目的 探究小青龙汤和苓甘五味姜辛汤中细辛-干姜-五味子不同剂量配伍对慢性阻塞性肺疾病（COPD）寒饮伏肺证大鼠的干预作用及对肠道菌群的影响。方法 SD大鼠随机分为对照组（8只）和造模组（32只），采用烟熏＋气管注射脂多糖（LPS） ＋寒冷刺激连续4周建立COPD寒饮伏肺证大鼠模型，从第3周开始将造模组分为模型组、细辛-干姜-五味子（配比6 g∶ 6 g∶ 6 g，AZS1，1.62 g·kg^-1）组、细辛-干姜-五味子（配比5 g∶ 9 g∶ 5 g，AZS2，1.71 g·kg^-1）组、氨茶碱（0.045 g·kg^-1）组，每组8只，给药干预2周。通过记录大鼠体质量、腓肠肌相对湿质量，观察肺、气管和结肠组织病理状态，ELISA法检测肺泡灌洗液（BALF）和血清中肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6和IL^-1β水平，免疫组化检测肺组织水通道蛋白5（AQP5）、黏蛋白5AC（MUC5AC）的表达，对模型及药物干预进行可靠性评价。采用16S rDNA测序分析各组大鼠肠道微生物丰度、多样性变化及差异菌群。结果 与对照组比较，模型组大鼠体质量和腓肠肌相对湿质量显著下降（P＜0.01），肺组织中AQP5相对表达量显著降低（P＜0.01），MUC5AC相对表达量显著升高（P＜0.01），BALF和血清中TNF-α、IL-6和IL^-1β水平显著升高（P＜0.01），门水平中变形菌门（Desulfobacterota）、放线菌门（Actinobacteriota）、髌骨细菌门（Patescibacteria）丰度显著升高（P＜0.05、0.01），属水平中乳杆菌属（Ligilactobacillus）、乳酸杆菌（Lactobacillus）、CAG-485、罗氏菌属（Romboutsia）丰度显著增加（P＜0.05、0.01），粪肠球菌（Faecousia）的菌群丰度显著下降（P＜0.01）；与模型组比较，各治疗组中大鼠体质量和腓肠肌相对湿质量均有不同程度升高（P＜0.01），BALF和血清中TNF-α、IL-6和IL^-1β含量均有不同水平降低（P＜0.01），肺组织中AQP5的相对表达均明显升高（P＜0.01），AZS1组和氨茶碱组MUC5CA的相对表达量均显著下降（P＜0.05、0.01），门水平中，AZS1给药后变形菌门、放线菌门、髌骨细菌门丰度显著降低（P＜0.05、0.01），氨茶碱干预后髌骨细菌门显著降低（P＜0.01）；在属水平上，AZS1配伍干预后，乳杆菌属、罗氏菌属丰度显著下降（P＜0.05、0.01），粪肠球菌、黏螺菌属丰度显著升高（P＜0.05、0.01），AZS2配伍组干预后，乳酸杆菌和CAG-485菌群丰度显著下降（P＜0.05），粪肠球菌丰度显著升高（P＜0.05），氨茶碱亦对乳杆菌属、粪肠球菌和罗氏菌属的丰度具有显著调节作用（P＜0.05、0.01）。结论 小青龙汤和苓甘五味姜辛汤中细辛-干姜-五味子不同剂量配伍均能有效增加COPD寒饮伏肺证大鼠体质量和腓肠肌相对湿质量，对肺组织局部和全身炎症反应有显著抑制作用，在肠道菌群的多样性和物种组成调节中具有一定的差异。

Objective To evaluate how varying dosage ratios of Asarum heterotropoides-Zingiber officinale-Schisandra chinensis (AZS) within Xiaoqinglong Decoction and Linggan Wuwei Jiangxin Decoction modulate chronic obstructive pulmonary diseases (COPD) progression and gut microbiota dynamics in a rat model of cold phlegm-obstructed lung syndrome. Methods SpragueDawley (SD) rats were randomly allocated into a control group (n = 8) and a model group (n = 32). The COPD rat model with cold phlegm obstruction of the lungs syndrome was established through consecutive 4-weeks exposure to cigarette smoke, tracheal injection of lipopolysaccharide (LPS), and cold stimulation. In the third week, the model group was subdivided into four subgroups (n = 8 of each group): model, Asarum heterotropoides-Zingiber officinale-Schisandra chinensis 6 g : 6 g : 6 g (AZS1) group, A. heterotropoides-Z. officinale-S. chinensis 5 g : 9 g : 5 g (AZS2) group, and aminophylline (0.045 g·kg^-1). Following a 2-weeks pharmacological intervention period, we systematically monitored somatic growth parameters including weekly body weight and terminal gastrocnemius muscle mass index. Histopathological examinations of lung, tracheal, and colonic tissues were performed. Serum and bronchoalveolar lavage fluid (BALF) concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL^-1β were quantified using enzymelinked immunosorbent assay (ELISA). Immunohistochemical staining was employed to assess aquaporin 5 (AQP5), mucin 5AC (MUC5AC) expression in lung tissues for model validation. Gut microbiota profiling was conducted through 16S ribosomal RNA (rRNA) gene sequencing to analyze microbial abundance, diversity, and intergroup differentials. Results Compared to control group, model-only demonstrated significant decreases in body weight and gastrocnemius wet weight ratio (P < 0.01), accompanied by reduced AQP5 expression (P < 0.01) and elevated MUC5AC expression (P < 0.01) in lung tissue. Serum and BALF concentrations of TNF-α, IL-6, and IL^-1β were significantly increased (P < 0.01). Taxonomic analysis revealed that at the phylum level, model rats showed increased abundances of Desulfobacterota, Actinobacteriota, and Patescibacteria (P < 0.05). Genus-level analysis indicated elevated abundances of Ligilactobacillus, Lactobacillus, CAG-485 (unclassified genus), and Romboutsia (P < 0.05), with a concurrent reduction in Faecalibaculum abundance (P < 0.05). All treatment groups exhibited statistically significant improvements in body weight parameters and gastrocnemius ratios compared to model-only (P < 0.05), alongside reduced pro-inflammatory cytokine concentrations (P < 0.01). Notably, all treatment regimens significantly upregulated AQP5 expression (P < 0.05), whereas selective downregulation of MUC5AC occurred exclusively in the AZS1 and aminophylline groups (P < 0.05). Microbiota analysis demonstrated that AZS1 treatment significantly decreased Desulfobacterota, Actinobacteriota, and Patescibacteria abundances (P < 0.05), with aminophylline specifically reducing Patescibacteria (P < 0.05). Genus-level modulation showed AZS1 decreased Ligilactobacillus (P < 0.01) and Romboutsia (P < 0.05) while increasing Faecalibaculum (P < 0.01) and Mucispirillum (P < 0.05). The AZS2 combination reduced Lactobacillus and CAG-485 (P < 0.05) while enhancing Faecalibaculum (P < 0.05). Aminophylline exerted significant modulatory effects on Ligilactobacillus, Faecalibaculum, and Romboutsia (P < 0.05). Conclusion The differential dosage combinations of A. heterotropoides-Z. officinale-Schisandra chinensis in Xiaoqinglong Decoction and Linggan Wuwei Jiangxin Decoction effectively ameliorated COPD with cold phlegm obstruction of the lung syndrome, as evidenced by restored gastrocnemius mass-to-body weight ratios. They have significant inhibitory effects on local and systemic inflammatory responses in lung tissue, and exhibit certain differences in regulating the diversity and species composition of gut microbiota.

R285.5

国家自然科学基金资助项目（81903815）；湖北省自然科学基金联合基金重点项目（2024AFD229）；湖北省中医药管理局面上项目（ZY2023M025）