Pulmonary cell fate and lung repair in rodent and porcine models of chlorine and phosgene inhalation injuries

氯和光气吸入损伤的啮齿动物和猪模型中的肺细胞命运和肺修复

基本信息

批准号：
10506127
负责人：
Satyanarayana Achanta
金额：
$ 48.2万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-02 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10506127
关键词：
Accidents Affect Alveolar Alveolar Cell Alveolus Amyloid Proteins Anatomy Animals Antibodies Basal Cell Blood capillaries Cell Communication Cell Survival Cells Cellular Structures Chemical Warfare Chemicals Chlorine Comparative Study Development Endothelial Cells Endothelium Epithelial Epithelial Cells Exposure to Family suidae Fibrinogen Functional disorder Gases Hour Human Industrial Accidents Inhalation Injury Location Long-Term Effects Lung Maintenance Maps Mechanical Stress Mechanical ventilation Methods Microscopy Modeling Molecular Monitor Mouse Strains Mus Natural History Occupational Oxygen Pathway Analysis Pattern Recognition Phosgene Population Positioning Attribute Prone Position Proteins Protocols documentation Recovery Reporter Risk Rodent Rodent Model Serum Slice Stretching Supine Position Terrorism Thick Tissues Transitional Cell Transportation Vascular Cell Adhesion Molecule-1 Ventilator adiponectin airway epithelium alveolar epithelium base cell type cellular imaging design endothelial regeneration epithelial repair healing improved insight lung health lung injury lung repair novel porcine model respiratory health single cell sequencing standard of care tissue regeneration vascular injury ventilation

项目摘要

Reactive chemicals such as chlorine and phosgene pose a grave threat to respiratory health. These agents were used in warfare, with a significant risk of diversion for terrorist attacks, and frequently cause injuries due to accidental release. Little progress has been made in developing countermeasures, with supportive treatment remaining standard of care. In this application, we hypothesize that inhalation of chlorine and phosgene damage different subsets of pulmonary cells critical for maintenance of epithelial and endothelial barriers, gas exchange, and tissue recovery. Our hypothesis is based on preliminary studies in rodent and porcine chlorine exposure models in which we discovered a novel lung repair mechanism relying on submucosal lung cells that repopulate and differentiate into new epithelia. In contrast to chlorine, phosgene initially spares upper airway cells and primarily damages pulmonary endothelial cells, including newly discovered alveolar endothelial cell subtypes, specialized aerocytes (“aCap”) and general capillary (“gCap”). Comparing mice and pigs, we noted that the identity and location of cell populations in the pig lung more closely resemble the human anatomy. The following specific aims are designed to comprehensively analyze the short- and long-term effects of chlorine and phosgene on lung cell populations in rodents and pigs: Aim 1. Monitor molecular identities and temporal dynamics of pulmonary cell populations after exposures to chlorine or phosgene and during recovery; Aim 2. Visualize pulmonary epithelial and alveolar cells and structures after chlorine or phosgene injury using thick slice microscopy; Aim 3. Compare effects of ventilator and oxygenation support and positional maneuvers on pulmonary cell survival after phosgene or chlorine exposure

氯和光气等反应性化学物质对呼吸系统健康构成严重威胁。用于战争，具有被恐怖袭击转移的重大风险，并且经常造成伤害由于意外泄漏，在制定对策方面进展甚微，但得到了支持。治疗仍维持标准护理。在此应用中，我们研究了吸入氯和光气会损害不同子集的肺细胞对于维持上皮和内皮屏障、气体交换和组织至关重要我们的假设基于对啮齿动物和猪氯暴露模型的初步研究。我们发现了一种新的肺修复机制，依赖于粘膜下肺细胞的重新增殖和与氯不同，光气最初会保护上呼吸道细胞并分化成新的上皮细胞。主要损害肺内皮细胞，包括新发现的肺泡内皮细胞我们注意到，比较小鼠和猪的亚型、特化有气细胞（“aCap”）和普通毛细血管（“gCap”）。猪肺中细胞群的身份和位置更接近人体解剖学。以下具体目标是为了综合分析短期和长期影响氯和光气对啮齿动物和猪肺细胞群的影响：目标 1. 监测分子特性和暴露于氯或光气后以及期间肺细胞群的时间动态目标 2. 观察氯气或光气后的肺上皮细胞和肺泡细胞及结构使用厚切片显微镜观察损伤；目标 3. 比较呼吸机和氧合支持的效果光气或氯暴露后的位置操作对肺细胞存活的影响