Xanthine Oxidase-Induced Vascular Dysfunction in Inhalation Toxicology

吸入毒理学中黄嘌呤氧化酶诱导的血管功能障碍

• 批准号: 10314560
• 负责人: Xena Marie Williams
• 金额: $ 4.6万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-17 至 2023-08-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314560
• 关键词: Ablation; Address; Allopurinol; Area; Automobile Driving; Binding; Blood Circulation; Blood Vessels; Clinic; Data; Dependence; Drug Targeting; Endothelium; Enzymes; Event; Exposure to; FDA approved; Financial compensation; Functional disorder; Generations; Genetic; Glycosaminoglycans; Goals; Healthcare; Hepatocyte; Homeostasis; In Vitro; Incentives; Inflammatory; Inflammatory Response; Inhalation; Inhalation Exposure; Inhalation Toxicology; Knock-out; Link; Liver; Lung; Mediating; Mitochondria; Mus; NADPH Oxidase; Nitrates; Nitric Oxide; Nitrites; Nitrogen Dioxide; Occupational; Occupations; Organ; Oxidants; Oxides; Particulate; Pathway interactions; Plasma; Play; Process; Production; Pulmonary Inflammation; Resistance; Role; Signal Transduction; Site; Source; Stimulus; Supplementation; Surface; Testing; Thoracic aorta; Tissues; Translations; Up-Regulation; Vascular Diseases; XDH gene; Xanthine Oxidase; base; cardiovascular effects; endothelial dysfunction; experimental study; febuxostat; inhibitor/antagonist; middle cerebral artery; mouse model; nano; nanoparticulate; novel; response; titanium dioxide; toxicant

Project Summary Exposure to titanium dioxide (TiO2) via inhalation is a considerable occupational healthcare issue as it results in not only in a local pulmonary inflammatory response but also mediates systemic vascular dysfunction. However, the signaling mechanisms underpinning the link between a primary inflammatory event in the lung with systemic vascular consequences are unclear; especially, if the toxicant remains localized primarily in the pulmonary tissue. One potential contributor to this process may be xanthine oxidoreductase (XOR), an enzyme that is upregulated under inflammatory conditions, can be released into the circulation and avidly bind to glycosaminoglycans (GAGs) on the endothelial surface and drive endothelial dysfunction via production of oxidants. We have recently demonstrated that a key source of circulating XOR is the liver whereby hepatocytes respond to inflammatory stimuli by releasing XOR to the circulation. This process seems to be specific to the liver as genetic ablation of hepatocellular XOR, in the context of inflammatory stimulus, significantly depletes circulating XOR levels in a manner absent of compensation by other organs/tissues. While the liver seems to play a master regulator role for controlling XOR levels in the circulation, the signaling from the primary off-site insult (lungs) to the hepatocyte remains undefined affirming the need for further exploration of this area. To this end, we provide preliminary data demonstrating a substantive increase in plasma XOR following inhalation exposure to TiO2 in a murine model. In addition, exposure to TiO2 results in endothelium-dependent dysfunction in both the middle cerebral artery and thoracic aorta that is restored by treatment with the XOR-specific inhibitor, febuxostat. Collectively, these data incentivize the hypothesis that inhalation of TiO2 mediates signaling from the lung to the liver upregulating XOR with subsequent release to the circulation where it contributes to vascular dysfunction. The following specific aims will test this hypothesis: 1) define XOR-mediated contributions to vascular dysfunction allied to inhalation of TiO2 and establish the liver as the source of amplified circulating XOR and 2) Identify the signaling from the lung to liver which mediates upregulation of XOR in response to TiO2 inhalation. Combined, these aims will establish a novel pathway whereby a primary insult to pulmonary tissue confers off-site upregulation of XOR and downstream vascular consequences. This is significant as XOR is targetable by FDA-approved compounds (febuxostat and allopurinol) whereas other sources of oxidants (e.g. mitochondria, NADPH oxidase, uncoupled eNOS etc.) contributory to vascular dysfunction are not and thus sets the stage for rapid translation of results to the clinic by off-target application.

项目摘要 通过吸入暴露于二氧化钛（TiO 2）是一个相当大的职业健康问题，因为它导致 不仅在局部肺部炎症反应中，而且还介导全身血管功能障碍。 然而，支持肺部原发性炎症事件与肺内炎症反应之间联系的信号传导机制， 与全身血管的后果尚不清楚;特别是，如果毒物仍然主要局限于 肺组织该过程的一个潜在贡献者可能是黄嘌呤氧化还原酶（XOR）， 在炎症条件下上调的酶，可以释放到循环中并与 与内皮表面上的糖胺聚糖（GAG）结合，并通过产生 氧化剂我们最近已经证明，循环XOR的一个关键来源是肝脏， 肝细胞通过向循环释放XOR来响应炎性刺激。这个过程似乎是 作为肝细胞XOR的基因消融，在炎症刺激的背景下， 以缺乏其他器官/组织补偿的方式显著消耗循环XOR水平。 虽然肝脏似乎在控制循环中的XOR水平方面发挥着主要的调节作用，但信号传导 从原发性非原位损伤（肺）到肝细胞的损伤仍然不确定，这证实需要进一步的 探索这个领域。为此，我们提供了初步数据，表明 在小鼠模型中吸入暴露于TiO 2后的血浆XOR。此外，暴露于TiO 2导致 大脑中动脉和胸主动脉的内皮依赖性功能障碍， 用XOR特异性抑制剂非布司他治疗。总的来说，这些数据激励了这样一种假设， 吸入TiO 2介导从肺到肝的信号传导，上调XOR，随后释放， 它会导致血管功能障碍。以下具体目标将检验这一假设： 1)定义XOR介导的与吸入TiO 2相关的血管功能障碍的贡献，并建立肝脏 作为放大的循环XOR的来源，以及2）鉴定从肺到肝的信号传导， 响应于TiO 2吸入的XOR的上调。结合起来，这些目标将建立一个新的途径， 由此对肺组织的原发性损伤赋予XOR和下游血管的非原位上调， 后果这一点很重要，因为XOR是FDA批准的化合物（非布司他和 别嘌呤醇），而其他氧化剂来源（例如线粒体、NADPH氧化酶、未偶联eNOS等） 因此，为将结果快速转化为临床结果奠定了基础 偏离目标的应用。