We evaluated the effects of melatonin on inflammatory response in chronic obstructive pulmonary disease (COPD), focusing on the regulation of SIRT1 expression.
Inhibition of elevated miR-570-3p in COPD small airway epithelial cells, using an antagomir, restores sirtuin-1 and suppresses markers of cellular senescence (p16<sup>INK4a</sup>, p21<sup>Waf1</sup>, and p27<sup>Kip1</sup>), thereby restoring cellular growth by allowing progression through the cell cycle.
Sirtuin 1 (SIRT1) is redox-sensitive protein belongs to class III histone/protein deacetylases, SIRT1 regulates the acetylation/expression of nuclear factor κB (NF-κB) and is involved in the airway inflammation of chronic obstructive pulmonary disease.
MicroRNA-34a (miR-34a), which is regulated by PI3K-mTOR signaling, plays a pivotal role in reducing sirtuin-1/6, and its inhibition with an antagomir results in their restoration, reducing markers of senescence, reducing senescence-associated secretory phenotype, and reversing cell cycle arrest in epithelial cells from peripheral airways of patients with COPD. miR-570 is also involved in reduction of sirtuin-1 and cellular senescence and is activated by p38 mitogen-activated protein kinase.
These findings suggest loss of SIRT1-driven antioxidant activity as relevant in COPD pathogenesis and identify SIRT1 activity as a potential convenient biomarker for identification of mild/moderate, stable COPD.
Silent information regulator 1 (SIRT1) plays an important role in the regulation of inflammatory mediators and correlates with lung function and COPD exacerbations.
The results of the present study indicated that lncRNA‑mediated SIRT1/p53 and FoxO3a signaling pathways may regulate AECII senescence in the pathogenesis of COPD, which may provide a novel experimental basis for the treatment of COPD.
Of note, we observed decreased SIRT1 levels in NE-treated primary human bronchial epithelial cells and in lung homogenates from both smokers and patients with COPD.
Therefore, Sirt1 and EPC-associated mRNAs were measured in blood samples from patients with COPD and from cultured CD34<sup>+</sup> progenitor cells to examine whether these genes are associated with COPD development.
Here, we show that oxidative stress (hydrogen peroxide) selectively elevates microRNA-34a (miR-34a) but not the related miR-34b/c, with concomitant reduction of SIRT1/-6 in bronchial epithelial cells (BEAS2B), which was also observed in peripheral lung samples from patients with COPD.
We previously showed that sirtuin1 (SIRT1), an antiaging protein, is reduced in lungs of CS-exposed mice and patients with COPD and that SIRT1 attenuates CS-induced lung inflammation and injury.
Targeting lung inflammation and cellular senescence as well as premature lung aging using pharmacological SIRT1 activators or polyphenols would be a promising therapeutic intervention for COPD/emphysema.
SIRT1 levels were reduced in macrophages and lungs of smokers and patients with COPD due to its post-translational modifications by cigarette smoke-derived reactive components, leading to increased acetylation of RelA/p65.