Vascular Consequences of Multi-Walled Carbon Nanotube Exposure

描述(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，人类对这些新的化学尺寸、形状和化合物的暴露经常被引入家庭、工作场所和作为治疗性药物输送平台。然而，ENM暴露的系统性健康后果仍不清楚。具体地说，多壁碳纳米管(MWCNT)由于其非常理想的机械性能和巨大的比表面积作为药物输送和相关工业的平台而得到了强劲的发展；然而，这些矛状的碳化合物被证明在吸入后嵌入到下肺中。虽然传统MWCNT暴露的肺部后果目前正在调查中，但这些MWCNT对心血管的影响和毒性尚未揭示，与非传统药物暴露途径(摄取、静脉注射)有关的结论仍有待探索。我们的实验室先前已经证明，暴露于二氧化钛纳米颗粒后会导致全身微血管功能障碍。然而，并不是所有的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。与这项研究相关的初步数据评估了时间进程和 MWCNT暴露的生物医学途径，揭示了灌胃、吸入或共同孵化MWCNT暴露引起的显著的心外膜下微血管功能障碍。吸入暴露后，冠状小动脉内皮依赖性微血管功能障碍持续到168小时。本研究建议通过在职业和个人环境中通常经历的途径使大鼠暴露于MWCNT：吸入、摄入或注射。具体目标1将确定EC50剂量、时间进程和MWCNT暴露途径，从而导致最大的心外膜下小动脉功能障碍。具体目标2将评估MWCNT暴露导致冠脉微循环损害的机制。这项应用的工作假设是，对急性MWCNT暴露的反应将导致显著的冠状动脉内皮依赖性功能障碍，这是由于NO的生物利用度与ROS清除增加一致的变化；然而，这些反应将严重依赖于暴露的时间进程、剂量和途径。这项研究具有创新性，因为它挑战了长期以来的教条，即肺是ENM毒性的主要目标，或者肺是与ENM暴露相关的生物效应所必需的。这项研究是前瞻性的，因为它预测了未来使用ENM将导致人类不可避免的非肺暴露途径。这项研究意义重大，因为如果要充分实现纳米技术的真正治疗潜力，必须首先确定其固有毒性。

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.