EPHEDRA: Enhanced PHthisic by Environmental Disruptors of Resolution Agonists

麻黄：通过消解激动剂的环境干扰剂增强肺结核

• 批准号: 10662073
• 负责人: Bruce D Levy
• 金额: $ 51.07万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10662073
• 关键词: Acute; Address; Agonist; Anabolism; Anti-Inflammatory Agents; Apoptotic; Area; Artificial nanoparticles; Bacteria; Bacterial Infections; Bacterial Pneumonia; Biology; CD59 Antigen; Chronic; Chronic lung disease; Collaborations; Consensus; Eicosanoids; Environmental Exposure; Environmental Health; Environmental Impact; Environmental Medicine; Environmental Protection; Excision; Exposure to; Family; Goals; Health; Homeostasis; Host Defense; Human; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Inhalation Exposure; Institutes; Lead; Leukotriene Production; Lipoxins; Lung; Lung infections; Maps; Mediator of activation protein; Mission; Molecular; Mus; National Institute of Environmental Health Sciences; Organ; Particulate Matter; Pathway interactions; Patient Care; Phagocytes; Pharmacology; Phase; Predisposition; Process; Production; Publishing; Pulmonary Inflammation; Regulation; Reporting; Resolution; Testing; Time; Tissues; United States National Institutes of Health; Viral; Virus; Virus Diseases; Widespread Disease; antimicrobial; base; cell type; cellular transduction; chronic inflammatory disease; environmental agent; improved; innovation; interest; lipid mediator; macrophage; microbial; microbial host; mimetics; nanomaterials; nanoparticle; nanoparticle exposure; neutrophil; novel; pathogenic microbe; programs; receptor; receptor expression; response

Abstract It now widely appreciated that uncontrolled inflammation is a unifying component in many widespread diseases 1, including chronic lung diseases 2,3. Inhalational exposure to respirable particulate matter can be an important precipitant or exacerbate of lung inflammation. From our earlier results, the resolution of inflammation is known today as an active process 4. There are several new families of specialized pro- resolving mediators (SPM) identified and characterized in acute inflammation 5. These protective mediators are enzymatically produced and are agonists at specific receptors transducing cell type specific functional responses critical in tissue resolution. Resolution programs of the inflammatory response are essentially uncharted in environmental health and medicine. Fundamental information is critically needed on the impact of new environmental agents within the resolution response and whether they perturb resolution to trigger chronic inflammatory responses and infections. Here, the B.D. Levy, C.N. Serhan and P. Demokritou labs unite to collaborate for NOT-ES-20018 and propose an innovative study entitled EPHEDRA: Enhanced PHthisic by Environmental Disruptors of Resolution Agonists, focusing on elucidating the impact of potentially hazardous environmental agents presented to the airway as nanoparticles on newly uncovered resolution programs that govern phagocyte functions and the return to homeostasis. Failed resolution or its disruption can lead to sustained lung inflammation and inefficient clearance of microbial pathogens, including viruses and bacteria. This proposal will test an innovative hypothesis, namely that specific environmental agents prime for sustained lung inflammation by disrupting cellular and molecular pro-resolving mechanisms that also increase susceptibility to lung infections; and replacement of resolvins and/or other specialized pro- resolving mediators that are potent agonists for resolution responses in lungs are required to protect lungs from hazardous environmental agents and restore effective microbial clearance. To test this hypothesis, we propose 3 specific aims to: 1) Determine the impact of environmental and engineered nanoparticles (NP) on the resolution of lung inflammation, 2) Establish the impact of NP disruptors of resolution on viral host responses and post-influenza secondary bacterial pneumonia, and 3) Determine the impact of NP exposure on macrophage efferocytosis, SPM production, pro-resolving receptors and SPM rescue. Results from these studies will elucidate fundamental mechanism(s) in the resolution of inflammation that are susceptible to disruptive environmental agents and toxic to resolution.

抽象的 现在人们普遍认识到，不受控制的炎症是许多广泛存在的疾病的一个统一组成部分。 疾病1，包括慢性肺部疾病2，3。吸入暴露于可吸入颗粒物可能会导致 肺部炎症的重要诱发因素或加剧因素。从我们之前的结果来看，分辨率为 今天，炎症被认为是一个活跃的过程4。有几个新的专门亲 在急性炎症中鉴定和表征的解决介质 (SPM) 5。这些保护性介质是 酶促产生，是特定受体的激动剂，转导细胞类型特定的功能 反应对组织分辨率至关重要。炎症反应的解决方案本质上是 在环境健康和医学领域是未知的。迫切需要关于影响的基本信息 决议反应中的新环境因素以及它们是否扰乱决议以引发慢性 炎症反应和感染。在这里，B.D.利维，C.N. Serhan 和 P. Demokritou 实验室联合起来 与 NOT-ES-20018 合作并提出一项题为 EPHEDRA：Enhanced PHthisic 的创新研究 解决激动剂的环境破坏者，重点阐明潜在危险的影响 在新发现的解决方案中，环境因素以纳米颗粒的形式呈现在气道中 控制吞噬细胞功能和恢复体内平衡。解决方案失败或破坏可能会导致 持续的肺部炎症和微生物病原体（包括病毒和细菌）清除效率低下。 该提案将测试一个创新假设，即特定的环境因素主要用于 通过破坏细胞和分子促解决机制来维持肺部炎症 增加肺部感染的易感性；和替换解析素和/或其他专业亲 需要解决介质是肺部解决反应的有效激动剂来保护 肺部免受有害环境因素的影响并恢复有效的微生物清除。为了测试这个 假设，我们提出 3 个具体目标： 1) 确定环境和工程纳米颗粒 (NP) 对肺分辨率的影响 炎， 2) 确定 NP 破坏分子对病毒宿主反应和流感后继发性的影响 细菌性肺炎，以及 3) 确定 NP 暴露对巨噬细胞胞吞作用、SPM 产生、促溶解的影响 受体和 SPM 救援。 这些研究的结果将阐明解决炎症的基本机制 容易受到破坏性环境因素的影响并且对解析有毒。