目的 基于肺-肠轴探讨荆防颗粒对哮喘模型小鼠气道炎症和气道重塑的干预作用，并阐明其潜在分子机制。方法 将BALB/c小鼠随机分为对照组、模型组及荆防颗粒低、中、高剂量（1、2、4 g/kg）组和地塞米松（1 mg/kg）组，通过ip卵清蛋白/氢氧化铝建立小鼠哮喘模型，给药干预后，检测血清中γ干扰素（interferon-γ，IFN-γ）、肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）和肺组织中白细胞介素-1β（interleukin-1β，IL-1β）、IL-6水平；苏木素-伊红（hematoxylin-eosin，HE）、PAS和Masson染色检测小鼠肺组织病理变化；免疫组化检测肺组织黏蛋白5AC（mucin 5AC，MUC5AC）蛋白表达；Western blotting检测肺组织转化生长因子-β1（transforming growth factor-β1，TGF-β1）/Smad2/3通路、NOD-核因子-κB（nuclear factor-κB，NF-κB）信号通路和肠道屏障相关蛋白表达；结合16S rRNA测序、非靶向代谢组学及蛋白质组学从多组学层面系统解析荆防颗粒干预哮喘的潜在机制。结果 与模型组比较，荆防颗粒显著降低哮喘模型小鼠血清中TNF-α和肺组织中IL-1β、IL-6水平（P＜0.01），升高血清中IFN-γ水平（P＜0.01），明显减轻肺组织炎症细胞浸润，减少肺组织MUC5AC表达，抑制TGF-β1/Smad2/3信号通路激活，从而减轻气道黏液分泌和气道重塑。多组学分析结果进一步表明，荆防颗粒可上调Occludin、Claudin1和ZO-1的表达，促进肠道屏障修复，并调节肠道菌群失衡及粪便代谢紊乱，同时抑制NOD-NF-κB信号通路异常激活。结论 荆防颗粒可能通过修复肠道屏障功能、改善肠道菌群结构、纠正粪便代谢紊乱，并调控NOD-NF-κB信号通路，进而改善哮喘小鼠气道炎症与气道重塑。

Objective To investigate the intervention effect of Jingfang Granules (荆防颗粒) on airway inflammation and airway remodeling in asthmatic mice based on lung-gut axis, and elucidate the underlying molecular mechanism. Methods BALB/c mice were randomly divided into control group, model group, Jingfang Granules low-, medium-, high-dose (1, 2, 4 g/kg) groups and dexamethasone (1 mg/kg) group. A mouse asthma model was established by ip ovalbumin/aluminum hydroxide. After drug intervention, levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) in serum and interleukin-1β (IL-1β), IL-6 in lung tissue were detected. Hematoxylin-eosin (HE), PAS and Masson staining were used to detect pathological changes in lung tissue of mice. Immunohistochemistry was used to detect mucin 5AC (MUC5AC) protein expression in lung tissue. Western blotting was used to detect the expressions of transforming growth factor-β1 (TGF-β1)/Smad2/3 pathway, NOD nuclear factor-κB (NF-κB) signaling pathway in lung tissue and intestinal barrier related proteins. 16S rRNA sequencing, untargeted metabolomics and proteomics analyses were integrated to systematically explore the potential mechanism of Jingfang Granules in asthma intervention from a multi-omics perspective. Results Compared with model group, Jingfang Granules significantly reduced the levels of TNF-α in serum and IL-1β, IL-6 in lung tissue of asthma model mice (P < 0.01), increased the level of IFN-γ in serum (P < 0.01), significantly reduced the infiltration of inflammatory cells in lung tissue, decreased the expression of MUC5AC in lung tissue, inhibited the activity of TGF-β1/Smad2/3 signaling pathway, thereby alleviating airway mucus secretion and airway remodeling. The results of multi-omics analysis further indicated that Jingfang Granules could upregulate the expressions of Occludin, Claudin1 and ZO-1, promote intestinal barrier repair, regulate gut microbiota imbalance and fecal metabolic disorders, and inhibit the abnormal activation of the NOD-NF-κB signaling pathway. Conclusion Jingfang Granules may ameliorate airway inflammation and airway remodeling in asthmatic mice by repairing intestinal barrier function, improving gut microbiota structure, correcting fecal metabolic disorders, and modulating NOD-NF-κB signaling pathway.

R285.5

山东省重点研发计划（重大科技创新工程）项目（2021CXGC010508）