Inflammatory cross-talk between heat events and air pollution

摘要 空气污染与气候变化密切相关，是其不利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和极端高温事件之间存在联系（另一个主要的原因是， 与气候相关的不利健康结果的驱动因素）。然而，机械地理解这些 在细胞和器官水平上相互作用的过程仍然是初步的。应对气候变化相关问题 不利的健康结果将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方面的知识空白： 1)详细说明空气污染是否会导致极端高温事件产生更大的炎症结果，2） 确定高温事件是否使个人容易受到空气污染暴露的不利后果的影响，以及3） 描述了一种新的统一机制，在肺部管理这些过程。根据我们初步的 观察，我们建议研究核苷酸结合寡聚化结构域，富含亮氨酸的重复含有X1 （NLRX 1）作为空气污染和热应激诱导的细胞信号传导的主要调节剂。NLRX 1是 线粒体定位的模式识别受体，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，Nlrx 1-/-小鼠的能力下降，安装有效的HSP mRNA 表达，并指出NLRX 1在对环境的有效适应性反应中的作用 应力该提案的首要目标是了解热事件和空气的相互作用结果 污染具体的假设是，空气污染和极端高温事件诱发了炎症串扰 是由NLRX 1-HSP通路相互作用介导的。为了验证这一假设，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，我们提出了两个具体的目标： 目的1：阐明超细CB+O3吸入联合暴露诱发更大炎症的能力 后续热应激事件的结局，具体目标2：阐明热应激事件 易受后续超细CB+O3吸入共同暴露的不良炎症结果的影响。 总的来说，这些新的研究将阐明热事件和NFLRX 1之间的串扰，作为一个中心枢纽， 调节多种气候变化相关暴露后诱导的细胞应激途径（热应激， 超细颗粒和O3）。

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).