Wang Yuqing, Zhu Xiaoyu, Li Lu, Su Duo, Ai Lingli, Xie Hao, Zhou Dongsheng, Yang Huiying, Li Boan
Department of Clinical Laboratory, the Fifth Medical Center of PLA General Hospital, Beijing, 100039, China.
Graduate School of PLA General Hospital, Beijing, 100853, China.
Arch Toxicol. 2025 May 3. doi: 10.1007/s00204-025-04067-3.
Ricin toxin (RT), a highly potent plant-derived toxin, represents a critical threat due to its capacity to induce fatal acute lung injury (ALI) upon inhalation. While the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase predominantly expressed on epithelial cells and fibroblasts, regulates cellular processes such as growth, proliferation, differentiation and inflammation, its involvement in RT-induced ALI remains unexplored. This study investigates this relationship using a mouse model of ALI induced by aerosolized RT at a dose of 2.0 × LD (approximately 0.01 mg kg ). The results demonstrate that damage to alveolar epithelial type II (AT2) cells leads to the release of heparin-binding epidermal growth factor-like growth factor (HB-EGF), which activates EGFR on fibroblasts, exacerbating lung injury pathology and reducing survival. Mechanistically, EGFR activation in fibroblasts induces the early growth response protein 1 (EGR1), which subsequently enhances chemokine C-X-C motif ligand 1 (CXCL1) secretion 24 h post-exposure, promoting neutrophil infiltration in the lung. RNA sequencing analysis corroborates these findings. Notably, pharmacological inhibition of EGFR phosphorylation using Erlotinib (ERL) significantly mitigates the inflammatory response in RT-induced ALI. These results not only illuminate the immune response in lung tissue but also highlight EGFR signaling in fibroblasts as a pivotal mediator of RT-induced ALI. This study identifies a novel therapeutic strategy targeting EGFR signaling in fibroblasts for the treatment of inflammatory lung diseases.
蓖麻毒素（RT）是一种剧毒的植物源毒素，因其吸入后可导致致命的急性肺损伤（ALI）而构成重大威胁。表皮生长因子受体（EGFR）是一种主要在上皮细胞和成纤维细胞中表达的受体酪氨酸激酶，可调节细胞生长、增殖、分化和炎症等过程，但其在RT诱导的ALI中的作用尚未得到研究。本研究使用雾化RT（剂量为2.0×LD，约0.01 mg/kg）诱导的ALI小鼠模型来研究这种关系。结果表明，肺泡II型上皮（AT2）细胞受损导致肝素结合表皮生长因子样生长因子（HB-EGF）释放，后者激活成纤维细胞上的EGFR，加剧肺损伤病理并降低存活率。机制上，成纤维细胞中的EGFR激活诱导早期生长反应蛋白1（EGR1），随后在暴露后24小时增强趋化因子C-X-C基序配体1（CXCL1）的分泌，促进中性粒细胞在肺中的浸润。RNA测序分析证实了这些发现。值得注意的是，使用厄洛替尼（ERL）对EGFR磷酸化进行药理抑制可显著减轻RT诱导的ALI中的炎症反应。这些结果不仅阐明了肺组织中的免疫反应，还突出了成纤维细胞中的EGFR信号作为RT诱导的ALI的关键介质。本研究确定了一种针对成纤维细胞中EGFR信号的新型治疗策略，用于治疗炎症性肺病。
