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.

项目摘要/摘要 有害的藻华（HABS）在全球范围内正在上升，并因此引起了严重的健康问题 氰毒素的释放，对人类和环境有害。微囊藻蛋白 LR（MC-LR）是最常见的蓝毒素之一，最近被检测到 在受影响的水体的正常运动产生的气溶胶中。在文学和我们的 自己的初步数据，已经观察到MC-LR暴露导致混合 粒细胞炎症，有丰富的1型嗜中性粒细胞反应。 粒细胞炎症驱动哮喘的5种内型中的4个，这是最常见的 世界上的气道状况，与心血管疾病的风险增加有关 和中风。但是，MC-LR暴露可能对超过3.3亿患者产生影响 预先存在的哮喘仍然未知。因此，总体假设是吸入 暴露于MC-LR会通过促进粒细胞的症状恶化中性粒细胞驱动的哮喘的症状 气道炎症的炎症和刺激效应的免疫介质。解决这个问题 假设，目标1是通过评估对气溶胶的反应来扩展我们的初步研究 由3-D人类气道上皮暴露于健康和哮喘的体外重建 捐助者。对于AIM 2，我们将评估关键的表型特征，例如肺功能和 接触MC-LR气溶胶后，在哮喘的鼠类哮喘模型中免疫浸润。这 在这项研究中收集的信息将为世界各地的社区提供有关的风险 暴露于雾化的MC-LR，以及这种环境毒素如何恶化 处于危险的人口，有可能影响当地政策以保护生活中或周围的人们 受影响的水体。对该项目的追求将为您提供极好的培训机会 暴露科学，肺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园可用的设备将启用这些小说 研究。此外，包括韦恩州立大学，大学在内的机构的专业人员 密歇根州和多个能源部国家实验室将提供指导和 强大技术的独特培训，可以确保强大的独立研究职业 这些感兴趣的领域。

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