SIRT2 Regulates Apoptosis Signaling in Hyperoxic Acute Lung Injury

Oxygen therapy is helpful for patients with breathing difficulties; however, sustained supplementation with high-concentration oxygen can cause hyperoxic acute lung injury. Sirtuin 2 (SIRT2), a nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase, has been shown to be involved in pulmonary fibrosis, apoptosis, and inflammation. Here, we elucidated the role of SIRT2 in hyperoxic acute lung injury.

Wild-type (WT) mice and SIRT2-deficient (SIRT2^-/-) mice were exposed to room air or hyperoxia for 72 h. Thereafter, changes in hyperoxia-induced responses were evaluated in WT and SIRT2^-/- mice.

SIRT2 expression was elevated in WT mice after hyperoxic exposure. We also observed that the levels of SIRT2 were higher in tracheal aspirates from newborns with bronchopulmonary dysplasia (BPD) than in those without BPD. Hyperoxia-induced inflammation and apoptosis were more considerably attenuated in SIRT2^-/- mice than in WT mice. We also observed an interaction between SIRT2 and forkhead box O3 (FOXO3), and that SIRT2 deficiency was associated with altered acetylation levels of FOXO3 and changes in the expression of its downstream targets. Further investigation of the therapeutic effect of SIRT2 showed that hyperoxic acute lung injury was alleviated when AGK2, a SIRT2 inhibitor, was administered.

Taken together, SIRT2 plays a critical role in the pathogenesis of hyperoxic acute lung injury by regulating apoptotic signaling. These findings indicated that SIRT2 is potentially a novel therapeutic strategy for hyperoxic acute lung injury.