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Lung injury, oxidative stress and fibrosis in mice following exposure to nitrogen mustard.

氮芥暴露后小鼠的肺损伤、氧化应激和纤维化。

  • 影响因子:3.94
  • DOI:10.1016/j.taap.2019.114798
  • 作者列表:"Sunil VR","Vayas KN","Abramova EV","Rancourt R","Cervelli JA","Malaviya R","Goedken M","Venosa A","Gow AJ","Laskin JD","Laskin DL
  • 发表时间:2020-01-15
Abstract

: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.

摘要

氮芥 (NM) 是一种细胞毒性发泡剂,已知可引起急性肺损伤进展为纤维化。在此,我们开发了 NM 诱导的肺毒性小鼠模型,目的是评估损伤的炎症机制。C57BL/6J 小鼠气管内暴露于 NM (0.08 mg/kg) 或 PBS 对照后 1-28 d 安乐死。NM 引起进行性肺泡上皮增厚,血管周围炎症,细支气管上皮增生,间质纤维化生和纤维化,暴露后 14 d 达到高峰。NM 后 14 d 肺内也观察到膨大的泡沫状巨噬细胞,同时支气管肺泡灌洗液 (BAL) 中微粒数量增加。NM 暴露后,BAL 细胞、蛋白、总磷脂和表面活性蛋白 (SP)-D 快速和延长增加。流式细胞分析显示,CD11b + Ly6G-F4/80 + Ly6Chi 促炎巨噬细胞在 NM 后聚集在肺内,3 d 达到高峰。这与巨噬细胞 HMGB1 和 tnf α 在组织学切片中的表达有关。CD11b + Ly6G-F4/80 + Ly6Clo 抗炎/促纤维化巨噬细胞在 14d NM 峰值后也增加,与 tgf β 表达增加和纤维化相协调。NM 暴露也导致肺力学改变,包括组织弹性增加,顺应性和静态顺应性降低,在 14 d 最显著。这些发现证明 NM 诱导肺部结构和炎症变化,与肺功能畸变相关。该小鼠模型将有助于芥末肺损伤的机理研究和评估潜在的对策。

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