山羊先兆子痫疾病模型的构建及母体生物学特性评价

doi:10.12300/j.issn.1674-5817.2023.036

实验动物与比较医学 ›› 2023, Vol. 43 ›› Issue (4): 371-380.DOI: 10.12300/j.issn.1674-5817.2023.036

山羊先兆子痫疾病模型的构建及母体生物学特性评价

卢今¹(), 王剑¹, 朱莲¹, 严国锋¹, 马政文¹, 李垚¹, 戴建军², 朱寅秋¹, 周晶¹()()

^1.上海交通大学医学院实验动物科学部, 上海 200025
^2.上海市农业科学研究院畜牧兽医研究所, 上海 201106

收稿日期:2023-03-21 修回日期:2023-06-06 出版日期:2023-08-25 发布日期:2023-09-14
通讯作者: 周晶（1985—），女，生物工程硕士，实验师，研究方向：实验动物医学。E-mail：zj2008@shsmu.edu.cn。ORCID：0009-0005-2626-1561
作者简介:卢今（1990—），女，兽医学硕士，实验师，研究方向：实验动物医学。E-mail：ashleelu@shsmu.edu.cn
基金资助:
上海市科学技术委员会科技创新行动计划“崇明白山羊先兆子痫及乳腺发育疾病模型的生物学特性评价”(19140900103);上海高校教师培养计划-实验技术队伍建设计划“周晶”

Establishment of Preeclampsia Model in Goat and Evaluation on Maternal Biological Characteristics

Jin LU¹(), Jian WANG¹, Lian ZHU¹, Guofeng YAN¹, Zhengwen MA¹, Yao LI¹, Jianjun DAI², Yinqiu ZHU¹, Jing ZHOU¹()()

^1.Department of Laboratory Animal Science, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
^2.Institution of Animal Husbandry & Veterinary Science, Shanghai 201106, China

Received:2023-03-21 Revised:2023-06-06 Published:2023-08-25 Online:2023-09-14
Contact: ZHOU Jing (ORCID: 0009-0005-2626-1561), E-mail: zj2008@shsmu.edu.cn

摘要/Abstract

摘要：

目的建立山羊先兆子痫动物模型，并收集该疾病模型各项生理指标和母体的生物学特性数据，与人类该疾病的发生发展特征相对照，为防治人类先兆子痫疾病的发生提供参考。方法将23头雌性崇明白山羊分为3组，其中对照组妊娠母羊临产期前不进行任何手术操作；假手术组在母羊妊娠（100±5）d时行先兆子痫假手术造模，仅暴露并游离其子宫体动脉；手术组于母羊妊娠（100±5）d时，在其一侧子宫体动脉上放置银质血管夹，夹闭动脉部分内径，制作先兆子痫模型。对妊娠100～140 d的对照组和手术组母羊连续监测其心率和后肢血压，并利用血流仪结合血流探头、动物生理信号采集仪采集假手术组母羊的子宫动脉侧支内血流数据，以及手术组母羊在放置血管夹前后子宫动脉侧支内的血流变化情况。在预期分娩日期前，取母羊颈静脉血进行血常规、肌酐、尿素氮和血液离子分析；同时采集各组母羊尿液，进行尿蛋白、尿肌酐分析。所有实验组均于母羊妊娠（140±5）d时行剖宫取胎术，然后取各组母羊的肝、肾、子宫和胎盘组织进行苏木精-伊红染色，以进行病理学观察。结果手术造模15 min后手术组母羊的子宫体动脉血流量保持稳定，血流流量差相对于对照组和假手术组均降低（P＜0.05，P＜0.01）。相较于对照组，手术组母羊在产前出现血清渗透压升高、血红蛋白降低、血糖和血清尿素氮值升高，以及钙、钠、氯离子含量增高等变化（均P＜0.05），并出现蛋白尿，尿肌酐及尿蛋白肌酐比均明显高于对照组和假手术组（均P＜0.05）。手术组动物的手术侧子宫体动脉弹力层较对侧增厚，但结构松散；手术侧胎盘出现细胞间质肿胀、炎性细胞浸润等病理变化。以上生理指标特征均与人类先兆子痫的临床指标较为一致。结论通过血流仪验证，以及妊娠后期母羊各项生理指标检测证明，本实验成功构建了山羊先兆子痫模型，并获得了该模型的相关生理指标数据，进一步验证了先兆子痫疾病与子宫动脉病变的相关性。

关键词: 先兆子痫, 动物模型, 血流分析, 生物学特性, 山羊

Abstract:

Objective Establish an animal model of preeclampsia in goats, collect data on various physiological indicators and maternal biological characteristics of the disease model to compare with clinical feature of the disease in humans, provide reference for the prevention and treatment of preeclampsia in humans. Methods Twenty-three goats bred in Chongming district were divided into three groups: Control group, no surgical procedure was performed on animals of this group; sham group, ewes in this group underwent the sham operation on the 100±5th day of gestation, and only the uterine artery was exposed and dissociated; surgical group, a silver vascular clamp was clipped on one side of the uterine body artery of the ewe to narrow the inner diameter of the artery at the same gestation period (100±5) days. Heart rate and hindlimb blood pressure were continuously monitored in control and surgical ewes from 100 to 140 d of gestation, and blood flow data within the lateral branches of the uterine arteries of ewes in the sham group were collected using a hemodynamometer in combination with a hemodynamic probe and an animal physiological signal collector, as well as changes in blood flow within the uterine arteries in the lateral branches of the uterine arteries of the surgical group before and after placement of vascular clips in the surgical ewes. At the expected date of delivery, jugular vein blood was taken from ewes for routine blood test, creatinine, urea nitrogen, and blood ion analysis; urine was also collected from ewes in each group for analysis of urinary protein and urinary creatinine. All experimental groups were subjected to cesarean section on the 140±5th day of gestation in ewes, and then liver, kidney, uterus and placenta tissues were taken from ewes in each group and stained with HE for pathological observation. Results After 15 minutes of preeclampsia modeling surgery, blood flow volume remained stable in the vessel stenosis segment and the volume differential was relatively reduced in comparison to the control group and sham group (P＜0.05，P＜0.01). Compared with the control group, the ewes in the surgical group showed prenatal changes such as increased serum osmolality, decreased hemoglobin, increased blood glucose and urea nitrogen values, as well as increased levels of calcium, sodium, and chloride ions (all P<0.05) and proteinuria, with urinary creatinine and urinary protein-creatinine ratios were significantly higher than those in the control group and sham group (all P<0.05). The elastic lamina of the uterine body arteries on the operated side of the animals in the surgical group was thicker than that on the opposite side, but the structure was loose. The placenta on the operated side showed pathological changes such as cell interstitial swelling and inflammatory cell infiltration. The above physiological index characteristics were more consistent with the clinical features of human preeclampsia disease. Conclusion In this experiment, we successfully constructed a goat preeclampsia model and obtained data on relevant physiological indexes of this model, which further verified the correlation between preeclampsia disease and uterine artery lesions.

Key words: Preeclampsia, Animal model, Blood flow analysis, Biological characteristics, Goat

中图分类号:

R-332

卢今, 王剑, 朱莲, 严国锋, 马政文, 李垚, 戴建军, 朱寅秋, 周晶. 山羊先兆子痫疾病模型的构建及母体生物学特性评价[J]. 实验动物与比较医学, 2023, 43(4): 371-380.

Jin LU, Jian WANG, Lian ZHU, Guofeng YAN, Zhengwen MA, Yao LI, Jianjun DAI, Yinqiu ZHU, Jing ZHOU. Establishment of Preeclampsia Model in Goat and Evaluation on Maternal Biological Characteristics[J]. Laboratory Animal and Comparative Medicine, 2023, 43(4): 371-380.

图/表 6

图1 子宫腹侧面血管走向和子宫体动脉上银夹放置位置示意图注：A为子宫腹侧面血管走向示意图（proximal，近心端；UA，子宫动脉；UB，子宫体；R，右侧子宫体动脉；L，左侧子宫体动脉；SC，银夹位置）；B 为银夹部分夹闭子宫体动脉。

Figure 1 Anterior exposure of uterine arteries and the position of the silver clamp placement on uterine body arteryNote：A， Anterior exposure of uterine arteries （UA， uterine artery；UB， uterine body；R， right uterine body artery；L， left uterine body artery；SC， placement of silver clamp）； B， Uterine body artery been partially closed by silver clamp.

图2 先兆子痫造模后妊娠山羊的血流量、血压及心率情况注：A，子宫体动脉血管内血流变化；B，后肢舒张压变化；C，后肢血压差压变化；D，心率变化（BPM即次/min）。对照组（n=11）妊娠母羊在临产期前不进行任何手术操作；假手术组（n=4）在母羊妊娠100 d时，行先兆子痫假手术造模，即仅暴露并游离其子宫体动脉；手术组（n=8）于母羊妊娠100 d时，在其一侧子宫体动脉上放置银质血管夹，夹闭动脉部分内径，制作先兆子痫模型。组间比较，*P<0.05，**P<0.01，***P<0.001，****P<0.000 1。

Figure 2 Blood flow， blood pressure and heart rate of pregnant goats after preeclampsia modellingNote：A， Blood flow changes of uterine body artery； B， Changes of hind limb diastolic blood pressure；C， Changes of hind limb pulse pressure； D， Change of heart rate （BPM， beat per min）. In control group （n=11）， no surgical operation was done on animals； in sham group （n=4）， sham surgery was performed on the 100th day of gestation， to be specific， only their uterine body arteries were exposed and freed； in surgical group （n=8）， preeclampsia modeling was performed by placing silver vascular clamps on one of the uterine body arteries of the animals on the 100th day of gestation to close their internal diameters partially. For comparison between groups， *P<0.05， **P<0.01， ***P<0.001， ****P<0.000 1.

表1 先兆子痫山羊模型的血常规组间比较 ()

Table 1 Comparison of blood routine between groups in preeclampsia goat model

项目 Item	手术组（n=8） Surgical group (n=8)		对照组（n=11） Control group (n=11)
项目 Item	术后5 d Postoperation 5 d	产前 Before parturition	对照组（n=11） Control group (n=11)
白细胞计数/(10³·μL^-1) White blood cell count/(10³·μL^-1)	38.26±2.81	34.00±2.99	40.62±1.70
淋巴细胞百分比/% Lymphocyte/%	58.68±2.28	58.42±4.22	60.94±2.05
中间细胞百分比/% Intermediate cell/%	7.20±1.07	7.60±1.09	6.61±0.73
粒细胞百分比/% Granulocyte/%	34.12±1.77	33.98±3.18	32.45±1.63
淋巴细胞计数/(10³·μL^-1) Lymphocyte count/(10³·μL^-1)	22.50±1.86	20.13±2.85	24.81±1.44
粒细胞计数/(10³·μL^-1) Granulocyte count/(10³·μL^-1)	12.90±0.81	11.30±0.64	13.06±0.68
红细胞计数/(10⁶·μL^-1) Red blood cell count/(10⁶·μL^-1)	1.14±0.14	0.65±0.04^*	1.58±0.17
血红蛋白计数/(g·L^-1) haemoglobin count/(g·L^-1)	101.40±4.24	87.75±4.71^*	117.27±5.32
血细胞压积/% Packed cell volume/%	4.52±0.62	2.50±0.16^*	6.49±0.76
平均红细胞压积/fL Mean corpuscular volume/fL	40.18±0.31	39.53±0.30^*	41.16±0.30
平均红细胞血红蛋白量/pg Mean corpuscular hemoglobin/pg	94.00±10.30	135.18±6.02^****	77.99±4.33
平均红细胞血红蛋白浓度/(g·L^-1) Mean corpusular hemoglobin concerntration/(g·L^-1)	2 397±286	3 526±154^****	1 924±118
红细胞分别宽度变异系数/% coefficient variation of red blood cell volume distribution width/%	17.26±0.61	16.33±0.69	17.41±0.43
中间细胞计数/(10³·μL^-1) Intermediate cell count/(10³·μL^-1)	2.58±0.44	2.40±0.22	2.99±0.34

图3 先兆子痫造模后妊娠山羊的血液及尿液生化指标检测结果注：A，血糖；B，肾功能指标；C，血清离子指标（PHOS指磷离子；Ca即钙离子；Na即钠离子；K即钾离子；Na/K指钠钾离子的比值；Cl即氯离子；OSM CALC指血浆渗透压；PHOS和Ca的浓度单位1 mg/L=884 μmol/L）；D，尿肌酐及尿蛋白；E，尿蛋白肌酐比。对照组（n=11）妊娠母羊在临产期前不进行任何手术操作；假手术组（n=4）在母羊妊娠100 d时，行先兆子痫假手术造模，即仅暴露并游离其子宫体动脉；手术组（n=8）于母羊妊娠100 d时，在其一侧子宫体动脉上放置银质血管夹，夹闭动脉部分内径，制作先兆子痫模型。组间比较，*P<0.05，**P<0.01，***P<0.001，****P<0.000 1。

Figure 3 Blood and urinary biochemical results of preeclampsia modeling goat before parturitionNote：A， Blood glucose； B， Renal functional indicators； C， Serum iron indicators （PHOS， phosphate； Ca， calcium； Na， Sodium； K， potassium； Na/K， sodium potassium ratio； Cl， chlorine； OSM CALC， osmotic pressure）； D， Urinary creatinine and urinary total protein； E， Creatinine/protein ratio. In the control group （n=11）， no surgical operation was done on animals； in sham group （n=4）， sham surgery was performed on the 100th day of gestation，to be specific， only their uterine body arteries were exposed and freed；and in surgical group （n=8）， preeclampsia modeling was performed by placing silver vascular clamps on one of the uterine body arteries of the animals on the 100th day of gestation to close some of their internal diameters. Comparison between groups， *P<0.05， **P<0.01， ***P<0.001， ****P<0.000 1.

图4 先兆子痫造模后妊娠山羊生产时的手术侧与非手术侧胎盘病理变化（苏木精-伊红染色）注：A，对照组母羊正常胎盘（×1.1；蓝色方框为B、C图的取样位置）；B，对照组母羊正常侧胎盘滋养层（×16.9）；C，对照组母羊正常侧胎盘绒毛间质（×27.2）；D，手术组母羊手术侧胎盘（×1.1；蓝色方框为E、F图的取样位置）；E，手术组母羊手术侧胎盘滋养层（×28.7）；F，手术组动物手术侧胎盘绒毛间质（×34.3）。A和D图的比例尺大小为1 000 μm；B、C、E和F图的比例尺大小为50 μm。

Figure 4 Pathologic changes in the placenta on the operated and non-operated side during parturition in goats after preeclampsia modeling（HE staining）Note：A， Normal placenta of ewes in control group （×1.1， the blue squares are the sampling sites for figure B and C ）； B， Trophoblasts of normal placenta in control group （×16.9）； C， Villous stroma of normal placenta in control group （×27.2）； D， Surgical side placenta of ewes in surgical group （×1.1， the blue squares are the sampling sites for figure E and F ）； E， Trophoblasts of surgical side placenta of ewes in surgical group （×28.7）； F， Villous stroma of surgical side placenta of ewes in surgical group （×34.3）. Scale bars of figure A and D are 1 000 μm. Proportional scales of figure B， C， E and F are 50 μm.

图5 先兆子痫造模后妊娠山羊生产时的两侧子宫体动脉外观及病理比较注：A，妊娠140 d的母羊子宫及动脉示意图（银夹放置在一侧子宫体动脉上）；B～D，苏木精-伊红染色观察子宫体动脉病理组织切片（B，非手术侧子宫动脉；C，手术侧造模位置近心端子宫动脉；E，手术侧造模位置远心端子宫动脉）。B～D图的比例尺大小为50 μm。

Figure 5 Comparison of the appearance and pathology of the uterine body arteries on surgical and non-surgical side of the uterus at the time of parturition in pregnant goats after preeclampsia modelingNote：A， Schematic diagram of the uterus and uterine arteries of ewes on the 140th day of gestation （silver clips were placed on one side of the uterine body arteries）； B-D， HE-stained histopathologic sections of the uterine body arteries （B， uterine arteries of the nonsurgical side； C， uterine arteries proximal to the surgical side； E， uterine arteries distal from the surgical side）. The scale bars figure B-D are 50 μm.

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山羊先兆子痫疾病模型的构建及母体生物学特性评价

Establishment of Preeclampsia Model in Goat and Evaluation on Maternal Biological Characteristics

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