Vascular Consequences of Multi-Walled Carbon Nanotube Exposure

多壁碳纳米管暴露对血管的影响

• 批准号: 8644117
• 负责人: Phoebe Stapleton
• 金额: $ 4.33万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644117
• 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; Microvascular Dysfunction; 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; 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; Microvascular Dysfunction; 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

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；一个维度小于100纳米的颗粒）几乎将自己扎根于日常生活的各个方面。随着药品和工业进步的继续，人类对这些新的化学尺寸，形状和化合物的暴露经常在家庭，工作场所和治疗性药物分发平台内引入。然而，ENM暴露的系统性健康后果尚不清楚。具体而言，由于其高度理想的机械性能和作为药物递送和相关行业的平台，多壁碳纳米管（MWCNT）的开发得到了强烈的开发。然而，这些长矛状的碳化合物已显示在吸入后在下肺中嵌入。虽然目前正在研究传统MWCNT暴露的肺结果；这些MWCNT的心血管效应和毒性尚未得到揭示，并且与非传统药理途径有关的结论（摄入，静脉注射）尚未探索。 我们的实验室先前已经表明，肺二氧化钛纳米颗粒暴露后，全身微血管功能障碍会发生。但是，并非所有纳米颗粒都应被认为是相同的，也不应将其生物活性或靶向组织视为相同。与这项研究有关的初步数据评估了时间表和 MWCNT暴露的生物医学途径，显示出明显的心脏下显微血管功能障碍，引起了饲料，吸入或共孵育MWCNT暴露。吸入后，冠状动脉动脉的内皮依赖性微血管功能障碍持续168小时。 本研究建议通过通常在职业和个人环境中经历的路线将大鼠暴露于MWCNT：吸入，摄入或注射。特定的目标1将建立EC50剂量，时间过程和MWCNT暴露路线，导致最大的心脏下动脉功能障碍。具体目标2将评估导致因MWCNT暴露引起的冠状动脉微循环损害的机制。该应用的工作假设是，对急性MWCNT暴露的反应将导致冠状动脉内皮依赖性功能障碍，这是由于无生物利用度与ROS清除增加一致的变化；但是，这些反应将在很大程度上取决于时间过程，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，即肺是ENM毒性的主要目标，或者肺对与ENM暴露有关的生物学作用是必需的。这项研究是前瞻性思维，因为它预见了人类不可避免的非肺暴露路线，这将是由于未来的ENM使用而导致的。这项研究很重要，因为如果要充分实现纳米技术的真正治疗潜力，则必须首先确定其固有的毒性。