Respiratory and Ocular Toxicity of Inhaled Nanomaterials

摘要 我们假设了工程纳米材料的组成、尺寸、直径和表面涂层的不同 (ENM)将调节雾化ENM在体内的沉积、分布和对肺部的生物效应 还有眼睛。在这个项目中，我们将系统地测试气雾化后的各种ENM，以确定关键 影响其毒性的特性。我们选择检查呼吸道对健康的影响 和眼睛，因为这两个器官系统都是接触雾化新城疫的主要途径。我们的重点是 将通过吸入来创造真实和相关的暴露情景，以主要类别的ENM，一个常见的 以及预期的接触途径。此外，肺和眼睛都是基于ENM的当前目标 治疗用药。我们在这项建议中的目标是系统地和定量地比较 这些器官系统上具有不同物理化学性质的纳米材料的生理学研究 相关模型。对健康的影响将包括详细的分子和病理生理变化 目标是ENM沉积和保留区。我们处于有利地位，为新的nhir做出贡献 财团在ENM上的努力。我们对所列的许多材料都有使用经验。因为一个 将对潜在的大量材料进行系统测试，这是一个具有明确指示的分层范例 ENM需要哪些活体测试将被使用。我们对新城疫对健康的影响有很好的出版记录 体内和体外研究，特别是包括实验室产生的干粉在内的新材料气雾剂 和雾化的液体气雾剂。我们的团队在金属、金属氧化物、碳颗粒、碳 纳米管和与之相结合的三维ENM是Van Winkle发展起来的新方法， Thomasy和Pinkerton实验室研究特定部位的细胞反应和表征良好的方法 在眼科医生眼科中常用的角膜和视网膜成像。这些新颖的方法 包括在组织中定位ENM的显微镜和组织学方法以及应用 显微解剖以研究ENM的保留和位置特异性的基因、蛋白质和细胞反应。此外，这三个人都是 研究人员有能力利用加州国家灵长类动物研究这一独特的资源 这使得在生理上与人类和非人类相关的模型中进行ENM效应的体外研究成为可能 灵长类的外植体和细胞。我们知道细胞系会给出不同的结果，所以在这方面拟议的研究 应用将强调我们感兴趣器官的原代细胞或组织外植体，再加上体内 该联盟定义的部分ENM气雾剂的研究。我们提案的具体目标提供了新颖的 和创新的方法来测量基于细胞的细胞毒性、炎症和重塑 完整呼吸道以及角膜和视网膜的损伤修复模型。

SUMMARY We hypothesize differences in composition, size, diameter and surface coating of engineered nanomaterials (ENM) will modulate the in vivo deposition, distribution and biologic effects of aerosolized ENM to the lungs and the eyes. In this project, we will systematically test diverse ENM following aerosolization to identify the key characteristics that influence their toxicity. We have chosen to examine health effects in the respiratory tract and the eye, since both organ systems represent the major route of exposure to aerosolized ENM. Our focus will be to create real and relevant exposure scenarios by inhalation to the major classes of ENMs, a common and expected route of exposure. Further, the lungs and the eyes are both current targets of ENM-based therapeutic delivery. Our goal in this proposal is to systematically and quantitatively compare the health effects of nanomaterials with different physicochemical properties on these organ systems using physiologically relevant models. The health effects will include detailed molecular and pathophysiologic changes that will be targeted to zones of ENM deposition and retention. We are well positioned to contribute to the new NHIR consortium efforts on ENM. We have experience working with many of the materials listed. Because a potentially large number of materials will be systematically tested, a tiered paradigm with clear indications for which ENM need in vivo testing will be used. We have a strong publication record of ENM health effects research in vivo and ex vivo, particularly of novel material aerosols including laboratory generated, dry powder and nebulized liquid aerosols. Our team has expertise in metals, metal oxides, carbon particles, carbon nanotubes and 3-dimensional ENM Coupled with this are the novel methods developed in the Van Winkle, Thomasy and Pinkerton laboratories to study site-specific cellular responses and well-characterized methods in corneal and retinal imaging commonly used in physician-based ophthalmology. These novel approaches include microscopic and histologic approaches to localize ENM in tissues as well as the application of microdissection to study ENM retention and site specific gene, protein and cellular responses. Further, all three investigators have the ability to take advantage of a unique resource, the California National Primate Research Center This enables in vitro studies of ENM effects in a model physiologically relevant to humans, nonhuman primate explants and cells. We know that cell lines give divergent results and so the proposed studies in this application will emphasize primary cells or tissue explants for our organs of interest, coupled with in vivo studies of select ENM aerosols as defined by the consortium. The specific aims of our proposal provide novel and innovative methods to measure cell-based cytotoxicity, inflammation and remodeling in both normal and injury repair models of the complete respiratory tract, as well as the cornea and retina.