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）：集中动物饲养操作（CAFO）的农民和工人患有与工作有关的呼吸道疾病，特别是慢性支气管炎和慢性阻塞性肺病（COPD）。虽然CAFO中的多种物质可能会导致疾病，但这些设施产生的灰尘被公认为是一种重要的呼吸道健康危害。我们以前的工作一直集中在定义CAFO粉尘导致肺部炎症的机制。重要的是，我们已经确定了这种CAFO粉尘诱导的肺部炎症机制的三个关键要素，我们提出这些要素是治疗这种重要的职业性肺部疾病的极好的治疗靶点：1）细胞因子释放，集中于IL-6和IL-8的TNF-α依赖性气道上皮细胞释放，依次激活气道上皮蛋白激酶C亚型（PKC）α，然后是IL-8; 2）环AMP依赖性蛋白激酶（PKA）的抗炎作用;和3）作为CAFO粉尘中存在的触发物的促炎蛋白酶。 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个可能抑制和/或逆转CAFO粉尘诱导的肺部疾病的机制要素的相对价值。为此，我们已经证明，吸入粉尘提取物在小鼠模型中引起体内呼吸道炎症，该模型具有在猪圈养设施中工作的人员中观察到的肺部疾病的所有突出特征。在这次更新中，我们提出了一种策略，在临床前研究中利用这种小鼠模型，旨在确定上述哪些治疗靶点是可行和有效的。我们假设：CAFO粉尘诱导的肺部炎症可通过阻断PKC亚型触发的气道细胞因子释放、激活PKA和抑制粉尘衍生的蛋白酶及其细胞靶点来治疗。我们将通过三个具体目标来检验这一假设：目标1：确定特异性靶向TNF-α、IL-6和IL-8的药物如何在体内调节粉尘提取物诱导的肺部炎症。目标二：确定增强PKA的药物，特别是治疗性β-肾上腺素能激动剂，如何抑制粉尘提取物诱导的PKC亚型激活并减轻体外和体内肺部炎症。目标3：确定蛋白酶在体外粉尘提取物诱导的TNF-α/IL-6/IL-8和体内组织炎症中的重要性，并确定减弱粉尘提取物蛋白酶诱导的炎症变化的潜在靶点。我们的提案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引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，我们确定了从猪密闭动物饲养操作中提取的粉尘导致气道内衬细胞通过细胞内信号蛋白激酶C（PKC）释放特定的炎症介质，即TNF-1，IL-6和IL-8。我们还证明了这种粉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。在本申请中，我们将使用我们的小鼠模型进行临床前研究，以确定靶向特定介质（TNF-1，IL-6和IL-8）和途径（PKC和cAMP依赖性蛋白激酶）以及粉尘中的物质（蛋白酶）是否会减少肺部炎症，长期目标是开发新的治疗策略，以在工人患病之前减少气道炎症。