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.

摘要 现在广泛认识到，不受控制的炎症是许多广泛传播的炎症的统一组成部分。 疾病1，包括慢性肺部疾病2，3。吸入性暴露于可吸入颗粒物可能是 是肺部炎症重要促发剂或加重剂。根据我们先前的结果， 炎症在今天被认为是一种主动过程4。有几个新的家庭的专业亲- 在急性炎症中鉴定和表征的消退介质（SPM）5。这些保护性介质是 是特异性受体的激动剂，转导细胞类型特异性功能 对组织分辨率至关重要的响应。炎症反应的解决方案基本上是 在环境健康和医学领域是前所未有的。迫切需要基本信息， 分辨率响应中的新环境因子以及它们是否干扰分辨率以触发慢性 炎症反应和感染。在这里，B. D。Levy，C.N. Serhan和P. Demokritou实验室联合起来， 合作NOT-ES-20018，并提出一项创新研究，名为EPHEPITIS：增强型PHTHISIC， 环境破坏者的决议激动剂，侧重于阐明的影响，潜在的危险 在新发现的解决方案中， 控制吞噬细胞的功能和体内平衡的恢复。解决方案失败或中断可能导致 持续的肺部炎症和微生物病原体（包括病毒和细菌）的无效清除。 这一提议将检验一个创新的假设，即特定的环境因素导致 通过破坏细胞和分子促分解机制来维持肺部炎症， 增加对肺部感染的易感性;以及替代消退素和/或其他专门的前 需要作为肺中消退反应的有效激动剂的消退介质来保护 肺部免受有害环境因子的影响，并恢复有效的微生物清除。为了验证这一 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）对肺部分辨率的影响 炎症， 2)确定NP分离度破坏物对病毒宿主应答和流感后继发性 细菌性肺炎，以及 3)确定NP暴露对巨噬细胞吞噬作用、SPM产生、促消退 受体和SPM救援。 这些研究的结果将阐明炎症消退的基本机制 易受破坏性环境因素影响并对分解有毒。