BACKGROUND Fuel oil-derived volatile organic compounds (VOCs) inhalation is associated with accidental marine spills. After the Prestige petroleum tanker sank off northern Spain in 2002 and the Deepwater Horizon oil rig catastrophe in 2009, subjects involved in environmental decontamination showed signs of ongoing or residual lung disease up to 5 y after the exposure. OBJECTIVES We aimed at investigating mechanisms driving persistent respiratory disease by developing an animal model of inhalational exposure to fuel oil-derived VOCs. METHODS Female Wistar and Brown Norway (BN) rats and C57BL mice were exposed to VOCs produced from fuel oil mimicking the Prestige spill. Exposed animals inhaled the VOCs 2 h daily, 5 d per week, for 3 wk. Airway responsiveness to methacholine (MCh) was assessed, and bronchoalveolar lavage (BAL) and lung tissues were analyzed after the exposure and following a 2-wk washout. RESULTS Consistent with data from human studies, both strains of rats that inhaled fuel oil-derived VOCs developed airway hyperresponsiveness that persisted after the washout period, in the absence of detectable inflammation in any lung compartment. Histopathology and quantitative morphology revealed the development of peripherally distributed pulmonary emphysema, which persisted after the washout period, associated with increased alveolar septal cell apoptosis, microvascular endothelial damage of the lung parenchyma, and inhibited expression of vascular endothelial growth factor (VEGF). DISCUSSION In this rat model, fuel oil VOCs inhalation elicited alveolar septal cell apoptosis, likely due to DNA damage. In turn, the development of a peculiar pulmonary emphysema pattern altered lung mechanics and caused persistent noninflammatory airway hyperresponsiveness. Such findings suggest to us that humans might also respond to VOCs through physiopathological pathways different from those chiefly involved in typical cigarette smoke-driven emphysema in chronic obstructive pulmonary disease (COPD). If so, this study could form the basis for a novel disease mechanism for lasting respiratory disease following inhalational exposure to catastrophic fuel oil spills. https://doi.org/10.1289/EHP4178.

中文翻译：

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啮齿动物模型中的气道高反应性，炎症和肺气肿，用于模拟实验性溢油过程中遇到的燃油衍生的挥发性有机化合物的暴露。

背景技术源自燃料油的挥发性有机化合物（VOC）的吸入与意外的海上泄漏有关。在2002年Prestige石油轮沉没在西班牙北部和2009年Deepwater Horizo​​n石油钻井平台灾难之后，参与环境净化的受试者在暴露后长达5年的时间显示出正在进行或残留的肺部疾病迹象。目的我们旨在通过开发吸入吸入源自燃油的挥发性有机化合物的动物模型来研究驱动持续性呼吸道疾病的机制。方法将Wistar和Brown Norway（BN）雌性大鼠和C57BL小鼠暴露于模拟Prestige泄漏的燃油中产生的VOC。暴露的动物每天2小时，每周5天，每周3周吸入VOC。评估气道对乙酰甲胆碱（MCh）的反应性，暴露后和2周冲洗后分析支气管肺泡灌洗（BAL）和肺组织。结果与人体研究的数据一致，两种吸入燃料油衍生的VOC的大鼠均出现气道高反应性，在冲洗期后仍持续存在，而在任何肺隔室中均未检测到炎症。组织病理学和定量形态学揭示了周围分布的肺气肿的发展，其在冲洗期后持续存在，与肺泡间隔细胞凋亡增加，肺实质的微血管内皮损伤和抑制血管内皮生长因子（VEGF）的表达有关。讨论在该大鼠模型中，燃油VOC的吸入可能引起肺泡间隔细胞凋亡，这可能是由于DNA损伤所致。反过来，特殊的肺气肿模式的发展改变了肺部力学，并导致持续的非炎性气道高反应性。这些发现向我们表明，人类也可能通过不同于主要参与慢性阻塞性肺病（COPD）中典型卷烟驱动的肺气肿的生理病理途径对VOC做出反应。如果是这样，这项研究可以为吸入暴露于灾难性燃油泄漏后持久呼吸道疾病的新型疾病机制奠定基础。https://doi.org/10.1289/EHP4178。这些发现向我们表明，人类也可能通过不同于主要参与慢性阻塞性肺病（COPD）中典型卷烟驱动的肺气肿的生理病理途径对VOC做出反应。如果是这样，这项研究可以为吸入暴露于灾难性燃油泄漏后持久呼吸道疾病的新型疾病机制奠定基础。https://doi.org/10.1289/EHP4178。这些发现向我们表明，人类也可能通过不同于主要参与慢性阻塞性肺病（COPD）中典型卷烟驱动的肺气肿的生理病理途径对VOC做出反应。如果是这样，这项研究可以为吸入暴露于灾难性燃油泄漏后持久呼吸道疾病的新型疾病机制奠定基础。https://doi.org/10.1289/EHP4178。