Inflammatory cross-talk between heat events and air pollution

热事件和空气污染之间的炎症串扰

• 批准号: 10838755
• 负责人: Salik Hussain
• 金额: $ 44.1万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10838755
• 关键词: Address; Air Pollutants; Air Pollution; Award; Binding; Biology; Carbon Black; Cardiovascular system; Cells; Cellular Stress; Cerebrum; Cessation of life; Classification; Climate; Data; Data Set; Disease; Disease susceptibility; Environment; Epidemiology; Event; Exposure to; Global Warming; Goals; Health; Heat Stress Disorders; Heat Waves; Heat-Shock Response; Human; Immune; Individual; Inflammatory; Infrastructure; Inhalation; Inhalation Exposure; Injury; Knowledge; Leucine-Rich Repeat; Link; Lung; Mediating; Mitochondria; Modeling; Mus; NF-kappa B; Nuclear; Nucleotides; Organ; Outcome; Oxidants; Oxidation-Reduction; Ozone; Parents; Particulate; Pathway interactions; Pattern recognition receptor; Physiology; Predisposition; Process; Proteins; Public Health; Pulmonary Inflammation; Research; Role; Signal Transduction; Stress; Testing; Toxicology; Ultrafine; United States; Weather; Wildfire; World Health Organization; adverse outcome; burden of illness; climate change; cost; exposed human population; extreme heat; extreme weather; mRNA Expression; mortality; novel; nucleotide protein interaction; particle; programs; protein protein interaction; pulmonary function; pulmonary function decline; respiratory; response; systemic inflammatory response; ultrafine particle

Abstract Air pollution is intricately related to climate change and is among the main drivers of its adverse health outcomes. Epidemiological evidence points towards a link between air pollution and extreme heat events (another main driver of climate-related adverse health outcomes). However, a mechanistic understanding of how these processes may interact at the cellular and organ level is still rudimentary. Addressing climate change-related adverse health outcomes will need a focus on both reduction in global warming and understanding the cellular mechanisms governing the susceptibility. With the proposed studies, we aim to fill in a three-fold knowledge gap: 1) elaborate if air pollution can predispose to a greater inflammatory outcome from extreme heat events, 2) define if heat events make individuals susceptible to adverse outcomes from air pollution exposure, and 3) describe a novel unifying mechanism that governs these processes in the lungs. Based on our preliminary observations, we propose to study nucleotide-binding oligomerization domain, leucine rich repeat containing X1 (NLRX1) as the master regulator for air pollution and heat stress-induced cellular signaling. NLRX1 is mitochondria localized pattern recognition receptor that is a negative regulator of nuclear factor-κB (NF-κB) signaling. Our preliminary data indicate a diminished ability of Nlrx1-/- mice to mount an effective HSP mRNA expression and points towards a role of NLRX1 in mounting an effective adaptive response to environmental stress. The overarching goal of this proposal is to understand the interactive outcomes of heat events and air pollution. The specific hypothesis is that air pollution and extreme heat events induced inflammatory cross-talk is mediated by NLRX1-HSP pathway interactions. To test this hypothesis and leverage our established mixed ultrafine carbon black (CB) and ozone (O3) inhalation co-exposure model, we propose two specific aims: Specific Aim 1: Elaborate the ability of ultrafine CB+O3 inhalation co-exposure to predispose for greater inflammatory outcomes from subsequent heat stress events, Specific Aim 2: Elucidate the ability of heat stress events to predispose for adverse inflammatory outcomes from subsequent ultrafine CB+O3 inhalation co-exposure. Overall, these novel studies will clarify the cross-talk between heat events and posit NLRX1 as a central hub for regulating cellular stress pathways induced after multiple climate change-related exposures (heat stress, ultrafine particles, and O3).

抽象的 空气污染与气候变化密切相关，是造成不良健康后果的主要驱动因素之一。 流行病学证据表明空气污染与极端高温事件之间存在联系（另一个主要因素） 气候相关不良健康结果的驱动因素）。然而，从机械角度理解这些 可能在细胞和器官水平上相互作用的过程仍处于初级阶段。应对气候变化相关问题 不良的健康结果需要关注减少全球变暖和了解细胞 控制易感性的机制。通过拟议的研究，我们的目标是填补三重知识空白： 1) 详细说明空气污染是否会导致极端高温事件导致更大的炎症后果，2) 定义高温事件是否会使个人容易受到空气污染暴露带来的不利后果的影响，以及 3) 描述了一种控制肺部这些过程的新颖的统一机制。根据我们的初步 观察结果，我们建议研究核苷酸结合寡聚化结构域，含有 X1 的富含亮氨酸重复序列 （NLRX1）作为空气污染和热应激诱导的细胞信号传导的主调节器。 NLRX1 是 线粒体定位模式识别受体，是核因子-κB (NF-κB) 的负调节因子 发信号。我们的初步数据表明 Nlrx1-/- 小鼠装载有效 HSP mRNA 的能力减弱 表达并指出 NLRX1 在对环境产生有效适应性反应中的作用 压力。该提案的总体目标是了解热事件和空气的相互作用结果 污染。具体假设是空气污染和极端高温事件引起炎症串扰 由 NLRX1-HSP 通路相互作用介导。为了检验这一假设并利用我们建立的混合 超细炭黑（CB）和臭氧（O3）吸入共暴露模型，我们提出两个具体目标： 目标 1：阐明超细 CB+O3 吸入共同暴露诱发更大炎症的能力 随后的热应激事件的结果，具体目标 2：阐明热应激事件的能力 容易因随后的超细 CB+O3 吸入共同暴露而产生不良炎症结果。 总的来说，这些新颖的研究将澄清热事件之间的串扰，并将 NLRX1 定位为热事件的中心枢纽。 调节多次气候变化相关暴露（热应激、 超细颗粒和 O3）。

项目成果

The pulmonary toxicity of carboxylated or aminated multi-walled carbon nanotubes in mice is determined by the prior purification method.

• DOI: 10.1186/s12989-020-00390-y
• 发表时间: 2020-11-26
• 期刊: Particle and fibre toxicology
• 影响因子: 10
• 作者: Taylor-Just AJ;Ihrie MD;Duke KS;Lee HY;You DJ;Hussain S;Kodali VK;Ziemann C;Creutzenberg O;Vulpoi A;Turcu F;Potara M;Todea M;van den Brule S;Lison D;Bonner JC
• 通讯作者: Bonner JC