Microvascular Health and Nanoparticle Exposure

微血管健康和纳米颗粒暴露

• 批准号: 7938733
• 负责人: Timothy R Nurkiewicz
• 金额: $ 50万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938733
• 关键词: Acute; Address; Adolescent; Adult; Aerosols; Age; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Area; Bioavailable; Biochemical; Biocompatible Materials; Biological; Biological Availability; Blood Vessels; Blood flow; Breathing; Carbon; Carbon Nanotubes; Cardiovascular system; Civilization; Coronary; Deposition; Development; Dose; Elderly; Endothelium; Exposure to; Fluorescence Microscopy; Functional disorder; Growth; Health; Heart; Hemeproteins; Histology; Hour; Image Analysis; Immunohistochemistry; Impairment; In Vitro; Inflammation; Inhalation Exposure; Laboratories; Leukocytes; Lung; Measurement; Measures; Methods; Microcirculation; Morbidity - disease rate; Muscle; Myocardium; Nanotechnology; Nature; Nitric Oxide; Outcome; Oxidants; Particulate; Particulate Matter; Pathology; Peroxidases; Pneumonia; Pollution; Population; Predisposition; Prevention; Production; Qualifying; Rat-1; Rattus; Reaction Time; Regulation; Reporting; Risk; Role; Route; Safety; Site; Skeletal Muscle; Skin; Solid; System; Techniques; Testing; Time; Titania; Work; aerosolized; age group; age related; arteriole; base; cardiovascular risk factor; clinically relevant; environmental toxicology; in vivo; intravital microscopy; mortality; nano; nanomaterials; nanometer; nanoparticle; nanoscale; particle; particle exposure; pollutant; public health relevance; research study; response; senescence; titanium dioxide; vascular bed; vasoactive agent; venule; young adult

DESCRIPTION (provided by applicant): This application directly addresses the Broad Challenge Area (13): Smart Biomaterials-Theranostics, and the Specific Challenge Topic: Methods to Evaluate the Health and Safety of Nanomaterials. We are a uniquely qualified laboratory to address this Challenge in that we regularly aerosolize diverse nanoparticles. Concurrently, we are the only laboratory in this area/topic to directly evaluate microvascular health after inhalation exposure to such nanoparticles. This is a critical consideration as the microcirculation is the principal site of origin for numerous vascular pathologies. Given the known health outcomes (cardiovascular morbidity and mortality) from exposure to larger particles and the considerably dynamic nature of nanotechnology, identifying the health effects of nanoparticle exposure may prove far more challenging. This is further confounded by the fact that current methods to evaluate the health effects of exposure to nanomaterials are either not well developed or improperly characterize target systems. This barrier can be overcome, and if the true potential of nanotechnology is to be fully realized, the health effects of nanoparticle exposure must first be clearly defined. Previous work by our laboratory indicates that microvascular function is profoundly impaired after nanoparticle exposure. This impairment is characterized by altered microvascular reactivity and inflammation. We have also characterized age-dependent differences in microvascular function, that may render the young and elderly more susceptible to nanoparticle exposures. We hypothesize that the intensity and duration of systemic microvascular dysfunction that follows pulmonary nanoparticle inhalation is specific to the nanomaterials one is exposed to, and highly dependent on developmental age. To this end, we will define the dose-response and temporal relationships between nanoparticle inhalation and systemic microvascular dysfunction in three distinct age-groups of rats: weanling (25-28 days), juvenile/young adult (42-45 days) and senescent (>1 year). Rats will be exposed to carbon nanotube or nano-titanium dioxide aerosols. After exposure, microvascular reactivity will be studied in skeletal muscle and the coronary microcirculation. Microvascular reactivity will be characterized by responsiveness to endothelium-dependent and -independent vasoactive agents and local inflammation will be characterized by identification of local reactive species, hemoprotein deposition, and nitric oxide bioavailability. Given the opportunity, we will also assess the effect of pre-existing pulmonary inflammation on nanoparticle-dependent microvascular dysfunction. Because nanoparticles interact with the body though non-pulmonary routes, we also propose to evaluate the effect(s) of nanoparticles on skin health and microvascular function. Considering the widespread use of titania based products and carbon nanotubes throughout the U.S., these studies will constitute a critical step in evaluating the vascular health/safety risks of nanoscale products. The biological characterization of microvascular reactivity to diverse nanoparticles is vital to the prevention and treatment of related health effects. This project will determine the microvascular health effects of pulmonary nanoparticle exposure. Rats will be exposed to titanium dioxide nanoparticles and carbon nanotubes via inhalation. Subsequently, intravital microscopy (skeletal muscle) and isolated- cannulated arteriole techniques (subepicardium) will be used to evaluate microvascular reactivity in terms of dose-response, time-course, and the role of aging. PUBLIC HEALTH RELEVANCE: This project will determine the microvascular health effects of pulmonary nanoparticle exposure. Rats will be exposed to titanium dioxide nanoparticles and carbon nanotubes via inhalation. Subsequently, intravital microscopy (skeletal muscle) and isolated-cannulated arteriole techniques (subepicardium) will be used to evaluate microvascular reactivity in terms of dose-response, time-course, and the role of aging.

描述（由申请人提供）：此申请直接解决了广泛的挑战领域（13）：智能生物材料 - 触角学和具体挑战主题：评估纳米材料的健康和安全的方法。我们是一个应对这一挑战的独特实验室，因为我们定期将各种纳米颗粒雾化。同时，我们是该领域/主题中唯一的实验室，可以在接触此类纳米颗粒后直接评估微血管健康。这是一个关键的考虑因素，因为微循环是众多血管病理学的主要原点部位。考虑到已知的健康结果（心血管发病率和死亡率），从暴露于较大的颗粒以及纳米技术的动态性质相当大，因此确定纳米粒子暴露的健康效应可能会更具挑战性。当前评估接触纳米材料的健康影响的事实进一步困惑，要么不当发达，要么不正确地表征目标系统。可以克服这种障碍，如果要充分实现纳米技术的真正潜力，则首先必须明确定义纳米颗粒暴露的健康影响。我们实验室的先前工作表明，纳米颗粒暴露后微血管功能严重受损。这种障碍的特征是微血管反应性和炎症的改变。我们还表征了微血管功能的年龄依赖性差异，这可能会使年轻和老年人更容易受到纳米颗粒暴露的影响。我们假设，肺纳米颗粒吸入​​后的全身微血管功能障碍的强度和持续时间与纳米材料的特有，它暴露于纳米材料，并且高度依赖于发育年龄。为此，我们将定义三个不同年龄段的大鼠年龄段的纳米颗粒吸入​​和全身微血管功能障碍之间的剂量反应和时间关系：断奶（25-28天），青少年/年轻成人（42-45天）和（42-45天）和senescent（> 1年）。大鼠将暴露于碳纳米管或二氧化二硝基气溶胶中。暴露后，将在骨骼肌和冠状动脉微循环中研究微血管反应性。微血管反应性的特征是对内皮依赖性和非依赖性血管活性剂的反应性，局部炎症的特征将以鉴定局部反应性物质，血op蛋白沉积和一氧化氮生物利用度的鉴定来表征。鉴于机会，我们还将评估预先存在的肺部炎症对纳米颗粒依赖性微血管功能障碍的影响。由于纳米颗粒通过非肺途径与身体相互作用，因此我们还建议评估纳米颗粒对皮肤健康和微血管功能的影响。考虑到整个美国的基于二氧化钛的产品和碳纳米管的广泛使用，这些研究将构成评估纳米级产品血管健康/安全风险的关键步骤。微血管对各种纳米颗粒的反应性的生物学表征对于预防和治疗相关的健康影响至关重要。该项目将确定肺纳米颗粒暴露的微血管健康影响。大鼠将通过吸入暴露于二氧化钛纳米颗粒和碳纳米管。随后，将使用浸没显微镜（骨骼肌）和分离的插管小动脉技术（下头膜下）来评估微血管反应性，以剂量 - 响应，时间顺序和衰老作用来评估微血管反应性。 公共卫生相关性：该项目将确定肺纳米颗粒暴露的微血管健康影响。大鼠将通过吸入暴露于二氧化钛纳米颗粒和碳纳米管。随后，将使用浸润显微镜（骨骼肌）和分离的小动脉技术（下头膜下）来评估微血管反应性，以剂量 - 响应，时间顺序和衰老作用来评估。