Leitragin Increases Transcription of Sirtuin 6 Gene under Conditions of Acute Lung In flammation in Mice

Sirtuins are NAD-dependent class III histone deacetylases, represented in mammals by seven isoforms that differ in substrate specificity and intracellular localization. Nuclear sirtuins 1 (SIRT1) and 6 (SIRT6) deacetylate components of pro-inflammatory signaling pathways, playing a key role in the resolution of inflammation. Leitragin, a peptide agonist of δ-opioid receptors, is a representative of a new promising class of anti-inflammatory drugs, whose known mechanism of action is associated with the activation of SIRT1 transcription. The aim of this study was to investigate the effect of inhaled Leitragin on the transcription of all seven isoforms of mammalian sirtuins in the lungs of C57BL/6Y mice under conditions of acute lung inflammation and ARDS modeling. This study is the first to demonstrate that inhalation of Leitragin significantly increases SIRT6 transcription in the lungs, in addition to the previously known effect of activating SIRT1 transcription under inflammatory conditions. This work clarifies the anti-inflammatory action of Leitragin, which involves the upregulation of SIRT1 and SIRT6 transcription, known negative regulators of pro-inflammatory signaling pathways where the NF-κB transcription factor plays a key role.