In this study, a ricin toxin (RT)-induced pulmonary intoxication model was established in mice by intratracheal-delivered RT at a dose of 2× LD50. 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.

中文翻译：

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通过气管内接种暴露于蓖麻毒蛋白的小鼠肺的时程转录组分析

在本研究中，通过气管内递送 RT 剂量为 2× LD50 在小鼠中建立了蓖麻毒素 (RT) 诱导的肺中毒模型。基于该模型，对暴露后 24 小时和 48 小时的肺进行组织病理学评估，并分析暴露后 4、12、24 和 48 小时肺的全基因组转录组。组织病理学分析显示，暴露后24 h有大量中性粒细胞浸润肺部，48 h时肺部出现轻度肺水肿和血管周围-细支气管周围水肿。转录组分析表明，暴露于 RT 后，与白细胞迁移和趋化性相关的大量基因在肺中的表达持续增加，以及参与急性期免疫和/或炎症反应的基因表达，在暴露于 RT 后 12 小时内也增加，这可以通过测量支气管肺泡灌洗液中的细胞因子，如 IL-1β、TNF-α 和 IL-6 来证实。而与细胞外基质的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，而与抗氧化活性相关的基因的表达也在最初的 12 小时内下降。在暴露后 4 小时，有 17 个差异表达基因 (DEG) 参与肺中的核糖毒性应激反应、内质网应激反应或免疫反应。这些 DEGs 的表达上调，这些 DEGs 的数量在 4 h 时占所有 DEGs 的 59% 左右。17DEGs可能在炎症的发生和发展中起重要作用。值得注意的是，Atf3、Egr1、Gdf15 和 Osm，研究不足的，可能是后续研究 RT 诱导的肺中毒的重要目标。本研究为放疗所致肺中毒提供了新的信息和见解，可为后续放疗所致肺中毒毒理机制和治疗方法的研究提供参考。