Mechanisms of Nanoparticle Modulation of Allergic Lung Disease

纳米粒子调节过敏性肺病的机制

基本信息

批准号：
10632116
负责人：
James Christopher Bonner
金额：
$ 49.22万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10632116
关键词：
Adsorption Airway Disease Airway Fibrosis Allergens Allergic Amines Area Artificial nanoparticles Asthma Binding Biological Biological Assay Bronchial Spasm Cell Communication Cell surface Cells Chronic Data Disease Environment Exposure to Extrinsic asthma G-Protein-Coupled Receptors Genetic Predisposition to Disease Goals Health House Dust Mite Allergens Human Immune In Vitro Industry Inflammation Inhalation Inhalation Exposure Interferons Knock-out Knockout Mice Knowledge Libraries Lung Lung diseases Macrophage Mediating Metaplasia Molecular Target Mucous body substance Mus PAR-2 Receptor Pathology Phenotype Predisposition Process Property Proteins Proteomics Public Health Pulmonary Fibrosis Pulmonary Inflammation Pyroglyphidae Reporting Research Project Grants Respiratory Disease Risk Rodent Rodent Model Role STAT1 gene STAT3 gene STAT6 gene Serine Protease Signal Transduction Surface Testing Therapeutic Wild Type Mouse Work airway hyperresponsiveness allergic airway disease cell type chemical addition chemical group chronic respiratory disease consumer product cytokine design double walled carbon nanotube eosinophilic inflammation hazard inhibitor nanoparticle novel profibrotic cytokine public health relevance response transcription factor

项目摘要

Project Summary Multi-walled carbon nanotubes (MWCNTs) are engineered nanoparticles with numerous applications and they are commonly ‘functionalized’ by the addition of chemical groups (e.g., carboxyl or amine groups) to modify their unique physicochemical properties. Increasing evidence in rodent models indicate that MWCNTs are an emerging risk for lung diseases. In particular, MWCNTs exacerbate allergen-induced airway disease in rodents, suggesting a potential hazard for humans with allergic asthma. The long-term pathology of asthma features airway fibrosis and mucous cell metaplasia, defined herein as allergic airway disease. Importantly, current asthma therapies treat inflammation and bronchospasm, but do not reduce allergic airway disease. Therefore, elucidating the mechanism(s) through which nanoparticles exacerbate allergic airway disease would fill critical knowledge and treatment gaps. We propose a mechanism of nanoparticle exacerbation of chronic airway disease mediated by the adsorption of proteolytic house dust mite (HDM) allergens to the surface of MWCNTs to form an ‘allergen corona’. Allergens in the corona have increased proteolytic activity and activate the protease-activated receptor-2 (PAR2) on lung macrophages. Triggering of PARs has been implicated in M2-like ‘pro- fibrotic’ polarization of macrophages, a process that is regulated by STAT transcription factors. Our preliminary data show that PAR2 deficiency in cells or mice increases STAT1 signaling but decreases STAT3 signaling. Therefore, we hypothesize that MWCNTs exacerbate allergic airway disease by enhancing the proteolytic activity of allergens to increase PAR2 activation in macrophages leading to induction of STAT3 signaling and suppression of STAT1 signaling. In Aim 1 we will characterize the allergen corona on MWCNTs exposed to HDM extract, determine that functionalization alters corona formation, and show that corona allergens have enhanced proteolytic activity. In Aim 2 we will determine whether MWCNTs with HDM allergen corona activate PAR2 in macrophages in vitro to induce STAT3 signaling or suppress STAT1 signaling to enhance pro-fibrotic cytokine expression. In Aim 3 we will determine whether MWCNTs with HDM allergen corona exacerbate allergic airway disease in mice and whether this is dependent on PAR2 induction of STAT3 activation or suppression of STAT1 activation. Completion of these studies will define a novel mechanism and fundamental basis through which nanoparticles exacerbate allergic airway disease. This work will have significant and broad implications for a variety of engineered nanoparticles and their impact on human health.

项目概要多壁碳纳米管（MWCNT）是工程纳米颗粒，具有许多应用中，它们通常通过添加化学基团进行“功能化”（例如，羧基或胺基）以改变其独特的物理化学性质。啮齿动物模型中的证据表明，多壁碳纳米管是一种新出现的肺部疾病风险。特别是，多壁碳纳米管加剧了啮齿类动物过敏原诱发的气道疾病，这表明对过敏性哮喘患者的潜在危害哮喘的长期病理学特征。气道纤维化和粘液细胞化生，本文定义为过敏性气道疾病。目前的哮喘疗法可以治疗炎症和支气管痉挛，但不能减少过敏性气道因此，阐明纳米颗粒恶化的机制。我们提出了一种机制，可以填补过敏性气道疾病的关键知识和治疗空白。纳米粒子吸附蛋白水解介导的慢性气道疾病恶化的研究屋尘螨（HDM）过敏原附着在多壁碳纳米管表面，形成“过敏原电晕”。电晕中的过敏原增加了蛋白水解活性并激活了蛋白酶肺巨噬细胞上的受体 2 (PAR2) 的触发与 M2 样“pro-”有关。巨噬细胞纤维化的极化，这是一个受 STAT 转录因子调节的过程。我们的初步数据表明，细胞或小鼠中 PAR2 缺陷会增加 STAT1 信号传导，但因此，我们发现 MWCNT 会加剧气道过敏。通过增强过敏原的蛋白水解活性来增加 PAR2 的激活，从而预防疾病巨噬细胞导致 STAT3 信号传导的诱导和 STAT1 信号传导的抑制。目标 1 我们将表征暴露于 HDM 提取物的 MWCNT 上的过敏原电晕，确定功能化改变了电晕的形成，并表明电晕过敏原已增强在目标 2 中，我们将确定 MWCNT 是否具有 HDM 过敏原电晕。体外激活巨噬细胞中的 PAR2 以诱导 STAT3 信号传导或抑制 STAT1 信号传导在目标 3 中，我们将确定 MWCNT 是否具有增强促纤维化细胞因子的表达。 HDM 过敏原电晕加剧小鼠过敏性气道疾病以及这是否具有依赖性 PAR2 诱导 STAT3 激活或抑制 STAT1 激活完成这些。研究将确定纳米颗粒的新机制和基本基础这项工作将对恶化的过敏性气道疾病产生重大而广泛的影响。各种工程纳米粒子及其对人类健康的影响。