Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis. Herein, we developed a murine model of NM-induced pulmonary toxicity with the goal of assessing inflammatory mechanisms of injury. C57BL/6J mice were euthanized 1-28 d following intratracheal exposure to NM (0.08 mg/kg) or PBS control. NM caused progressive alveolar epithelial thickening, perivascular inflammation, bronchiolar epithelial hyperplasia, interstitial fibroplasia and fibrosis, peaking 14 d post exposure. Enlarged foamy macrophages were also observed in the lung 14 d post NM, along with increased numbers of microparticles in bronchoalveolar lavage fluid (BAL). Following NM exposure, rapid and prolonged increases in BAL cells, protein, total phospholipids and surfactant protein (SP)-D were also detected. Flow cytometric analysis showed that CD11b+Ly6G-F4/80+Ly6Chi proinflammatory macrophages accumulated in the lung after NM, peaking at 3 d. This was associated with macrophage expression of HMGB1 and TNFα in histologic sections. CD11b+Ly6G-F4/80+Ly6Clo anti-inflammatory/pro-fibrotic macrophages also increased in the lung after NM peaking at 14 d, a time coordinate with increases in TGFβ expression and fibrosis. NM exposure also resulted in alterations in pulmonary mechanics including increases in tissue elastance and decreases in compliance and static compliance, most prominently at 14 d. These findings demonstrate that NM induces structural and inflammatory changes in the lung that correlate with aberrations in pulmonary function. This mouse model will be useful for mechanistic studies of mustard lung injury and for assessing potential countermeasures.

中文翻译：

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暴露于氮芥末后的小鼠肺损伤，氧化应激和纤维化。

氮芥（NM）是一种已知会引起急性肺损伤并发展为纤维化的细胞毒性表面活性剂。在这里，我们建立了NM诱导的肺毒性的小鼠模型，其目的是评估损伤的炎症机制。气管内暴露于NM（0.08 mg / kg）或PBS对照后，将C57BL / 6J小鼠安乐死1-28 d。NM引起进行性肺泡上皮增厚，血管周炎症，细支气管上皮增生，间质性纤维化和纤维化，在暴露后14 d达到高峰。在NM后14天，在肺部也观察到泡沫状巨噬细胞增大，并且支气管肺泡灌洗液（BAL）中的微粒数量增加。NM暴露后，还检测到BAL细胞，蛋白质，总磷脂和表面活性剂蛋白质（SP）-D迅速且长期增加。流式细胞仪分析显示CD11b + Ly6G-F4 / 80 + Ly6Chi促炎巨噬细胞在NM后聚集在肺中，在3 d达到峰值。这与组织切片中HMGB1和TNFα的巨噬细胞表达有关。NM在14 d达到峰值后，肺中CD11b + Ly6G-F4 / 80 + Ly6Clo抗炎/促纤维化巨噬细胞也增加，时间与TGFβ表达和纤维化增加相关。NM暴露还导致肺力学改变，包括组织弹性增加，顺应性和静态顺应性降低，最明显的是14 d。这些发现表明，NM诱导肺中与肺功能异常相关的结构和炎症变化。