Novel Approaches for Improving Inflammation Resolution Following Chronic Exposure to Air Pollutants

摘要 炎症是对损伤、感染和环境暴露的必要生物反应，并且是一种良好的- 精心策划的生理过程，如果不加以控制，会产生不良毒性。未消退的炎症 会导致因环境暴露而加剧的慢性疾病的发展。分子 炎症消退的机制和参与者还没有很好地理解。在这个应用程序中，我们将 检查两个新的途径，我们假设在炎症的解决中发挥关键作用。1.我们 先前报道，柴油机尾气颗粒提取物和相关的多环芳烃抑制了 小鼠巨噬细胞中COX 2依赖性类花生酸合成。虽然COX2通常被认为是亲- 炎症性Cox2巨噬细胞特异性敲除（Cox2MKO）小鼠在进食时发生肠道炎症 高脂肪饮食因此，巨噬细胞COX2似乎提供了对慢性炎症的抑制性分子检查 通过饮食和环境暴露介导。在初步的实验中，我们表明，COX2的损失 在小鼠原代巨噬细胞中受损的巨噬细胞和COX 2调节巨噬细胞的产生， 依赖性脂质炎症介质不仅影响继发性红细胞增多症， 肠上皮类器官的修复表型。在具体目标1下，根据已公布和最近 初步结果，我们将测试假设，巨噬细胞COX 2依赖性类花生酸发挥关键作用， 环境污染物加剧的慢性炎症性疾病。2.我们的实验室开创了 两亲性肽的开发，其模拟抗氧化剂和抗炎特性， 载脂蛋白A-I（apoA-I）。ApoA-I模拟肽（4F）抑制炎性疾病的发展， 通过饮食和环境暴露，包括动脉粥样硬化和肠道炎症， 我们证明，4F减弱环境超细颗粒（UFP）介导的氧化应激，脂质代谢， 动脉粥样硬化和肠道炎症。4F在所有这些疾病中的保护作用的共同机制 模型是通过将炎症脂质介质的净平衡倾斜到抗炎状态， 循环和组织。在初步的结果中，我们证明了apoA-I模拟肽可以增强 离体和体内经肠脂质转运（TILT）。在具体目标2下，我们将检验以下假设： TILT是炎症消退的关键介质，在慢性炎症的发展中起重要作用。 因环境暴露而加剧的炎症性疾病。顺利完成拟议的研究 在这个新的R01应用中，不仅将促进我们对生物学和分子机制的理解， 揭示了环境暴露对炎症消退的影响，但也提供了新的 在我们对抗因空气污染而加剧的慢性炎症性疾病的斗争中，

Abstract Inflammation is a necessary biological response to injury, infection, and environmental exposures, and a well- orchestrated physiological process, which if unchecked produces undesirable toxicity. Unresolved inflammation contributes to the development of chronic diseases exacerbated by environmental exposures. The molecular mechanisms and players of resolution of inflammation are not well understood. In this application, we will examine two novel pathways that we hypothesize to play a critical role in the resolution of inflammation. 1. We previously reported that diesel exhaust particle extracts and associated polycyclic aromatic hydrocarbons inhibit COX2-dependent eicosanoid synthesis in murine macrophages. While COX2 is commonly thought to be pro- inflammatory, Cox2 macrophage-specific knock-out (Cox2MKO) mice develop intestinal inflammation when fed a high fat diet. Macrophage COX2 thus appears to provide an inhibitory molecular check on chronic inflammation mediated by dietary and environmental exposures. In preliminary experiments, we show that loss of COX2 impaired efferocytosis in mouse primary macrophages and COX2 modulated the production of efferocytosis- dependent lipid inflammatory mediators that not only affect secondary efferocytosis but also induce a tissue repair phenotype in intestinal epithelial organoids. Under specific aim 1, based on published and recent preliminary results, we will test the hypothesis that macrophage COX2-dependent eicosanoids play a critical role in chronic inflammatory diseases exacerbated by environmental pollutants. 2. Our laboratory pioneered the development of amphipathic peptides that mimic the antioxidant and anti-inflammatory properties of apolipoprotein A-I (apoA-I). ApoA-I mimetic peptides (4F) inhibit the development of inflammatory diseases that are exacerbated by dietary and environmental exposures including atherosclerosis and intestinal inflammation. We demonstrated that 4F attenuates ambient ultrafine particle (UFP)-mediated oxidative stress, lipid metabolism, atherosclerosis and intestinal inflammation. A common mechanism of protective action of 4F in all these disease models is by tilting the net balance of lipid mediators of inflammation to an anti-inflammatory state, in the circulation and tissues. In preliminary results, we demonstrated that apoA-I mimetic peptides enhance transintestinal lipid transport (TILT) ex vivo and in vivo. Under specific aim 2, we will test the hypothesis that TILT is a key mediator of resolution of inflammation and plays an important role in the development of chronic inflammatory diseases exacerbated by environmental exposures. Successful completion of the studies proposed in this new R01 application will not only advance our understanding of the biology and molecular mechanisms underlying the effects of environmental exposures on the resolution of inflammation but also provide novel therapeutic strategies in our fight against chronic inflammatory diseases exacerbated by air pollution.