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

基本信息

批准号：
8702943
负责人：
DEBRA J ROMBERGER
金额：
$ 49.88万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8702943
关键词：
Targeting Airway Inflammation Concentrated Animal

项目摘要

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）：集中动物饲养场 (CAFO) 的农民和工人患有与工作相关的呼吸道疾病，特别是慢性支气管炎和慢性阻塞性肺病 (COPD)。尽管 CAFO 中的多种物质可能会导致疾病，但这些设施中的灰尘被公认为是重要的呼吸道健康危害。我们之前的工作重点是确定 CAFO 粉尘导致肺部炎症的机制。重要的是，我们已经确定了 CAFO 粉尘引起的肺部炎症机制的三个关键要素，我们建议这些要素成为治疗这种重要职业性肺部疾病的极好治疗靶点：1）细胞因子释放，重点关注 TNF-α 依赖性气道上皮细胞释放IL-6 和 IL-8 的连续激活气道上皮蛋白激酶 C 同种型 (PKC)，α 随后是 epsilon； 2）环AMP依赖性蛋白激酶（PKA）的抗炎作用； 3) CAFO 粉尘中存在促炎性蛋白酶作为触发因素。该提案概述了我们将如何使用临床前动物模型来破译针对这三个机制要素的相对价值，这些要素可能会抑制和/或逆转 CAFO 粉尘引起的肺部疾病。为此，我们已经证明，吸入粉尘提取物会在小鼠模型中引起体内呼吸道炎症，该小鼠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显着特征。在本次更新中，我们提出了一种在临床前研究中利用该小鼠模型的策略，旨在确定上述哪些治疗目标是可行且有效的。我们假设：CAFO 粉尘引起的肺部炎症可以通过阻断 PKC 同工型触发的气道细胞因子释放、激活 PKA 并抑制粉尘衍生蛋白酶及其细胞靶标来治疗。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 2：确定增强 PKA 的药物，尤其是治疗性 β-肾上腺素能激动剂，如何在体外和体内抑制粉尘提取物诱导的 PKC 异构体激活并减轻肺部炎症。目标 3：确定蛋白酶在粉尘提取物诱导的体外 TNF-α/IL-6/IL-8 和体内组织炎症中的重要性，并确定减轻粉尘提取物蛋白酶诱导的炎症变化的潜在靶标。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。）公共健康相关性：在我们之前的工作中，我们确定猪圈养动物饲养作业中的灰尘提取物会导致气道内壁细胞通过细胞内信号蛋白激酶 C 释放特定的炎症介质，即 TNF-1、IL-6 和 IL-8 （PKC）。我们还证明，这种灰尘提取物会引起小鼠模型的炎症，该小鼠模型具有与工人相似的特征。在此应用中，我们将使用我们的小鼠模型进行临床前研究，以确定是否针对特定介质（TNF-1、IL-6 和 IL-8）和通路（PKC 和 cAMP 依赖性蛋白激酶）以及粉尘（蛋白酶）将减少肺部炎症，长期目标是开发新的治疗策略，在气道炎症导致工人患病之前减少气道炎症。

项目成果

期刊论文数量（37）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Respiratory health effects of large animal farming environments.

大型动物养殖环境对呼吸系统健康的影响。

DOI：
发表时间：
2012
期刊：
影响因子：
0
作者：
May, Sara;Romberger, Debra J;Poole, Jill A
通讯作者：
Poole, Jill A

Dust from hog confinement facilities impairs Ca2+ mobilization from sarco(endo)plasmic reticulum by inhibiting ryanodine receptors.

生猪圈养设施中的灰尘通过抑制兰尼碱受体，损害肌（内）质网中的 Ca2+ 动员。

DOI：
发表时间：
2013-03-01
期刊：
影响因子：
0
作者：
Tian, Chengju;Moore, Caronda J;Dodmane, Puttappa;Shao, Chun Hong;Romberger, Debra J;Toews, Myron L;Bidasee, Keshore R
通讯作者：
Bidasee, Keshore R

Toll-Like Receptor 4 Signaling Pathway Mediates Inhalant Organic Dust-Induced Bone Loss.

Toll 样受体 4 信号通路介导吸入有机粉尘引起的骨丢失。

DOI：
发表时间：
2016
期刊：
影响因子：
3.7
作者：
Staab, Elizabeth;Thiele, Geoffrey M;Clarey, Dillon;Wyatt, Todd A;Romberger, Debra J;Wells, Adam D;Dusad, Anand;Wang, Dong;Klassen, Lynell W;Mikuls, Ted R;Duryee, Michael J;Poole, Jill A
通讯作者：
Poole, Jill A

Influence of farming exposure on the development of asthma and asthma-like symptoms.

农业暴露对哮喘和哮喘样症状发展的影响。

DOI：
发表时间：
2014-11
期刊：
影响因子：
5.6
作者：
Wells, Adam D;Poole, Jill A;Romberger, Debra J
通讯作者：
Romberger, Debra J

Toll-like receptor 2 regulates organic dust-induced airway inflammation.

Toll 样受体 2 调节有机粉尘引起的气道炎症。

DOI：
发表时间：
2011-10
期刊：
影响因子：
6.4
作者：
Poole, Jill A;Wyatt, Todd A;Kielian, Tammy;Oldenburg, Peter;Gleason, Angela M;Bauer, Ashley;Golden, Gregory;West, William W;Sisson, Joseph H;Romberger, Debra J
通讯作者：
Romberger, Debra J