目的 系统评估金振口服液（Jinzhen Oral Liquid，JZOL）对慢性阻塞性肺疾病（chronic obstructive pulmonary disease，COPD）合并痰热证病理模型的治疗作用，并从肺功能改善、全身炎症抑制、气道黏液分泌调节、Th1/Th2和Th17/Treg免疫平衡恢复以及转录组表达谱调控等维度，阐明其药理作用机制。方法 采用香烟烟雾联合脂多糖（lipopolysaccharide，LPS）鼻腔滴注的方式，持续8周建立大鼠COPD模型；随后通过风热暴露联合LPS滴注9 d，构建COPD合并痰热证复合模型。将模型大鼠随机分为模型组、地塞米松（0.2 mg/kg）组和JZOL低、中、高剂量（0.8、1.6、3.2 g/kg）组，连续给药7 d。通过检测肺功能指标、全身症状及体征、血清炎症因子、肺组织病理以及肺组织T细胞亚群比例，综合评价JZOL的药效；进一步采用转录组测序及qRT-PCR技术，验证JZOL对脂质运载蛋白2（lipocalin 2，Lcn2）、吲哚胺2,3-双加氧酶1（indoleamine 2,3-dioxygenase 1，Ido1）、细胞周期蛋白E1（cyclin E1，Ccne1）、同源框B8（homeobox protein B8，HoxB8）、G蛋白偶联受体17（G protein-coupled receptor 17，Gpr17）等关键差异基因的调控作用。结果 复合造模成功诱导了大鼠严重的气流受限、发热、便秘症状，以及组织和细胞病理学变化。与模型组比较，JZOL显著改善肺功能（P＜0.05、0.01、0.001），显著降低血清中肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）、白细胞介素-6（interleukin-6，IL-6）、C反应蛋白（C-reactive protein，CRP）和中性粒细胞弹性蛋白酶（neutrophil elastase，NE）水平（P＜0.001），显著减轻支气管上皮杯状细胞增生及酸性黏蛋白分泌（P＜0.05、0.001），并纠正失衡的Th1/Th2和Th17/Treg细胞比例（P＜0.05、0.001）。转录组及qRT-PCR验证结果显示，JZOL通过下调免疫微环境与蛋白酶失衡相关基因、抑制异常细胞周期与气道重塑基因、上调肺再生关键因子并调节发育因子，以及激活组织修复与炎症消退路径等多途径机制改善COPD。结论 JZOL通过多靶点抑制全身及局部炎症反应、调节T细胞免疫平衡，从而有效改善COPD合并痰热证大鼠的肺功能及全身症状。

Objective To systematically evaluate the therapeutic effects of Jinzhen Oral Liquid (金振口服液, JZOL) on a pathological model of chronic obstructive pulmonary disease (COPD) complicated with phlegm-heat syndrome, and to elucidate its pharmacological mechanisms from multiple dimensions, including improvement of pulmonary function, suppression of systemic inflammation, regulation of airway mucus secretion, restoration of Th1/Th2 and Th17/Treg immune balance, and modulation of transcriptomic expression profiles. Methods A rat COPD model was established through eight weeks of cigarette smoke exposure combined with intranasal lipopolysaccharide (LPS) instillation. Subsequently, a compound model of COPD with phlegm-heat syndrome was induced by 9 d of wind-heat exposure combined with LPS instillation. Model rats were randomly assigned to model group, dexamethasone (0.2 mg/kg) group and JZOL low-, medium-, high-dose (0.8, 1.6, 3.2 g/kg) groups, and received continuous oral administration for 7 d. Therapeutic efficacy was comprehensively evaluated by assessing pulmonary function parameters, systemic symptoms and signs, inflammatory factors in serum, lung histopathological changes and proportions of lung T cell subsets in lung tissue. Furthermore, transcriptomic sequencing and qRT-PCR were employed to validate the regulatory effects of JZOL on key differentially expressed genes, including lipocalin-2 (Lcn2), indoleamine 2,3-dioxygenase 1 (Ido1), cyclin E1 (Ccne1), homeobox protein B8 (Hoxb8) and G protein-coupled receptor 17 (Gpr17). Results The compound modeling successfully induced severe airflow limitation, fever, constipation, and histopathological and cytopathological alterations in rats. Compared with model group, JZOL significantly improved lung function (P < 0.05, 0.01, 0.001), significantly reduced levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP) and neutrophil elastase (NE) in serum (P < 0.001), significantly reduced bronchial epithelial goblet cell proliferation and acid mucin secretion (P < 0.05, 0.001), and corrected imbalanced Th1/Th2 and Th17/Treg cells ratios (P < 0.05, 0.001). The transcriptome and qRT-PCR validation results showed that JZOL improved COPD through multiple mechanisms, including downregulation of immune microenvironment and protease imbalance related genes, inhibition of abnormal cell cycle and airway remodeling genes, upregulation of key lung regeneration factors and regulation of developmental factors, as well as activation of tissue repair and inflammation resolution pathways. Conclusion JZOL effectively improves lung function and systemic symptoms in COPD rats with phlegm heat syndrome by inhibiting systemic and local inflammatory responses through multiple targets, regulating T cell immune balance.

R285.5

国家产业基础再造和制造业高质量发展专项（TC2308068）；基因组学研究平台建设（SKL2023D01009）