Therapeutic Effects of SRT2104 on Lung Injury in Rats with Emphysema via Reduction of Type II Alveolar Epithelial Cell Senescence

Abstract

Chronic obstructive pulmonary disease (COPD) is one of the most prevalent and severe diseases worldwide with high societal and health care costs. The pathogenesis of COPD is very complicated, and no curative treatment is available. Cellular senescence promotes the development of COPD. Type II alveolar epithelial cells (AECII) play a momentous role in lung tissue repair and maintenance of alveolar homeostasis. Sirtuin 1 (SIRT1), an antiaging molecule involved in the response to chronic inflammation and oxidative stress, regulates many pathophysiological changes including stress resistance, apoptosis, inflammation, and cellular senescence. This study aimed to investigate whether the pharmacological SIRT1 activator SRT2104 protects against AECII senescence in rats with emphysema. Our findings confirmed that SRT2104 administration reduced the pathological characteristics of emphysema and improved lung function parameters, including pulmonary resistance, pulmonary dynamic compliance, and peak expiratory flow. Moreover, SRT2104 treatment upregulated the expression of surfactant proteins A and C, SIRT1, and forkhead box O 3a (FoxO3a), decreased senescence-associated-β-galactosidase (SA-β-gal) activity, increased SIRT1 deacetylase activity, and downregulated the levels of p53 and p21. Therefore, SRT2104 administration protected against AECII senescence in rats with emphysema via SIRT1/FoxO3a and SIRT1/p53 signaling pathways and may provide a novel potential therapeutic strategy for COPD.

Keywords:

• Sirtuin 1
• alveolar epithelial cells
• cellular senescence
• cigarette smoking
• chronic obstructive pulmonary disease

Declaration of interest

The authors declare that there is no conflict of interest. The authors are responsible for the content and writing of this paper.

Additional information

Funding

This study was supported by a grant from the Science and Technology Project of Jiaxing (No. 2017AY33010), the Talent Cultivation Project of The First Hospital of Jiaxing (No. 2018-GG-03) and the Key Discipline of Jiaxing Respiratory Medicine Construction Project (No. 2019-zc-04).