Sepsis-induced lung injury is a clinical syndrome characterized by injury of alveolar epithelium cells (AECs). Previous investigations illustrate that exosomes secreted from adipose-derived stem cells (ADSCs) have therapeutic effects in a variety of disease treatments, but roles and mechanisms regarding ADSC-derived exosomes in sepsis-induced lung injury are unclear. In this study, high-throughput sequencing was used to explore the molecular delivery of ADSC exosomes. A sepsis-induced lung injury mouse model and a lipopolysaccharide-induced AEC damage model were used for mechanistic analysis. The results showed that ADSC exosomes have high levels of the circular RNA (circ)-Fryl. Downregulation of circ-Fryl suppressed ADSC protective effects exosomes against sepsis-induced lung injury by decreasing apoptosis and inflammatory factor expression. Bioinformatics and luciferase reporting experiments showed that miR-490-3p and SIRT3 are downstream targets of circ-Fryl. miR-490-3p overexpression or SIRT3 silencing reversed ADSC exosome protective effects. Studying the mechanism showed that overexpression of circ-Fryl promoted autophagy activation by inducing SIRT3/AMPK signaling. Autophagy activation can suppress sepsis-induced lung injury by decreasing apoptosis and inflammatory factor expression. Taken together, our results suggest that exosomes derived from ADSCs attenuate sepsis-induced lung injury by delivery of circ-Fryl and regulation of the miR-490-3p/SIRT3 pathway.

脓毒症引起的肺损伤是一种以肺泡上皮细胞（AECs）损伤为特征的临床综合征。先前的研究表明，脂肪干细胞 (ADSC) 分泌的外泌体在多种疾病治疗中具有治疗作用，但 ADSC 衍生的外泌体在脓毒症诱导的肺损伤中的作用和机制尚不清楚。在本研究中，高通量测序用于探索 ADSC 外泌体的分子递送。使用败血症诱导的肺损伤小鼠模型和脂多糖诱导的 AEC 损伤模型进行机理分析。结果表明，ADSC 外泌体具有高水平的环状 RNA (circ)-Fryl。circ-Fryl 的下调通过降低细胞凋亡和炎症因子的表达来抑制 ADSC 外泌体对脓毒症诱导的肺损伤的保护作用。生物信息学和荧光素酶报告实验表明 miR-490-3p 和 SIRT3 是 circ-Fryl 的下游靶标。miR-490-3p 过表达或 SIRT3 沉默可逆转 ADSC 外泌体保护作用。研究机制表明，circ-Fryl 的过表达通过诱导 SIRT3/AMPK 信号传导来促进自噬激活。自噬激活可以通过降低细胞凋亡和炎症因子的表达来抑制脓毒症引起的肺损伤。总之，我们的研究结果表明，源自 ADSC 的外泌体通过传递 circ-Fryl 和调节 miR-490-3p/SIRT3 通路来减轻脓毒症诱导的肺损伤。研究机制表明，circ-Fryl 的过表达通过诱导 SIRT3/AMPK 信号传导来促进自噬激活。自噬激活可以通过降低细胞凋亡和炎症因子的表达来抑制脓毒症引起的肺损伤。总之，我们的研究结果表明，源自 ADSC 的外泌体通过传递 circ-Fryl 和调节 miR-490-3p/SIRT3 通路来减轻脓毒症诱导的肺损伤。研究机制表明，circ-Fryl 的过表达通过诱导 SIRT3/AMPK 信号传导来促进自噬激活。自噬激活可以通过降低细胞凋亡和炎症因子的表达来抑制脓毒症引起的肺损伤。总之，我们的研究结果表明，源自 ADSC 的外泌体通过传递 circ-Fryl 和调节 miR-490-3p/SIRT3 通路来减轻脓毒症诱导的肺损伤。