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

基本信息

批准号：
9912608
负责人：
Andrij Holian
金额：
$ 21.91万
依托单位：
UNIVERSITY OF MONTANA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-18 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912608
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 therapeutics particle premature pulmonary function recruit respiratory response sex steroid hormone trend

项目摘要

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.

抽象的吸入工程纳米材料（例如多壁碳纳米管）后的不良后果（多壁碳纳米管）已在职业环境中被发现。不幸的是，长期后果和敏感人口仍未确定。慢性呼吸道疾病通常表现出疾病的性别偏见流行率。例如，与其他女性相比，成年女性的哮喘发病率更高且严重程度更高男人。我们的初步研究表明，多壁碳纳米管暴露的结果遵循以下趋势：增加与男性相比，女性的肺部炎症和损伤。因此，进行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。有实验和临床证据性类固醇激素会影响肺部疾病的发展。激素信号传导的一个可能目标是肺泡巨噬细胞（AM）是肺内主要的常驻免疫细胞。表型和功能 AMs 是促进对吸入物质的特异性免疫反应的重要因素，并可能有助于无意的免疫介导的肺损伤。该项目将研究激素信号传导对 AM 的作用表型以及这如何导致暴露于多壁碳纳米管后肺功能受损。当前文献表明雌激素受体 a (ERa) 信号传导促进 M2a 巨噬细胞表型过度增强。这 M2a 表型促进 B 细胞产生抗体，因此与过敏和哮喘有关； MWCNT 还被证明可以在 AM 中诱导 M2a 表型。 M2a 表型的扩增极化会导致信号分子的产生增加，从而导致不适当的免疫细胞肺复张和炎症，最终导致肺损伤加剧和功能下降。这些数据与我们的初步结果相结合，为女性对过敏原和纳米材料的敏感性增加。该项目将解决以下假设：通过 ERa 的雌激素信号传导促进女性 AM 中夸大的 M2a 表型，这有助于女性颗粒物引起的呼吸道疾病的发生率和严重程度增加。