State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China.
Laboratory Animal Center, Academy of Military Medical Science, Beijing, 100071, China.
Toxicol Lett. 2021 Feb 1;337:57-67. doi: 10.1016/j.toxlet.2020.11.012. Epub 2020 Nov 21.
In this study, a ricin toxin (RT)-induced pulmonary intoxication model was established in mice by intratracheal-delivered RT at a dose of 2× LD. Based on this model, the histopathological evaluation of the lungs at 24 h and 48 h post-exposure was executed, and the genome-wide transcriptome of the lungs at 4, 12, 24 and 48 h post-exposure was analyzed. Histopathological analysis showed that a large number of neutrophils infiltrated the lungs at 24 h post-exposure, and slight pulmonary edema and perivascular-peribronchiolar edema appeared in the lungs at 48 h. Transcriptome analysis showed that the expression of a large number of genes related to leukocyte migration and chemotaxis consistently increased in the lungs upon exposure to RT, and the expression of genes that participate in acute phase immune and/or inflammatory response, also increased within 12 h of exposure to RT, which could be confirmed by the measurement of cytokines, such as IL-1β, TNF-α and IL-6, in bronchoalveolar lavage fluid. While the expression of genes related to cellular components of the extracellular matrix and cell membrane integrity consistently decreased in the lungs, and the expression of genes related to antioxidant activity also decreased within the first 12 h. There are 17 differentially expressed genes (DEGs) that participate in ribotoxic stress response, endoplasmic reticulum stress response or immune response in the lungs at 4 h post-exposure. The expression of these DEGs was upregulated, and the number of these DEGs accounted for about 59 % of all DEGs at 4 h. The 17 DEGs may play an important role in the occurrence and development of inflammation. Notably, Atf3, Egr1, Gdf15 and Osm, which are poorly studied, may be important targets for the subsequent research of RT-induced pulmonary intoxication. This study provides new information and insights for RT-induced pulmonary intoxication, and it can provide a reference for the subsequent study of the toxicological mechanism and therapeutic approaches for RT-induced pulmonary intoxication.
在这项研究中，通过气管内给予 2×LD 剂量的蓖麻毒素（RT），建立了一个 RT 诱导的肺中毒小鼠模型。基于该模型，在暴露后 24 小时和 48 小时进行了肺的组织病理学评估，并分析了暴露后 4、12、24 和 48 小时肺的全基因组转录组。组织病理学分析表明，暴露后 24 小时大量中性粒细胞浸润肺，48 小时肺出现轻微肺水肿和血管周围-细支气管周围水肿。转录组分析表明，暴露于 RT 后，大量与白细胞迁移和趋化相关的基因在肺中的表达持续增加，参与急性免疫和/或炎症反应的基因的表达也在暴露于 RT 后 12 小时内增加，这可以通过测量细胞因子（如 IL-1β、TNF-α 和 IL-6）在支气管肺泡灌洗液中得到证实。而与细胞外基质细胞成分和细胞膜完整性相关的基因在肺中的表达持续下降，与抗氧化活性相关的基因在最初 12 小时内也下降。在暴露后 4 小时的肺中，有 17 个差异表达基因（DEG）参与核糖体毒性应激反应、内质网应激反应或免疫反应。这些 DEG 的表达上调，并且这些 DEG 的数量在 4 小时时占所有 DEG 的约 59%。这 17 个 DEG 可能在炎症的发生和发展中发挥重要作用。值得注意的是，Atf3、Egr1、Gdf15 和 Osm 等研究较少的基因可能是 RT 诱导的肺中毒后续研究的重要靶点。本研究为 RT 诱导的肺中毒提供了新的信息和见解，可为 RT 诱导的肺中毒毒理学机制和治疗方法的后续研究提供参考。
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