宣白承气汤对流感病毒和肺炎链球菌共感染致肺肠免疫损伤的影响

Effect of Xuanbai Chengqi Decoction on Pulmonary and Intestinal Immune Injury Induced by Co-infection of Influenza Virus and Streptococcus Pneumoniae

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DOI：10.7661/j.cjim.20230809. 211

中文关键词: 共感染基于叉头盒P3/维甲酸相关核孤儿受体γt 宣白承气汤肺肠损伤肠道菌群中药复方

英文关键词:co-infection Foxp3/ROR γ t Xuanbai Chengqi Decoction lung and intestine injury intestinal flora Chinese herbal compound

基金项目:中医药循证能力建设项目课题（No.2019XZZX-LG006）;国家自然科学基金面上项目（No.81973907）

作者	单位
徐文涛;王雪峰;杨建树;张秀英;齐心;蔡壮	1.辽宁中医药大学研究生学院（沈阳 110847）,2.辽宁中医药大学附属医院儿科（沈阳 110032）

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中文摘要:

目的基于叉头盒 P3（Foxp3）/维甲酸相关核孤儿受体γt（RORγt）免疫失衡机制分析相关细胞因子及肠道菌群的变化，探讨宣白承气汤对流感病毒（IV）和肺炎链球菌（Spn）共感染所致肺肠损伤的作用机制。方法将96只小鼠按随机数字表法分为正常组、模型组、中药组、西药组，每组24只。除正常组外，其余组用流感病毒溶液滴鼻，72 h后用肺炎链球菌滴鼻，24 h后形成共感染模型。中药组予宣白承气汤1.0 g/kg灌胃，西药组予奥司他韦22.8 mg/kg联合头孢56.9 mg/kg灌胃，空白组与模型组予以等量生理盐水，各组均每天1次，持续给药7天。在3、5、7天时HE染色观察肺肠组织病理变化；采用ELISA法检测小鼠血清IL-17、IL-10表达；采用Western Blot法检测肺肠组织中Foxp3、RORγt蛋白的表达；采用16S rDNA测序观察小鼠肠道菌群结构与组成情况。结果与正常组比较，模型组小鼠肺泡间隔破裂，肺间质水肿，大量炎性细胞聚集，肠组织单层柱状上皮细胞间紧密连接破坏，数量减少，黏膜层有大量炎性细胞浸润；肺指数升高（P＜0.01）；血清IL-17水平升高、IL-10水平降低（P＜0.01），Foxp3蛋白表达量降低，RORγt蛋白表达量升高（P＜0.01），肠道菌群丰度与多样性均降低。与模型组比较，中药组与西药组小鼠的肺肠组织病理损伤有明显改善；肺指数降低（P＜0.01）；血清IL-17水平降低、IL-10水平增高（P＜0.05，P＜0.01）；明显上调肺肠组织Foxp3蛋白表达水平、下调RORγt蛋白表达水平（P＜0.05，P＜0.01）；各药物组干预后肠道菌群丰度和多样性均升高。结论宣白承气汤干预治疗IV/SPN共感染，可以进一步调节肺肠Foxp3、RORγt及其相关细胞因子表达，调节免疫微环境，可能通过调整肠道菌群的结构和多样性对IV/SPN共感染所致肺肠损伤起到治疗作用。

英文摘要:

Objective Based on the Forkhead Box P3（Foxp3） / Retinoic acid-related orphan receptorγt（RORγt）immune imbalance mechanism， to analyze the changes of related cytokines and intestinal flora， and to explore the mechanism of Xuanbai Chengqi Decoction（XBCQD） on lung and intestinal injury caused by influenza virus （IV）and Streptococcus pneumoniae（SPN）co-infection. Methods Totally 96 mice were divided into normal group， model group， Chinese medicine group， and Western medicine group according to the random number table， with 24 mice in each group. Except for the normal group， all groups were intranasally administered IV solution. After 72 h， Streptococcus pneumoniae was intranasally administered， and a co-infection model was formed after 24 h. The Chinese medicine group was given XBCQD 1.0 g/kg by gavage. The Western medicine group was given oseltamivir 22.8 mg/kg combined with cephalosporin 56.9 mg/kg by gavage， and the blank group and the model group were given an equivalent amount of normal saline. Each group was administered one dose per day for 7 days. HE staining was used to observe the pathological changes of lung and intestinal tissues at 3， 5 and 7 days. The expression of IL-17 and IL-10 in the sera of mice was detected using ELISA. The expression of Foxp3 and RORγt proteins in lung and intestinal tissues was detected via Western Blot. The structure and composition of intestinal flora in mice were observed through 16 S rDNA sequencing. Results Compared with the normal group， the alveolar septum of the mice in the model group was ruptured， pulmonary interstitial edema was present， many inflammatory cells converged， the tight junction between the single-layer columnar epithelial cells of the intestinal tissue was destroyed， the number was reduced， and a large number of inflammatory cells infiltrated in the mucosal layer. The lung index increased （P＜0.01）. The serum IL-17 level increased， the IL-10 level decreased（P＜0.01）， the expression of Foxp3 protein decreased， and the expression of RORγt protein increased（P＜0.01）. The abundance and diversity of intestinal flora decreased. Compared with the model group， the pathological damage of lung and intestinal tissues in the Chinese medicine group and the Western medicine group was significantly improved. The lung index significant decrease （P＜0.01）. The serum IL-17 level decreased， and the IL-10 level increased（P＜0.05， P＜0.01）. The expression of Foxp3 protein in lung and intestinal tissue up-regulated， and the expression of RORγt protein down-regulated（P＜0.05，P＜0.01）. The abundance and diversity of intestinal flora increased after intervention in each drug group. Conclusions The intervention of XBCQD in the treatment of IV/SPN co-infection can further regulate the expression of Foxp3， RORγt， and related cytokines in lung and intestinal tissues. Furthermore， this intervention can regulate the immune microenvironment， which may play a therapeutic role in lung and intestinal injury caused by IV/SPN co-infection by modulating the structure and diversity of intestinal flora.

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