Vascular Consequences of Multi-Walled Carbon Nanotube Exposure

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）已经牢固地扎根于日常生活的几乎每一个方面。随着制药和工业的不断进步，人类接触这些新尺寸、形状和化合物的化学物质经常被引入家庭、工作场所，并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。具体来说，多壁碳纳米管（MWCNT）由于其高度理想的机械性能和大量的表面积作为药物输送和相关行业的平台而得到了蓬勃发展；然而，这些矛状的碳化合物被证明在吸入后会嵌入肺部下部。传统多碳纳米管暴露的肺部后果目前正在调查中；这些MWCNT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）的结论尚未探索。我们实验室先前的研究表明，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。与本研究相关的初步数据评估了时间进程和

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.