Effects of [D-ALA²]-Dynorphin(1-7)Amide Heptapeptide on Sirtuin Transcription in Mouse Model of Acute Lung Inflammation

[D-Ala²]-dynorphin(1-7)amide is a synthetic opioid heptapeptide (H-Tyr-D-Ala-Gly-Phe-Leu-Arg-Arg-NH₂₎ and a structural analog of natural dynorphin(1-7). While natural dynorphin(1-7) exhibits potent anti-inflammatory activity in the picomolar concentration range, its application is limited by low stability and a short half-life in biological media. Sirtuins are NAD-dependent class III histone deacetylases, represented in mammals by seven isoforms with distinct substrate selectivity and intracellular localization. Nuclear sirtuins 1 (SIRT1) and 6 (SIRT6) play a key role in the resolution of inflammation by deacetylating components of pro-inflammatory signaling pathways. This study aimed to evaluate the effects of inhaled [D-Ala²]-dynorphin(1-7)amide on the transcription of all seven sirtuin isoforms in the lungs of C57BL/6Y mice during simulated acute lung inflammation and acute respiratory distress syndrome. This study is the first to demonstrate that inhalation of the specified heptapeptide significantly increases the transcription of major sirtuins (SIRT1, SIRT6), as well as SIRT2, SIRT5, and SIRT7, in inflamed lungs. Thus, the findings clarify the anti-inflammatory mechanism of [D-Ala²]-dynorphin(1-7)amide, which primarily involves enhancing the transcription of nuclear SIRT1 and SIRT6, established negative regulators of inflammation.

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