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

反应性化学物质（例如氯和磷酸化学物质）对呼吸健康构成了严重威胁。这些代理被用于战争由于意外释放。在开发对策方面取得了很少的进展，并获得了支持治疗剩余的护理标准。在此应用中，我们假设吸入氯和磷损伤的不同子集的不同子集肺部细胞对于维持上皮和内皮屏障，气体交换和组织至关重要恢复。我们的假设基于在啮齿动物和猪氯暴露模型中的初步研究我们发现了一种新型的肺修复机制，该机制依靠粘膜下肺细胞，这些肺部细胞重新填充和分化为新的上皮。与氯相反，磷酸最初省略了上气道细胞和主要损害肺内皮细胞，包括新发现的肺泡内皮细胞亚型，专门的气囊（“ ACAP”）和一般毛细管（“ GCAP”）。比较小鼠和猪，我们注意到猪肺中细胞群体的身份和位置更类似于人体解剖结构。以下特定目的旨在全面分析啮齿动物和猪的肺细胞种群上的氯和磷酸盐：目标1。监测分子身份和暴露于氯或磷酸后以及期间的肺部细胞群体的临时动力学恢复; AIM 2。可视化肺或磷酸盐后的肺上皮细胞和肺泡细胞以及结构使用厚切片显微镜损伤；目标3。比较通风和氧合支持的影响以及肺细胞或氯暴露后肺部细胞存活的位置操纵