1. Academic Validation
  2. Fibroblast EGFR signaling mediates ricin toxin-induced acute lung injury via EGR1/CXCL1 axis

Fibroblast EGFR signaling mediates ricin toxin-induced acute lung injury via EGR1/CXCL1 axis

  • Arch Toxicol. 2025 May 3. doi: 10.1007/s00204-025-04067-3.
Yuqing Wang # 1 2 Xiaoyu Zhu # 3 Lu Li 3 Duo Su 3 Lingli Ai 3 Hao Xie 3 Dongsheng Zhou 3 Huiying Yang 4 Boan Li 5
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, the Fifth Medical Center of PLA General Hospital, Beijing, 100039, China.
  • 2 Graduate School of PLA General Hospital, Beijing, 100853, China.
  • 3 State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, 100071, China.
  • 4 State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, 100071, China. yhy80324@163.com.
  • 5 Department of Clinical Laboratory, the Fifth Medical Center of PLA General Hospital, Beijing, 100039, China. 15300085578@163.com.
  • # Contributed equally.
Abstract

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 × LD50 (approximately 0.01 mg kg -1). 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.

Keywords

ALI; CXCL1; EGFR; EGR1; Inflammatory response; RT.

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