目的 探究小青龍湯和苓甘五味姜辛湯中細(xì)辛-干姜-五味子不同劑量配伍對(duì)慢性阻塞性肺疾病（COPD）寒飲伏肺證大鼠的干預(yù)作用及對(duì)腸道菌群的影響。方法 SD大鼠隨機(jī)分為對(duì)照組（8只）和造模組（32只），采用煙熏＋氣管注射脂多糖（LPS） ＋寒冷刺激連續(xù)4周建立COPD寒飲伏肺證大鼠模型，從第3周開始將造模組分為模型組、細(xì)辛-干姜-五味子（配比6 g∶ 6 g∶ 6 g，AZS1，1.62 g·kg^-1）組、細(xì)辛-干姜-五味子（配比5 g∶ 9 g∶ 5 g，AZS2，1.71 g·kg^-1）組、氨茶堿（0.045 g·kg^-1）組，每組8只，給藥干預(yù)2周。通過記錄大鼠體質(zhì)量、腓腸肌相對(duì)濕質(zhì)量，觀察肺、氣管和結(jié)腸組織病理狀態(tài)，ELISA法檢測(cè)肺泡灌洗液（BALF）和血清中腫瘤壞死因子（TNF）-α、白細(xì)胞介素（IL）-6和IL^-1β水平，免疫組化檢測(cè)肺組織水通道蛋白5（AQP5）、黏蛋白5AC（MUC5AC）的表達(dá)，對(duì)模型及藥物干預(yù)進(jìn)行可靠性評(píng)價(jià)。采用16S rDNA測(cè)序分析各組大鼠腸道微生物豐度、多樣性變化及差異菌群。結(jié)果 與對(duì)照組比較，模型組大鼠體質(zhì)量和腓腸肌相對(duì)濕質(zhì)量顯著下降（P＜0.01），肺組織中AQP5相對(duì)表達(dá)量顯著降低（P＜0.01），MUC5AC相對(duì)表達(dá)量顯著升高（P＜0.01），BALF和血清中TNF-α、IL-6和IL^-1β水平顯著升高（P＜0.01），門水平中變形菌門（Desulfobacterota）、放線菌門（Actinobacteriota）、髕骨細(xì)菌門（Patescibacteria）豐度顯著升高（P＜0.05、0.01），屬水平中乳桿菌屬（Ligilactobacillus）、乳酸桿菌（Lactobacillus）、CAG-485、羅氏菌屬（Romboutsia）豐度顯著增加（P＜0.05、0.01），糞腸球菌（Faecousia）的菌群豐度顯著下降（P＜0.01）；與模型組比較，各治療組中大鼠體質(zhì)量和腓腸肌相對(duì)濕質(zhì)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），肺組織中AQP5的相對(duì)表達(dá)均明顯升高（P＜0.01），AZS1組和氨茶堿組MUC5CA的相對(duì)表達(dá)量均顯著下降（P＜0.05、0.01），門水平中，AZS1給藥后變形菌門、放線菌門、髕骨細(xì)菌門豐度顯著降低（P＜0.05、0.01），氨茶堿干預(yù)后髕骨細(xì)菌門顯著降低（P＜0.01）；在屬水平上，AZS1配伍干預(yù)后，乳桿菌屬、羅氏菌屬豐度顯著下降（P＜0.05、0.01），糞腸球菌、黏螺菌屬豐度顯著升高（P＜0.05、0.01），AZS2配伍組干預(yù)后，乳酸桿菌和CAG-485菌群豐度顯著下降（P＜0.05），糞腸球菌豐度顯著升高（P＜0.05），氨茶堿亦對(duì)乳桿菌屬、糞腸球菌和羅氏菌屬的豐度具有顯著調(diào)節(jié)作用（P＜0.05、0.01）。結(jié)論 小青龍湯和苓甘五味姜辛湯中細(xì)辛-干姜-五味子不同劑量配伍均能有效增加COPD寒飲伏肺證大鼠體質(zhì)量和腓腸肌相對(duì)濕質(zhì)量，對(duì)肺組織局部和全身炎癥反應(yīng)有顯著抑制作用，在腸道菌群的多樣性和物種組成調(diào)節(jié)中具有一定的差異。

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

國(guó)家自然科學(xué)基金資助項(xiàng)目（81903815）；湖北省自然科學(xué)基金聯(lián)合基金重點(diǎn)項(xiàng)目（2024AFD229）；湖北省中醫(yī)藥管理局面上項(xiàng)目（ZY2023M025）