Differential responses of males and females to multi-walled carbon nanotubes

摘要 吸入多壁碳纳米管等工程纳米材料后的不良后果 (多壁碳纳米管)，已在职业环境中确定。不幸的是，长期后果和敏感 人口仍然没有定义。慢性呼吸道疾病常常表现出疾病中的性别偏见 流行率。例如，与成年女性相比，成年女性哮喘发生的频率更高，病情也更严重 男人。我们的初步研究表明，接触多壁碳纳米管的结果遵循这一趋势： 与男性相比，女性的肺部炎症和损伤。因此，对其进行研究是合乎逻辑和必要的。 可能导致这些性别差异的生物因素。有实验和临床证据 性类固醇激素影响肺部疾病的发展。激素信号的一个可能目标是 肺泡巨噬细胞(AM)，肺内主要的常驻免疫细胞。细胞的表型和功能 AM是促进对吸入物质的特定免疫反应的重要因素，并可能有助于 不经意间免疫介导的肺损伤。本项目将研究激素信号在AM中的作用 多壁碳纳米管暴露后的表型及其对肺功能损害的影响。当代文学 提示雌激素受体a(Era)信号促进夸大的M2a巨噬细胞表型。这个 M2a表型促进B细胞产生抗体，因此与过敏和哮喘有关； 多壁碳纳米管也被证明可以诱导AM的M2a表型。M2a表型的扩增 极化可导致信号分子的产生增加，从而导致不适当的免疫细胞 募集和炎症，最终导致肺损伤增加和功能下降。这些 结合我们的初步结果，数据提供了一种潜在的激素依赖机制 妇女对过敏原和纳米材料的易感性增加。这个项目将解决这样的假设 雌激素通过ERA信号促进女性AM中夸大的M2a表型，这有助于 颗粒物引起的呼吸系统疾病在妇女中的发生率和严重性增加。

Abstract Adverse outcomes following the inhalation of engineered nanomaterials, such as multi-walled carbon nanotubes (MWCNTs), have been identified in occupational settings. Unfortunately, long-term consequences and sensitive populations remain undefined. Chronic respiratory diseases often demonstrate sex-biases in disease prevalence. For example, asthma occurs more often and with increased severity in adult women compared to men. Our preliminary studies indicate that the outcomes of MWCNT exposure follow this trend: there is increased lung inflammation and injury in females compared to males. Therefore, it is logical and necessary to investigate the biological factors that may contribute to these sex-differences. There is experimental and clinical evidence that sex-steroid hormones influence the development of lung disease. A likely target of hormone signaling is alveolar macrophages (AMs), the primary resident immune cell within the lungs. The phenotype and function of AMs is an important factor in promoting specific immune responses to inhaled materials, and may contribute to inadvertent immune-mediated lung injury. This project will investigate the role of hormone signaling on AM phenotype and how this contributes to impaired lung function after exposure to MWCNTs. Current literature suggests that estrogen receptor a (ERa) signaling promotes an exaggerated M2a macrophage phenotype. The M2a phenotype promotes antibody production by B cells and is therefore associated with allergy and asthma; MWCNTs have also been shown to induce an M2a phenotype in AMs. Amplification of M2a phenotype polarization can lead to increased production of signaling molecules that cause inappropriate immune cell recruitment and inflammation, which eventually results in increased lung injury and decreased function. These data, combined with our preliminary results, provides a potential hormone-dependent mechanism for the increased susceptibility of women to allergens and nanomaterials. This project will address the hypothesis that estrogen signaling through ERa promotes an exaggerated M2a phenotype in female AMs, which contributes to the increased occurrence and severity of particle-induced respiratory diseases in women.