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

摘要 炎症是对伤害、感染和环境暴露的一种必要的生物学反应，是一种良好的- 精心安排的生理过程，如果不加以控制，会产生不良的毒性。未消退的炎症 导致慢性疾病的发展，并因环境暴露而加剧。分子 炎症消退的机制和作用机制尚不清楚。在此应用程序中，我们将 检查两条我们假设在炎症消退中发挥关键作用的新途径。1.我们 此前报道，柴油废气颗粒提取物和相关的多环芳烃抑制 小鼠巨噬细胞中依赖于COX2的二十烷类化合物的合成。虽然COX2通常被认为是亲- 炎症，COX2巨噬细胞特异性基因敲除(Cox2MKO)小鼠在喂养时发生肠炎 高脂肪饮食。因此，巨噬细胞COX2似乎为慢性炎症提供了一种抑制分子检查 受饮食和环境暴露的影响。在初步实验中，我们证明了COX2的丢失 小鼠原代巨噬细胞泡腾功能受损，COX2调节泡腾功能的产生 依赖的脂类炎症介质，不仅影响继发性胞吐，而且还能诱导组织 肠上皮器官的修复表型。在具体目标1下，根据已公布的和最近的 初步结果，我们将检验巨噬细胞COX2依赖的二十烷基类化合物发挥关键作用的假设 因环境污染物而加重的慢性炎症性疾病。2.我们的实验室率先推出了 模拟沙门氏菌抗氧化和抗炎特性的两亲性多肽的研究进展 载脂蛋白A-I(apoA-I)。载脂蛋白A-I模拟肽(4F)抑制炎症性疾病的发展 饮食和环境暴露，包括动脉粥样硬化和肠道炎症，会加剧这种疾病。 我们证明，4F可以减弱环境中超细颗粒(UFP)介导的氧化应激，脂质代谢， 动脉粥样硬化和肠道炎症。4F在所有这些疾病中保护作用的共同机制 模型是通过将炎症的脂质介质的净平衡倾斜到抗炎状态，在 血液循环和组织。在初步结果中，我们证明了apoA-I模拟多肽可以增强 体内外跨肠脂质转运(TILT)在特定目标2下，我们将检验假设 TILT是炎症消退的关键介质，在慢性肾小球疾病的发生发展中起重要作用 因环境暴露而加剧的炎症性疾病。圆满完成建议的研究 在这一新的R01中的应用不仅将促进我们对生物学和分子机制的理解 环境暴露对炎症消退的潜在影响也提供了新的 在我们对抗因空气污染而加剧的慢性炎症性疾病方面的治疗战略。

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.