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作者通常会暴露于雾化的环境灰尘 由于气道炎症反应夸大，慢性肺疾病的风险越高。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 炎症抑制以防止肺损伤。我们当前的建议旨在确定控制机制 损坏气道暴露后的肺恢复，因为炎症的启动和分辨率都是至关重要的 疾病是否发展。 我们的试点数据表明表皮生长因子受体（EGFR）激动剂两次末期（AREG） 在暴露于尘埃提取物（DE）之后，促进肺修复途径（DE） 动物喂养行动。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）可能会增强暴露后AREG的产生 并防止肺部炎症和损伤。因此，我们的总体目标是确定 炎症有机吸入暴露后，AREG对肺修复途径的贡献。通过识别 规范性肺修复过程的监管模式，我们旨在确定改善干预策略 患有肺部疾病的农业工人的肺修复过程。我们假设Areg- 有机粉尘暴露后介导的信号传导促进肺修复活动，并 这些规范性肺修复过程的失调导致农业工人的肺部疾病。 我们开发了三个特定的目的来检验这一假设： AIM 1：确定有机粉尘暴露后介导肺修复中AREG的功能。我们 建议（a）确定体外和体内暴露后ARG产生的时间过程，（b） 确定使用AREG抑制对使用体内肺炎症和恢复过程的影响的影响 我们成熟的小鼠模型，（c）确定外源AREG治疗对去诱导肺的影响 体内炎症和恢复过程，（d）描述AREG对人支气管的功能效应 使用新型的肺脚手架模型在DE暴露期间，上皮细胞（HBEC）伤口愈合过程。 目标2：定义有机粉尘暴露后肺中调节AREG活动的机制。 我们将（a）确定在体内暴露后AREG的肺细胞贡献，（b）确定 EGFR介导的Pro-Repair信号传导事件下游的AREG结合在脱离暴露的HBEC中，（c）识别 肿瘤坏死因子-A转化酶（TACE）对重复后肺恢复的贡献 在体内暴露和（d）确定TACE在HBEC伤口愈合过程中的作用 DE暴露。 AIM 3：确定PUFA如何调节AREG介导的有机粉尘暴露后的肺修复。我们 提议（a）确定PUFA调节AREG在De-Treateate的信号传导机制 HBEC，（b）评估DE之后DE之后的高欧米茄3（N-3）和6（n-6）饮食在肺修复过程中的作用 在体内暴露，（c）研究N-3和N-6 PUFA在HBEC肺修复过程中的作用，并且（D） 利用与农业暴露和慢性肺疾病的老兵队列一起评估PUFA 摄入量，AREG产生和肺部疾病的参数。 呢 呢