Mechanisms of mast cell directed carbon nanotube toxicity

肥大细胞定向碳纳米管毒性机制

• 批准号: 8249077
• 负责人: Jared Michael Brown
• 金额: $ 37.2万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-10 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249077
• 关键词: Adverse effects; Alveolar; Alveolar Macrophages; Biotechnology; Blood Vessels; Breathing; C57BL/6 Mouse; Carbon Nanotubes; Cardiovascular Pathology; Cardiovascular system; Cells; Collagen; Cromolyn Sodium; Data; Deposition; Early treatment; Effector Cell; Engineering; Epithelial Cells; Event; Exposure to; Fibrosis; Hour; IgE; In Vitro; Industry; Inflammation; Inflammation Mediators; Inflammatory; Laboratories; Lead; Lung; Lung Inflammation; Macrophage Activation; Marketing; Mediating; Mediator of activation protein; Medicine; Modeling; Mus; Nanotubes; Peripheral; Pneumonia; Production; Property; Pulmonary Fibrosis; Pulmonary Pathology; Reporting; Role; Safety; Science; Screening procedure; Societies; Testing; Tissues; Toxic effect; Toxicity Tests; Work; alveolar epithelium; base; biological systems; design; in vitro Model; in vivo; mast cell; multi walled carbon nanotube; nanomaterials; nanoparticle; novel; osteopontin; prevent; public health relevance; respiratory; single walled carbon nanotube; tool

DESCRIPTION (provided by applicant): Engineered nanomaterials, including carbon nanotubes (CNT), have unique physicochemical properties with potential to impact diverse aspects of society. While there are currently over 800 products on the market that contain nanomaterials, there is a significant lack of toxicity testing associated with these products despite emerging observations of adverse respiratory and cardiovascular effects associated with nanomaterials. In addition, due to their unique properties, nanomaterials have the potential to interact with biological systems in a distinctive manner. However, to date there is only a limited understanding of how nanomaterials interact with biological systems; and therefore we lack the ability to predict which nanomaterials are safe and which are toxic; and how nanomaterials might be engineered to avoid toxic side effects. Inhalation of single-walled CNT (SWCNT) or multi-walled CNT (MWCNT) has been reported to cause lung inflammation and fibrosis. In addition, recent work in our laboratory suggests that exposure to MWCNT impacts the cardiovascular system. Mast cells may well be critical effector cells in inducing these toxic effects. We have preliminary, but convincing evidence that CNT pulmonary exposure activates resident mast cells, either directly or indirectly, thereby contributing to both pulmonary and cardiovascular pathology. Our preliminary findings support the hypothesis that CNT exposure activates mast cells through an IL-33 dependent mechanism which results in pulmonary inflammation and adverse cardiovascular events due to the resultant release of inflammatory mediators, including osteopontin (OPN). We will test this hypothesis by: 1) examining mast cell activation in lungs of mice exposed to MWCNTs; 2) examining the role of IL-33 in mediating mast cell activation; 3) elucidating the role of mast cells in contributing to altered vascular reactivity within the cardiovascular system; 4) using cell based models to establish the mechanisms by which MWCNTs lead to mast cell activation. This proposal is novel in that it identifies an unrecognized, yet significant mechanism by which CNTs lead to toxicity. Understanding this mechanism will allow us to design better models and in vitro screening tools to predict nanomaterial toxicity. Lastly, this proposal provides an important translational application in that by elucidating the proposed mechanism, we will provide support for the use of mast cell directed strategies, such as cromolyn sodium, to intervene early after exposure to prevent subsequent inflammation and fibrosis. PUBLIC HEALTH RELEVANCE: The use of engineered nanomaterials in the biotechnology industry and manufacturing setting has increased dramatically in recent years. Yet, the properties that make nanoparticles useful in science and medicine also present potential safety concerns. This proposal will elucidate a mechanism, involving mast cell activation, by which multi-walled carbon nanotubes elicit pulmonary and cardiovascular toxicities. Completion of this proposal will provide the data needed to assess the toxicity associated with additional nanomaterials and will provide important translational implications as the data will begin to support the notion that early intervention with mast cell directed medicines following nanotube exposure may provide beneficial therapy.

描述（由申请人提供）：工程纳米材料，包括碳纳米管（CNT），具有独特的物理化学特性，有可能影响社会的各个方面。尽管目前市场上有超过 800 种产品含有纳米材料，但尽管不断观察到与纳米材料相关的不良呼吸和心血管影响，但与这些产品相关的毒性测试却严重缺乏。此外，由于其独特的性质，纳米材料有可能以独特的方式与生物系统相互作用。然而，迄今为止，人们对纳米材料如何与生物系统相互作用的了解还很有限。因此我们缺乏预测哪些纳米材料是安全的、哪些是有毒的能力；以及如何设计纳米材料以避免毒副作用。据报道，吸入单壁碳纳米管 (SWCNT) 或多壁碳纳米管 (MWCNT) 会导致肺部炎症和纤维化。此外，我们实验室最近的研究表明，接触多壁碳纳米管会影响心血管系统。肥大细胞很可能是诱导这些毒性作用的关键效应细胞。我们有初步但令人信服的证据表明，CNT 肺部暴露会直接或间接激活常驻肥大细胞，从而导致肺部和心血管病理学。我们的初步研究结果支持这样的假设：CNT 暴露通过 IL-33 依赖性机制激活肥大细胞，由于骨桥蛋白 (OPN) 等炎症介质的释放，导致肺部炎症和不良心血管事件。我们将通过以下方式检验这一假设：1）检查暴露于多壁碳纳米管的小鼠肺部肥大细胞的激活情况； 2)检查IL-33在介导肥大细胞激活中的作用； 3）阐明肥大细胞在改变心血管系统内血管反应性方面的作用； 4) 使用基于细胞的模型建立多壁碳纳米管导致肥大细胞激活的机制。该提案的新颖之处在于它确定了碳纳米管导致毒性的一种未被认识但重要的机制。了解这一机制将使我们能够设计更好的模型和体外筛选工具来预测纳米材料的毒性。最后，该提案提供了一个重要的转化应用，通过阐明所提出的机制，我们将为使用肥大细胞定向策略（例如色甘酸钠）提供支持，以在暴露后早期进行干预，以防止随后的炎症和纤维化。 公共健康相关性：近年来，工程纳米材料在生物技术行业和制造环境中的使用急剧增加。然而，使纳米粒子在科学和医学中有用的特性也存在潜在的安全问题。该提案将阐明一种涉及肥大细胞激活的机制，多壁碳纳米管可通过该机制引起肺部和心血管毒性。该提案的完成将提供评估与其他纳米材料相关的毒性所需的数据，并将提供重要的转化意义，因为数据将开始支持这样的观点，即在纳米管暴露后早期使用肥大细胞定向药物进行干预可能会提供有益的治疗。