Mechanisms of mast cell directed carbon nanotube toxicity

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性质，有可能影响社会的各个方面。虽然目前市场上有800多种含有纳米材料的产品，但尽管新出现了与纳米材料相关的不良呼吸和心血管影响的观察结果，但这些产品严重缺乏毒性测试。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，对纳米材料如何与生物系统相互作用的了解有限;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有毒副作用。据报道，吸入单壁CNT（SWCNT）或多壁CNT（MWCNT）会导致肺部炎症和纤维化。此外，我们实验室最近的工作表明，接触多壁碳纳米管会影响心血管系统。肥大细胞可能是诱导这些毒性作用的关键效应细胞。我们有初步的，但令人信服的证据表明，CNT肺暴露激活居民肥大细胞，直接或间接，从而有助于肺和心血管病理。我们的初步研究结果支持了CNT暴露通过IL-33依赖性机制激活肥大细胞的假设，该机制导致肺部炎症和不良心血管事件，这是由于炎症介质（包括骨桥蛋白（OPN））的最终释放。我们将通过以下方式检验这一假设：1）检查暴露于MWCNT的小鼠肺中的肥大细胞活化; 2）检查IL-33在介导肥大细胞活化中的作用; 3）阐明肥大细胞在促成心血管系统内血管反应性改变中的作用; 4）使用基于细胞的模型来建立MWCNT导致肥大细胞活化的机制。该提议是新颖的，因为它确定了CNT导致毒性的未被识别但重要的机制。了解这种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翻译应用，通过阐明所提出的机制，我们将为使用肥大细胞定向策略（如克罗埃因钠）在暴露后早期干预以预防随后的炎症和纤维化提供支持。 公共卫生相关性：近年来，工程纳米材料在生物技术行业和制造业中的使用急剧增加。然而，使纳米颗粒在科学和医学中有用的特性也存在潜在的安全问题。这项提议将阐明一种机制，涉及肥大细胞活化，通过这种机制，多壁碳纳米管引起肺和心血管毒性。本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纳米管暴露后肥大细胞导向药物的早期干预可能提供有益治疗的概念。

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.