Resolving Occupational Exposure-Induced Lung Disease

解决职业暴露引起的肺部疾病

• 批准号: 10630849
• 负责人: Jill A Poole
• 金额: $ 57.41万
• 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/10630849
• 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性疾病的主要原因 疾病的频率、严重性和可预防性。大多数职业性肺病是由反复、 长期接触有害物质，但即使是严重的单一接触也会损害肺部。确实有 目前尚无药物疗法可以在不产生不良副作用的情况下减轻肺损伤/炎症 效果。职业性炎症性暴露后不能充分治疗工人会导致慢性 疾病，患有呼吸道疾病的工人申请残疾的几率比那些 没有呼吸道疾病。重要的是，传统的呼吸系统职业危害再次出现。 由细菌引起的生物制剂，如内毒素。农业中暴露于内毒素的风险很高 生产和新兴行业，如废物处理、回收、生物技术食品生产和加工 工业。COVID19大流行迅速演变为一种由职业性呼吸道病毒引起的毁灭性疾病 健康疾病严重影响了疗效有限的食品加工厂的工人。如果没有 关于职业性暴露所致肺损伤/炎症的管理指南或治疗方法，有 确定减少疾病负担的替代办法的迫切和未得到满足的需要。我们的长期目标是 寻找新的策略以促进职业性暴露相关肺部炎症性疾病的解决 在它发展成不可逆转的肺部疾病之前。我们使用单细胞RNA测序的最新发现 再加上流式细胞术，强烈地牵涉到招募的单核/巨噬细胞，我们发现 提供双调节素和白介素10作为肺部导向疗法似乎有益于肺部 恢复过程是职业暴露后的过程。我们的中心假设是靶向细胞和介质 各种职业性炎性吸入剂暴露后的干预方法可以发展为 促进肺功能恢复，减少疾病发展。对职业细菌和病毒成分进行建模- 将使用诱导肺部炎症、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检验我们的假设。在目标1中，我们将确定 职业性肺损伤后细胞和特异性单核/巨噬细胞事件的时间依赖性 暴露以及靶向这些细胞是否会加速肺部恢复。在目标2中，我们将确定 安非他明作为一种潜在的肺导向治疗方法在解决吸入性职业暴露中的作用。 在目标3中，我们将确定吸入剂IL-10治疗如何在恢复过程中促进修复 职业性接触引起的肺部炎症。这些研究的结果将具有重要的 积极影响，因为它们为了解关键细胞和介质奠定了临床前基础 反应，以及治疗职业性暴露所致肺的新策略的最终发展 炎症先于不可逆转的肺部疾病发展。

项目成果

Interleukin (IL)-33 immunobiology in asthma and airway inflammatory diseases.

• DOI: 10.1080/02770903.2021.2020815
• 发表时间: 2022-12
• 期刊: The Journal of asthma : official journal of the Association for the Care of Asthma

Relationships of serum CC16 levels with smoking status and lung function in COPD.

• DOI: 10.1186/s12931-022-02158-8
• 发表时间: 2022-09-16
• 期刊: Respiratory research
• 影响因子: 5.8

Genetic, social, and environmental risk factors in rheumatoid arthritis-associated interstitial lung disease.

• DOI: 10.1016/j.semarthrit.2022.152098
• 发表时间: 2022-12
• 期刊: SEMINARS IN ARTHRITIS AND RHEUMATISM
• 影响因子: 5
• 作者: Wheeler, Austin M.;Baker, Joshua F.;Poole, Jill A.;Ascherman, Dana P.;Yang, Yangyuna;Kerr, Gail S.;Reimold, Andreas;Kunkel, Gary;Cannon, Grant W.;Wysham, Katherine D.;Singh, Namrata;Lazaro, Deana;Monach, Paul;Bridges, S. Louis;Mikuls, Ted R.;England, Bryant R.
• 通讯作者: England, Bryant R.

Nrf2 Activation Protects Against Organic Dust and Hydrogen Sulfide Exposure Induced Epithelial Barrier Loss and K. pneumoniae Invasion.

• DOI: 10.3389/fcimb.2022.848773
• 发表时间: 2022
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7

Dietary Inflammatory Potential and Bone Outcomes in Midwestern Post-Menopausal Women.

• DOI: 10.3390/nu15194277
• 发表时间: 2023-10-07
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Jackson MK;Bilek LD;Waltman NL;Ma J;Hébert JR;Price S;Graeff-Armas L;Poole JA;Mack LR;Hans D;Lyden ER;Hanson C
• 通讯作者: Hanson C