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Background <p>Lung transplantation is the primary treatment for end-stage lung diseases. However, ischemia-reperfusion injury (IRI) significantly impacts transplant outcomes. 4-Octyl itaconate (4-OI) has shown potential in mitigating organ IRI, although its effects in lung transplantation require further exploration.</p> Methods <p>BEAS-2B cells were used to model transplantation, assessing the effects of 4-OI through viability, apoptosis, and ROS assays. qRT-PCR analyzed cytokine transcription post-cold ischemia/reperfusion (CI/R). RNA sequencing and Gene Ontology analysis elucidated 4-OI’s mechanisms of action, confirmed by Western blotting. ALI-airway and lung transplantation organoid models evaluated improvements in bronchial epithelial morphology and function due to 4-OI. ELISA measured IL-6 and IL-8 levels. Rat models of extended cold preservation and non-heart-beating transplantation assessed 4-OI’s impact on lung function, injury, and inflammation.</p> Results <p>Our findings indicate that 4-OI (100 µM) during cold preservation effectively maintained cell viability, decreased apoptosis, and reduced ROS production in BEAS-2B cells under CI/R conditions. It also downregulated pro-inflammatory cytokine transcription, including IL1B, IL6, and TNF. Inhibition of Nrf2 partially reversed these protective effects. In cold preservation solutions, 4-OI upregulated Nrf2 target genes such as NQO1, HMOX1, and SLC7A11. In ALI airway models, 4-OI enhanced bronchial epithelial barrier integrity and ciliary beat function after CI/R. In rat models, 4-OI administration improved lung function and reduced pulmonary edema, tissue injury, apoptosis, and systemic inflammation following extended cold preservation or non-heart-beating lung transplantation.</p> Conclusions <p>Incorporating 4-OI into cold preservation solutions appears promising for alleviating CI/R-induced bronchial epithelial injury and enhancing lung transplant outcomes via Nrf2 pathway activation.</p>

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Activation of Nrf2 pathway by 4-Octyl itaconate enhances donor lung function in cold preservation settings

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月27日

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  • Xinliang Gao,
  • Mingbo Tang,
  • Jialin Li,
  • Jianzun Ma,
  • Zhengrui Liu,
  • Wei Liu

摘要

Background

Lung transplantation is the primary treatment for end-stage lung diseases. However, ischemia-reperfusion injury (IRI) significantly impacts transplant outcomes. 4-Octyl itaconate (4-OI) has shown potential in mitigating organ IRI, although its effects in lung transplantation require further exploration.

Methods

BEAS-2B cells were used to model transplantation, assessing the effects of 4-OI through viability, apoptosis, and ROS assays. qRT-PCR analyzed cytokine transcription post-cold ischemia/reperfusion (CI/R). RNA sequencing and Gene Ontology analysis elucidated 4-OI’s mechanisms of action, confirmed by Western blotting. ALI-airway and lung transplantation organoid models evaluated improvements in bronchial epithelial morphology and function due to 4-OI. ELISA measured IL-6 and IL-8 levels. Rat models of extended cold preservation and non-heart-beating transplantation assessed 4-OI’s impact on lung function, injury, and inflammation.

Results

Our findings indicate that 4-OI (100 µM) during cold preservation effectively maintained cell viability, decreased apoptosis, and reduced ROS production in BEAS-2B cells under CI/R conditions. It also downregulated pro-inflammatory cytokine transcription, including IL1B, IL6, and TNF. Inhibition of Nrf2 partially reversed these protective effects. In cold preservation solutions, 4-OI upregulated Nrf2 target genes such as NQO1, HMOX1, and SLC7A11. In ALI airway models, 4-OI enhanced bronchial epithelial barrier integrity and ciliary beat function after CI/R. In rat models, 4-OI administration improved lung function and reduced pulmonary edema, tissue injury, apoptosis, and systemic inflammation following extended cold preservation or non-heart-beating lung transplantation.

Conclusions

Incorporating 4-OI into cold preservation solutions appears promising for alleviating CI/R-induced bronchial epithelial injury and enhancing lung transplant outcomes via Nrf2 pathway activation.