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，具有影响社会各个方面的潜力。虽然目前市场上有800多种含有纳米材料的产品，但尽管出现了与纳米材料相关的不良呼吸和心血管影响的新观察，但与这些产品相关的毒性测试明显缺乏。此外，由于其独特的性质，纳米材料具有以独特的方式与生物系统相互作用的潜力。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理解有限；因此，我们没有能力预测哪些纳米材料是安全的，哪些是有毒的；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）可引起肺部炎症和纤维化。此外，我们实验室最近的工作表明，暴露于MWCNT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，碳纳米管暴露于肺部直接或间接地激活了常驻肥大细胞，从而导致肺部和心血管病理。我们的初步研究结果支持了碳纳米管暴露通过IL-33依赖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，这是由于炎症介质的释放，包括骨桥蛋白（OPN）。我们将通过以下方法来验证这一假设：1)检测暴露于MWCNTs的小鼠肺部肥大细胞的活化；2)研究IL-33在介导肥大细胞活化中的作用；3)阐明肥大细胞在心血管系统血管反应性改变中的作用；4)利用基于细胞的模型建立MWCNTs导致肥大细胞活化的机制。这一建议是新颖的，因为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，该建议提供了一个重要的转化应用，通过阐明所提出的机制，我们将为肥大细胞定向策略的使用提供支持，如色莫利钠，在暴露后早期干预，以防止随后的炎症和纤维化。

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.