Elfsmark Linda, Ågren Lina, Akfur Christine, Jonasson Sofia
Swedish Defence Research Agency, CBRN Defence and Security, Umeå, Sweden.
Inhal Toxicol. 2022;34(5-6):145-158. doi: 10.1080/08958378.2022.2064566. Epub 2022 Apr 22.
Ammonia (NH) is a corrosive alkaline gas that can cause life-threatening injuries by inhalation. The aim was to establish a disease model for NH-induced injuries similar to acute lung injury (ALI) described in exposed humans and investigate the progression of lung damage, respiratory dysfunction and evaluate biomarkers for ALI and inflammation over time.
Female BALB/c mice were exposed to an NH dose of 91.0 mg/kg·bw using intratracheal instillation and the pathological changes were followed for up to 7 days.
NH instillation resulted in the loss of body weight along with a significant increase in pro-inflammatory mediators in both bronchoalveolar lavage fluid (e.g. IL-1β, IL-6, KC, MMP-9, SP-D) and blood (e.g. IL-6, Fibrinogen, PAI-1, PF4/CXCL4, SP-D), neutrophilic lung inflammation, alveolar damage, increased peripheral airway resistance and methacholine-induced airway hyperresponsiveness compared to controls at 20 h. On day 7 after exposure, deteriorating pathological changes such as increased macrophage lung infiltration, heart weights, lung hemorrhages and coagulation abnormalities (elevated plasma levels of PAI-1, fibrinogen, endothelin and thrombomodulin) were observed but no increase in lung collagen. Some of the analyzed blood biomarkers (e.g. RAGE, IL-1β) were unaffected despite severe ALI and may not be significant for NH-induced damages.
NH induces severe acute lung injuries that deteriorate over time and biomarkers in lungs and blood that are similar to those found in humans. Therefore, this model has potential use for developing diagnostic tools for NH-induced ALI and for finding new therapeutic treatments, since no specific antidote has been identified yet.
氨（NH₃）是一种腐蚀性碱性气体，吸入可导致危及生命的损伤。本研究旨在建立一种类似于人类暴露后发生的急性肺损伤（ALI）的NH₃诱导损伤的疾病模型，研究肺损伤的进展、呼吸功能障碍，并评估ALI和炎症的生物标志物随时间的变化。
采用气管内滴注法，使雌性BALB/c小鼠暴露于91.0 mg/kg·bw的NH₃剂量下，并对其病理变化进行长达7天的跟踪观察。
与对照组相比，滴注NH₃后20小时，小鼠体重减轻，支气管肺泡灌洗液（如IL-1β、IL-6、KC、MMP-9、SP-D）和血液（如IL-6、纤维蛋白原、PAI-1、PF4/CXCL4、SP-D）中的促炎介质显著增加，出现中性粒细胞性肺炎症、肺泡损伤、外周气道阻力增加和乙酰甲胆碱诱导的气道高反应性。暴露后第7天，观察到病理变化恶化，如巨噬细胞肺浸润增加、心脏重量增加、肺出血和凝血异常（血浆PAI-1、纤维蛋白原、内皮素和血栓调节蛋白水平升高），但肺胶原蛋白未增加。尽管存在严重的ALI，但一些分析的血液生物标志物（如RAGE、IL-1β）未受影响，可能对NH₃诱导的损伤不具有重要意义。
NH₃可诱导严重的急性肺损伤，且损伤会随时间恶化，肺和血液中的生物标志物与人类相似。因此，由于尚未确定特异性解毒剂，该模型在开发NH₃诱导的ALI诊断工具和寻找新的治疗方法方面具有潜在用途。
