脏痹方治疗类风湿关节炎间质性肺疾病小鼠关节炎及肺脏并发症的疗效研究

doi:10.12114/j.issn.1007-9572.2023.0257

中国全科医学 ›› 2024, Vol. 27 ›› Issue (24): 3015-3022.DOI: 10.12114/j.issn.1007-9572.2023.0257

• 论著·中医·中西医结合研究 • 上一篇下一篇

脏痹方治疗类风湿关节炎间质性肺疾病小鼠关节炎及肺脏并发症的疗效研究

杨灿¹^,²^,³, 李宁¹^,²^,³, 李雪菲¹^,²^,³, 赵力¹^,²^,³, 徐浩¹^,²^,³, 施杞¹^,²^,³, 王拥军¹^,²^,³, 梁倩倩¹^,²^,³^,^*()

1．200032　上海市，上海中医药大学附属龙华医院
2．200032　上海市，上海中医药大学脊柱病研究所
3．200032　上海市筋骨理论与治法教育部重点实验室

收稿日期:2023-03-30 修回日期:2023-08-15 出版日期:2024-08-20 发布日期:2024-05-08
通讯作者: 梁倩倩
作者贡献：
杨灿负责动物取材，实验指标检测，数据分析，论文撰写与修改；李宁负责修改论文；李雪菲、赵力负责实验动物的饲养与处理，数据整理；徐浩负责图像采集与分析；施杞、王拥军负责研究的设计与可行性分析；梁倩倩负责研究的设计与可行性分析、论文修改，对稿件整体监督负责。
基金资助:
上海市卫生健康委员会中医药科研项目创新团队类项目(2022CX001); 上海市医院中药制剂产业转化协同创新中心项目; 上海市重中之重研究中心建设项目(2022ZZ01009)

Efficacy of Zang Bi Formula in Treating Arthritis and Its Pulmonary Complications in Rheumatoid Arthritis Interstitial Lung Disease Mice

YANG Can¹^,²^,³, LI Ning¹^,²^,³, LI Xuefei¹^,²^,³, ZHAO Li¹^,²^,³, XU Hao¹^,²^,³, SHI Qi¹^,²^,³, WANG Yongjun¹^,²^,³, LIANG Qianqian¹^,²^,³^,^*()

1. Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
2. Spine Institute, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
3. Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai 200032, China

Received:2023-03-30 Revised:2023-08-15 Published:2024-08-20 Online:2024-05-08
Contact: LIANG Qianqian

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摘要/Abstract

摘要： 背景类风湿关节炎间质性肺疾病（RA-ILD）是类风湿关节炎（RA）常见的并发症之一，严重损害了RA患者的生活质量及生存期。脏痹方在临床多用于RA经久不愈者，但其作用机制及对RA-ILD的疗效仍不清楚。目的探讨脏痹方在RA和RA-ILD中的治疗可能性和潜在机制。方法研究时间为2022年1月—2023年3月。将14只肿瘤坏死因子α转基因（TNF-Tg）小鼠随机分为生理盐水组（Saline组）、脏痹方组（ZBF组），每组各7只。同时随机挑选7只同窝野生型小鼠作为对照组（WT组）。ZBF组给予脏痹方灌胃（1.4 g/mL，1次/d，0.2 mL/次），WT组和Saline组小鼠给予等量0.9%氯化钠溶液灌胃，连续8周。干预完成后小鼠踝关节组织分别采用苏木素-伊红（HE）染色检测炎性细胞面积，阿尔新蓝-橙黄染色检测软骨面积、骨面积占比，抗酒石酸酸性磷酸酶（TRAP）染色测量破骨细胞面积。小鼠肺组织分别采用HE染色检测炎性细胞面积占比，Masson染色检测肺纤维化情况，免疫荧光染色检测肺组织T淋巴细胞和B淋巴细胞面积占比。结果 Saline组小鼠的踝关节内炎性细胞浸润明显增多，滑膜增生，关节组织被破坏。ZBF组踝关节的炎症减轻。Saline组小鼠炎性细胞面积占比高于ZBF组、WT组，ZBF组炎性细胞面积占比高于WT组（P<0.05）。Saline组小鼠踝关节距骨矢状面被严重破坏，骨侵蚀严重，ZBF组小鼠踝关节骨与软骨侵蚀明显改善，距骨矢状面轮廓逐渐清晰，骨量明显增加。Saline组软骨面积、骨面积占比低于ZBF组、WT组，ZBF组软骨面积、骨面积占比低于WT组（P<0.05）。Saline组小鼠踝关节中出现大片红色破骨细胞浸润，ZBF组小鼠破骨细胞浸润情况明显改善。ZBF组破骨细胞面积明显低于Saline组（P<0.05）。Saline组小鼠肺间质、血管和支气管周围弥漫有轻度至中度的炎性细胞浸润，中、小动脉壁增厚，肺泡间隔缩小，肺组织破坏明显；ZBF组小鼠肺间质和气管血管周围的炎性细胞减少，肺组织渐清晰，结构得到改善。Saline组炎性细胞面积占比高于ZBF组、WT组，ZBF组高于WT组。Saline组小鼠肺组织中血管和气管周围蓝色胶原纤维面积明显增多，肺泡或支气管壁增厚，ZBF组肺脏血管和支气管周围蓝色胶原纤维面积减少，肺脏结构改善明显。Saline组肺组织纤维化积分高于ZBF组、WT组，ZBF组肺组织纤维化积分高于WT组。Saline组小鼠肺组织T淋巴细胞、B淋巴细胞明显增多，大多围绕在肺脏血管和支气管周围，形成缺乏生发中心的卵泡样结构。ZBF组小鼠肺脏中的卵泡样结构减少。Saline组B淋巴细胞、T淋巴细胞面积占比高于ZBF组、WT组，ZBF组B淋巴细胞、T淋巴细胞面积占比高于WT组。结论脏痹方不仅减轻了RA-ILD小鼠的踝关节损伤，而且对其肺脏炎症和纤维化也有改善作用，减少了肺组织中的B淋巴细胞和T淋巴细胞数目。

关键词: 关节炎，类风湿, 肺疾病，间质性, 脏痹方, 肿瘤坏死因子α转基因小鼠, 治疗结果

Abstract:

Background

Rheumatoid arthritis interstitial lung disease (RA-ILD) is one of the most common complications of rheumatoid arthritis (RA) that severely impairs the quality of life and survival. Zang Bi Formula (ZBF) is mostly used in clinical practice for patients with recurrent occurrence of RA. However, its mechanism of action and efficacy in RA-ILD still remain unclear. Objective To investigate the therapeutic possibilities and potential mechanisms of the ZBF on RA and RA-ILD.

Objective

To investigate the therapeutic possibilities and potential mechanisms of the ZBF on RA and RA-ILD.

Methods

From January 2022 to March 2023, a total of 14 tumor necrosis factor alpha-transgenic (TNF-Tg) mice were randomly divided into Saline group and ZBF group, with 7 mice in each group. At the same time, 7 wild-type (WT) mice in the same litter were randomly selected as the control group (WT group). Intragastric administration of ZBF 1.4 g/mL with 0.2 mL per time was given to mice of ZBF group once a day, and those in the WT group and Saline group were given an equal amount of normal saline via intragastric administration. After the intervention for 8 weeks, hematoxylin&eosin (H&E) staining of mouse ankle tissues was performed to observe the inflammatory cell area. Alcian blue-orange and tartrate-resistant acid phosphatase (TRAP) staining was performed to observe the cartilage area and bone area ratio, as well as the osteoclast area, respectively. The area proportion of inflammatory cells, fibrosis and T-cell/B-cell proportion in mouse lung tissues were observed by H&E staining, Masson staining and immunofluorescence staining, respectively.

Results

Mice in the Saline group had significantly increased inflammatory cell infiltration, synovial hyperplasia, and ankle tissue destruction. Inflammation of the ankle joint was alleviated in the ZBF group. The proportion of inflammatory cells in the Saline group was significantly higher than that of the ZBF group and WT group, which was significantly higher in the ZBF group than that of the WT group (P<0.05). Mice in the Saline group had significant damages to the sagittal plane of the talus of the ankle joint and bone erosion. Bone damages of the ankle joint and erosion were significantly alleviated in ZBF group, showing a gradually cleared boundary of the sagittal plane of the talus and increased bone mass. The proportions of cartilage area and bone area in the Saline group were significantly lower than those of ZBF group and WT group, which were significantly lower in the ZBF group than those of WT group (P<0.05). Mice in the Saline group presented massive infiltration of red-stained osteoclasts in the ankle joint, which was significantly alleviated in mice of ZBF group. The area of osteoclasts in the ZBF group was significantly smaller than that of the Saline group (P<0.05). Mice in the Saline group had mild-to-moderate inflammatory cell infiltration diffusely around the pulmonary interstitium, blood vessels and bronchi, thickening of the walls of the middle and small arteries, reduced alveolar intervals and obvious damages to lung tissues. Inflammatory cells infiltrated in the pulmonary interstitium surrounding tissues of the trachea and blood vessels were reduced and the boundary of the lungs were cleared in mice of ZBF group, presenting an improved lung structure. The proportion of inflammatory cells area in the Saline group was significantly higher than that of the ZBF group and WT group, which was significantly higher in the ZBF group than that of the WT group (P<0.05). Mice in the Saline group had significantly enlarged areas of blue collagen fibers around blood vessels and trachea and thickening of the alveolar or bronchial walls. Mice in the ZBF group had reduced areas of blue collagen fibers around blood vessels and trachea and improved lung structure. Pulmonary fibrosis scores of the lung were significantly higher in the Saline group than those of ZBF group and WT group, which were significantly higher in the ZBF group than those of WT group (P<0.05). T lymphocytes cells and B lymphocytes cells increased significantly in mouse lung tissue of the Saline group, and most of them surrounded the pulmonary blood vessels and bronchi, forming a follicle-like structure lacking a germinal center. The follicle-like structures were less observed in mouse lungs of the ZBF group. The area proportions of B lymphocytes cells and T lymphocytes cells in the Saline group were significantly higher than those of the ZBF group and WT group, which were significantly higher in the ZBF group than those of WT group (P<0.05) .

Conclusion

ZBF not only reduced ankle injury in TNF-Tg mice, but also improved their lungs inflammation and fibrosis, reducing the numbers of B lymphocytes cells and CD₃⁺ T lymphocytes cells in lung tissue.

Key words: Arthritis, rheumatoid, Lung Diseases, interstitial, Zang Bi Formula, TNF-Tg mice, Treatment outcome

杨灿,李宁,李雪菲,等. 脏痹方治疗类风湿关节炎间质性肺疾病小鼠关节炎及肺脏并发症的疗效研究[J]. 中国全科医学, 2024, 27(24): 3015-3022. DOI: 10.12114/j.issn.1007-9572.2023.0257.
YANG Can,LI Ning,LI Xuefei, et al. Efficacy of Zang Bi Formula in Treating Arthritis and Its Pulmonary Complications in Rheumatoid Arthritis Interstitial Lung Disease Mice[J]. Chinese General Practice, 2024, 27(24): 3015-3022. DOI: 10.12114/j.issn.1007-9572.2023.0257.

图/表 9

图1 3组小鼠踝关节HE染色结果（×200）注：WT组=对照组，Saline组=生理盐水组，ZBF组=脏痹方组。

Figure 1 HE staining results of ankle joints in 3 groups of mice

表1 3组小鼠踝关节病理染色结果

Table 1 Pathological staining results of ankle joints in 3 groups of mice

组别	只数	炎性细胞面积占比（%）	软骨面积（mm²）	骨面积占比（%）	破骨细胞面积（mm²）
WT组	7	6.96±2.30	0.41±0.06	36.09±4.42	0
Saline组	7	22.04±4.97^a	0.12±0.05^a	25.84±3.13^a	0.05±0.01
ZBF组	7	14.24±4.83^ab	0.24±0.04^ab	31.42±2.10^ab	0.02±0.01^b
F值		22.40	54.08	16.38	71.42
P值		<0.001	<0.001	<0.001	<0.001

图2 3组小鼠踝关节阿尔新蓝-橙黄染色结果（×200）注：黑色箭头指向软骨组织。

Figure 2 Alcian blue-orange staining results of ankle joints in 3 groups of mice

图3 3组小鼠踝关节TRAP染色结果（×200）注：TRAP=抗酒石酸酸性磷酸酶；红色为破骨细胞。

Figure 3 Results of TRAP staining of ankle joints in 3 groups of mice

图4 3组小鼠肺组织HE染色结果（×100）

Figure 4 HE staining results of lung tissue of 3 groups of mice

表2 3组小鼠肺组织病理染色结果

Table 2 Pathological staining results of lung tissue in 3 groups of mice

组别	只数	炎性细胞面积占比（%）	纤维化评分（分）	B淋巴细胞面积占比（%）	T淋巴细胞面积占比（%）
WT组	7	5.07±1.21	0.29±0.09	0.23±0.06	0.23±0.07
Saline组	7	16.06±2.17^a	4.00±0.82^a	1.63±0.42^a	1.23±0.27^a
ZBF组	7	9.13±2.30^ab	2.71±0.76^ab	0.93±0.14^ab	0.66±0.19^ab
F值		56.73	50.61	50.86	45.73
P值		<0.000 1	<0.000 1	<0.000 1	<0.000 1

图5 3组小鼠肺组织Masson染色结果（×200）注：黑色箭头代表蓝色胶原纤维。

Figure 5 Results of Masson staining on lung tissue of 3 groups of mice

图6 3组小鼠肺组织B淋巴细胞免疫荧光染色结果（×200）注：白色箭头代表B淋巴细胞。

Figure 6 Results of immunofluorescence staining of lung B cells in 3 groups of mice

图7 3组小鼠肺组织T淋巴细胞免疫荧光染色结果（×100）注：白色箭头代表T淋巴细胞。

Figure 7 Results of immunofluorescence staining of T cells in lung tissue of mice in 3 groups

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脏痹方治疗类风湿关节炎间质性肺疾病小鼠关节炎及肺脏并发症的疗效研究

Efficacy of Zang Bi Formula in Treating Arthritis and Its Pulmonary Complications in Rheumatoid Arthritis Interstitial Lung Disease Mice

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