Nitrite dependent protection against Cl2 gas toxicity_role of chlorinated lipids

亚硝酸盐依赖性对 Cl2 气体毒性的保护_氯化脂质的作用

基本信息

批准号：
8544644
负责人：
RAKESH P. PATEL
金额：
$ 54.66万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2013-09-18 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8544644
关键词：
Acute Lung Injury Alcohols Aldehydes Animals Apoptotic Attenuated Bioenergetics Biological Availability Biological Markers Breathing Canis familiaris Cell Death Cells Chlorine Collaborations Complement Complex Cyanides Data Development Diet Disease Dose Drug Approval Endothelial Cells Epithelial Epithelial Cells FDA approved Fatty Acids Functional disorder Gases Glean Goals Human Inflammation Inflammatory Injection of therapeutic agent Injury Intramuscular Intramuscular Injections Intranasal Administration Intravenous Lipids Lung Mediating Mediator of activation protein Molecular Mus Nitrites Oryctolagus cuniculus Peripheral Permeability Phase Plasmalogens Poisoning Proteins Protocols documentation Publishing Rattus Reaction Reperfusion Injury Research Research Institute Role Route Safety Signal Transduction Syndrome System Testing Therapeutic Therapeutic Effect Time Tissues Toxic effect Toxicology Treatment Efficacy Treatment Protocols Vasodilation airway hyperresponsiveness animal rule extracellular improved in vivo indexing insight mitochondrial dysfunction mortality novel prevent public health relevance

项目摘要

DESCRIPTION (provided by applicant): Chlorine (Cl2) gas mediated injury is complex involving a direct toxicity that occurs during the exposure and a robust post exposure toxicity that occurs over hrs-days to the airways, pulmonary and systemic vasculature. Preliminary data and our recently published studies show that injury post Cl2 exposure includes significant decreases in NO-bioavailability as indexed by diminution of eNOS-dependent vasodilation in the pulmonary and extrapulmonary vasculature and demonstration that post Cl2 exposure administration of nitrite (an NO- repleting strategy) by a single IM injection, protects against acute lung injury, airway hyper-reactivity and importantly, mortality. In this proposal we will i) establish a therapeutic framework for the development for the use of nitrite as a post exposure therapeutic that can be administered in mass casualty scenarios. How post- Cl2 gas injury occurs is unclear. We show novel data that Cl2 gas increases lung and circulating chlorinated lipids (Cl-lip), which are ¿-chloro fatty acids derived from plasmalogens. Cl-lip may serve as novel biomarkers for Cl2 exposure, but we also provide evidence that these species can themselves cause acute lung injury and airway epithelial cell dysfunction. Importantly, Cl-lip dependent toxicity can also be prevented by post-exposure nitrite therapy. Taken together, we hypothesize that Cl-lip are novel biomarkers and mediators of post Cl2 gas toxicity and that post-exposure nitrite therapy will attenuate Cl2 gas and Cl-lip dependent toxicity and will test this via the following Specific Aims: 1. Determine the role of Cl-lip in mediating Cl2 gas induced toxicity, 2. Determine optimal nitrite therapeutic conditions for attenuating lethal and sub-lethal Cl2 gas toxicity, 3. Determine safety / toxicology profiles for IM nitrite administration under GLP conditions. A combination of in vivo Cl2 gas exposure with ex vivo studies is proposed. We feel this research is both timely and important and anticipate will yield novel insights into molecular mechanisms of Cl2 gas toxicity and identify and develop therapeutic (countermeasure) strategies.

描述（由申请人提供）：氯 (Cl2) 气体介导的损伤很复杂，涉及暴露期间发生的直接毒性以及数小时内对气道、肺部和全身脉管系统发生的强烈暴露后毒性。最近发表的研究表明，Cl2 暴露后的损伤包括一氧化氮生物利用度的显着降低，表现为肺和肺外 eNOS 依赖性血管舒张的减少血管系统和证明，Cl2 暴露后通过单次肌注注射亚硝酸盐（一种 NO 补充策略）可以预防急性肺损伤、气道高反应性以及重要的是死亡率。在本提案中，我们将 i) 建立一个治疗框架：使用亚硝酸盐作为一种可用于大规模伤亡情况的暴露后治疗剂的开发尚不清楚。我们显示的新数据表明，Cl2 气体会增加肺部和循环氯化脂质。（Cl-lip），它们是 ¿缩醛磷脂衍生的氯脂肪酸可以作为 Cl2 暴露的新生物标志物，但我们也提供证据表明这些物种本身可以引起急性肺损伤和气道上皮细胞功能障碍，重要的是，Cl-lip 依赖性毒性也可能是这样的。综上所述，我们认为 Cl-lip 是 Cl2 气体毒性的新型生物标志物和介质，并且暴露后亚硝酸盐治疗会减弱。 Cl2 气体和 Cl-lip 依赖性毒性，并将通过以下具体目标进行测试： 1. 确定 Cl-lip 在介导 Cl2 气体诱导毒性中的作用， 2. 确定减轻致死和亚致死作用的最佳亚硝酸盐治疗条件 Cl2 气体毒性，3. 根据 GLP 确定肌注亚硝酸盐给药的安全性/毒理学特征我们认为这项研究既及时又重要，预计将产生对 Cl2 气体毒性的分子机制的新见解，并确定和开发治疗（对策）策略。