Su Duo, Gan Changjiao, Jiao Zhouguang, Deng Mengyun, Li Sha, Ju Yingjiao, Qiu Yefeng, Hu Lingfei, Gao Bo, Zhou Dongsheng, Zhao Yuee, Yang Huiying
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
Basic Medical Laboratory, Anhui Medical University, Hefei, China.
J Appl Toxicol. 2021 Sep;41(9):1479-1490. doi: 10.1002/jat.4140. Epub 2021 Feb 2.
Botulinum neurotoxin type A (BoNT/A) is traditional medicine and well known for its therapeutic use as an anesthetic and in cosmetic applications that work through the inhibition of acetylcholine exocytosis in neuronal cells. BoNT/A also has the potential to function as a biological weapon due to its high mortality rate and ease of dispersal. Emerging evidence suggests that BoNT/A exhibits biological effects on nonneuronal cells. In cytology experiments, BoNT/A induces global gene expression alterations. However, pulmonary effects from exposure to aerosolized BoNT/A have not been evaluated. This study investigated the global transcriptional profile of lung tissues after botulism inhalation. A mice model of inhaled botulism was established using intratracheal exposure to aerosolized BoNT/A and described through histological examination and flow cytometry. Transcriptomic analysis revealed that genes related to acute inflammatory responses were upregulated at 12-h postexposure. Increased expression of multiple anti-inflammatory marker genes and decreased expression of pro-inflammatory marker genes were observed at 48- to 72-h postexposure, underscoring a transcriptional shift toward a pro-reparative phenotype. Histological examination and cell proportions analysis mirrored these expression patterns. Accordingly, the orchestration of a quick phenotype transition prompted by BoNT/A may have the potential for promoting the resolution of the inflammatory lung. To our knowledge, this study represents the first research to investigate the pulmonary transcriptional responses of aerosolized BoNT/A exposure; the results may provide new insights in elucidating the molecular mechanism for pulmonary inhaled botulism and highlight the potential therapeutic application of BoNT/A in mitigating inflammatory conditions.
A型肉毒杆菌神经毒素（BoNT/A）是一种传统药物，因其在麻醉和美容应用中的治疗用途而广为人知，其作用机制是通过抑制神经元细胞中的乙酰胆碱胞吐作用。由于其高死亡率和易于传播，BoNT/A也有作为生物武器的潜在可能。新出现的证据表明，BoNT/A对非神经元细胞具有生物学效应。在细胞学实验中，BoNT/A会引起整体基因表达改变。然而，吸入雾化BoNT/A后的肺部影响尚未得到评估。本研究调查了吸入肉毒杆菌中毒后肺组织的整体转录谱。通过气管内暴露于雾化BoNT/A建立了吸入性肉毒杆菌中毒的小鼠模型，并通过组织学检查和流式细胞术进行了描述。转录组分析显示，暴露后12小时与急性炎症反应相关的基因上调。在暴露后48至72小时观察到多种抗炎标记基因的表达增加和促炎标记基因的表达减少，这突出了转录向促修复表型的转变。组织学检查和细胞比例分析反映了这些表达模式。因此，由BoNT/A引发的快速表型转变的调控可能具有促进炎症肺消退的潜力。据我们所知，本研究是首次调查雾化BoNT/A暴露后的肺部转录反应；这些结果可能为阐明肺部吸入性肉毒杆菌中毒的分子机制提供新的见解，并突出BoNT/A在减轻炎症状态方面的潜在治疗应用。
