Late Breaking Abstract - KLF2 inhibits mechanical ventilation-induced lung injury by restoring the mitochondrial function of AEC2

<bold>Background:</bold> The mechanisms of mitochondria damage of AEC2 in ventilation-induced lung injury (VILI) remained unclear. <bold>Objective:</bold> To determine whether KLF2 (Krüppel-like factor 2) inhibits VILI via alleviating mitochondria damage of AEC2 through facilitating mitophagy. <bold>Methods:</bold> Transmission electron microscope (TEM), seahorse XF, RNA-seq, Sftpc-CreERT2-Klf2f/f mice, primary AEC2, Adeno-associated virus (AAV) and molecular biology methods were used. <bold>Results:</bold> The mitochondria function were compromised in AEC2 of the Mice ventilation model and RNAseq together with GEO data analysis showed KLF2 was downregulated. Loss of function of KLF2 in mice AEC2 exacerbated VILI. Overexpression of KLF2 in mice AEC2 using the AAV system significantly alleviated VILI. The key markers of mitochondrial quality control (biogenesis, fission/fusion and mitophagy) were analyzed and found that PINK1 was decreased upon ventilation but was restored by KLF2 overexpression. As a transcriptional factor, KLF2 could bind to the promoter region of PINK1 and facilitate its transcription. Furthermore, we demonstrated that GC-1 a thyroid hormone receptorβ selective agonist could inhibit VILI by upregulating KLF2. <bold>Conclusions:</bold> We unveiled KLF2 as a novel and vital mediator that restores the mitochondrial function of AEC2 by facilitating mitophagy. Pharmaceutically activating KLF2 expression with GC-1 could alleviate VILI. <fig><object-id>erj;64/suppl_68/PA4435/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>