长春瑞滨诱导大鼠足背静脉炎模型的动态评价

doi:10.12300/j.issn.1674-5817.2024.163

实验动物与比较医学 ›› 2025, Vol. 45 ›› Issue (3): 251-258.DOI: 10.12300/j.issn.1674-5817.2024.163

• 人类疾病动物模型 • 下一篇

长春瑞滨诱导大鼠足背静脉炎模型的动态评价

姜萌¹()(), 郝淑兰¹, 仝立国¹, 仲启明¹, 高振飞², 王永辉², 王晞星¹()(), 吉海杰¹()()

^1.山西省中医药研究院中心实验室, 太原 030012
^2.山西中医药大学方剂学教研室, 太原 030619

收稿日期:2024-11-06 修回日期:2025-02-07 出版日期:2025-07-07 发布日期:2025-06-25
通讯作者: 王晞星（1959—），男，医学学士，主任医师，国医大师，研究方向：中医药防治肿瘤病临床与基础研究。E-mail：wangxx315@163.com。ORCID： 0000-0003-2444-7248；
吉海杰（1982—），男，医学博士，主任药师，硕士生导师，研究方向：中药药效物质基础研究。E-mail：jihaijie82@hotmail.com。
作者简介:姜萌（1998—），女，医学硕士，中医师，研究方向：中药药效物质基础研究。E-mail：876240961@qq.com
基金资助:
国家自然科学基金面上项目“基于血管内皮细胞Ang/Tie2轴探讨化疗性静脉炎发生及复方藤芷膏干预机制”(81973672);山西省基础研究计划“藤芷膏贴治疗化学性静脉炎的机制研究”(202203021221291);山西省科技创新人才团队专项“中药药效物质发现与开发”(202204051001032);山西省中医药科技创新工程项目“基于国医大师验方治疗化疗后静脉炎的中药新药临床前研究”（2023）;山西省中医药重点研究室建设项目“中药药效物质研究重点研究室建设”(ZYYYJS2024005);山西省重点实验室建设项目“山西省中医药管理局重点研究室项目-方药配伍及功用重点研究室”(zyyyjs2024023);山西省外聘专家工作室“项耀祖血管炎性疾病研究山西工作室”(2025W62)

Dynamic Evaluation of Vinorelbine-Induced Phlebitis of Dorsalis Pedis Vein in a Rat Model

JIANG Meng¹()(), HAO Shulan¹, TONG Liguo¹, ZHONG Qiming¹, GAO Zhenfei², WANG Yonghui², WANG Xixing¹()(), JI Haijie¹()()

^1.Department of Central Laboratory, Shanxi Province Academy of Traditional Chinese Medicine, Taiyuan 030012, China
^2.Department of Formulas of Chinese Medicine, Shanxi University of Chinese Medicine, Taiyuan 030619, China

Received:2024-11-06 Revised:2025-02-07 Published:2025-06-25 Online:2025-07-07
Contact: WANG Xixing (0000-0003-2444-7248), E-mail: wangxx315@163.com;
JI Haijiee (0009-0006-7219-6649), E-mail: jihaijie82@hotmail.com

摘要/Abstract

摘要：

目的动态观察经大鼠足背静脉注射长春瑞滨溶液诱导静脉炎模型的临床症状和病理变化。方法 28只11周龄雄性SPF级SD大鼠随机分为模型组（20只）和对照组（8只）：模型组经右后肢足背静脉单次注射0.1 mL长春瑞滨溶液（4 mg/mL），对照组同法注射等体积生理盐水。每日观察两组大鼠的静脉炎发生情况并记录其分级，采用排水法测量患肢体积并计算肿胀率，双足平衡测痛仪测试患肢承重占比，红外热像仪检测患肢皮肤温度，连续9 d。模型组从第1天起隔日处死3只大鼠，取从注射点至向心端1 cm处的静脉组织，采用苏木精-伊红染色法观察静脉组织病理学改变，用扫描电子显微镜观察血管内膜表面微观结构变化。结果与对照组大鼠比较，模型组大鼠第1天出现红肿，至第3天肿胀率达到（81.89±15.75）%（P<0.001），而后红肿逐渐缓解，至第9天降至（15.41±0.33）%（P<0.01）；模型组大鼠患肢第1天出现痛觉，至第3天明显加剧，承重占比降低至（36.35±4.91）%（P<0.001），同时患肢病灶皮肤发热，第5天明显升高至（36.36±0.40）℃（P<0.001），痛觉和发热在第9天均基本恢复至正常。模型组大鼠患肢静脉炎分级显示，第1天Ⅱ级占75.0%；第3天Ⅲ级、Ⅳ级各占37.5%；第5 ~ 9天多数出现条索状静脉，以Ⅲ级为主。患肢静脉组织从第1天的周围水肿和炎性细胞浸润，逐渐进展为第3 ~ 9天的内膜破溃、管壁增厚，甚至管腔狭窄；同时静脉内膜亦从内皮细胞紧密连接破坏、血细胞粘附，进展为内膜表面粗糙、褶皱及隆起。结论经后肢足背静脉单次注射0.1 mL长春瑞滨溶液（4 mg/mL）建立的静脉炎大鼠模型在第3 ~ 5天以局部红、肿、热、痛为典型特征，至第9天基本消退，但仍可见条索状静脉；随病程延长，静脉组织出现水肿、管壁增厚及管腔狭窄，静脉内膜破溃、表面粗糙甚至完全缺失。

关键词: 静脉炎, 足背静脉, 长春瑞滨, 大鼠

Abstract:

Objective To dynamically observe the clinical symptoms and pathological changes in a rat model of vinorelbine-induced phlebitis via injection into the dorsalis pedis vein. Methods Twenty-eight 11-week-old male SPF-grade SD rats were randomly divided into a model group (n=20) and a control group (n=8). The model group received a single injection of 0.1 mL vinorelbine solution (4 mg/mL) via the right hind limb dorsalis pedis vein, while the control group received an equal volume of normal saline via the same method. The occurrence and grading of phlebitis in both groups were observed and recorded daily. The volume of the injured limb was measured by the drainage method to calculate the swelling rate. The weight-bearing ratio of the injured limb was assessed using a bipedal balance pain meter, and the skin temperature of the injured limb was measured by infrared thermal imaging. These measurements were conducted for 9 consecutive days. Starting from day 1, three rats from the model group were euthanized every other day. A 1-cm segment of the vein extending proximally from the injection site was collected. Pathological changes in the vein tissue were examined by hematoxylin-eosin staining, and ultrastructural changes of the vascular endothelium were observed using scanning electron microscopy. Results Compared to the control group, the injected hindlimb of model rats showed redness and swelling on day 1, with the swelling rate peaking at (81.89±15.75) % on day 3 (P<0.001), then gradually alleviating and decreasing to (15.41±0.33) % by day 9 (P<0.01). Pain was observed in the affected limbs of model rats on day 1 and worsened markedly on day 3, with the weight-bearing ratio decreasing to (36.35±4.91)% (P<0.001). Meanwhile, the skin temperature of the lesion site increased, reaching (36.36±0.40) ℃ on day 5 (P<0.001). Both pain and fever returned to near normal levels by day 9. Phlebitis grading in the model group showed that 75.0% of rats were grade Ⅱ on day 1; grade Ⅲ and Ⅳ each accounted for 37.5% on day 3; from days 5 to 9, most rats exhibited cord-like veins, predominantly grade III. Venous tissue showed peripheral edema and inflammatory cell infiltration on day 1, which gradually progressed to intimal rupture, vessel wall thickening, and even lumen narrowing from day 3 to 9. The venous intima exhibited destruction of tight junctions between endothelial cells and adhesion of blood cells, progressing to roughened, wrinkled, and protruding intimal surfaces. Conclusion The vinorelbine-induced phlebitis of dorsal foot vein in rat model is characterized by local redness, swelling, warmth, and pain from days 3 to 5, which largely resolve by day 9, although cord-like veins can still be observed. With disease progression, venous tissue develops edema, vessel wall thickening, and lumen narrowing. The venous intima shows rupture, roughening, and in some cases, complete loss.

Key words: Phlebitis, Dorsalis pedis vein, Vinorelbine, Rats

中图分类号:

Q95-33

姜萌,郝淑兰,仝立国,等. 长春瑞滨诱导大鼠足背静脉炎模型的动态评价[J]. 实验动物与比较医学, 2025, 45(3): 251-258. DOI: 10.12300/j.issn.1674-5817.2024.163.

JIANG Meng,HAO Shulan,TONG Liguo,et al. Dynamic Evaluation of Vinorelbine-Induced Phlebitis of Dorsalis Pedis Vein in a Rat Model[J]. Laboratory Animal and Comparative Medicine, 2025, 45(3): 251-258. DOI: 10.12300/j.issn.1674-5817.2024.163.

图/表 4

图1 足背静脉炎模型大鼠不同时间点的患肢外观（A）和红外热成像（B）图注：A，患肢外观；B，红外热成像（平均温度：>35.5 ℃且≤35.9 ℃呈绿色，>35.9 ℃且≤36.5 ℃呈蓝色，>36.5 ℃呈红色）。对照组大鼠于右后肢足背静脉注射0.1 mL生理盐水，模型组大鼠于右后肢足背静脉注射0.1 mL长春瑞滨溶液（4 mg/mL），连续观察9 d（Day 1、Day 3、Day 5、Day 7和Day 9分别指模型组第1、3、5、7和9天）。

Figure 1 Appearances （A） and infrared thermal images （B） of the injured limbs of phlebitis model rats at different time pointsNote： A， appearance of the injured hindlimb； B， infrared thermal imaging （average temperature： >35.5 ℃ and ≤35.9 ℃， green； >35.9 ℃ and ≤36.5 ℃， blue； >36.5 ℃， red）. The control group rats were injected with 0.1 mL of saline solution into the dorsal vein of the right hind limb， while the model group rats were injected with 0.1 mL of vinorelbine solution （4 mg/mL）. Observation continued for 9 consecutive days. Day 1， Day 3， Day 5， Day 7， and Day 9 refer to the first， third， fifth， seventh， and ninth day after modeling， respectively.

表1 足背静脉炎模型大鼠不同时间点的患肢肿胀率、承重占比和平均温度 (xˉ±s)

Table 1 Swelling rate, weight-bearing ratio, and average temperature of the injured limb of phlebitis model rats at different time points

时间点 Time points	肿胀率/% Swelling rate/%		承重占比/% Proportion of weight-bearing capacity/%		平均温度/℃ Average temperature/℃
时间点 Time points	对照组 Control group	模型组 Model group	对照组 Control group	模型组 Model group	对照组 Control group	模型组 Model group
Day 1	0.91±0.89	25.49±7.93^**	51.44±0.04	44.58±0.86^**	34.35±0.58	34.75±0.68
Day 3	0.99±0.53	81.89±15.75^***	49.92±1.75	36.35±4.91^***	33.85±0.42	35.17±0.81^**
Day 5	1.51±0.30	63.03±1.41^***	49.49±0.09	44.29±0.08^**	34.03±0.77	36.36±0.40^***
Day 7	1.58±0.44	29.75±5.91^**	49.90±1.85	47.71±0.25	35.10±0.43	35.28±0.80
Day 9	0.30±0.17	15.41±0.33^**	50.86±1.49	49.67±1.19	34.40±0.44	34.88±0.63

表2 足背静脉炎模型大鼠在不同时间点的静脉炎分级 (n（%）)

Table 2 Grading of phlebitis model rats at different time points

组别 Groups	0级 0 grade	Ⅰ级 Ⅰ grade	Ⅱ级 Ⅱ grade	Ⅲ级 Ⅲ grade	Ⅳ级 Ⅳ grade	P值 P value
Control group	8 (100.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	-
Day 1	0 (0.0)	2 (25.0)	6 (75.0)	0 (0.0)	0 (0.0)	1.000
Day 3	0 (0.0)	0 (0.0)	2 (25.0)	3 (37.5)	3 (37.5)	0.001^***
Day 5	0 (0.0)	0 (0.0)	2 (25.0)	4 (50.0)	2 (25.0)	0.001^***
Day 7	0 (0.0)	0 (0.0)	3 (37.5)	5 (62.5)	0 (0.0)	0.014^*
Day 9	0 (0.0)	0 (0.0)	3 (37.5)	5 (62.5)	0 (0.0)	0.014^*

图2 足背静脉炎模型大鼠在不同时间点的静脉组织病理学（×400）和血管内膜微观结构（×1 000）注：A为HE染色观察静脉组织病理学变化（绿色箭头指示内膜不规则破溃；黑色箭头指示内膜纤维性增生；红色箭头指示血栓）；B为电子显微镜观察静脉血管内膜微观结构（绿色箭头指示内膜破溃；黑色箭头指示血细胞粘附；红色箭头指示内皮细胞隆起）。对照组大鼠于右后肢足背静脉注射0.1 mL生理盐水，模型组大鼠于右后肢足背静脉注射0.1 mL长春瑞滨溶液（4 mg/mL），连续观察9 d（Day 1、Day 3、Day 5、Day 7和Day 9分别为造模第1、3、5、7和9天）。

Figure 2 Histopathology of vein tissues （×400） and microstructure of vascular intima （×1 000） in phlebitis model rats at different time pointsNote： A， histopathological changes of vein tissue stained by hematoxylin-eosin （HE）（green arrows indicate irregular rupture of the inner membrane； black arrows indicate intimal fibrous hyperplasia； red arrows indicate thrombosis）； B， microstructure of vascular intima observed by scanning electron microscopy （SEM）（green arrows indicate inner membrane rupture； black arrows indicate adhesion of blood cells； red arrows indicate elevated endothelial cells）. The control group rats were injected with 0.1 mL of saline solution into the dorsal vein of the right hind limb， while the model group rats were injected with 0.1 mL of vinorelbine solution （4 mg/mL）. Observation continued for 9 consecutive days. Day 1， Day 3， Day 5， Day 7， and Day 9 refer to the first， third， fifth， seventh， and ninth days after modeling， respectively.

参考文献 19

[1]	BIGDELI SHAMLOO M B, NASIRI M, MANEIY M, et al. Effects of topical sesame (Sesamum indicum) oil on the pain severity of chemotherapy-induced phlebitis in patients with colorectal cancer: a randomized controlled trial[J]. Complement Ther Clin Pract, 2019, 35:78-85. DOI:10.1016/j.ctcp.2019.01.016 .
[2]	GREGORY R K, SMITH I E. Vinorelbine: a clinical review[J]. Br J Cancer, 2000, 82(12):1907-1913. DOI:10.1054/bjoc.2000.1203 .
[3]	刘花, 陈延绅, 尤慧柠, 等. 长春瑞滨药动学及毒副作用研究进展[J]. 中国药房, 2022, 33(11):1403-1408. DOI: 10.6039/j.issn.1001-0408.2022.11.21 .
	LIU H, CHEN Y S, YOU H N, et al. Research progress on pharmacokinetics and toxicity of vinorelbine[J]. China Pharm, 2022, 33(11):1403-1408. DOI: 10.6039/j.issn.1001-0408.2022.11.21 .
[4]	HUANG L, CHEN G, HU Q, et al. Construction of a rabbit model with vinorelbine administration via peripherally inserted central catheter and dynamic monitoring of changes in phlebitis and thrombosis[J]. Exp Ther Med, 2022, 23(3):212. DOI:10.3892/etm.2022.11135 .
[5]	GE G F, SHI W W, YU C H, et al. Baicalein attenuates vinorelbine-induced vascular endothelial cell injury and chemotherapeutic phlebitis in rabbits[J]. Toxicol Appl Pharmacol, 2017, 318:23-32. DOI:10.1016/j.taap.2017.01.013 .
[6]	张咏梅, 宋凌霞, 王玲, 等. 虎杖膏预防高渗药液致兔耳缘静脉炎的实验研究[J]. 护理学杂志, 2013, 28(21):36-38. DOI: 10.3870/hlxzz.2013.21.036 .
	ZHANG Y M, SONG L X, WANG L, et al. Experimental study on giant knotweed cream for prevention of inflammation of rabbit ear vein induced by intravenously administered hypertonic solution[J]. J Nurs Sci, 2013, 28(21):36-38. DOI: 10.3870/hlxzz.2013.21.036 .
[7]	LIU P, YE L C, REN Y S, et al. Chemotherapy-induced phlebitis via the GBP5/NLRP3 inflammasome axis and the therapeutic effect of aescin[J]. Br J Pharmacol, 2023, 180(8):1132-1147. DOI:10.1111/bph.16002 .
[8]	WANG Z, MA L J, WANG X B, et al. Cimetidine attenuates vinorelbine-induced phlebitis in mice by militating E-selectin expression[J]. Cancer Chemother Pharmacol, 2014, 74(2):239-247. DOI:10.1007/s00280-014-2487-8 .
[9]	ZHANG H Y, GONG J, ZHANG S Y, et al. N-acetylcysteine attenuates the incidence of phlebitis induced by carbomer / vinorelbine gel[J]. Heliyon, 2023, 9(11): e21235. DOI:10.1016/j.heliyon.2023.e21235 .
[10]	王淑敏, 郝淑兰, 冯玛莉, 等. 长春瑞滨诱导化疗性静脉炎大鼠模型的构建和评价[J]. 中国实验动物学报, 2023, 31(12):1539-1544. DOI: 10.3969/j.issn.1005-4847.2023.12.003 .
	WANG S M, HAO S L, FENG M L, et al. Construction and evaluation of a chemotherapeutic phlebitis rat model induced by vinorelbine via the dorsalis pedis vein[J]. Acta Lab Anim Sci Sin, 2023, 31(12):1539-1544. DOI: 10.3969/j.issn.1005-4847.2023.12.003 .
[11]	GORSKI L A, HADAWAY L, HAGLE M E, et al. Infusion therapy standards of practice, 8th edition[J]. J Infus Nurs, 2021, 44(1S ): S1-S224. DOI:10.1097/NAN.0000000000000396 .
[12]	中华中医药学会. 化疗后静脉炎中医诊疗专家共识[EB/OL]. [2024-11-05]. .
	China Association of Chinese Medicine. Consensus of Traditional Chinese Medicine experts on diagnosis and treatment of phlebitis after chemotherapy[EB/OL]. [2024-11-05]. .
[13]	ALWORTH L C, KELLY L M, COOPER T L, et al. Unassisted blood collection from unanesthetized rats and gerbils[J]. Lab Anim (NY), 2012, 41(6):155-156. DOI:10.1038/laban0612-155 .
[14]	郝淑兰, 王晞星, 吉海杰, 等. 一种化疗性静脉炎大鼠模型的构建方法: CN115568441A[P]. 2023-01-06.
	HAO S L, WANG X X, JI H J, et al. Construction method of a rat model of chemotherapy-induced phlebitis: CN115568441A[P]. 2023-01-06.
[15]	姜萌, 郝淑兰, 仝立国, 等. 复方藤芷凝胶贴膏剂制备工艺及透皮主要成分研究[J]. 辽宁中医药大学学报, 2024, 26(9):57-63. DOI: 10.13194/j.issn.1673-842x.2024.09.011 .
	JIANG M, HAO S L, TONG L G, et al. Research on the preparation process and transdermal main components of Fufang Tengzhi gel plaster [J]. J Liaoning Univ Tradit Chin Med, 2024, 26(9):57-63. DOI: 10.13194/j.issn.1673-842x.2024.09.011 .
[16]	KIM H, KWAK S H, BYEON J Y, et al. An experimental and clinical study of flap monitoring with an analysis of the clinical course of the flap using an infrared thermal camera[J]. Bioengineering (Basel), 2024, 11(7):688. DOI:10.3390/bioengineering11070688 .
[17]	LEE H W, XU Y Y, HE L Q, et al. Role of venous endothelial cells in developmental and pathologic angiogenesis[J]. Circulation, 2021, 144(16):1308-1322. DOI:10.1161/CIRCULATIONAHA.121.054071 .
[18]	TOMBOR L S, JOHN D, GLASER S F, et al. Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction[J]. Nat Commun, 2021, 12(1):681. DOI:10.1038/s41467-021-20905-1 .
[19]	JIANG M, ZHANG Y X, BU W J, et al. Piezo1 channel activation stimulates ATP production through enhancing mitochondrial respiration and glycolysis in vascular endothelial cells[J]. Br J Pharmacol, 2023, 180(14):1862-1877. DOI:10.1111/bph.16050 .

长春瑞滨诱导大鼠足背静脉炎模型的动态评价

Dynamic Evaluation of Vinorelbine-Induced Phlebitis of Dorsalis Pedis Vein in a Rat Model

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