Vascular Consequences of Multi-Walled Carbon Nanotube Exposure

多壁碳纳米管暴露对血管的影响

基本信息

批准号：
8454811
负责人：
Phoebe Stapleton
金额：
$ 5.22万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8454811
关键词：
Acute Address Adult Area Biological Availability Blood Vessels Breathing Calcium Cardiovascular system Charge Chemicals Coronary Data Dimensions Dose Drug Delivery Systems Endothelium Engineering Epidemiology Epithelial Cells Evolution Exposure to Functional disorder Future Health Home environment Homeostasis Hour Human Impairment Industry Inflammatory Ingestion Inhalation Exposure Injection of therapeutic agent Intake Investigation Laboratories Lead Life Lung Measures Mechanics Microcirculation Morbidity - disease rate Nanotechnology Nitric Oxide Occupational Outcome Particulate Matter Peripheral Pharmacologic Substance Plant Roots Production Property Prostaglandins Protocols documentation Rattus Reaction Time Reactive Oxygen Species Risk Route Shapes Signal Transduction Solubility Sprague-Dawley Rats Structure Surface Testing Therapeutic Thinking Time Tissues Toxic effect Work Workplace aerosolized arteriole base carbon compound dosage experience exposed human population innovation intravenous injection male mortality multi walled carbon nanotube nano nanomaterials nanometer nanoparticle particle public health relevance pulmonary function research study response stem titanium dioxide tool

项目摘要

DESCRIPTION (provided by applicant): Nanotechnology and engineered nanomaterials (ENM; particles less than 100 nanometers in one dimension) have firmly rooted themselves into nearly every aspect of daily life. As pharmaceutical and industrial advancements continue, human exposures to these new chemical sizes, shapes, and compounds are frequently introduced within the home, workplace, and as therapeutic drug-delivery platforms. Yet, the systemic health consequences of ENM exposures remain unclear. Specifically, multi-walled carbon nanotubes (MWCNT) have been robustly developed due to their highly desirable mechanical properties and substantial surface area as platforms of drug delivery and related industries; however these spear-like carbon compounds have been shown to imbed in the lower lungs after inhalation. While the pulmonary outcomes of traditional MWCNT exposure are currently under investigation; the cardiovascular effects and toxicities of these MWCNT have yet to be revealed and conclusions pertaining to non-traditional pharmacologic routes of exposure (ingestion, intravenous injection) have yet to be explored. Our laboratory has previously shown that systemic microvascular dysfunction follows after pulmonary titanium-dioxide nanoparticle exposure. However, not all nanoparticles should be considered identical, nor should their bioactivity or target tissues. Preliminary data related to this study evaluated the time-course and biomedical routes of MWCNT exposure, revealing significant sub-epicardial microvascular dysfunction stemming from gavage, inhalation, or co-incubation MWCNT exposure. The endothelium-dependent microvascular dysfunction of the coronary arterioles persists up to 168-hours after inhalation exposure. The present study proposes exposing rats to MWCNT via routes typically experienced in occupational and personal settings: inhalation, ingestion, or injection. Specific Aim 1 will establish the EC50 dosage, time- course, and MWCNT exposure route leading to the greatest sub-epicardial arteriolar dysfunction. Specific Aim 2 will evaluate the mechanisms leading to impairment of the coronary microcirculation due to MWCNT exposure. The working hypothesis of this application is that responses to acute MWCNT exposures will lead to significant coronary endothelium-dependent dysfunction due to alterations in NO bioavailability consistent with increased ROS scavenge; however these responses will be heavily dependent on the time course, dosage, and route of exposure. This study is innovative because it challenges the long-standing dogma that the lung is the primary target of ENM toxicity, or that the lung is necessary for biologic effects associated with ENM exposure. This study is forward thinking as it anticipates the inevitable non-pulmonary exposure routes in humans that will result from future ENM use. This study is significant because if the true therapeutic potential of nanotechnology is to be fully realized, its inherent toxicity must first b determined.

描述（由申请人提供）：纳米技术和工程纳米材料（ENM；一维小于 100 纳米的颗粒）已牢牢扎根于日常生活的几乎各个方面。随着制药和工业的不断进步，人类经常在家庭、工作场所以及作为治疗药物输送平台接触这些新的化学尺寸、形状和化合物。然而，ENM 暴露对系统健康的影响仍不清楚。具体而言，多壁碳纳米管（MWCNT）由于其非常理想的机械性能和巨大的表面积，作为药物输送和相关行业的平台得到了大力发展；然而，这些矛状碳化合物已被证明在吸入后会嵌入下肺。目前正在研究传统多壁碳纳米管暴露对肺部的影响；这些多壁碳纳米管的心血管效应和毒性尚未揭示，有关非传统药理学暴露途径（摄入、静脉注射）的结论也尚未探索。我们的实验室此前已表明，肺部二氧化钛纳米颗粒暴露后会出现全身微血管功能障碍。然而，并非所有纳米颗粒都应该被认为是相同的，它们的生物活性或靶组织也不应该被认为是相同的。与本研究相关的初步数据评估了时间进程和多壁碳纳米管暴露的生物医学途径，揭示了由于强饲、吸入或共孵育多壁碳纳米管暴露而导致的显着的心外膜下微血管功能障碍。吸入暴露后，冠状动脉内皮依赖性微血管功能障碍持续长达 168 小时。本研究建议通过职业和个人环境中通常经历的途径将大鼠暴露于多壁碳纳米管：吸入、摄入或注射。具体目标 1 将确定导致最大心外膜下小动脉功能障碍的 EC50 剂量、时程和 MWCNT 暴露途径。具体目标 2 将评估由于 MWCNT 暴露而导致冠状动脉微循环受损的机制。本申请的工作假设是，由于 NO 生物利用度的变化与 ROS 清除的增加一致，对急性 MWCNT 暴露的反应将导致显着的冠状动脉内皮依赖性功能障碍。然而，这些反应在很大程度上取决于时间进程、剂量和暴露途径。这项研究具有创新性，因为它挑战了长期存在的教条，即肺部是 ENM 毒性的主要目标，或者肺部是与 ENM 暴露相关的生物效应所必需的。这项研究具有前瞻性，因为它预测了未来 ENM 使用将导致人类不可避免的非肺部暴露途径。这项研究意义重大，因为如果要充分发挥纳米技术的真正治疗潜力，必须首先确定其固有的毒性。