Shashen Maidong Decoction Improves Pulmonary Function in Aged Mice With Chronic Obstructive Pulmonary Disease by Inhibiting cGAS-STING-NF-κB-Mediated Inflammaging

Abstract

Objective

To investigate the effect of Shashen Maidong Decoction (SMD) on inflammaging in a mouse model of chronic obstructive pulmonary disease (COPD), and to determine whether its efficacy is mediated by regulating the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING)-nuclear factor-kappa B (NF-κB) signaling pathway.

Methods

Female and male C57BL/6JNifdc mice (half male and half female) aged 18-20 months were selected to establish a COPD model was subsequently established via cigarette smoke exposure combined with intranasal lipopolysaccharide instillation. The mice were randomly assigned to 6 groups, including a normal control group, a model group, low-, medium-, and high-dose SMD groups (receiving 8.3, 16.5, and 33.0 g/kg, respectively), and a dexamethasone group (3 mg/kg), with 8 mice in each group (4 males and 4 females). Starting on the day after modelling, the mice received daily intragastric administration for 12 weeks (normal control and model groups received sodium carboxymethyl cellulose at 0.15 mL/10 g). Pulmonary function parameters, including resistance of the respiratory system (Rrs), elastance of the respiratory system (Ers), the ratio of forced expiratory volume in 0.2 seconds to forced vital capacity (FEV0.2/FVC), and forced expiratory flow at 50% of vital capacity (FEF50%), were measured. Lung histopathology was evaluated by hematoxylin and eosin (HE) and Masson's trichrome stains. Serum inflammatory factors, including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor α (TNF-α), as well as oxidative stress markers, including superoxide dismutase (SOD) and malondialdehyde (MDA), were assessed. In addition, the mRNA and protein expression levels of senescence-associated proteins (p16 and p21) and the cGAS-STING-NF-κB pathway molecules in lung tissues were determined.

Results

Compared with the normal control group, mice in the model group exhibited impaired pulmonary function, characterized by increased Rrs and decreased Ers, FEV0.2/FVC, and FEF50%. Histopathologic examination demonstrated massive inflammatory cell infiltration, bronchiolar wall thickening, and destruction of alveolar structures. The levels of serum inflammatory factors and MDA were increased, whereas SOD activity was decreased, demonstrating statistically significant differences (all P < 0.01). Furthermore, the mRNA and protein expression levels of senescence-associated proteins and cGAS-STING-NF-κB pathway molecules were significantly elevated in lung tissues (all P < 0.01). Compared with the model group, the medium- and high-dose SMD groups showed significantly improved lung function parameters, decreased serum inflammatory factors and MDA levels, and increased SOD activity (all P < 0.05). In addition, the expression levels of senescence-associated proteins and cGAS-STING-NF-κB pathway molecules in lung tissues were significantly downregulated (all P < 0.05).

Conclusion

SMD ameliorates lung function impairment, particularly FEV0.2/FVC, in COPD mice. The underlying mechanism may have involved the inhibition of inflammaging mediated by the cGAS-STING-NF-κB signaling pathway. SMD can protect against lung function impairment, particularly centered on FEV0.2/FVC, in COPD mice. The potential mechanism may involve the inhibition of inflammaging mediated by the cGAS-STING-NF-κB signaling pathway.

Keywords: Pulmonary disease, chronic obstructive, Shashen Maidong Decoction , Aging, Inflammation, Nuclear factor-kappa B