Compromised Resolution of Inflammation following Nanoparticle Exposure in Metabolic Syndrome

项目总结/摘要 代谢综合征（MetS）患者在美国和全球范围内占显著且不断增长的比例。 人口（> 25%）。已经确定，慢性疾病如MetS的存在增强并 环境污染引起的炎症。MetS患者表现出增强的 由于暴露于环境颗粒物（其中很大一部分是纳米级的）而导致的炎症。的 与这种增强的易感性相关的机制代表了我们知识中的一个重大空白。安装 来自Shannahan实验室的数据表明，炎症消退的失调有助于 在MetS中观察到的毒性和疾病进展加剧。具体来说，纳米颗粒吸入暴露 诱导由于MetS而加重和延长的肺部炎症反应。这种炎症 反应对应于抑制促进炎症的专门促消退介质 分辨率我们的数据表明，吸入后，纳米颗粒在其表面获得独特的生物冠， 增强促炎反应，同时抑制消退信号传导。此外，我们的初步数据显示， 表明MetS破坏ω-3脂肪酸代谢，损害分辨率。本提案审查了 假设在纳米颗粒暴露后炎症消退失调介导了 通过加剧炎症反应和促进发展， 慢性疾病的进展。该假设将通过三个主要目标的完成来检验：1） 在代谢综合征的发展过程中描述肺纳米颗粒-生物冠的变化， 炎症信号传导的结果; 2）确定炎症消退和专门的促炎性细胞因子的表达。 在MetS和健康小鼠模型中纳米颗粒暴露后的分辨介质动力学; 3）阐明 的差异ω-3脂肪酸代谢的MetS后纳米颗粒暴露。这些机制代表了 在MetS中失调的潜在关键调节因子，促进加重的反应，也是潜在的 治疗干预的目标。通常情况下，研究和治疗策略，解决糖尿病引起的 炎症集中于抑制促炎途径，而不是阐明和有效 刺激分解过程。项目的完成将产生新的知识， 了解流行和敏感亚群（如MetS）的不同毒性机制。阐发 这些机制将允许新的疾病预防和治疗策略，同时也扩大公众 健康保护到环境暴露。

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.