Sevoflurane with Low Concentration Decrease DNA Methylation on Chronic Obstructive Pulmonary Disease (COPD)-Related Gene Promoter in COPD Rat

Chronic obstructive pulmonary disease (COPD) is a difficult-to-cure disease that mainly affects the respiratory system. Inhaled anesthetic drug such as sevoflurane plays a controversial role in COPD by different concentration, but the underlying epigenetic mechanism remains unclear. Here, we prepared lipopolysaccharide (LPS)-induced COPD rat model, and isolated Alveolar type II (ATII) cells. We mainly focused DNA methylation on the promoter of COPD-related genes including Sftpa1, Napsa, Ca2, Sfta2, Lamp3, Wif1, Pgc, and Etv5. We observed COPD rat treated by sevoflurane with low (0.5%) and high (2%) concentrations displayed an opposite DNA methylation pattern. These six genes' promoter were all hypomethylated by 0.5% sevoflurane whereas hypermethylated by 2% sevoflurane, accompanied with the opposite transcriptional activity. We further verified that the DNMT1 binding ability contributed to DNA methylation these six genes' promoter. Moreover, we also captured DNMT1 and identified REC8 meiotic recombination protein (REC8) as the specific binding protein only existed in ATII cells treated with 0.5% sevoflurane rather than 2% and control. The binding ability of REC8 on these target genes' promoter showed highly positive correlation with DNMT1. In summary, we uncovered a potential epigenetic role of sevoflurane with low concentration in ATII cells of COPD that may help us deeply understand the pathogenesis and treatment mechanism of inhaled anesthesia drugs in COPD via a dose-dependent manner.

COPD; DNA methylation; DNMT1; REC8; sevoflurane.