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: 8133473
• 负责人: DEBRA J ROMBERGER
• 金额: $ 45.76万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133473
• 关键词: Targeting; Airway; Inflammation; Concentrated; Animal

DESCRIPTION (provided by applicant): Farmers and workers in concentrated animal feeding operations (CAFOs) experience work-related respiratory disease, particularly chronic bronchitis and chronic obstructive pulmonary disease (COPD). Although multiple substances in CAFOs may contribute to disease, dust from these facilities is well recognized as an important respiratory health hazard. Our previous work has been focused on defining mechanisms by which CAFO dust results in lung inflammation. Importantly, we have identified three critical elements of this CAFO dust-induced lung inflammation mechanism that we propose make excellent therapeutic targets for treatment of this important occupational lung disorder: 1) cytokine release, focusing on the TNF-alpha-dependent airway epithelial cell release of IL-6 and IL-8 with sequential activation of the airway epithelial protein kinase C isoforms (PKC), alpha followed by epsilon; 2) the anti-inflammatory effects of the cyclic AMP dependent protein kinase (PKA); and 3) pro-inflammatory proteases as triggers present in CAFO dust. This proposal outlines how we will use a pre-clinical animal model to decipher the relative value of targeting these three mechanistic elements that may dampen and/or reverse CAFO dust-induced lung disease. Toward this end, we have demonstrated that inhaled dust extract causes respiratory inflammation in vivo in a mouse model that has all of the prominent features of the pulmonary disorders seen in persons working in swine confinement facilities. In this renewal we propose a strategy to utilize this mouse model in preclinical studies aimed at determining which of the therapeutic targets outlined above are feasible and efficacious. We hypothesize that: CAFO dust-induced lung inflammation is treatable by blocking PKC isoform-triggered airway cytokine release, activating PKA and inhibiting dust-derived proteases and their cellular targets. We will test this hypothesis via three specific aims: Aim 1: Establish how agents that specifically target TNF-alpha, IL-6, and IL-8 modulate dust extract-induced lung inflammation in vivo. Aim 2: Determine how agents that augment PKA, especially therapeutic beta-adrenergic agonists, dampen dust extract-induced PKC isoform activation and attenuate lung inflammation in vitro and in vivo. Aim 3: Determine the importance of proteases in dust extract-induced TNF-alpha/IL-6/IL-8 in vitro and in tissue inflammation in vivo and identify potential targets for attenuating the dust extract protease-induced inflammatory changes. Our proposal is designed to provide pre-clinical cell, lung slice, and animal data that will facilitate translational studies aimed at bringing potential interventions into the workplace. ) PUBLIC HEALTH RELEVANCE: In our previous work, we determined that dust extract from swine confined animal feeding operations causes cells lining airways to release specific inflammatory mediators, namely TNF-1, IL-6, and IL-8 via the intracellular signal protein kinase C (PKC). We have also demonstrated that this dust extract causes inflammation in a mouse model that has features similar to that seen in workers. In this application, we will perform pre-clinical studies using our mouse model to determine if targeting specific mediators (TNF-1, IL-6, and IL-8) and pathways (PKC and cAMP dependent protein kinase) as well as substances in the dust (proteases) will decrease inflammation in the lungs, with a long-term goal of developing new treatment strategies to reduce airway inflammation before it causes disease in workers.

描述（由申请人提供）：集中动物喂养手术（CAFO）的农民和工人经历与工作有关的呼吸道疾病，尤其是慢性支气管炎和慢性阻塞性肺疾病（COPD）。尽管CAFO中的多种物质可能会导致疾病，但这些设施的灰尘被广泛认为是重要的呼吸健康危害。我们以前的工作一直集中在定义CAFO粉尘会导致肺部炎症的机制上。 Importantly, we have identified three critical elements of this CAFO dust-induced lung inflammation mechanism that we propose make excellent therapeutic targets for treatment of this important occupational lung disorder: 1) cytokine release, focusing on the TNF-alpha-dependent airway epithelial cell release of IL-6 and IL-8 with sequential activation of the airway epithelial protein kinase C isoforms （PKC），Alpha，其次是Epsilon； 2）环状AMP依赖性蛋白激酶（PKA）的抗炎作用； 3）促炎蛋白酶作为CAFO粉尘中存在的触发因素。 该提案概述了我们将如何使用临床前动物模型来破译靶向这三种机械元素的相对价值，这些机械元素可能会抑制和/或反向CAFO CAFO粉尘诱导的肺部疾病。为此，我们已经证明，在小鼠模型中，吸入的灰尘提取物在体内引起呼吸道炎症，该模型具有在猪限制设施中工作的人所看到的所有肺部疾病的突出特征。在此续约中，我们提出了一种在临床前研究中利用该小鼠模型的策略，旨在确定上面概述的哪些治疗靶标是可行有效的。我们假设：CAFO粉尘引起的肺部炎症是可以通过阻断PKC同工型触发的气道细胞因子释放，激活PKA并抑制粉尘衍生的蛋白酶及其细胞靶标而治疗的。我们将通过三个特定目的来检验这一假设：目标1：确定专门针对TNF-Alpha，IL-6和IL-8的试剂如何调节体内灰尘提取物诱导的肺部炎症。 AIM 2：确定增强PKA的药物，尤其是治疗性β-肾上腺素激动剂，抑制粉尘提取物诱导的PKC同工型激活并减轻体外和体内的肺部炎症。目标3：确定蛋白酶在粉尘提取引起的TNF-α/IL-6/IL-8体外和组织炎症中的重要性，并确定潜在的靶标，以减弱粉尘提取蛋白酶诱导的炎症性变化。我们的建议旨在提供临床前细胞，肺切片和动物数据，以促进旨在将潜在干预措施带入工作场所的转化研究。 ） 公共卫生相关性：在我们以前的工作中，我们确定猪的尘埃提取物通过细胞内信号蛋白激酶C（PKC）释放衬有螺旋的动物喂养操作，即衬有气道的细胞释放特定的炎症介质，即TNF-1，IL-6和IL-8。我们还证明，这种灰尘提取物在小鼠模型中引起炎症，该模型具有与工人相似的特征。在此应用中，我们将使用鼠标模型进行临床前研究，以确定针对特定的介体（TNF-1，IL-6和IL-8）和途径（PKC和CAMP依赖性蛋白激酶）以及粉尘（蛋白酶）中的物质是否会减少肺部的炎症，并减少在新的治疗策略中，以减少促进空中疾病的疾病。