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: 10315462
• 负责人: Joshua David Breidenbach
• 金额: $ 3.97万
• 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 2024-08-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315462
• 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; 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/文摘