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<p>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<sub>50</sub> (approximately 0.01&#xa0;mg&#xa0;kg <sup>−1</sup>). 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&#xa0;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&#xa0;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&#xa0;a&#xa0;novel therapeutic strategy targeting EGFR signaling in fibroblasts for the treatment of inflammatory lung diseases.</p>

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

  • 期刊论文

  • 发表日期：

    2025年5月3日

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  • Yuqing Wang,
  • Xiaoyu Zhu,
  • Lu Li,
  • Duo Su,
  • Lingli Ai,
  • Hao Xie,
  • Dongsheng Zhou,
  • Huiying Yang,
  • Boan Li

摘要

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.