Resolving Occupational Exposure-Induced Lung Disease

解决职业暴露引起的肺部疾病

• 批准号: 10463530
• 负责人: Jill A Poole
• 金额: $ 56.02万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10463530
• 关键词: Resolving; Occupational; Exposure; Induced; Lung

Occupational lung diseases are the primary cause of occupation-associated illness in the U.S. based on frequency, severity, and preventability of the illnesses. Most occupational lung diseases are caused by repeated, long-term exposure to hazardous agents, but even a severe single exposure can damage the lungs. There are currently no medical therapies available to ameliorate lung injury/inflammation without exerting untoward side effects. The inability to adequately treat workers following occupational inflammatory exposure leads to chronic disease, and workers with respiratory disease have a higher incidence of filing for disability compared to those without respiratory disease. Importantly, there is a re-emergence in traditional respiratory occupational hazards caused by bacteria biological agents such as endotoxin. Exposures to endotoxin are high in agricultural production and emerging sectors such as waste treatment, recycling, biotech food production and processing industries. The COVID19 pandemic rapidly transpired as a devastating occupational respiratory viral-induced health illness significantly impacting workers of food processing plants with limited efficacious therapies. Without guidelines or therapies for the management of occupational exposure-induced lung injury/inflammation, there is an urgent and unmet need to identify alternative approaches to reduce disease burden. Our long-term goal is to find new strategies to promote the resolution of occupational exposure-associated lung inflammatory disease before it progresses to irreversible lung disease. Our recent discoveries using single cell RNA sequencing coupled with flow cytometry strongly implicate the recruited monocyte/macrophage, and we uncovered that delivering amphiregulin and interleukin (IL)-10 as lung-directed therapies appear to beneficially effect lung recovery processes post-occupational exposures. Our central hypothesis is that targeted cellular and mediator interventional approaches following various occupational inflammatory inhalant exposures can be developed to hasten lung recovery to reduce disease development. To model occupational bacterial and viral component- induced lung inflammation, Toll-like receptor (TLR) agonists and agriculture organic dust extract will be utilized. We seek to test our hypothesis by addressing three independent and synergistic aims. In Aim 1, we will determine the time-dependent cellular and specific monocyte/macrophage lung cell events following occupational exposures and whether targeting these cells hastens lung recovery. In Aim 2, we will determine the role of amphiregulin as a potential lung-directed therapeutic approach in the resolution inhalant occupational exposures. In Aim 3, we will determine how inhalant IL-10 treatment works to promote repair in the recovery process after lung inflammation induced by occupational exposures. The results of these studies will have an important positive impact because they lay the pre-clinical groundwork for understanding key cellular and mediator responses, and the ultimate development of new strategies to treat occupational exposure-induced lung inflammation prior to the development of irreversible lung disease.

职业性肺病是美国职业相关疾病的主要原因， 疾病的频率、严重程度和可预防性。大多数职业性肺病是由反复， 长期暴露于有害物质，但即使是严重的单次暴露也会损害肺部。有 目前没有可用的医学疗法来改善肺损伤/炎症而不产生不利的副作用 方面的影响.无法充分治疗工人以下职业炎症暴露导致慢性 患有呼吸道疾病的工人申请残疾的发生率高于患有呼吸道疾病的工人， 没有呼吸道疾病。重要的是，传统的呼吸道职业危害重新出现 由细菌生物制剂如内毒素引起。暴露于内毒素是高农业 生产和新兴部门，如废物处理，回收，生物技术食品生产和加工 行业COVID 19大流行迅速蔓延，是一场毁灭性的职业呼吸道病毒引起的疾病， 严重影响食品加工厂工人的健康疾病，有效疗法有限。没有 对于职业暴露引起的肺损伤/炎症的管理指南或疗法，有 确定减少疾病负担的替代办法的迫切需要尚未得到满足。我们的长期目标是 寻找新的策略来促进职业性肺炎相关性肺炎的解决 以免发展成不可逆的肺病我们最近的发现使用单细胞RNA测序 再加上流式细胞术强烈暗示招募单核细胞/巨噬细胞，我们发现， 递送双调蛋白和白细胞介素（IL）-10作为肺定向疗法似乎有益地影响肺 职业暴露后的恢复过程。我们的中心假设是，靶向细胞和介质 可以开发各种职业性炎症吸入剂暴露后的干预方法， 加速肺部恢复以减少疾病发展。为了模拟职业性细菌和病毒成分- 诱导的肺部炎症、Toll样受体（TLR）激动剂和农业有机粉尘提取物。 我们试图通过解决三个独立和协同的目标来测试我们的假设。在目标1中，我们将确定 职业性肺损伤后时间依赖性细胞和特异性单核/巨噬细胞肺细胞事件 暴露以及靶向这些细胞是否加速肺恢复。在目标2中，我们将确定 双调蛋白作为一种潜在的肺定向治疗方法，在解决吸入性职业暴露。 在目标3中，我们将确定吸入性IL-10治疗如何促进恢复过程中的修复， 职业暴露引起的肺部炎症。这些研究的结果将对 积极的影响，因为它们为理解关键的细胞和介质奠定了临床前基础 反应，并最终开发新的策略来治疗职业性肺结核 炎症之前的发展不可逆的肺部疾病。