4.7 Article

miR-125b-5p in adipose derived stem cells exosome alleviates pulmonary microvascular endothelial cells ferroptosis via Keap1/Nrf2/GPX4 in sepsis lung injury

Journal

REDOX BIOLOGY
Volume 62, Issue -, Pages -

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ELSEVIER
DOI: 10.1016/j.redox.2023.102655

Keywords

ADSCs exosome; Sepsis; Acute lung injury; Ferroptosis; GPX4; Nrf2

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This study explored the protective effect and mechanism of ADSCs exosomes on excessive inflammation-induced injury in pulmonary microvascular endothelial cells (PMVECs). ADSCs exosomes reduced ROS accumulation and cell injury in PMVECs by inhibiting excessive inflammatory response. They also alleviated ferroptosis induced by excessive inflammatory response and upregulated GPX4 expression. Furthermore, specific delivery of miR-125b-5p by ADSCs exosomes inhibited Keap1 and alleviated ferroptosis. In a sepsis model, ADSCs exosomes relieved lung tissue injury, reduced the death rate, and alleviated oxidative stress injury and ferroptosis of lung tissue.
Background: Sepsis is a fatal disease with a high rate of morbidity and mortality, during which acute lung injury is the earliest and most serious complication. Injury of pulmonary microvascular endothelial cells (PMVECs) induced by excessive inflammation plays an important role in sepsis acute lung injury. This study is meant to explore the protective effect and mechanism of ADSCs exosomes on excessive inflammation PMVECs injury. Results: We successfully isolated ADSCs exosomes, the characteristic of which were confirmed. ADSCs exosomes reduced excessive inflammatory response induced ROS accumulation and cell injury in PMVECs. Besides, ADSCs exosomes inhibited excessive inflammatory response induced ferroptosis while upregulated expression of GPX4 in PMVECs. And further GPX4 inhibition experiments revealed that ADSCs exosomes alleviated inflammatory response induced ferroptosis via upregulating GPX4. Meanwhile, ADSCs exosomes could increase the expression and nucleus translocation of Nrf2, while decrease the expression of Keap1. miRNA analysis and further inhibition experiments verified that specific delivery of miR-125b-5p by ADSCs exosomes inhibited Keap1 and alleviated ferroptosis. In CLP induced sepsis model, ADSCs exosomes could relieve the lung tissue injury and reduced the death rate. Besides, ADSCs exosomes alleviated oxidative stress injury and ferroptosis of lung tissue, while remarkably increase expression of Nrf2 and GPX4. Conclusion: Collectively, we illustrated a novel potentially therapeutic mechanism that miR-125b-5p in ADSCs exosomes could alleviate the inflammation induced PMVECs ferroptosis in sepsis induced acute lung injury via regulating Keap1/Nrf2/GPX4 expression, hence improve the acute lung injury in sepsis.

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