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

氯气和光气等活性化学品对呼吸系统健康构成严重威胁。这些试剂 用于战争，有很大的转移用于恐怖袭击的风险，并经常造成伤害 由于意外释放。在制定对策方面进展甚微， 治疗仍为标准治疗。 在这个应用中，我们假设吸入氯气和光气会损害不同的亚群， 对维持上皮和内皮屏障、气体交换和组织至关重要的肺细胞 复苏我们的假设是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， 分化成新的上皮细胞。与氯气相反，光气最初不影响上呼吸道细胞， 主要损害肺内皮细胞，包括新发现的肺泡内皮细胞 亚型，特化气细胞（“aCap”）和普通毛细血管（“gCap”）。比较小鼠和猪，我们注意到 猪肺中细胞群的身份和位置更接近于人体解剖学。 以下具体目标旨在全面分析 氯气和光气对啮齿动物和猪肺细胞群的影响：目的1。监测分子身份， 暴露于氯或光气后和暴露期间肺细胞群的时间动态 恢复;目标2.氯气或光气后可使肺上皮和肺泡细胞及结构可视化 使用厚切片显微镜观察损伤; Aim 3.比较呼吸机和氧合支持的效果， 位置操作对光气或氯气暴露后肺细胞存活的影响

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