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

• 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
• 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

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。这些代理 用于战争，有很大的转移恐怖袭击的风险，并且经常造成伤害 由于意外释放。在制定对策方面进展甚微，但缺乏支持 治疗仍维持标准护理。 在此应用中，我们假设吸入氯和光气会损害不同的子集 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 恢复。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 分化成新的上皮细胞。与氯相反，光气最初不会伤害上呼吸道细胞， 主要损害肺内皮细胞，包括新发现的肺泡内皮细胞 亚型，特化有气细胞（“aCap”）和普通毛细血管（“gCap”）。比较老鼠和猪，我们注意到 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 恢复;目标 2. 观察氯或光气后的肺上皮和肺泡细胞及结构 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