Mechanisms of Nanoparticle Modulation of Allergic Lung Disease

项目摘要 多壁碳纳米管(MWCNTs)是一种经过工程设计的纳米颗粒，具有许多 并且它们通常通过添加化学基团(例如， 羧基或胺基)来修饰其独特的物理化学性质。渐增 在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……里面 特别是，多壁碳纳米管加重了变应原诱导的啮齿动物呼吸道疾病，表明 对患有过敏性哮喘的人类有潜在危险。哮喘的长期病理特点 呼吸道纤维化和粘液细胞化生，在此定义为过敏性呼吸道疾病。重要的是 目前的哮喘治疗方法可以治疗炎症和支气管痉挛，但不能减少过敏性呼吸道 疾病。因此，阐明纳米颗粒加剧的机制(S) 过敏性呼吸道疾病将填补关键知识和治疗空白。我们提出了一种机制 蛋白水解物吸附介导的纳米颗粒加重慢性呼吸道疾病 屋尘(HDM)变应原附着在多壁碳纳米管表面，形成“过敏原日冕”。 日冕中的过敏原增加了蛋白分解活性，并激活了激活的蛋白水解酶 肺巨噬细胞上的受体-2(PAR2)。触发PAR已牵涉到类似M2的PRO 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。 我们的初步数据显示，细胞或小鼠中缺乏PAR2会增加STAT1信号转导，但 减少STAT3信令。因此，我们假设多壁碳纳米管加重过敏性呼吸道反应。 通过增强变应原的蛋白分解活性来增加PAR2的激活 巨噬细胞导致STAT3信号的诱导和STAT1信号的抑制。在……里面 目的1研究HDM提取物对多壁碳纳米管上变应原电晕的影响。 这种功能化改变了日冕的形成，并表明日冕过敏原已经增强 蛋白水解性。在目标2中，我们将确定具有HDM变应原电晕的多壁碳纳米管 体外激活巨噬细胞PAR2诱导STAT3信号或抑制STAT1信号 增强促纤维化细胞因子的表达。在目标3中，我们将确定MWCNTs是否具有 HDM变应原电晕加重小鼠过敏性呼吸道疾病及其是否依赖 关于PAR2诱导STAT3激活或抑制STAT1激活。完成这些工作 研究将定义一种新的机制和基本基础，通过它纳米颗粒 加重过敏性呼吸道疾病。这项工作将对 各种工程纳米颗粒及其对人类健康的影响。

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.