Compromised Resolution of Inflammation following Nanoparticle Exposure in Metabolic Syndrome

项目摘要/摘要 代谢综合征(METS)患者在美国和全球占很大比例，而且比例不断上升 人口(&gt；25%)。现已证实，慢性疾病，如甲型肝炎的存在，会增强和 延长环境暴露引起的炎症。患有大都会医院的人表现出了增强的 暴露在环境中的颗粒物引起的炎症，其中很大一部分是纳米级的。这个 与这种增强的敏感性相关的机制代表着我们知识中的一个重大缺口。安装 来自沙纳汉实验室的数据表明，炎症分解的失调有助于 在蛋氨酸中观察到的加重毒性和疾病进展。具体地说，纳米颗粒吸入暴露 诱发肺部炎症反应，这种反应会因甲硫氨酸而加剧和延长。这是一种炎症性的 反应与抑制促进炎症的专门的促消解介质相对应 决议。我们的数据表明，吸入后，纳米颗粒在其表面获得独特的生物冠状结构 增强促炎反应，同时抑制分解信号。此外，我们的初步数据 证明蛋氨酸扰乱了ω-3脂肪酸代谢，损害了分辨率。这份提案审查了 假设纳米颗粒暴露后炎症分解的失调介导了 通过加剧炎症反应和促进发育和治疗观察到甲硫氨酸的易感性 慢性疾病的进展。这一假设将通过完成三个主要目标来检验：1) 代谢综合征发生和发展过程中肺纳米颗粒-生物冠状改变的描绘 炎症信号转导后果；2)炎症消退的测定和特殊的促炎作用。 在蛋氨酸和健康小鼠模型中纳米颗粒暴露后的介质分解动力学；3)阐明 纳米颗粒暴露后蛋氨酸中差异ω-3脂肪酸代谢的研究。这些机制代表了 潜在的关键调节因子在蛋氨酸代谢综合征中调控失调，促进了加剧的反应，也是潜在的 治疗干预的目标。通常，针对暴露诱导的研究和治疗策略 炎症侧重于抑制促炎途径，而不是阐明和有效 对分解过程的刺激。该项目的完成将产生所需的新知识 了解流行和敏感亚群(如蛋氨酸)的不同毒性机制。澄清 这些机制将允许新的疾病预防和治疗战略，同时也扩大公众 环境暴露的健康保护。

Project Summary / Abstract Individuals with metabolic syndrome (MetS) compose a significant and growing proportion of our U.S. and global population (> 25%). It has been established that the presence of chronic diseases, such as MetS, enhances and prolongs environmental exposure-induced inflammation. Individuals with MetS have demonstrated enhanced inflammation due to ambient particulate matter exposures of which a significant proportion is nano-sized. The mechanisms associated with this enhanced susceptibility represent a significant gap in our knowledge. Mounting data from the Shannahan laboratory suggests that dysregulation of inflammatory resolution contributes to the exacerbated toxicity and disease progression observed in MetS. Specifically, nanoparticle inhalation exposures induce a pulmonary inflammatory response that is exacerbated and extended due to MetS. This inflammatory response corresponds with suppression of specialized pro-resolving mediators that facilitate inflammatory resolution. Our data suggests following inhalation, nanoparticles gain unique biocoronas on their surface that enhance the pro-inflammatory response while inhibiting resolution signaling. Further, our preliminary data demonstrates MetS disrupts ω-3 fatty acid metabolism impairing resolution. This proposal examines the hypothesis that dysregulation of inflammatory resolution following nanoparticle exposure mediates the susceptibility observed in MetS by exacerbating inflammatory responses and facilitating development and progression of chronic disease. The hypothesis will be tested through the completion of three main goals: 1) Delineation of pulmonary nanoparticle-biocorona alterations throughout metabolic syndrome development and the inflammation signaling consequences; 2) Determination of inflammatory resolution and specialized pro- resolving mediator kinetics following nanoparticle exposure in MetS and healthy mouse models; 3) Elucidation of differential ω-3 fatty acid metabolism in MetS following nanoparticle exposure. These mechanisms represent potential key regulators that are dysregulated in MetS, facilitating exacerbated responses and also are potential targets of therapeutic interventions. Typically, research and treatment strategies addressing exposure-induced inflammation focus on suppression of pro-inflammatory pathways rather than elucidation and effective stimulation of resolution processes. Completion of the project will generate new knowledge required to understand distinct mechanisms of toxicity in prevalent and sensitive subpopulations such as MetS. Elucidation of these mechanisms will allow for new disease prevention and treatment strategies while also broadening public health protections to environmental exposures.