Mechanisms of Nanoparticle Modulation of Allergic Lung Disease

纳米粒子调节过敏性肺病的机制

• 批准号: 10298297
• 负责人: James Christopher Bonner
• 金额: $ 48.62万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 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/10298297
• 关键词: Adsorption; Airway Disease; Allergens; Allergic; Amines; Area; Artificial nanoparticles; Asthma; Binding; Biological; Biological Assay; Bronchial Spasm; Cell surface; Cells; Chronic; Data; Disease; Environment; Exposure to; Extrinsic asthma; Fibrosis; 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 Inflammation; Lung diseases; Mediating; Metaplastic Cell; Molecular Target; Mucous body substance; Mus; PAR-2 Receptor; Pathology; Phenotype; Process; Property; Proteins; Proteomics; Public Health; Pulmonary Fibrosis; Pyroglyphidae; Reporting; Research Project Grants; 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; consumer product; cytokine; design; double walled carbon nanotube; eosinophilic inflammation; hazard; inhibitor/antagonist; macrophage; nanoparticle; novel; public health relevance; response; transcription factor

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.

项目摘要 多壁碳纳米管（MWCNT）是具有许多纳米结构的工程化纳米颗粒。 并且它们通常通过添加化学基团（例如， 羧基或胺基）以改变其独特的物理化学性质。增加 啮齿动物模型中的证据表明，多壁碳纳米管是肺部疾病的新风险。在 特别是，多壁碳纳米管加剧了啮齿动物过敏原诱导的气道疾病，这表明 对过敏性哮喘患者的潜在危害。哮喘的长期病理特征 气道纤维化和粘液细胞化生，在此定义为变应性气道疾病。重要的是， 目前的哮喘疗法治疗炎症和支气管痉挛，但不能减少过敏性气道 疾病因此，阐明纳米颗粒加剧 过敏性气道疾病将填补关键知识和治疗空白。我们提出了一个机制 纳米颗粒通过蛋白水解吸附介导的慢性气道疾病恶化 将屋尘螨（HDM）过敏原吸附到MWCNT表面以形成“过敏原冠”。 过敏原在冠有增加蛋白水解活性和激活蛋白酶激活 受体2（PAR 2）。PAR的触发与M2类似的“亲- 巨噬细胞的纤维化极化，这是一个由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PAR 2的缺乏会增加STAT 1信号传导， 减少STAT 3信号传导。因此，我们假设多壁碳纳米管加剧过敏性气道 通过增强过敏原的蛋白水解活性来增加PAR 2的活化， 这导致STAT 3信号传导的诱导和STAT 1信号传导的抑制。在 目的1我们将表征暴露于HDM提取物的多壁碳纳米管上的过敏原冠， 功能化改变了冠状形成，并表明冠状过敏原增强了 蛋白水解活性在目标2中，我们将确定具有HDM过敏原冠的MWCNT是否 体外激活巨噬细胞中的PAR 2以诱导STAT 3信号传导或抑制STAT 1信号传导 以增强促纤维化细胞因子的表达。在目标3中，我们将确定是否具有 HDM过敏原冠加重小鼠过敏性气道疾病及其依赖性 对PAR 2诱导STAT 3活化或抑制STAT 1活化的影响。完成这些 研究将定义一种新的机制和基本基础， 加重过敏性气道疾病。这项工作将有重大和广泛的影响， 各种工程纳米粒子及其对人类健康的影响。