Department of Toxicology, Fourth Military Medical University, Xi'an, China.
Inhal Toxicol. 2011 Nov;23(13):842-52. doi: 10.3109/08958378.2011.618849.
The principal acute mode of action of inhaled phosgene gas is related to an increase alveolar fluid exudation under pathologic conditions. This paper considers some aspects in modeling phosgene-induced acute lung injury (ALI) in an acute rat bioassay and whether edema formation can be modulated by inhaled nitric oxide (iNO). Protein analysis in bronchoalveolar lavage (BAL) fluid is amongst the most sensitive method to quantify the phosgene-induced non-cardiogenic, pulmonary high-permeability edema following acute inhalation exposure. Maximum concentrations in BAL-protein occur within one day postexposure, typically within a latency period up to about 15 h as a consequence of an increasingly exhausted lymphatic drainage. An almost similar sensitivity was given by the functional endpoint 'enhanced pause (Penh)' when measured by non-invasive whole-body barometric plethysmography over a time period of 20 h. The magnitude of edema formation follows a concentration x time (C¹xt) relationship, although animal model-specific deviations may occur at very short exposure durations (1-20 min) due to a rodent-specific, reflexively induced transient decreased ventilation. This has to be accounted for when simulating accidental exposure scenarios to study the mechanisms involved in pharmacological modulation of fluid transport in this type of ALI. Therefore, a special focus has to be given to the dosimetry of inhaled phosgene, otherwise any change in effect magnitude, as a result of under-dosing of phosgene, may be misconceived as promising therapy. This study demonstrates that accidental exposures can be modeled best in rats by exposure durations of at least 20-30 min. Lung function measurements (Penh) show that pathophysiological effects appear to occur concomitant with the exposure to phosgene; however, its full clinical manifestation requires a gross imbalance of pulmonary fluid clearance. When applying this concept, post-phosgene exposure iNO at 1.5 ppm × 6 h or 15 pm × 20 h led to an aggravation of edema formation while L-NAME, a non-selective inhibitor of nitric oxide synthase, led to attenuation. Ethyl pyruvate, given either prophylactically or therapeutically, was ineffective.
吸入光气气体的主要急性作用模式与病理条件下肺泡液体渗出增加有关。本文考虑了在急性大鼠生物测定中模拟光气诱导的急性肺损伤（ALI）的一些方面，以及吸入一氧化氮（iNO）是否可以调节水肿形成。支气管肺泡灌洗液（BAL）中的蛋白质分析是定量分析光气诱导的非心源性、肺高通透性水肿的最敏感方法之一，这种水肿是急性吸入暴露后的结果。在暴露后一天内，BAL 蛋白中的最大浓度出现，通常在潜伏期内，约 15 小时，这是由于淋巴管引流逐渐耗尽所致。在 20 小时的时间内，通过非侵入性全身气压容积描记术测量的功能终点“增强暂停（Penh）”也具有相似的敏感性。水肿形成的程度遵循浓度 x 时间（C¹xt）关系，尽管在非常短的暴露时间（1-20 分钟）下，由于啮齿动物特有的、反射性诱导的短暂通气减少，可能会出现动物模型特异性偏差。在模拟意外暴露情况以研究这种类型的 ALI 中流体运输的药理学调节机制时，必须考虑到这一点。因此，必须特别关注吸入光气的剂量学，否则由于光气剂量不足而导致的效应幅度变化可能会被误解为有希望的治疗方法。本研究表明，在大鼠中，通过至少 20-30 分钟的暴露时间可以最好地模拟意外暴露。肺功能测量（Penh）表明，病理生理效应似乎与光气暴露同时发生；然而，其完全临床表现需要肺部液体清除的严重失衡。当应用这一概念时，在暴露于光气后给予 1.5ppm×6h 或 15ppm×20h 的 iNO 会导致水肿形成加重，而非选择性一氧化氮合酶抑制剂 L-NAME 则会导致水肿形成减轻。预防性或治疗性给予乙基丙酮酸均无效。
