Spil-mediated sEH overexpression contributes to the senescence of alveolar epithelial cells during pulmonary fibrosis in mice.

Abstract

Alveolar epithelial cell (AEC) senescence is a crucial driver of pulmonary fibrosis (PF). Epoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid through the cytochrome P450 cyclooxygenase (CYP) pathway. We have reported that EETs inhibit AEC senescence, alleviating bleomycin (BLM)-induced PF in mice. However, EETs have a short half-life in vivo and are rapidly degraded to low-active end-product diols by soluble epoxide hydrolase (sEH). We observed a significant increase in sEH expression in senescent AECs, but the underlying mechanism remains unclear. In this study, we found that inhibition of sEH significantly attenuated senescence in AECs and lung senescence in premature aging mice. Mechanistically, bioinformatics results showed that the spleen focus forming virus proviral integration oncogene (Spi1) might be a key transcription factor upstream of sEH in AECs. ChIP assay showed that Spi1 could bind to the sEH promoter. Knockout of Spi1 in AECs mediated by lentivirus significantly reduced BLM-induced sEH expression and AEC senescence, while overexpression of Spi1 had the opposite effect. Furthermore, specific silencing of Spi1 in AECs significantly inhibited BLM-induced PF in mice. Taken together, these findings provide new ideas for the treatment of PF by targeting Spi1 to improve AEC senescence. KEY MESSAGES: Spi1 is a key transcription factor upstream of sEH in AECs. Inhibition of Spi1 significantly attenuated AEC senescence. Inhibition of Spi1 alleviated pulmonary fibrosis in aging mice.