Targeting airway inflammation from concentrated animal feeding operation dust

包括农村退伍军人在内的农业工人经常暴露在雾化环境粉尘中 由于夸大的呼吸道炎症反应，患慢性肺部疾病的风险增加。我们的 工作的重点是定义有机粉尘暴露的炎症方面，并研究 抑制炎症，预防肺损伤。我们目前的提案旨在确定控制 损伤呼吸道暴露后的肺恢复，因为炎症的开始和消退都是至关重要的。 疾病是否会发展。 我们的初步数据表明，表皮生长因子受体(EGFR)激动剂两用调节素(AREG) 促进暴露于猪浓缩粉尘提取物(DE)后的肺修复途径 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) 饮食获得的二十二碳六烯酸(DHA)可促进DE暴露后AREG的产生 并对DE诱导的肺部炎症和损伤具有保护作用。因此，我们的总体目标是确定 AREG在炎性有机吸入剂暴露后肺修复途径中的作用。通过识别 规范肺修复过程的监管模式，我们的目标是确定干预策略，以改进 患有肺病的农业工人的肺修复过程。我们假设AREG- 有机粉尘暴露后的中介信号促进肺修复活动，并且 这些标准的肺修复过程的失调会导致农业工人的肺部疾病。 我们制定了三个具体目标来检验这一假设： 目的1：明确AREG在有机粉尘暴露后肺修复中的作用。我们 建议(A)确定体外和体内DE暴露后AREG产生的时间进程，(B) 在体法测定AREG抑制对DE诱导的肺炎性反应和恢复过程的影响 我们已建立的小鼠模型，(C)确定外源性AREG治疗对DE诱导的肺的影响 活体炎症和恢复过程，(D)描述AREG对人支气管的功能影响 使用一种新的肺支架模型，在DE暴露期间，上皮细胞(HBEC)伤口愈合过程。 目的2：明确有机粉尘暴露后肺内AREG活性的调节机制。 我们将(A)确定体内DE暴露后AREG对肺细胞的贡献，(B)确定 在DE暴露的HBEC中，EGFR介导的AREG结合下游的促修复信号事件，(C)识别 肿瘤坏死因子-a转换酶在反复肺损伤后肺功能恢复中的作用 (D)在以下情况下确定TACE在HBEC伤口愈合过程中的作用 免去曝光。 目的3：明确多不饱和脂肪酸对有机粉尘暴露后AREG介导的肺修复的调节作用。我们 建议(A)确定多不饱和脂肪酸调节DE处理的AREG产生的信号机制 HBEC，(B)评估高omega 3(n-3)和6(n-6)饮食在DE后肺修复过程中的作用 活体暴露，(C)研究n-3和n-6多不饱和脂肪酸在体外HBEC肺修复过程中的作用和(D) 利用有农业接触和慢性肺部疾病的退伍军人队列来评估多不饱和脂肪酸 摄入量、AREG产量和肺部疾病参数。 好了！ 好了！

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. ! !