Yanghe Pingchuan granules inhibit cellular senescence in airway smooth muscle cells to improve bronchial asthma via modulating Nrf2 acetylation.

Abstract

Background: Bronchial asthma (BA) is regarded as one of the most prevalent chronic respiratory diseases worldwide. Yanghe Pingchuan Granules (YPG), a traditional Chinese medicine (TCM) compound, has been employed extensively in treating BA. However, the precise mechanism by which it exerts its therapeutic effects remains to be fully elucidated. This study aimed to investigate the therapeutic mechanisms of YPG in BA model rats, focusing on the interventional effects on cellular senescence of airway smooth muscle cells (ASMCs) in vivo and in vitro.

Methods: In this study, OVA was utilized to induce the replication of an asthmatic rat model, α-smooth muscle actin (α-SMA) was employed to identify ASMCs, and a series of in vitro experiments were conducted. These experiments included β-galactosidase (β-gal), Enzyme-linked immunosorbent assay (ELISA), biochemical assay, western blotting, Co-Immunoprecipitation (CO-IP), overexpression/silencing of Sirtuin 1 (SIRT1) and Nuclear factor E2-related factor 2 (Nrf2) was studied in ASMCs. Subsequently, Hematoxylin and Eosin (H&E), Masson, Alcian Blue-Periodic Acid Schiff (AB-PAS), ELISA, biochemical assay, western blotting, Co-Immunofluorescence (CO-IF), and CO-IP were employed to examine the histopathological damage, acetylation, oxidative stress, senescence-related protein expression, and senescence-associated secretion phenotype (SASP) secretion of bronchial tubes in asthmatic rats. This comprehensive approach was undertaken to elucidate the mechanism by which YPG inhibits the senescence of ASMCs.

Results: The results of in vivo and in vitro experiments demonstrated that SIRT1 overexpression and YPG inhibited the senescence of ASMCs and significantly reduced P16 and P21 proteins, as well as cellular SASP (Interleukin-1β (IL-1β), Interleukin-4 (IL-4), and Interleukin-17 (IL-17)). Moreover, YPG demonstrated a substantial reduction in histopathological alterations in BA rats. Furthermore, the study observed a decline in Malondialdehyde (MDA) expression, concomitant with an augmentation in the expression levels of SIRT1, Nrf2, oxygenase-1 (HO-1), Superoxide dismutase (SOD), and Catalase (CAT). It substantiated the interaction of SIRT1 with Nrf2 and the decrease in the expression level of Nrf2 acetylation.

Conclusions: These results suggest that YPG can activate the SIRT1/Nrf2/HO-1 signaling pathway by regulating the expression level of SIRT1 to regulating the acetylated expression level of Nrf2, to inhibit the senescence of ASMCs, leading to the treatment of asthma.