Sciuto A M, Strickland P T, Gurtner G H
Pharmacology Division, Neurotoxicology Branch, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425, USA.
J Appl Toxicol. 1998 Sep-Oct;18(5):321-9. doi: 10.1002/(sici)1099-1263(1998090)18:5<321::aid-jat516>3.0.co;2-4.
This study investigated the post-treatment effect of isoproterenol (ISO) on pulmonary parameters in rabbits whole-body-exposed to a lethal dose of the toxic gas phosgene. Phosgene is widely used in industry as a chemical intermediate for the production of plastics, drugs and polyurethane products. The results of this study are from five study groups: 10-min perfused baseline; uninjured controls exposed to air; phosgene-exposed; phosgene-exposed isoproterenol-treated intravascularly and intratracheally (ISO i.v.+i.t.); and phosgene-exposed isoproterenol-treated intratracheally (ISO i.t.). Treatment with ISO was administered as either a continuous intravascular infusion (24 microg min(-1)) from the beginning to end of perfusion (i.v.) and a 24-microg intratracheal bolus (i.t.) or just an i.t. bolus immediately prior to the start of perfusion. Rabbits of 2.5-3 kg were exposed to a cumulative dose of phosgene to attain a concentration x time exposure-effect of 1500 ppm x min. Lungs were isolated in situ and perfused 50-60 min after the start of exposure with Krebs-Henseleit buffer at 40 ml min(-1). Pulmonary artery pressure (Ppa), tracheal pressure (Pt) and lung weight gain (lwg) were continuously measured. Leukotrienes (LT) C4/D4/E4 were measured in the perfusate every 20 min during perfusion. At the immediate conclusion of the experiment, lung tissue was frozen in liquid N2 and analyzed for glutathione (GSH) and cyclic 3',5'-adenosine monophosphate (cAMP). Post-treatment with ISO by either i.v.+i.t. or i.t. routes 50+ min after phosgene exposure significantly lowered Ppa, Pt and lwg. Phosgene-exposed rabbits post-treated with ISO i.t. had significantly higher levels of reduced GSH (3 +/- 0.4 nmol mg(-1) protein), GSH/GSSG ratios (3.3 +/- 0.6 nmol mg(-1) protein) and percentage of total as reduced GSH (75 +/- 2.5%) compared with phosgene-exposed rabbits: 1.9 +/- 0.3, 2 +/- 0.3 and 58 +/- 6.3%, respectively. The ISO (i.v.+i.t.) post-treatment route significantly increased reduced GSH (6.2 +/- 1.7 nmol mg(-1) protein), GSH/GSSG ratio (5.9 +/- 0.8 nmol mg(-1) protein) and percentage of total as reduced GSH (85 +/- 1.7%) when compared to the phosgene-only group. The ISO i.t. and ISO i.v.+i.t. treatments significantly reduced perfusate LTC4/D4/E4 150 min after the start of exposure by 90% and 48%, respectively. These data suggest that protective mechanisms for ISO involve reduced vascular pressure, decreased LTC4/D4/E4-mediated pulmonary capillary permeability and a favorable lung tissue redox state compared with untreated phosgene-exposed rabbits.
本研究调查了异丙肾上腺素（ISO）对全身暴露于致死剂量毒性气体光气的家兔肺部参数的治疗后效果。光气在工业上广泛用作生产塑料、药物和聚氨酯产品的化学中间体。本研究结果来自五个研究组：10分钟灌注基线；暴露于空气的未受伤对照组；暴露于光气组；光气暴露后经血管内和气管内给予异丙肾上腺素治疗组（ISO静脉内+气管内）；以及光气暴露后经气管内给予异丙肾上腺素治疗组（ISO气管内）。ISO治疗采用从灌注开始至结束持续血管内输注（24微克/分钟）（静脉内）和24微克气管内推注（气管内），或仅在灌注开始前即刻进行气管内推注。将体重2.5 - 3千克的家兔暴露于累积剂量的光气，以达到1500 ppm×分钟的浓度×时间暴露效应。在暴露开始后50 - 60分钟，原位分离肺部，并用克雷布斯 - 亨塞尔特缓冲液以40毫升/分钟的速度进行灌注。连续测量肺动脉压（Ppa）、气管压（Pt）和肺重量增加（lwg）。在灌注期间每隔20分钟测量灌注液中的白三烯（LT）C4/D4/E4。在实验结束时，将肺组织在液氮中冷冻，并分析谷胱甘肽（GSH）和环磷腺苷（cAMP）。光气暴露50多分钟后通过静脉内+气管内或气管内途径给予ISO进行治疗后，显著降低了Ppa、Pt和lwg。与光气暴露的家兔相比，经气管内给予ISO治疗的光气暴露家兔的还原型GSH水平（3±0.4纳摩尔/毫克蛋白）、GSH/GSSG比值（3.3±0.6纳摩尔/毫克蛋白）以及还原型GSH占总GSH的百分比（75±2.5%）显著更高，光气暴露家兔的相应数值分别为1.9±0.3、2±0.3和58±6.3%。与仅光气组相比，ISO（静脉内+气管内）治疗后途径显著提高了还原型GSH（6.2±1.7纳摩尔/毫克蛋白）、GSH/GSSG比值（5.9±0.8纳摩尔/毫克蛋白）以及还原型GSH占总GSH的百分比（85±1.7%）。ISO气管内和ISO静脉内+气管内治疗在暴露开始150分钟后分别使灌注液中LTC4/D4/E4显著降低了90%和48%。这些数据表明，与未治疗的光气暴露家兔相比，ISO的保护机制包括降低血管压力、降低LTC4/D4/E4介导的肺毛细血管通透性以及有利的肺组织氧化还原状态。
