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，人们广泛赞赏不受控制的炎症是许多广泛的统一组成部分 疾病1，包括慢性肺部疾病2,3。吸入暴露于可呼吸的颗粒物可能是 肺部炎症的重要沉淀物或恶化。从我们较早的结果，解决 炎症如今被称为活跃过程4。 在急性炎症5中确定和表征的分辨介质（SPM）5。这些保护性介体是 酶促产生的，并且是特定受体转导细胞类型功能的激动剂 反应在组织分辨率中至关重要。炎症反应的解决方案本质上是 在环境健康与医学领域未知。基本信息至关重要 分辨率响应中的新环境代理以及它们是否扰动解决方案以触发慢性 炎症反应和感染。在这里，B.D. Levy，C.N。 Serhan和P. Demokritou Labs团结 为NOT-ES-20018合作，并提出了一项题为Ephedra的创新研究：增强的疗法 分辨率激动剂的环境破坏者，重点是阐明潜在危险的影响 环境代理商以纳米粒子的形式向气道展示了新发现的解决方案 控制吞噬细胞功能和恢复体内平衡。分辨率失败或破坏可能导致 包括病毒和细菌在内的微生物病原体的持续肺部炎症和效率低下的清除率。 该提议将检验一个创新的假设，即特定的环境推动者 持续的肺部炎症是通过破坏细胞和分子促促促疾病的机制 增加对肺部感染的敏感性；并替换Resolvins和/或其他专业专业 需要解决肺部解决方案反应的有效激动剂的介体以保护 来自危险环境药物的肺并恢复有效的微生物清除率。测试这个 假设，我们提出了3个特定目的： 1）确定环境和工程纳米颗粒（NP）对肺部分辨率的影响 炎， 2）确定NP分辨率对病毒宿主反应和Influenza次要的影响 细菌性肺炎和 3）确定NP暴露对巨噬细胞的影响，SPM产生，促分解 受体和SPM救援。 这些研究的结果将阐明炎症解决方面的基本机制 容易受到破坏性环境药物的影响，并且有毒是有毒的。