throughput screening insight macromolecule mass spectrometer novel particle protein folding public health relevance response ultrafine particle

项目摘要

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.

描述（由申请人提供）：香烟烟雾（CS）是分布在焦油相和气相之间的活性化学物质的有毒混合物。许多这些化合物通过产生活性氧（ROS）或通过消耗含巯基的抗氧化剂而直接或间接具有破坏性。因此，吸入香烟烟雾可能会对肺上皮细胞成分造成不可逆的氧化应激损伤，并且与心血管疾病和慢性阻塞性肺病的发病机制有关。 CS 诱导的氧化应激还可能导致 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香烟品牌的亲电子和/或氧化还原活性共轭酮的毒性作用，这些香烟品牌经过改良以减少危害。共轭酮，例如不饱和α,β-醛和醌具有重要的毒理学意义，因为它们会促进氧化应激，并最终通过共价修饰细胞大分子导致肺部细胞损伤。这些高活性化学物质在卷烟燃烧产物中检测到的浓度很大，但浓度各不相同。然而，可燃性降低风险烟草产品的比较排放数据很少，并且缺乏烟草行业之外的全面毒性评估。我们的总体假设是，可以通过测量 CS 气相和焦油提取物中的亲电子和氧化还原活性成分来表征不同类型的香烟，并且这些化合物的不同毒性将通过无细胞和细胞中的不同抗氧化反应反映出来。基于生物测定。我们将通过以下三个目标来检验我们的假设： 1. 改进香烟烟雾中亲电子气相羰基和焦油相醌的生成、采样和定量方法。 2. 评估不同类型卷烟烟气提取物中气相羰基和焦油相醌的亲电子电势和氧化还原电势 3. 评估改良烟草产品的卷烟烟雾成分对培养初级小气道抗氧化防御机制的不同影响上皮细胞 (SAEC) 这将是首批比较不同类型卷烟中不同 CS 部分中的亲电子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。拟议的研究将为标准香烟和所谓的“减害香烟”中的亲电子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。该研究还有望指导对香烟烟雾中亲电羰基和醌的生物学和临床影响的进一步研究。