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）：本申请直接解决广泛的挑战领域 (13)：智能生物材料治疗诊断学，以及具体的挑战主题：评估纳米材料健康和安全的方法。我们是一个具有独特资格的实验室，可以应对这一挑战，因为我们定期雾化不同的纳米颗粒。同时，我们是该领域/主题中唯一能够直接评估吸入暴露于此类纳米颗粒后微血管健康状况的实验室。这是一个重要的考虑因素，因为微循环是许多血管病变的主要起源部位。考虑到暴露于较大颗粒导致的已知健康后果（心血管发病率和死亡率）以及纳米技术相当动态的性质，确定纳米颗粒暴露对健康的影响可能更具挑战性。目前评估暴露于纳米材料对健康影响的方法要么不成熟，要么不正确地表征目标系统，这一事实进一步混淆了这一点。这一障碍是可以克服的，如果要充分发挥纳米技术的真正潜力，首先必须明确界定纳米颗粒暴露对健康的影响。我们实验室之前的工作表明，暴露于纳米颗粒后微血管功能受到严重损害。这种损伤的特征是微血管反应性和炎症改变。我们还描述了微血管功能随年龄变化的差异，这可能使年轻人和老年人更容易受到纳米颗粒暴露的影响。我们假设肺部纳米颗粒吸入​​后全身微血管功能障碍的强度和持续时间特定于所接触的纳米材料，并且高度依赖于发育年龄。为此，我们将在三个不同年龄组的大鼠中定义纳米颗粒吸入​​与全身微血管功能障碍之间的剂量反应和时间关系：断奶期（25-28天）、青少年/青年（42-45天）和衰老大鼠（>1 年）。老鼠将暴露于碳纳米管或纳米二氧化钛气溶胶。暴露后，将研究骨骼肌和冠状微循环的微血管反应性。微血管反应性的特征在于对内皮依赖性和非依赖性血管活性剂的反应性，局部炎症的特征在于局部活性物质、血红素沉积和一氧化氮生物利用度的识别。如果有机会，我们还将评估先前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部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。考虑到二氧化钛基产品和碳纳米管在美国的广泛使用，这些研究将构成评估纳米级产品的血管健康/安全风险的关键一步。微血管对不同纳米颗粒反应性的生物学特征对于预防和治疗相关的健康影响至关重要。该项目将确定肺部纳米颗粒暴露对微血管健康的影响。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，活体显微镜（骨骼肌）和离体插管小动脉技术（心外膜下）将用于评估剂量反应、时程和衰老作用方面的微血管反应性。 公共健康相关性：该项目将确定肺部纳米颗粒暴露对微血管健康的影响。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，活体显微镜（骨骼肌）和离体插管小动脉技术（心外膜下）将用于评估剂量反应、时程和衰老作用方面的微血管反应性。