EPHEDRA: Enhanced PHthisic by Environmental Disruptors of Resolution Agonists

摘要 现在人们普遍认识到，不受控制的炎症是许多广泛传播的 疾病1，包括慢性肺部疾病2，3.吸入可吸入颗粒物可导致 肺部炎症的重要诱因或加重。从我们早先的结果来看，解决方案 炎症在今天被认为是一种活跃的过程4。有几个新的专门化促炎因子家族 在急性炎症中识别和表征的分解介质(SPM)5.这些保护性介质是 酶促产生并是特定受体的激动剂，转导细胞类型特定的功能 对组织分辨率至关重要的反应。炎症反应的解决方案本质上是 在环境健康和医学方面是未知的。迫切需要基本信息，以应对 新的环境因子在分解反应中的作用以及它们是否扰乱分解以触发慢性 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 为NOT-ES-20018合作，并提出一项创新研究，题为麻黄：通过 拆分激动剂的环境干扰物，侧重于阐明潜在危险的影响 在新发现的解决方案中，环境制剂以纳米颗粒的形式出现在呼吸道中 控制吞噬细胞的功能和恢复动态平衡。解决方案失败或中断可能会导致 持续的肺部炎症和对包括病毒和细菌在内的微生物病原体的清除效率低下。 这项提议将检验一个创新的假设，即特定的环境因素对 通过扰乱细胞和分子的促分解机制来维持肺部炎症 增加对肺部感染的易感性；以及更换解毒剂和/或其他专门的 在肺中作为有效的分解反应激动剂的分解介体需要保护 防止有害环境物质进入肺部，恢复有效的微生物清除。为了测试这一点 假设，我们提出了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 发炎， 2)确定NP分解干扰物对病毒宿主反应和流感后继发性反应的影响 细菌性肺炎，以及 3)确定NP暴露对巨噬细胞泡沫化、SPM产生、前分解的影响 受体与SPM救援。 这些研究结果将阐明炎症消退的基本机制(S) 容易受到破坏性环境因素的影响，而且解决起来是有毒的。

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.