Project 2 :Specialized Pro-Resolving Lipid Mediators

项目 2：专业化脂质调节剂

基本信息

批准号：
8375337
负责人：
Bruce D Levy
金额：
$ 38.46万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8375337
关键词：
Acids Acute Acute Lung Injury Address Adult Respiratory Distress Syndrome Air Alkaline Phosphatase Anabolism Anti-Inflammatory Agents Anti-inflammatory Biological Process CD59 Antigen Cell Communication Cells Clinical Collaborations Critical Illness Data Development Docosahexaenoic Acids Dose Edema Epithelial Epithelial Cells Epithelium Experimental Models Gastric Acid Gene Targeting Generations Genotype Health Homeostasis Host Defense Human Hydrochloric Acid Infection Inflammation Inflammatory Inflammatory Response Injury Instruction Intervention Lead Leukocyte Trafficking Leukocytes Lipids Liquid substance Lower respiratory tract structure Lung Lung Inflammation Mechanics Mediating Mediator of activation protein Medical Molecular Morbidity - disease rate Mucous Membrane Organ Pharmacology Phase Polyunsaturated Fatty Acids Predisposition Program Research Project Grants Property Proteins Publishing Pulmonary aspiration of gastric contents Regulation Reporting Resolution Resources Respiratory Mechanics Role Secondary to Series Severities Signal Pathway Signal Transduction Stimulus Structure of parenchyma of lung Structure-Activity Relationship Surface Testing Time Tissue Model Tissues airway epithelium airway inflammation antimicrobial bactericide base comparative design heme oxygenase-1 inhibitor/antagonist injured injured airway insight interest lipid mediator microbial microbial host mortality neutrophil novel therapeutic intervention novel therapeutics prevent research study respiratory response restoration

项目摘要

The proposed experiments in Project 2 will test the hypothesis that in health, mucosal epithelial injury by noxious stimuli initiates airway formation of specialized pro-resolving mediators that promote resolution of acute inflammation and restitution of airway homeostasis. Published reports and preliminary data from ongoing collaborations with Projects 1, 3 and 4 have identified pivotal roles for airway epithelia and leukocytes in regulating acute inflammation, injury and host defense. In the common clinical setting of aspiration, disruption of airway epithelial integrity by gastric acid leads to tissue injury and an increased susceptibility to infection that can result in the acute respiratory distress syndrome. Polyunsaturated fatty acids, including docosahexaenoic acid (C22:6), are present during airway inflammation and converted to bioactive lipid mediators. Some ofthese mediators, namely protectins, D-series resolvins, and maresins display anti-inflammatory and pro-resolving actions, including regulation of leukocyte trafficking to protect against neutrophil-mediated tissue injury, increased microbial clearance and enhanced mucosal epithelial host defense. Generation ofthe C22:6-derived protectins, D-series resolvins and maresins in airway injury and their capacity to block inflammation and promote resolution in the airway has not been evaluated. In addition to generation ofthese specialized pro-resolving mediators, their roles for organ protection at mucosal surfaces will be the focus of Project 2. To test our hypothesis, we propose three specific aims: * Determine the time course for specialized pro-resolving mediator formation after airway injury ¿ Actions of specialized pro-resolving mediators on airway epithelial functional responses, and * Establish the regulation of acute lung injury resolution by specialized pro-resolving mediators Project 2's specific aims on airway resolution pharmacology will be greatly facilitated by the synergy and unique resources to be provided by the proposed research program Projects and Cores and will enable us to (i) uncover new molecular insights into lipid-derived signaling pathways engaged during mucosal injury to the lower respiratory tract; and (ii) design novel therapeutic strategies that lessen the severity and consequent morbidity of acute lung injury and critical illnesses. .

项目 2 中提出的实验将检验以下假设：在健康状态下，有害刺激引起的粘膜上皮损伤会启动专门的促消退介质的气道形成，从而促进急性炎症的消退和气道稳态的恢复已发表的报告和来自与我们正在进行的合作的初步数据。项目 1、3 和 4 已经确定了气道上皮和白细胞在调节常见临床环境中的急性炎症、损伤和宿主防御方面的关键作用。误吸、胃酸破坏气道上皮完整性会导致组织损伤和感染易感性增加，从而导致急性呼吸窘迫综合征，包括二十二碳六烯酸 (C22:6) 在内的多不饱和脂肪酸在气道炎症期间存在并转化。其中一些介质，即保护素、D 系列消退素和 maresins，具有抗炎和促消退作用，包括调节白细胞运输以防止中性粒细胞介导的组织损伤，增加微生物清除和增强粘膜上皮宿主防御，在气道损伤中产生 C22:6 衍生的保护素、D 系列消解素和 maresins，以及它们阻止炎症和促进消退的能力。除了生成这些专门的促消解介质外，气道尚未得到评估，它们在粘膜表面的器官保护作用将是项目 2 的重点。为了检验我们的假设，我们提出了三个具体目标： * 确定气道后专门的促解决介质形成的时间进程受伤 ¿专门的促解决介质对气道上皮功能反应的作用，和 *通过专门的解决方案建立急性肺损伤解决的调节机制调解员拟议的研究计划“项目和核心”提供的协同作用和独特资源将极大地促进项目 2 在气道溶解药理学方面的具体目标，并使我们能够 (i) 揭示粘膜过程中参与的脂质衍生信号通路的新分子见解。下呼吸道损伤；和（ii）设计新的治疗策略，减轻严重程度和后果急性肺损伤和危重疾病的发病率。。