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：
8009873
负责人：
Judith A Voynow
金额：
$ 36.13万
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 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8009873
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. PUBLIC HEALTH RELEVANCE: Ozone is an environmental health threat to vulnerable populations including patients with chronic cardiopulmonary disease. We propose that a candidate for a genetic susceptibility factor related to ozone-induced pulmonary toxicity is NADPH quinone oxidoreductase 1 (NQO1). We hypothesize that NQO1 functions as a gate-keeper in airway epithelial cells to transmit ozone-generated oxidant stress to an inflammatory response which causes ozone-triggered airway disease.