Microvascular Health and Nanoparticle Exposure

描述（由申请人提供）：本申请直接涉及广泛挑战领域（13）：智能生物材料-治疗诊断学，以及特定挑战主题：评估纳米材料健康和安全性的方法。我们是一个独特的合格实验室，以应对这一挑战，因为我们定期雾化不同的纳米粒子。同时，我们是该领域/主题中唯一直接评估吸入暴露于此类纳米颗粒后微血管健康的实验室。这是一个关键的考虑因素，因为微循环是许多血管病变的主要起源部位。鉴于已知的健康结果（心血管发病率和死亡率）暴露于较大的颗粒和纳米技术的相当动态的性质，确定纳米颗粒暴露的健康影响可能更具挑战性。目前评估接触纳米材料的健康影响的方法要么没有得到很好的开发，要么没有正确地描述目标系统，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，必须首先明确纳米颗粒暴露对健康的影响。我们实验室以前的工作表明，微血管功能在纳米颗粒暴露后严重受损。这种损伤的特征在于改变的微血管反应性和炎症。我们还表征了微血管功能的年龄依赖性差异，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与暴露的纳米材料有关，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），幼年/年轻成年（42-45天）和衰老（>1岁）。大鼠将暴露于碳纳米管或纳米二氧化钛气溶胶。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。微血管反应性将通过对内皮依赖性和非依赖性血管活性剂的反应性来表征，局部炎症将通过鉴定局部反应性物质、血红素蛋白沉积和一氧化氮生物利用度来表征。如果有机会，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部途径与身体相互作用，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整个美国的广泛使用，这些研究将构成评估纳米级产品的血管健康/安全风险的关键步骤。微血管对不同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，将使用活体显微镜检查（骨骼肌）和离体插管小动脉技术（心外膜下）评价微血管反应性的剂量反应、时间过程和老化作用。 公共卫生相关性：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，将使用活体显微镜检查（骨骼肌）和分离插管小动脉技术（心外膜下）评价微血管反应性的剂量反应、时间过程和老化作用。

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.