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

男性和女性对多壁碳纳米管的不同反应

• 批准号: 10266754
• 负责人: Andrij Holian
• 金额: $ 18.2万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266754
• 关键词: Acute; Address; Adopted; Adoptive Transfer; Adult; Adult asthma; Allergens; Allergic; Alveolar Macrophages; Antibody Formation; Asthma; B-Lymphocytes; Biological; Biological Factors; Bone Marrow; Castration; Cells; Cessation of life; Chimera organism; Chronic; Chronic lung disease; Clinical; Complex; Data; Development; Disease; Engineering; Environment; Environmental Exposure; Environmental and Occupational Exposure; Epidemiology; Estrogen Receptor alpha; Estrogens; Etiology; Exhibits; Exposure to; Extrinsic asthma; Female; Fibrosis; Flow Cytometry; Germ Cells; Gonadal Steroid Hormones; Health; Hormonal; Hormone Receptor; Hormones; Human; Hypersensitivity; Immune; Immune response; Immune system; Impairment; Individual; Inflammation; Inhalation; Investigation; Knowledge; Laboratories; Lead; Literature; Lung; Lung Inflammation; Lung diseases; Mediating; Methods; Modeling; Myelogenous; Occupational; Occupational Safety; Outcome; Ovalbumin; Pathology; Pharmacologic Substance; Phenotype; Population; Predisposition; Prevalence; Prevention; Production; Pulmonary Pathology; Receptor Signaling; Regulation; Research; Respiratory physiology; Risk; Role; Severities; Sex Bias; Sex Differences; Signal Transduction; Signaling Molecule; Testing; Therapeutic; Tissues; Translating; Woman; adverse outcome; airway hyperresponsiveness; base; consumer product; cytokine; double walled carbon nanotube; experience; exposed human population; hormonal signals; improved; in vivo; innovation; interest; lung development; lung injury; macrophage; male; men; methacholine; nanomaterials; novel therapeutic intervention; particle; premature; pulmonary function; recruit; respiratory; response; sex; steroid hormone; trend

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.

摘要 吸入工程纳米材料（如多壁碳纳米管）后的不良后果 （多壁碳纳米管），已确定在职业环境。不幸的是，长期的后果和敏感的 人口仍然不确定。慢性呼吸道疾病往往表现出疾病的性别偏见 普遍性。例如，哮喘在成年女性中发生得更频繁， 男人我们的初步研究表明，多壁碳纳米管暴露的结果遵循这一趋势： 与雄性相比，雌性的肺部炎症和损伤。因此，调查是合乎逻辑和必要的 可能导致这些性别差异的生物学因素。有实验和临床证据表明 性类固醇激素会影响肺部疾病的发展激素信号的一个可能的目标是 肺泡巨噬细胞（AM），肺内的主要常驻免疫细胞。的表型和功能 AM是促进对吸入物质的特异性免疫应答的重要因素， 免疫介导的肺损伤。本课题将研究激素信号在AM中的作用 表型以及这如何导致暴露于MWCNT后肺功能受损。当前文献 提示雌激素受体α（ER α）信号传导促进了夸张的M2 a巨噬细胞表型。的 M2 a表型促进B细胞产生抗体，因此与变态反应和哮喘有关; MWCNT还显示在AM中诱导M2 a表型。M2 a表型扩增 极化可导致信号分子的产生增加， 募集和炎症，最终导致肺损伤增加和功能下降。这些 数据，结合我们的初步结果，提供了一个潜在的依赖性机制， 妇女对过敏原和纳米材料的敏感性增加。这个项目将解决的假设， 通过ER α的雌激素信号传导促进了女性AM中M2 a表型的扩大，这有助于 颗粒物引起的呼吸道疾病在妇女中的发生率和严重程度增加。