沙参麦冬汤通过抑制cGAS-STING-NF-κB介导的炎性衰老改善老年COPD小鼠肺功能^*

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

摘要

目的 观察沙参麦冬汤对慢性阻塞性肺疾病（COPD）模型小鼠炎性衰老的影响，明确其是否通过调控环鸟苷酸-腺苷酸合成酶（cGAS）-干扰素基因刺激因子（STING）-核因子-κB（NF-κB）通路起效。方法 选用18～20月龄雌雄各半C57BL/6JNifdc小鼠，以香烟烟雾暴露联合鼻滴脂多糖构建COPD模型，随机分6组：正常组、模型组、沙参麦冬汤低/中/高剂量组（8.3、16.5、33.0 g/kg）、地塞米松组（3 mg/kg），每组8只（雌雄各4只）。造模次日起每日灌胃（正常/模型组灌羧甲基纤维素钠，0.15 mL/10 g），周期12周。检测各组小鼠肺功能〔气道阻力（Rrs）、肺弹性阻力（Ers）、0.2 s用力呼气量与用力肺活量比值（FEV_0.2/FVC）、50%肺活量时的用力呼气流量（FEF_50%）〕、肺组织病理（HE染色、Masson染色）、血清炎症因子〔白细胞介素-6（IL-6）、单核细胞趋化蛋白-1（MCP-1）、肿瘤坏死因子-α（TNF-α）〕、氧化应激指标〔超氧化物歧化酶（SOD）、丙二醛（MDA）〕，以及肺组织衰老蛋白（p16、p21）、cGAS-STING-NF-κB通路分子的mRNA与蛋白表达。结果 与正常组相比，模型组小鼠肺功能受损，表现为Rrs升高，Ers、FEV_0.2/FVC及FEF_50%降低；肺组织出现大量炎症细胞浸润、细支气管壁增厚以及肺泡结构破坏；血清炎症因子及MDA升高、SOD降低，差异均有统计学意义（P<0.01）；肺组织衰老蛋白与cGAS-STING-NF-κB通路分子的mRNA及蛋白表达量亦升高（P<0.01）。与模型组相比，沙参麦冬汤中、高剂量组上述肺功能指标得到改善；血清炎症因子与MDA水平下降、SOD活性升高（P<0.05）；同时，肺组织衰老蛋白与通路分子的表达下调（P<0.05）。结论 沙参麦冬汤可改善COPD小鼠以FEV_0.2/FVC为核心的肺功能受损，其潜在机制可能为抑制cGAS-STING-NF-κB通路介导的炎性衰老。

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 (FEV_0.2/FVC), and forced expiratory flow at 50% of vital capacity (FEF_50%), 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, FEV_0.2/FVC, and FEF_50%. 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 FEV_0.2/FVC, in COPD mice. The underlying mechanism may have involved the inhibition of inflammaging mediated by the cGAS-STING-NF-κB signaling pathway.

关键词

肺疾病，慢性阻塞性 / 沙参麦冬汤 / 衰老 / 炎症 / NF-κB

Key words

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

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基金资助

*国家自然科学基金青年科学基金项目(82405276)

河北省中医药管理局科研计划项目(2023116)

河北省高等学校科研技术研究项目(BJK2024112)