Targeting airway inflammation from concentrated animal feeding operation dust

针对集中动物饲养操作粉尘引起的气道炎症

• 批准号: 10417028
• 负责人: DEBRA J ROMBERGER
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417028
• 关键词: Acute; Aerosols; Agonist; Agricultural Workers; Agriculture; Amphiregulin; Animal Feed; Animals; Binding; Cause of Death; Cells; Chronic Bronchitis; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Clinical; Clinical Management; Data; Diagnosis; Diet; Dietary Fatty Acid; Disease; Docosahexaenoic Acids; Dust; Environment; Environmental Exposure; Environmental Health; Enzymes; Epidermal Growth Factor Receptor; Epithelial Cells; Event; Exposure to; Family suidae; Goals; Healthcare Systems; Housing; Human; In Vitro; Individual; Industry; Inflammation; Inflammatory; Inflammatory Response; Inhalant dose form; Inhalation; Intake; Intervention; Investigation; Knowledge; Lead; Lung; Lung diseases; Meat; Mediating; Modality; Modeling; Necrosis; Occupational; Occupational Health; Omega-3 Fatty Acids; Pathway interactions; Patients; Pattern; Pilot Projects; Polyunsaturated Fatty Acids; Prevention; Process; Production; Public Health; Publishing; Pulmonary Inflammation; Recovery; Recurrence; Regulation; Resolution; Risk; Role; Rural; Signal Transduction; TNF gene; TNF-alpha converting enzyme; Testing; Therapeutic; Time; Translating; United States; Up-Regulation; Veterans; Work; aerosolized; airway inflammation; bronchial epithelium; clinical care; cohort; design; drug efficacy; exposed human population; health management; improved; in vivo; in vivo Model; lung injury; lung repair; mouse model; novel; operation; pre-clinical; preclinical study; prevent; pulmonary function decline; receptor-mediated signaling; repaired; respiratory health; response; rural area; rural patients; scaffold; treatment strategy; wound healing

Agricultural workers including rural veterans are routinely exposed to aerosolized environmental dust and are at heightened risk for chronic lung disease due to exaggerated airway inflammatory responses. Our work has focused on defining inflammatory aspects of organic dust exposures and investigated strategies of inflammation inhibition to prevent lung injury. Our current proposal aims to identify mechanisms for controlling lung recovery after damaging airway exposures as both the initiation and resolution of inflammation are critical in whether disease develops. Our pilot data suggests the epidermal growth factor receptor (EGFR) agonist amphiregulin (AREG) promotes lung repair pathways following exposures to dust extracts (DE) derived from swine concentrated animal feeding operations. Importantly, our preclinical studies suggest the polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) obtained by diet may enhance the production of AREG following DE exposure and protect against DE-induced lung inflammation and injury. Thus, our overall objective is to determine the contribution of AREG to lung repair pathways following inflammatory organic inhalant exposures. By identifying regulatory patterns of normative lung repair processes, we aim to identify intervention strategies to improve lung repair processes in agricultural workers suffering from lung disease. We hypothesize that AREG- mediated signaling following organic dust exposures promotes lung repair activities, and dysregulation of these normative lung repair processes leads to lung disease in agriculture workers. We have developed three specific aims to test this hypothesis: Aim 1: Identify the function of AREG in mediating lung repair following organic dust exposures. We propose to (a) determine the time course of AREG production following DE exposures in vitro and in vivo, (b) determine the effect of AREG inhibition on DE-induced lung inflammatory and recovery processes in vivo using our well-established mouse model, (c) identify the effect of exogenous AREG treatment on DE-induced lung inflammatory and recovery processes in vivo,(d) delineate the functional effects of AREG on human bronchial epithelial cell (HBEC) wound healing processes during DE exposures using a novel lung scaffolding model. Aim 2: Define the mechanisms regulating AREG activities in the lung following organic dust exposures. We will (a) determine the lung cellular contributions of AREG following DE exposures in vivo, (b) identify the EGFR-mediated pro-repair signaling events downstream of AREG binding in DE-exposed HBEC, (c) identify the contributions of tumor necrosis factor-a converting enzyme (TACE) on lung recovery following repetitive DE exposures in vivo and (d) determine the role of TACE on HBEC wound healing processes in the context of DE exposures. Aim 3: Identify how PUFA regulate AREG-mediated lung repair following organic dust exposures. We propose to (a) identify the signaling mechanism by which PUFA modulate AREG production in DE-treated HBEC, (b) assess the role of high omega 3 (n-3) and 6 (n-6) diets on lung repair processes following DE exposure in vivo, (c) investigate the role of n-3 and n-6 PUFA on HBEC lung repair processes ex vivo and (d) utilize an established cohort of veterans with agriculture exposures and chronic lung disease to assess PUFA intake, AREG production, and parameters of lung disease. ! !

包括农村退伍军人在内的农业工人经常接触雾化的环境灰尘 由于气道炎症反应过度，患慢性肺病的风险更高。我们的 工作重点是定义有机粉尘暴露的炎症方面，并研究了以下策略： 抑制炎症，防止肺损伤。我们当前的提案旨在确定控制机制 气道暴露受损后的肺部恢复，因为炎症的发生和消退都至关重要 是否发生疾病。 我们的试验数据表明表皮生长因子受体 (EGFR) 激动剂双调蛋白 (AREG) 暴露于猪浓缩物提取物 (DE) 后促进肺部修复途径 动物饲养作业。重要的是，我们的临床前研究表明多不饱和脂肪酸 (PUFA) 通过饮食获得的二十二碳六烯酸 (DHA) 可能会在接触 DE 后增强 AREG 的产生 并防止 DE 引起的肺部炎症和损伤。因此，我们的总体目标是确定 AREG 对炎症有机物吸入暴露后肺修复途径的贡献。通过识别 规范肺修复过程的调节模式，我们的目标是确定干预策略以改善 患有肺部疾病的农业工人的肺部修复过程。我们假设 AREG- 有机粉尘暴露后介导的信号传导促进肺部修复活动，并且 这些规范性肺部修复过程的失调会导致农业工人罹患肺部疾病。 我们制定了三个具体目标来检验这一假设： 目标 1：确定 AREG 在介导有机粉尘暴露后肺部修复中的功能。我们 建议 (a) 确定体外和体内 DE 暴露后 AREG 产生的时间过程，(b) 确定 AREG 抑制对 DE 诱导的肺部炎症和体内恢复过程的影响 我们完善的小鼠模型，(c) 确定外源性 AREG 治疗对 DE 诱导的肺的影响 体内炎症和恢复过程，(d) 描述 AREG 对人支气管的功能影响 使用新型肺支架模型研究 DE 暴露期间上皮细胞 (HBEC) 伤口愈合过程。 目标 2：确定有机粉尘暴露后肺部 AREG 活动的调节机制。 我们将 (a) 确定体内 DE 暴露后 AREG 对肺细胞的贡献，(b) 确定 DE 暴露的 HBEC 中 AREG 结合下游的 EGFR 介导的促修复信号传导事件，(c) 鉴定 肿瘤坏死因子-a 转换酶 (TACE) 对重复性肺恢复的贡献 DE 体内暴露和 (d) 确定 TACE 在 HBEC 伤口愈合过程中的作用 DE 暴露。 目标 3：确定 PUFA 如何调节有机粉尘暴露后 AREG 介导的肺部修复。我们 建议 (a) 确定 PUFA 在 DE 处理中调节 AREG 产生的信号机制 HBEC，(b) 评估高 omega 3 (n-3) 和 6 (n-6) 饮食对 DE 后肺修复过程的作用 体内暴露，(c) 研究 n-3 和 n-6 PUFA 对离体 HBEC 肺修复过程的作用，以及 (d) 利用一组患有农业暴露和慢性肺病的退伍军人来评估 PUFA 摄入量、AREG 产生和肺部疾病参数。 ！ ！