Evaluation of an in vitro screening model to assess phosgene inhalation injury

IF 2.8 4区 医学 Q2 TOXICOLOGY Toxicology Mechanisms and Methods Pub Date : 2017-01-02 DOI:10.1080/15376516.2016.1243183
D. Olivera, Heidi M Hoard-Fruchey, A. Sciuto
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引用次数: 11

Abstract

Abstract Therapeutic development against exposure to toxic gases is hindered by the lack of appropriate models to evaluate candidate compounds prior to animal efficacy studies. In this study, an in vitro, air-liquid interface exposure model has been tested to examine its potential application for screening treatments for phosgene (carbonyl chloride)-induced pulmonary injury. Epithelial cultures on Transwell® inserts, combined with a Vitrocell® exposure apparatus, provided a physiologically relevant exposure environment. Differentiated human bronchial epithelial (16HBE) cultures were exposed for 8 min to phosgene ranging from 0 to 64 ppm and assessed for changes in transepithelial electrical resistance (TEER, epithelial barrier integrity), cellular viability (XTT) and post-exposure (PE) cellular metabolic energy status. Exposure to phosgene concentrations ≥8 ppm caused dose-dependent and significant decreases in TEER and XTT which did not recover within 24-h PE. In addition, at 64 ppm the rate of oxidative glutamine metabolism was significantly inhibited at 6 and 24 h after exposure. Glycolytic activities (glucose utilization and lactate production) were also inhibited, but to a lesser extent. Decreased glycolytic function can translate to insufficient energy sources to counteract barrier function failure. Consistent and sensitive markers of phosgene exposure were TEER, cell viability and decreased metabolism. As such, we have assessed an appropriate in vitro model of phosgene inhalation that produced quantifiable alterations in markers of lung cell metabolism and injury in human airway epithelial cells. Data indicate the suitability of this model for testing classes of anti-edemagenic compounds such as corticosteroids or phosphodiesterase inhibitors for evaluating phosgene therapeutics.
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评估光气吸入损伤的体外筛选模型的评价
摘要在动物疗效研究之前,由于缺乏适当的模型来评估候选化合物,阻碍了针对暴露于有毒气体的治疗发展。在本研究中,测试了一种体外气液界面暴露模型,以检验其在筛选光气(羰基氯)诱导的肺损伤治疗中的潜在应用。Transwell®插入物上的上皮培养物与Vitrocell®暴露装置相结合,提供了生理相关的暴露环境。分化的人支气管上皮(16HBE)培养物暴露8 最小光气含量为0至64 ppm,并评估跨上皮电阻(TEER,上皮屏障完整性)、细胞活力(XTT)和暴露后(PE)细胞代谢能量状态的变化。暴露于光气浓度≥8 ppm引起TEER和XTT的剂量依赖性和显著降低,在24小时PE内没有恢复。此外,在64 ppm氧化谷氨酰胺代谢速率在6和24时被显著抑制 暴露后h。糖酵解活性(葡萄糖利用和乳酸生成)也受到抑制,但程度较小。糖酵解功能下降可转化为能量来源不足,无法抵消屏障功能衰竭。光气暴露的一致和敏感标志物是TEER、细胞活力和代谢降低。因此,我们评估了一种合适的光气吸入体外模型,该模型在人类气道上皮细胞的肺细胞代谢和损伤标志物中产生了可量化的改变。数据表明,该模型适用于测试抗水肿化合物类别,如皮质类固醇或磷酸二酯酶抑制剂,以评估光气疗法。
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来源期刊
自引率
3.10%
发文量
66
期刊介绍: Toxicology Mechanisms and Methods is a peer-reviewed journal whose aim is twofold. Firstly, the journal contains original research on subjects dealing with the mechanisms by which foreign chemicals cause toxic tissue injury. Chemical substances of interest include industrial compounds, environmental pollutants, hazardous wastes, drugs, pesticides, and chemical warfare agents. The scope of the journal spans from molecular and cellular mechanisms of action to the consideration of mechanistic evidence in establishing regulatory policy. Secondly, the journal addresses aspects of the development, validation, and application of new and existing laboratory methods, techniques, and equipment. A variety of research methods are discussed, including: In vivo studies with standard and alternative species In vitro studies and alternative methodologies Molecular, biochemical, and cellular techniques Pharmacokinetics and pharmacodynamics Mathematical modeling and computer programs Forensic analyses Risk assessment Data collection and analysis.
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