贝伐珠单抗注射液对食蟹猴皮肤伤口愈合的影响

doi:10.12300/j.issn.1674-5817.2022.128

实验动物与比较医学 ›› 2023, Vol. 43 ›› Issue (1): 21-29.DOI: 10.12300/j.issn.1674-5817.2022.128

• 人类疾病动物模型：药学专题 • 上一篇下一篇

贝伐珠单抗注射液对食蟹猴皮肤伤口愈合的影响

杨平¹, 崔立¹()(), 俞诚², 温智越¹

^1.上海交通大学农业与生物学院, 上海 201209
^2.澎立生物医药技术(上海)股份有限公司, 上海 201203

收稿日期:2022-08-17 修回日期:2022-10-30 出版日期:2023-02-25 发布日期:2023-03-09
通讯作者: 崔立（1971—），女，博士，研究员，研究方向：人兽共患病与比较医学。E-mail： lcui@sjtu.edu.cn。ORCID： 0000-0001-5202-9671；
作者简介:杨平（1986—），男，硕士研究生，执业兽医师，研究方向：临床前药物药理药效评价。E-mail：pingyang@sjtu.edu.cn
基金资助:
上海市科委科技计划项目-实验动物专项“基于肠类器官3D培养和高内涵成像的药物毒性和安全性评价模型研究”(21140901400)

Effects of Bevacizumab Injection on the Skin Wound Healing in Cynomolgus Monkeys

Ping YANG¹, Li CUI¹()(), Cheng YU², Zhiyue WEN¹

^1.Shanghai Jiao Tong University School Of Agriculture And Biology, Shanghai 201209, China
^2.PharmaLegacy Laboratories (Shanghai) Co. , Ltd. , Shanghai 201203, China

Received:2022-08-17 Revised:2022-10-30 Published:2023-02-25 Online:2023-03-09
Contact: CUI Li (ORCID: 0000-0001-5202-9671), E-mail: lcui@sjtu.edu.cn

摘要/Abstract

摘要：

目的通过观察贝伐珠单抗注射液对食蟹猴背部皮肤伤口愈合速度及损伤皮肤组织中CD34表达的影响，验证贝伐珠单抗注射液对食蟹猴伤口愈合的延迟作用，为临床肿瘤手术患者使用贝伐珠单抗治疗时提供剂量和频次的用药参考。方法 6只雄性食蟹猴采用背部全层皮肤切除术建立伤口愈合评估模型，随机选取3只食蟹猴作为生理盐水组，其余3只食蟹猴为贝伐珠单抗组。贝伐珠单抗组食蟹猴在手术后第0、4、8、11天静脉注射30 mg/kg 贝伐珠单抗注射液，生理盐水组静脉注射等量生理盐水；术后进行血常规检测，并观察各组食蟹猴的伤口愈合情况，Image J软件分析伤口愈合率，用评分法对伤口状态的严重程度进行评价。4周后对6只食蟹猴伤口愈合皮肤取材，通过免疫组织化学法检查皮肤组织中CD34的表达水平。结果成功构建食蟹猴伤口愈合评估模型。术后第3天的食蟹猴血液中白细胞、中性粒细胞数量明显升高（P<0.05），第7天后白细胞数量逐渐恢复正常，而红细胞、血红蛋白、红细胞压积没有明显变化，提示动物营养状态良好。与生理盐水组相比，贝伐珠单抗组的伤口愈合率在术后7 d、28 d明显降低（P<0.01，P<0.001），愈合皮肤组织中CD34表达水平明显降低（P<0.01）。结论贝伐珠单抗注射给药可能通过抑制食蟹猴伤口新生皮肤组织中的微血管生成，延缓伤口愈合。临床中患者手术后使用贝伐珠单抗注射液时应该权衡利弊，科学合理地选择干预时间点、剂量、频次。

关键词: 贝伐珠单抗注射液, 伤口愈合, 伤口评分, CD34, 食蟹猴

Abstract:

Objective By observing the impact of Bevacizumab injection on the speed of wound healing and the expression of CD34 in cynomolgus monkeys, to verify its delayed wound healing mechanism, and to provide clinical reference for the dosage and frequency of Bevacizumab treatment for oncology surgery patients. Methods Six male cynomolgus monkeys underwent full-thickness skin resection on the back to establish a wound healing evaluation model. Three cynomolgus monkeys were randomly selected as the saline group, and the other three cynomolgus monkeys were allocated to the Bevacizumab treatment group. The monkeys of Bevacizumab group were administrated with Bevacizumab injection (30 mg/kg, i.v.) on day 0, day 4, day 8, and day 11, respectively. The monkeys of saline group were injected with the same volume of saline as the group receiving Bevacizumab. The blood routine test was conducted, and the wound healing of each group of cynomolgus monkeys was observed 28 days after operation. The wound healing rate was analyzed by software Image J, and the severity of the wound was assessed by scoring method. Wound healing skin samples of 6 cynomolgus monkeys were obtained after 4 weeks, and the expression level of CD34 in the wound skin tissues was detected using immunohistochemistry. Results A skin excision wound model has already been established in cynomolgus monkeys. The number of white blood cells and neutrophils in the blood of cynomolgus monkeys increased significantly on the 3^rd day after operation (P<0.05), and the number of white blood cells gradually returned to normal on the 7^th day, while the number of red blood cells, hemoglobin and hematocrit did not change significantly, suggesting that the animals were in good nutritional status. The Bevacizumab injection group wound healing rate was significantly slower than that of the saline group on day 7, and day 28^{(P<0.01, P<0.001). Microvessel density in the wound skin of Bevacizumab group appeared to be significantly lower than that of the saline group (P<0.01). Conclusion The injection of Bevacizumab may delay the wound healing by inhibiting the angiogenesis in the new skin tissue of the cynomolgus monkey. In clinical practice, the timing of giving a tumor patient a bevacizumab injection after surgery should be based on the pros and cons, and the duration, dosage, and frequency of the intervention should be chosen in a rational way.}

Key words: Bevacizumab injection, Wound healing, Wound score, CD34, Cynomolgus monkey

中图分类号:

Q95-33

杨平, 崔立, 俞诚, 温智越. 贝伐珠单抗注射液对食蟹猴皮肤伤口愈合的影响[J]. 实验动物与比较医学, 2023, 43(1): 21-29.

Ping YANG, Li CUI, Cheng YU, Zhiyue WEN. Effects of Bevacizumab Injection on the Skin Wound Healing in Cynomolgus Monkeys[J]. Laboratory Animal and Comparative Medicine, 2023, 43(1): 21-29.

图/表 5

表1 食蟹猴背部伤口评分表

Table 1 The back wound score in cynomolgus monkeys

项目 Item	得分Score	描述 Description
伤口周围的皮肤颜色（距离伤口2 cm） Skin color around the wound (2 cm from the wound)	0	正常颜色或粉红色
	1	淡红色或有压之褪色的发红
	2	白色或灰白色
	3	深红色或压之不褪色的发红
	4	黑色或色素沉着过度
伤口周围组织水肿 Edema in wound surrounding tissue	0	无水肿或肿胀
	1	伤口周围非凹陷水肿范围<2 cm
	2	伤口周围非凹陷水肿范围≥2 cm
	3	伤口周围凹陷水肿范围<2 cm
	4	伤口周围凹陷水肿范围≥2 cm
渗出液类型 Type of exudate	0	无渗出液
	1	红色
	2	粉红色
	3	薄而透明，水性
	4	黄色或绿色，气味难闻
渗出量 Exudate amount	0	无渗出液
	1	伤口组织微湿，但无法测量
	2	伤口组织湿润，浸泡<25%的敷料
	3	伤口组织湿润，浸泡敷料的25%～75%
	4	伤口组织湿润，浸泡>75%的敷料

表2 食蟹猴血常规检测结果

Table 2 Blood routine examination results of cynomolgus monkeys

指标及组别 Index and group	手术后时间 Time after surgery/d
指标及组别 Index and group	0	3	7	14	28
WBC/(10⁹·L^-1)
生理盐水组 Saline group	13.20±0.08	31.00±1.05^△	14.65±0.10	15.64±0.08	18.70±0.69
贝伐珠单抗组 Bevacizumab group	12.15±0.09	25.25±0.08^△	13.48±0.04	15.72±0.50	17.14±0.23
RBC/(10¹²·L^-1)
生理盐水组 Saline group	5.80±0.21	6.01±0.48	6.22±0.13	5.88±0.35	5.99±0.34
贝伐珠单抗组Bevacizumab group	6.10±0.16	5.84±0.43	5.97±0.15	5.72±0.11	5.84±0.18
NEU/%
生理盐水组 Saline group	44.03±2.23	81.80±3.98^△	50.97±4.83	61.57±6.75	60.73±17.91
贝伐珠单抗组 Bevacizumab group	59.67±4.58	66.50±10.38	61.6±4.85	58.57±7.83	74.40±4.97
NEU/(10⁹·L^-1)
生理盐水组 Saline group	5.81±0.30	25.41±1.93^△△	7.46±0.66	9.61±1.01	11.53±3.54
贝伐珠单抗组 Bevacizumab group	7.26±0.59	16.80±2.62^△	8.31±0.66	9.25±1.39	12.74±0.83
LYM/%
生理盐水组 Saline group	50.37±2.92	14.53±3.75	43.17±3.76	30.97±6.64	30.37±14.77
贝伐珠单抗组 Bevacizumab group	33.30±4.35	28.43±9.75^*△	33.93±5.04	34.53±7.23	20.30±4.66
LYM/(10⁹·L^-1)
生理盐水组 Saline group	6.65±0.38	4.44±1.08	6.33±0.59	4.86±1.06	5.52±2.52
贝伐珠单抗组 Bevacizumab group	4.05±0.52	7.18±2.48	4.58±0.68	5.40±1.05	3.48±0.78
HG1B ρ/(g·L^-1)
生理盐水组 Saline group	140.00±3.06	147.00±7.00	149.33±5.84	144.33±7.17	139.00±3.61
贝伐珠单抗组 Bevacizumab group	150.00±5.57	142.33±7.06	142.67±7.84	140.67±2.73	140.33±3.84
HCT/%
生理盐水组 Saline group	45.93±1.13	47.27±2.20	47.93±2.15	45.73±2.22	44.97±1.90
贝伐珠单抗组 Bevacizumab group	48.70±1.65	45.40±2.39	45.93±2.05	45.87±1.22	45.30±1.56
EOS/%
生理盐水组 Saline group	0.87±0.29	0.43±0.34	1.23±0.29	2.13±0.95	3.50±3.06
贝伐珠单抗组Bevacizumab group	0.83±0.38	0.47±0.20	0.27±0.03	1.57±0.75	0.73±0.35
EOS/(10⁹·L^-1)
生理盐水组 Saline group	0.12±0.04	0.14±0.10	0.18±0.04	0.33±0.15	0.62±0.54
贝伐珠单抗组 Bevacizumab group	0.10±0.05	0.11±0.05	0.03±0.01	0.24±0.11	0.13±0.06

表2 食蟹猴血常规检测结果

Table 2 Blood routine examination results of cynomolgus monkeys

指标及组别 Index and group	手术后时间 Time after surgery/d
指标及组别 Index and group	0	3	7	14	28
WBC/(10⁹·L^-1)
生理盐水组 Saline group	13.20±0.08	31.00±1.05^△	14.65±0.10	15.64±0.08	18.70±0.69
贝伐珠单抗组 Bevacizumab group	12.15±0.09	25.25±0.08^△	13.48±0.04	15.72±0.50	17.14±0.23
RBC/(10¹²·L^-1)
生理盐水组 Saline group	5.80±0.21	6.01±0.48	6.22±0.13	5.88±0.35	5.99±0.34
贝伐珠单抗组Bevacizumab group	6.10±0.16	5.84±0.43	5.97±0.15	5.72±0.11	5.84±0.18
NEU/%
生理盐水组 Saline group	44.03±2.23	81.80±3.98^△	50.97±4.83	61.57±6.75	60.73±17.91
贝伐珠单抗组 Bevacizumab group	59.67±4.58	66.50±10.38	61.6±4.85	58.57±7.83	74.40±4.97
NEU/(10⁹·L^-1)
生理盐水组 Saline group	5.81±0.30	25.41±1.93^△△	7.46±0.66	9.61±1.01	11.53±3.54
贝伐珠单抗组 Bevacizumab group	7.26±0.59	16.80±2.62^△	8.31±0.66	9.25±1.39	12.74±0.83
LYM/%
生理盐水组 Saline group	50.37±2.92	14.53±3.75	43.17±3.76	30.97±6.64	30.37±14.77
贝伐珠单抗组 Bevacizumab group	33.30±4.35	28.43±9.75^*△	33.93±5.04	34.53±7.23	20.30±4.66
LYM/(10⁹·L^-1)
生理盐水组 Saline group	6.65±0.38	4.44±1.08	6.33±0.59	4.86±1.06	5.52±2.52
贝伐珠单抗组 Bevacizumab group	4.05±0.52	7.18±2.48	4.58±0.68	5.40±1.05	3.48±0.78
HG1B ρ/(g·L^-1)
生理盐水组 Saline group	140.00±3.06	147.00±7.00	149.33±5.84	144.33±7.17	139.00±3.61
贝伐珠单抗组 Bevacizumab group	150.00±5.57	142.33±7.06	142.67±7.84	140.67±2.73	140.33±3.84
HCT/%
生理盐水组 Saline group	45.93±1.13	47.27±2.20	47.93±2.15	45.73±2.22	44.97±1.90
贝伐珠单抗组 Bevacizumab group	48.70±1.65	45.40±2.39	45.93±2.05	45.87±1.22	45.30±1.56
EOS/%
生理盐水组 Saline group	0.87±0.29	0.43±0.34	1.23±0.29	2.13±0.95	3.50±3.06
贝伐珠单抗组Bevacizumab group	0.83±0.38	0.47±0.20	0.27±0.03	1.57±0.75	0.73±0.35
EOS/(10⁹·L^-1)
生理盐水组 Saline group	0.12±0.04	0.14±0.10	0.18±0.04	0.33±0.15	0.62±0.54
贝伐珠单抗组 Bevacizumab group	0.10±0.05	0.11±0.05	0.03±0.01	0.24±0.11	0.13±0.06

图 1 食蟹猴背部伤口状态注：A，生理盐水组与贝伐珠单抗组的代表性伤口，切除皮肤面积为4 cm×4 cm；B，生理盐水组与贝伐珠单抗组的伤口愈合叠加图，各时间点的叠加图以伤口中心4 cm×4 cm区域获得。D0、D0.08、D2、D5、D7、D9、D11、D14、D17、D21、D24、D28分别表示全层皮肤切除手术后即刻、第2小时，以及第2、5、7、9、11、14、17、21、24和28天。

Figure 1 The picture of back wound state in cynomolgus monkeysNote：A， Representative wound pictures in saline group and Bevacizumab group， the resection area of skin was 4 cm×4 cm； B， Wound healing overlap diagrams in saline group and Bevacizumab group， which the 4 cm×4 cm images of the wound center were obtained at each superimposed time point. D0， D0.08， D2， D5， D7， D9， D11， D14， D17， D21， D24， and D28 represent minute 2， hour 2， day 2， day 5， day 7， day 9， day 11， day 14， day 17， day 21， day 24 and day 28 after full-thickness skin resection， respectively.

图2 食蟹猴背部伤口状态评分及愈合指标的统计图注：同一个时间点贝伐珠单抗组与生理盐水组比较，*P<0.05，**P<0.01，***P<0.001。每组3只食蟹猴（n=3）。

Figure 2 Statistical chart of back wound score and wound healing index in back of cynomolgus monkeysNote：T-test was used to compare Bevacizumab group with saline group at the same time point, *P<0.05, **P<0.01, ***P<0.001, n=3.

图3 食蟹猴伤口愈合部位皮肤组织中CD34免疫组织化学染色和皮肤厚度分析注：A为生理盐水组和贝伐珠单抗组伤口愈合皮肤组织中CD34免疫组织化学染色（DAB，×400），图中箭头指示微细血管内皮细胞内CD34被染色为棕黄色或者棕褐色颗粒，标尺为50 μm。B为两组伤口愈合皮肤组织中，CD34阳性表达的微血管面积占选区面积的百分比（即微血管密度）（**P<0.01， n=3）。C为两组新生皮肤最厚部位的厚度。

Figure 3 Immunohistochemical staining of CD34 and skin thickness analysis in the wound healing site of cynomolgus monkeysNote：A， CD34 immunohistochemical staining in the wound skin tissues of saline group and Bevacizumab group， showing skin characteristics of each group under 400× microscope with a scale bar of 50 μm. The arrow in the figure indicates that the CD34 in the cytoplasm of microvascular endothelial cells is stained with tan or brown particles.B， Comparison of percentage of microvessel area of CD34 positive expression （showing microvessel density） in the wound healing skin tissues between the two groups （**P<0.01， n=3）. C， The thickness of the thickest part of newborn skin in the two groups.

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贝伐珠单抗注射液对食蟹猴皮肤伤口愈合的影响

Effects of Bevacizumab Injection on the Skin Wound Healing in Cynomolgus Monkeys

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