NQO1: Linking Oxidant Stress to Inflammation in Airway Epithelial Cells

NQO1：氧化应激与气道上皮细胞炎症的联系

基本信息

批准号：
8397683
负责人：
Judith A Voynow
金额：
$ 27.69万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8397683
关键词：
Accident and Emergency department Aldehydes Animals Antioxidants Arachidonic Acids Asthma B-Lymphocytes Biological Models Breathing Cell membrane Cells Chronic Complex Data Dicumarol Disease Electrons Environment Environmental Health Epidemiologic Studies Epithelial Epithelial Cells Equilibrium Exposure to F2-Isoprostanes Genetic Genetic Predisposition to Disease Genetic Transcription Genotype Glutathione Disulfide Hospitalization Human Hydrogen Peroxide IL8 gene In Vitro Individual Inflammation Inflammatory Response Injury Isoprostanes Knockout Mice Lentivirus Vector Link Lipids Lung Mediating Membrane Lipids MicroRNAs Molecular Mus NAD(P)H dehydrogenase (quinone) 1, human NADP NF-kappa B Oxidants Oxidation-Reduction Oxidoreductase Ozone Patients Predisposition Production Pulmonary Heart Disease Quinones Reactive Oxygen Species Recycling Regulation Relative (related person)Role Schools Sentinel Serum Signal Transduction Testing Tocopherols Toxic effect Ubiquinone Up-Regulation Visit Vitamin E Vulnerable Populations Wild Type Mouse activating transcription factor airway hyperresponsiveness airway inflammation airway obstruction chemokine cyclopentenone epidemiologic data in vivo inhibitor/antagonist keratinocyte lipid mediator mRNA Expression mouse model neutrophil oxidant stress ozone exposure peroxidation public health relevance response tocopherylquinone transcription factor transmission process

项目摘要

DESCRIPTION (provided by applicant): Individual responses to ozone vary widely with some individuals having a much lower threshold of ozone sensitivity for pulmonary toxicity. Therefore, a complex of individual genetic factors likely controls the transmission and propagation of oxidant signaling following ozone exposure. Epidemiologic studies support the role of the wild-type NADPH quinone oxidoreductase1 (NQO1) genotype as an asthma susceptibility factor in the presence of ozone. NQO1 catalyzes the obligate 2-electron reduction of quinones and is considered an intracellular antioxidant. Our preliminary data demonstrate that NQO1 is required for ozone-induced IL-8/ KC expression, increased neutrophilic airway inflammation, and airway hyperresponsiveness in mice. This poses a conundrum to explain how an oxidoreductase that recycles antioxidants propagates ROS signaling linking oxidant stress to an inflammatory response. We will use primary human airway epithelial cells and mouse (wild-type and NQO1-null) model systems to test the following unprecedented hypothetical mechanism to explain how NQO1 links oxidant stress to epithelial inflammation: NQO1 and ozone-generated ROS are central regulators of airway inflammation following ozone exposure. We propose that NQO1 regulates the intracellular redox environment resulting in a shift in the balance of isoprostanes (isoP). In the presence of NQO1, ROS and F2-isoP activate NF-(B, resulting in increased IL-8/ KC expression and increased neutrophilic inflammation. In the absence of NQO1, the cell favors A2-isoP production, which inhibits NF-(B activation, causing the paradoxical effect of blocking IL-8/ KC expression and neutrophilic inflammation. The specific aims are: Aim 1a: To determine whether following ozone exposure, NQO1 mediates neutrophilic inflammation and airway hyperresponsiveness via upregulation of the neutrophil chemokines KC/ IL-8. Aim 1b: To determine whether NQO1 expression in structural airway epithelial cells and/or in hematopoetic cells is required for pulmonary responses to ozone. Aim 2a: To determine whether NQO1 alters the cellular redox state, inducing a relative reducing environment as determined by levels of reduced: oxidized (-tocopherol, reduced: oxidized ubiquinone and reduced: oxidized glutathione. Aim 2b: To determine whether following ozone exposure, NQO1 causes a shift in isoprostane production with a relative increase in F2- isoP formation and conversely, a loss of NQO1 in vivo, causes increased formation of A2-isoP. Aim 3a: To determine whether following ozone exposure, F2-isoP and/or ozone-generated ROS upregulate IL-8/KC expression by NF-(B activation. Aim 3b: To determine whether this regulation is abrogated in the absence of NQO1 by A2-isoP inhibition of NF-(B release from I(B.

描述（由申请人提供）：对臭氧的个体反应差异很大，一些人对臭氧对肺毒性的敏感性的阈值要低得多。因此，单个遗传因素的复合物可能控制臭氧暴露后氧化剂信号传导的传播和传播。流行病学研究支持野生型NADPH喹酮氧化还原酶1（NQO1）基因型作为臭氧存在下的哮喘易感因子的作用。 NQO1催化了Quinones的强制性2-电子还原，被认为是细胞内抗氧化剂。我们的初步数据表明，NQO1是臭氧诱导的IL-8/ kC表达，中性粒细胞气道炎症增加以及小鼠气道高反应性所必需的。这提出了一个难题，以解释氧化剂回收抗氧化剂的氧化还原酶如何传播ROS信号传导将氧化剂应激与炎症反应联系起来。我们将使用原发性人类气道上皮细胞和小鼠（野生型和NQO1-NULL）模型系统来测试以下前所未有的假设机制，以解释NQO1如何将氧化应激与上皮炎症联系起来：NQO1和臭氧产生的ROS是Airway炎症的中心调节剂。我们建议NQO1调节细胞内氧化还原环境，从而导致异丙烷（ISOP）平衡发生变化。在存在NQO1的情况下，ROS和F2-ISOP激活NF-（B，导致IL-8/ KC表达增加并增加中性粒细胞炎症。在缺乏NQO1的情况下，细胞有利于A2-ISOP产生，从而抑制Nf-（B激活，引起障碍性的疾病，构成了IL-8/ KC的疾病均具有障碍的疾病。 1a：确定臭氧暴露是否会通过上调中性粒细胞趋化因子KC/ IL-8的上调，而NQO1是否介导了中性粒细胞的炎症和气道超响应性。氧化还原状态，诱导相对还原的环境，取决于降低的水平：氧化（ - 皮质酚，还原：氧化的泛氨酸酮和还原：氧化的谷胱甘肽2B：氧化剂2B：确定臭氧暴露，NQO1是否会导致异位烷的相对损失和交流的相对形式的相对形式增加，nqO1会导致相对增长的偏移，并逐渐增加，并且会导致f2-ISOP的相对形式增加，并且是f2-iSOP的形式，并且是f 2-iSOP的损失。 A2-ISOP。目标3A：确定是否在臭氧暴露，F2-ISOP和/或臭氧产生的ROS是否通过NF-上调IL-8/KC表达（B激活。AIP。AIM 3B：确定在没有NF-释放nF-释放I（B中）的NQO1的情况下，该法规是否会消除该法规（b。