目的 探究紫雪散防治重度创伤性脑损伤（STBI）继发肺感染的药效及其潜在机制。方法 将SD雄性大鼠随机分为假手术组、STBI造模后第1天（M1D）组、造模后第7天（M7D）组及紫雪散低、高剂量[(0.54（临床等效剂量）、2.16 g·kg^-1)]组。采用控制性皮质撞击法（CCI）建立STBI实验模型；通过苏木素-伊红（HE）染色观察肺组织病理变化，肺功能检测系统测定呼吸频率（F）、吸气时间（Ti）、潮气量（Tv），细菌培养法计数肺组织细菌菌落数；结合代谢组学与网络药理学分析紫雪散的作用机制；血糖仪检测血糖水平；酶联免疫吸附实验（ELISA）检测血清胰高血糖素水平，肺组织晚期糖基化终末产物（AGEs）、晚期糖基化终产物受体（RAGE）及肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、IL-6、单核细胞趋化蛋白-1（MCP-1）等炎症因子水平；Western blotting检测肺组织磷酸化c-Jun氨基末端激酶（p-JNK）、磷酸化p38丝裂原活化蛋白激酶（p-p38）的表达；免疫荧光技术观察核因子（NF）-κB p65的核转位情况。结果 与M7D组相比，紫雪散高剂量组大鼠肺泡壁增厚、肺组织水肿等病理损伤显著改善；Ti、Tv显著升高（P<0.05、0.01）,F显著降低（P<0.001），肺组织细菌菌落数显著减少（P<0.001），且上述效应呈剂量相关性。血清代谢组学分析提示，胰高血糖素代谢紊乱是STBI继发肺感染的关键病理环节，实验验证显示：与假手术组相比，M1D组、M7D组大鼠血糖及血清胰高血糖素水平均显著升高（P<0.001）。网络药理学筛选出128个紫雪散治疗STBI继发肺感染的潜在药效靶点，提示其可能通过调控AGE-RAGE信号通路发挥作用。机制验证显示：与M7D组相比，紫雪散高剂量组大鼠肺组织AGE、RAGE相对含量显著下调（P<0.01、0.001）,p-JNK、p-p38蛋白表达水平显著降低（P<0.05）,NF-κB p65核转位减少，IL-1β、IL-6、TNF-α及MCP-等炎症因子水平显著降低（P<0.05），且效应呈剂量相关性。结论 紫雪散可通过调控AGE-RAGE信号通路，抑制下游炎症通路激活及炎症因子释放，显著减轻STBI大鼠肺部炎症损伤。

Objective To explore the efficacy and potential mechanism of Zixue Powder in preventing and treating secondary pulmonary infection in severe traumatic brain injury（STBI）. Methods SD male rats were randomly divided into sham operation group, STBI model day 1（M1D） group, STBI model day 7（M7D） group, and low-dose(0.54 g·kg^-1) and high-dose(2.16 g·kg^-1) Zixue Powder groups. The STBI model was established by controlled cortical impact（CCI）. The pathological changes of lung tissue were observed by hematoxylin-eosin（HE） staining. The respiratory rate（F）, inspiratory time（Ti）, and tidal volume（Tv） were measured by a pulmonary function detection system. The bacterial colony count in lung tissue was determined by bacterial culture. The mechanism of Zixue Powder was analyzed by combining metabolomics and network pharmacology. Blood glucose levels were monitored with a glucometer. The levels of glucagon, advanced glycation end products（AGEs）, receptor for advanced glycation end products（RAGE）, and inflammatory factors such as tumor necrosis factor-α（TNF-α）, interleukin-1β（IL-1β）, IL-6, and monocyte chemoattractant protein-1（MCP-1） in lung tissue were detected by enzyme-linked immunosorbent assay（ELISA）. The expression of phosphorylated c-Jun N-terminal kinase（p-JNK） and phosphorylated p38 mitogen-activated protein kinase（p-p38） in lung tissue was detected by Western blotting. The nuclear translocation of nuclear factor（NF）-κB p65 was observed by immunofluorescence. Results Compared with the M7D group, the pathological damage of thickened alveolar walls and pulmonary edema in the high-dose Zixue Powder group was significantly improved. Ti and Tv were significantly increased（P ＜0.05, 0.01）, F was significantly decreased（P ＜0.001）, and the bacterial colony count in lung tissue was significantly reduced（P ＜0.001）, and the above effects were dose-dependent. Serum metabolomics analysis suggested that glucagon metabolism disorder was a key pathological link in secondary pulmonary infection after STBI. Experimental verification showed that the blood glucose and serum glucagon levels in the M1D group and M7D group were significantly increased compared with the sham operation group（P ＜0.001）. Network pharmacology screened out 128 potential therapeutic targets of Zixue Powder for secondary pulmonary infection after STBI, suggesting that it may act through regulating the AGE-RAGE signaling pathway. Mechanism verification showed that compared with the M7D group, the relative contents of AGE and RAGE in lung tissue in the high-dose Zixue Powder group were significantly downregulated（P ＜0.01, 0.001）, the protein expression levels of p-JNK and p-p38 were significantly decreased（P ＜0.05）, the nuclear translocation of NF-κB p65 was reduced, and the levels of IL-1β, IL-6, TNF-α, and MCP-1 were significantly decreased（P ＜0.05）, and the effects were dose-dependent. Conclusion Zixue Powder can significantly alleviate pulmonary inflammatory damage in STBI rats by regulating the AGE-RAGE signaling pathway and inhibiting the activation of downstream inflammatory pathways and the release of inflammatory factors.

R285.5;R965

国家资助博士后研究人员计划资助项目(GZC20231925); 中国博士后科学基金第75批面上资助项目(2024M752398); 现代中医药海河实验室科技项目(25HHZYSS00012); 青年科学基金项目(C类)(82505296)