Abstract：
Pulmonary alveolar epithelial cell injury is considered the main pathological and physiological change in acute lung injury. Ferroptosis in alveolar epithelial cells is one of crucial factors contributing to acute lung injury (ALI). Therefore, reducing ferroptosis and repair epithelial barrier is very necessary. More and more evidence suggested that FGF10 plays an important role in lung development and repair after injury. However, the relationship between FGF10 and ferroptosis remains unclear. This study aims to explore the regulatory role of FGF10 on ferroptosis in ALI. Differential gene expression analysis indicated that genes associated with ferroptosis showed that FGF10 can significantly alleviate LPS induced lung injury and epithelial barrier damage by decreasing levels of malonaldehyde(MDA), and lipid ROS. SIRT1 activator (Resveratrol) and inhibitor (EX527) are used in vivo showed that FGF10 protects ferroptosis of pulmonary epithelial cells through SIRT1 signal. Furthermore, knockdown of FGFR2 gene reduced the protective effect of FGF10 on acute lung injury in mice and SIRT1 activation. After the application of NRF2 inhibitor ML385 in vitro, the results showed that SIRT1 regulated the expression of ferroptosis related proteins NRF2, GPX4 and FTH1 are related to activation of NRF2. These data indicate that SIRT-ferroptosis was one of the critical mechanisms contributing to LPS-induced ALI. FGF10 is promising as a therapeutic candidate against ALI through inhibiting ferroptosis.
摘要：
肺泡上皮细胞损伤被认为是急性肺损伤的主要病理生理变化。肺泡上皮细胞的铁凋亡是导致急性肺损伤（ALI）的关键因素之一。因此,减少铁性凋亡和修复上皮屏障是非常必要的。越来越多的证据表明，FGF10在肺损伤后的发育和修复中起着重要作用。然而,FGF10与铁凋亡之间的关系尚不清楚.本研究旨在探讨FGF10对ALI铁凋亡的调控作用。差异基因表达分析表明,FGF10可通过降低丙二醛(MDA)水平,显著减轻LPS诱导的肺损伤和上皮屏障损伤,和脂质ROS。体内使用SIRT1激活剂(白藜芦醇)和抑制剂(EX527)表明FGF10通过SIRT1信号保护肺上皮细胞的铁凋亡。此外，FGFR2基因敲除降低FGF10对小鼠急性肺损伤的保护作用及SIRT1的激活。在体外应用NRF2抑制剂ML385后，结果表明，SIRT1调节铁凋亡相关蛋白NRF2、GPX4和FTH1的表达，与NRF2的激活有关。这些数据表明SIRT-铁死亡是导致LPS诱导的ALI的关键机制之一。FGF10有望通过抑制铁凋亡作为抗ALI的治疗候选物。
