Development of a Microinstillation Model of Inhalation Exposure to Assess Lung Injury Following Exposure to Toxic Chemicals and Nerve Agents in Guinea Pigs
Development of a Microinstillation Model of Inhalation Exposure to Assess Lung Injury Following Exposure to Toxic Chemicals and Nerve Agents in Guinea Pigs
复制标题
开发吸入暴露的微滴注模型以评估豚鼠接触有毒化学品和神经毒剂后的肺损伤
DOI：
10.1080/15376510600748760
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发表时间：
2006
影响因子：
3.2
通讯作者：
A. Sciuto
中科院分区：
文献类型：
--
作者：
M. Nambiar;B. S. Wright;Peter E. Rezk;Kelvin B Smith;R. K. Gordon;T. S. Moran;S. M. Richards;A. Sciuto
化学战神经毒剂造成的呼吸紊乱是这些恐怖和大规模毁灭性武器造成大规模伤亡的起点和主要死因。然而，很少有研究评估CWNA，特别是甲基硫代膦酸S-（2-（双（1-甲基乙基）氨基）乙基）O-乙酯（VX）诱导的呼吸毒性和加重。在这项研究中，我们开发了一种吸入暴露的微滴注技术，以评估暴露于CWNAs和有毒化学品后的肺损伤。通过将微导管置于气管分叉中心上方1.5至2.0 cm处，轻轻插管豚鼠。该位置对于将雾化剂均匀地递送到肺叶至关重要。通过测量从上门牙到气管分叉的距离来计算插管的位置，对于同等大小和体重范围为250 g至300 g的豚鼠，该距离通常为8.5 cm。导管能够承受100 psi的压力;末端有五个外围孔，用于泵送空气，使在中心孔中输送的神经毒剂雾化。微导管由中央控制系统调节，以低于豚鼠潮气量的体积输送雾化剂。递送的神经毒剂的平均粒度为1.48 ± 0.07微米。微滴注技术已通过将动物暴露于考马斯亮蓝进行验证，考马斯亮蓝显示染料在不同肺叶中均匀分布。此外，肺中染料的浓度与暴露剂量/时间相关。此外，组织病理学分析证实了微量灌注后不存在气压伤。这种新型技术安全地输送药剂，需要更少的药剂量，避免暴露于皮肤、毛皮和眼睛，并避免了由于呼吸从鼻腔切换到口鼻而导致颗粒在鼻腔和调色板中沉积的担忧。全身动态室或仅鼻暴露。目前，我们正在使用这种吸入暴露技术来研究直接暴露于VX后的肺损伤和呼吸障碍。
Respiratory disturbances due to chemical warfare nerve agents (CWNAs) are the starting point of mass casualty and the primary cause of death by these weapons of terror and mass destruction. However, very few studies have been implemented to assess respiratory toxicity and exacerbation induced by CWNAs, especially methylphosphonothioic acid S-(2-(bis(1-methylethyl)amino)ethyl)O-ethyl ester (VX). In this study, we developed a microinstillation technique of inhalation exposure to assess lung injury following exposure to CWNAs and toxic chemicals. Guinea pigs were gently intubated by placing a microcatheter into the trachea 1.5 to 2.0 cm centrally above the bifurcation. This location is crucial to deliver aerosolized agents uniformly to the lung's lobes. The placement of the tube is calculated by measuring the distance from the upper front teeth to the tracheal bifurcation, which is typically 8.5 cm for guinea pigs of equivalent size and a weight range of 250 g to 300 g. The catheter is capable of withstanding 100 psi pressure; the terminus has five peripheral holes to pump air that aerosolizes the nerve agent that is delivered in the central hole. The microcatheter is regulated by a central control system to deliver the aerosolized agent in a volume lower than the tidal volume of the guinea pigs. The average particle size of the nerve agent delivered was 1.48 ± 0.07 micrometer. The microinstillation technology has been validated by exposing the animals to Coomassie brilliant blue, which showed a uniform distribution of the dye in different lung lobes. In addition, the concentration of the dye in the lungs correlated with the dose/time of exposure. Furthermore, histopathological analysis confirmed the absence of barotraumas following micoinstillation. This novel technique delivers the agent safely, requires less amount of agent, avoids exposure to skin, pelt, and eye, and circumvents the concern of deposition of the particles in the nasal and palette due to the switching of breathing from nasal to oronasal in whole-body dynamic chamber or nose only exposure. Currently, we are using this inhalation exposure technique to investigate lung injuries and respiratory disturbances following direct exposure to VX.