Toxicologic pathological mechanism of acute lung injury induced by oral administration of benzalkonium chloride in mice
Toxicologic pathological mechanism of acute lung injury induced by oral administration of benzalkonium chloride in mice
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DOI：
10.1007/s43188-023-00178-0
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发表时间：
2023-04
影响因子：
2.3
通讯作者：
H. Sekijima;T. Oshima;Yuno Ueji;Naoko Kuno;Yukino Kondo;Saera Nomura;T. Asakura;Kae Sakai-Sugino;M. Kawano;H. Komada;H. Kotani
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文献类型：
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作者：
H. Sekijima;T. Oshima;Yuno Ueji;Naoko Kuno;Yukino Kondo;Saera Nomura;T. Asakura;Kae Sakai-Sugino;M. Kawano;H. Komada;H. Kotani
苯扎氯铵（BAC）中毒可引起致命的肺损伤，如急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）。然而，BAC摄入诱导的ALI/ARDS的发病机制知之甚少。本研究旨在阐明BAC摄入小鼠模型后的肺毒性机制。将BAC以100、250和1250 mg/kg的剂量经口给予C57 BL/6小鼠。给药后，通过液相色谱串联质谱法评价血液和肺中的BAC浓度。通过组织学和蛋白质分析评价肺组织损伤。经口给药后血液和肺BAC浓度水平以剂量依赖性方式增加，浓度与给药剂量成正比。经口给予1250 mg/kg BAC后，肺损伤的严重程度随时间推移而恶化。1250 mg/kg BAC给药后，在肺中观察到末端转移酶dUTP缺口末端标记阳性细胞和裂解的半胱天冬酶-3水平增加。此外，还观察到裂解的半胱天冬酶-9水平增加和线粒体细胞色素c释放到胞质溶胶中。这些结果表明，肺组织损伤与过度凋亡有助于BAC诱导的ALI的发展和加重。我们的研究结果提供了有用的信息，开发一种有效的治疗由BAC摄入引起的ALI/ARDS。
Benzalkonium chloride (BAC) intoxication causes fatal lung injuries, such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, the pathogenesis of ALI/ARDS induced by BAC ingestion is poorly understood. This study aimed to clarify the mechanism of lung toxicity after BAC ingestion in a mouse model. BAC was orally administered to C57BL/6 mice at doses of 100, 250, and 1250 mg/kg. After administration, BAC concentrations in the blood and lungs were evaluated via liquid chromatography with tandem mass spectrometry. Lung tissue injury was evaluated via histological and protein analyses. Blood and lung BAC concentration levels after oral administration increased in a dose-dependent manner, with the concentrations directly proportional to the dose administered. The severity of lung injury worsened over time after the oral administration of 1250 mg/kg BAC. An increase in the terminal transferase dUTP nick end labeling-positive cells and cleaved caspase-3 levels was observed in the lungs after 1250 mg/kg BAC administration. In addition, increased cleaved caspase-9 levels and mitochondrial cytochrome c release into the cytosol were observed. These results suggest that lung tissue injury with excessive apoptosis contributes to BAC-induced ALI development and exacerbation. Our findings provide useful information for developing an effective treatment for ALI/ARDS induced by BAC ingestion.