Inhalation Exposure to Aerosolized Cyanotoxins Worsens Pre-Existing Asthma via Activation of Granulocytic Inflammation

吸入暴露于雾化的蓝藻毒素会通过激活粒细胞炎症而加重已有的哮喘

• 批准号: 10525227
• 负责人: Joshua David Breidenbach
• 金额: $ 2.06万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-27 至 2023-04-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525227
• 关键词: 3-Dimensional; Address; Adrenal Cortex Hormones; Aerosols; Affect; Airway Disease; Algal Blooms; Animal Model; Asthma; Awareness; Biological Response Modifiers; Cells; Cessation of life; Characteristics; Colitis; Communities; Cyanobacterium; Cyanotoxin; Data; Dendritic Cells; Department of Energy; Development; Disease; Environment; Epithelial; Epithelial Cells; Equipment; Exposure to; Frequencies; Fresh Water; Health; Health Sciences; Human; Immune; Immune signaling; Immunity; Immunotoxicology; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Ingestion; Inhalation Exposure; Institution; Laboratories; Lead; Literature; Lung; Measurable; Mediating; Mediator of activation protein; Michigan; Microcystis; Modeling; Motion; Mus; Neutrophilia; Okadaic Acid; Pathway interactions; Patients; Persons; Phenotype; Phosphotransferases; Policies; Populations at Risk; Production; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Public Health; Publishing; Reporting; Research; Risk; Science; Stroke; Study models; Surveys; Symptoms; Techniques; Testing; Tissues; Toxic Environmental Substances; Toxin; Training; Tumor-infiltrating immune cells; Universities; Water; Work; Xenobiotics; aerosolized; airway epithelium; airway hyperresponsiveness; airway inflammation; airway remodeling; asthma model; asthmatic; asthmatic patient; cardiovascular disorder risk; career; cytokine; cytotoxicity; disease phenotype; experience; exposure route; granulocyte; harmful algal blooms; healthy volunteer; human tissue; in vivo; in vivo Model; interest; irritation; microcystin; mouse model; neutrophil; non-alcoholic fatty liver disease; novel; pulmonary function; recruit; respiratory; response; therapy resistant; three-dimensional modeling; training opportunity

PROJECT SUMMARY/ABSTRACT Harmful algal blooms (HABs) are on the rise globally and pose serious health concerns due to the release of cyanotoxins, which are harmful to both humans and the environment. Microcystin- LR (MC-LR) is one of the most frequently produced cyanotoxins and has recently been detected in aerosols generated by the normal motions of affected bodies of water. In the literature and our own preliminary data, it has been observed that MC-LR exposure of the airways leads to mixed granulocytic inflammation, with abundant indications of a Type 1 neutrophilic response. Granulocytic inflammation drives 4 of the 5 endotypes of asthma, which is the most common airway condition in the world and is associated with an increased risk of cardiovascular disease and stroke. However, the impact that MC-LR exposure may have on the over 330 million patients with pre-existing asthma remains unknown. Therefore, the overall hypothesis is that inhalation exposure to MC-LR worsens the symptoms of neutrophil-driven asthma by promoting granulocytic inflammation and stimulating effector immune mediators of airway inflammation. To address this hypothesis, Aim 1 is to expand on our preliminary studies by assessing the response to aerosol exposure by a 3-D human airway epithelium reconstructed in vitro from healthy and asthmatic donors. For Aim 2, we will assess key phenotypic characteristics such as lung function and immune infiltrates in a murine model of asthma after inhalation exposure to MC-LR aerosols. The information gathered in this study will inform communities around the world of the risks associated with exposure to aerosolized MC-LR, and how this environmental toxin may worsen disease in at-risk populations, potentially influencing local policies to protect people living on or around affected bodies of water. The pursuit of this project will provide excellent training opportunities in diverse models for exposure science, pulmonary science, and immunotoxicology. Specialized equipment available at the University of Toledo Health Science Campus will enable these novel studies. Furthermore, professionals from institutions including Wayne State University, University of Michigan and multiple Department of Energy National Laboratories will provide guidance and unique training in powerful techniques which will assure a strong independent research career in these fields of interest.

项目总结/摘要 有害藻华在全球范围内呈上升趋势，并造成严重的健康问题， 释放对人类和环境有害的蓝藻毒素。微囊藻毒素- LR（MC-LR）是最常见的蓝藻毒素之一，最近被检测到 在受影响水体的正常运动产生的气溶胶中。在文学和我们的 根据我们自己的初步数据，已经观察到气道的MC-LR暴露导致混合的 粒细胞炎症，具有1型嗜中性粒细胞反应的丰富迹象。 粒细胞炎症驱动哮喘的5种内源性中的4种，这是最常见的 呼吸道疾病，并与心血管疾病的风险增加有关 和中风然而，MC-LR暴露可能对超过3.3亿患者产生的影响 是否患有哮喘还不得而知因此，总的假设是吸入 暴露于MC-LR通过促进粒细胞减少来减轻嗜中性粒细胞驱动的哮喘症状， 炎症和刺激气道炎症的效应免疫介质。为了解决这个 假设，目的1是扩大我们的初步研究，评估气溶胶的反应 健康人和哮喘患者气道上皮细胞的体外三维重建 捐助者。对于目标2，我们将评估关键的表型特征，如肺功能， 小鼠哮喘模型吸入暴露于MC-LR气雾剂后免疫浸润。的 本研究收集的信息将告知世界各地的社区， 暴露于雾化的MC-LR，以及这种环境毒素如何使疾病恶化， 面临风险的人口，可能影响当地政策，以保护生活在或周围的人 受影响的水体追求这个项目将提供良好的培训机会， 用于暴露科学、肺部科学和免疫毒理学的多种模型。专门 托莱多大学健康科学校区提供的设备将使这些新的 问题研究此外，来自包括韦恩州立大学， 密歇根州和多个能源部国家实验室将提供指导， 在强大的技术，这将确保一个强大的独立的研究生涯， 这些兴趣领域。

项目成果

Microcystin-LR (MC-LR) Triggers Inflammatory Responses in Macrophages.

• DOI: 10.3390/ijms22189939
• 发表时间: 2021-09-14
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Su RC;Breidenbach JD;Alganem K;Khalaf FK;French BW;Dube P;Malhotra D;McCullumsmith R;Presloid JB;Wooten RM;Kennedy DJ;Haller ST
• 通讯作者: Haller ST

As We Drink and Breathe: Adverse Health Effects of Microcystins and Other Harmful Algal Bloom Toxins in the Liver, Gut, Lungs and Beyond.

• DOI: 10.3390/life12030418
• 发表时间: 2022-03-14
• 期刊: Life (Basel, Switzerland)
• 作者: Lad A;Breidenbach JD;Su RC;Murray J;Kuang R;Mascarenhas A;Najjar J;Patel S;Hegde P;Youssef M;Breuler J;Kleinhenz AL;Ault AP;Westrick JA;Modyanov NN;Kennedy DJ;Haller ST
• 通讯作者: Haller ST

GeneToList: A Web Application to Assist with Gene Identifiers for the Non-Bioinformatics-Savvy Scientist.

• DOI: 10.3390/biology11081113
• 发表时间: 2022-07-26
• 期刊: Biology
• 影响因子: 4.2