吸入含有环境持久性自由基的微粒物质会通过空气-血液界面的 AhR 激活诱导内皮功能障碍。

IF 3.4 3区 医学 Q2 TOXICOLOGY
Ankit Aryal, Ashlyn C Harmon, Kurt J Varner, Alexandra Noël, Stephania A Cormier, Divine B Nde, Peter Mottram, Jemiah Maxie, Tammy R Dugas
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引用次数: 0

摘要

含有环境持久性自由基(EPFR)的颗粒物(PM)是由有机废物不完全燃烧形成的,导致污染物化学吸附到含有氧化还原活性过渡金属的 PM 表面。在之前对小鼠的研究中,吸入 EPFR 会损害内皮依赖性血管扩张。这些发现与肺泡 II 型(AT-II)细胞中芳基烃受体(AhR)的激活有关,AT-II 细胞构成了肺部的气血界面。因此,我们假设 AT-II 细胞中的 AhR 激活会促进全身介质的释放,而介质的释放会导致肺外周内皮功能障碍。为了验证我们的假设,我们敲除了雄性和雌性小鼠AT-II细胞中的AhR,并将它们暴露在280微克/立方米的EPFR lo(2.7e + 16自由基/克)或EPFR(5.5e + 17自由基/克)与过滤空气中,每天暴露4小时,持续1天或5天。AT-II-AhR 激活诱导 EPFR 介导的内皮功能障碍,使内皮依赖性血管舒张减少 59%,eNOS 表达减少 50%。它还以旁分泌方式增加了肺部内皮素-1 mRNA 水平和血浆中的肽水平,以及可溶性血管细胞粘附分子-1 和 iNOS mRNA 的表达,这可能是通过 NF-kB 激活实现的。最后,AhR 依赖性抗氧化反应信号的增加,加上暴露于 EPFR 的同窝对照小鼠肺中 3-硝基酪氨酸水平的增加,表明 ATII 特异性 AhR 激活会促进氧化和硝化压力。因此,气血界面的 AhR 激活介导了肺外周观察到的内皮功能障碍,这可能是通过释放全身介质实现的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhalation of particulate matter containing environmentally persistent free radicals induces endothelial dysfunction mediated via AhR activation at the air-blood interface.

Particulate matter (PM) containing environmentally persistent free radicals (EPFR) is formed by the incomplete combustion of organic wastes, resulting in the chemisorption of pollutants to the surface of PM containing redox-active transition metals. In prior studies in mice, EPFR inhalation impaired endothelium-dependent vasodilation. These findings were associated with aryl hydrocarbon receptor (AhR) activation in the alveolar type-II (AT-II) cells that form the air-blood interface in the lung. We thus hypothesized that AhR activation in AT-II cells promotes the systemic release of mediators that promote endothelium dysfunction peripheral to the lung. To test our hypothesis, we knocked down AhR in AT-II cells of male and female mice and exposed them to 280 µg/m3 EPFR lo (2.7e + 16 radicals/g) or EPFR (5.5e + 17 radicals/g) compared with filtered air for 4 h/day for 1 day or 5 days. AT-II-AhR activation-induced EPFR-mediated endothelial dysfunction, reducing endothelium-dependent vasorelaxation by 59%, and eNOS expression by 50%. It also increased endothelin-1 mRNA levels in the lungs and peptide levels in the plasma in a paracrine fashion, along with soluble vascular cell adhesion molecule-1 and iNOS mRNA expression, possibly via NF-kB activation. Finally, AhR-dependent increases in antioxidant response signaling, coupled to increased levels of 3-nitrotyrosine in the lungs of EPFR-exposed littermate control but not AT-II AhR KO mice suggested that ATII-specific AhR activation promotes oxidative and nitrative stress. Thus, AhR activation at the air-blood interface mediates endothelial dysfunction observed peripheral to the lung, potentially via release of systemic mediators.

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来源期刊
Toxicological Sciences
Toxicological Sciences 医学-毒理学
CiteScore
7.70
自引率
7.90%
发文量
118
审稿时长
1.5 months
期刊介绍: The mission of Toxicological Sciences, the official journal of the Society of Toxicology, is to publish a broad spectrum of impactful research in the field of toxicology. The primary focus of Toxicological Sciences is on original research articles. The journal also provides expert insight via contemporary and systematic reviews, as well as forum articles and editorial content that addresses important topics in the field. The scope of Toxicological Sciences is focused on a broad spectrum of impactful toxicological research that will advance the multidisciplinary field of toxicology ranging from basic research to model development and application, and decision making. Submissions will include diverse technologies and approaches including, but not limited to: bioinformatics and computational biology, biochemistry, exposure science, histopathology, mass spectrometry, molecular biology, population-based sciences, tissue and cell-based systems, and whole-animal studies. Integrative approaches that combine realistic exposure scenarios with impactful analyses that move the field forward are encouraged.
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