小型猪后肢去负荷模拟失重模型的建立与组织损伤研究

doi:10.12300/j.issn.1674-5817.2024.038

实验动物与比较医学 ›› 2024, Vol. 44 ›› Issue (5): 475-486.DOI: 10.12300/j.issn.1674-5817.2024.038

• 实验动物资源开发与利用 • 上一篇下一篇

小型猪后肢去负荷模拟失重模型的建立与组织损伤研究

涂颖欣¹(), 纪依澜¹(), 王菲²(), 杨东明¹, 王冬冬¹, 孙芷馨¹, 戴悦欣¹, 王言吉², 阚广捍², 吴斌², 赵德明¹, 杨利峰¹()()

^1.中国农业大学动物医学院, 北京 100193
^2.中国航天员科研训练中心, 北京 100094

收稿日期:2024-03-05 修回日期:2024-07-02 出版日期:2024-10-25 发布日期:2024-10-25
通讯作者: 杨利峰（1980—），女，博士，教授，博士生导师，主要从事基础兽医学研究。E-mail： yanglf@cau.edu.cn。ORCID： 0000-0001-5175-7589
作者简介:涂颖欣（1999—），女，硕士，研究实习员，研究方向：兽医病理学。E-mail： novatu@163.com；
纪依澜（1997—），女，硕士，研究方向：兽医病理学。E-mail： jyl599@sina.com；
王菲（1988—），女，硕士，助理研究员，研究方向：航空航天实施医学。E-mail：182211493@qq.com
基金资助:
国家重点研发计划“实验动物新品种、新品系开发与评价”(2022YFF0710501);航天医学基础与应用国家重点实验室研究基金资助自主研究项目“模拟失重和压力变化复合因素对小型巴马猪咽鼓管功能变化规律研究”(SMFA22B05)

Evaluation of Simulated Weightlessness Model of Hindlimb Unloading Miniature Pigs and Their Tissue Damage

TU Yingxin¹(), JI Yilan¹(), WANG Fei²(), YANG Dongming¹, WANG Dongdong¹, SUN Zhixin¹, DAI Yuexin¹, WANG Yanji², KAN Guanghan², WU Bin², ZHAO Deming¹, YANG Lifeng¹()()

^1.College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
^2.China Astronaut Research and Training Center, Beijing 100094, China

Received:2024-03-05 Revised:2024-07-02 Published:2024-10-25 Online:2024-10-25
Correspondence to: YANG Lifeng (ORCID: 0000-0001-5175-7589), E-mail: yanglf@cau.edu.cn

摘要/Abstract

摘要：

目的利用小型猪多个系统组织结构和功能接近于人类的特性，建立模拟失重动物模型，观察其病理生理学变化，为航空航天失重环境研究提供新方法。方法选取9头普通级小型猪，随机分为实验组（n=7）和对照组（n=2）。实验组小型猪使用定制金属笼固定，帆布吊带悬挂使其后肢离地去负荷，身体与地面呈-20°角，模拟失重30 d（每天24 h）。通过采集不同时间点各组小型猪的体重、血容量、血生化指标等数据，对其基础体征的变化进行统计分析。实验结束后，对小型猪实施安乐死并解剖取材，对心血管、骨骼、骨骼肌等各系统组织脏器进行HE、Masson染色后的组织病理学观察，并对各动脉血管厚度、骨骼肌肌纤维直径进行统计分析。同时，采用蛋白质免疫印迹法检测骨骼肌肌肉萎缩蛋白包括肌环指蛋白1（muscle-specific RING finger protein 1，MuRf-1）和肌萎缩素1（muscle atrophy F-box，MAFbx，又称Atrogin-1）的表达量，并采用免疫组织化学染色法检测脑内星形胶质细胞激活相关蛋白即胶质纤维酸性蛋白（glial fibrillary acidic protein，GFAP）的表达量，以反映各系统的病理生理学功能变化。结果后肢去负荷造模后，实验组小型猪体重显著下降（P<0.001），血容量也显著下降（P<0.01）。实验期间，实验组小型猪的血红蛋白、红细胞比容和红细胞计数水平显著降低（P<0.05），随后逐渐恢复；丙氨酸氨基转移酶和γ-谷氨酰转移酶表达水平呈现先下降（P<0.05）后回升的趋势，白蛋白水平显著下降（P<0.001），球蛋白水平显著上升（P<0.01），肌酐水平显著下降（P<0.05）。实验组小型猪腓肠肌的平均肌纤维直径显著缩短（P<0.05），肌纤维直径分布左移，小直径肌纤维增多；同时腓肠肌、椎旁肌肉Atrogin-1的表达水平显著增加（P<0.05）。这些变化与航天失重对人和动物的影响基本一致。此外，实验组小型猪的脑皮质顶叶、额叶和海马区域部分神经元变性，小脑区域浦肯野细胞数量轻度减少，而海马区的GFAP阳性信号显著增强（P<0.05）。结论 -20°角后肢去负荷30 d的小型猪可作为一种新的模拟失重动物模型，用于航空航天领域相关研究。

关键词: 模拟失重, 小型猪, 动物模型, 后肢去负荷

Abstract:

Objective To establish a weightlessness simulation animal model using miniature pigs, leveraging the characteristic of multiple systems’ tissue structures and functions similar to those of humans, and to observe pathophysiological changes, providing a new method for aerospace research. Methods Nine standard-grade miniature pigs were selected and randomly divided into an experimental group (n=7) and a control group (n=2). The experimental group was fixed using customized metal cages, with canvas slings suspending their hind limbs off the ground, and the body positioned at a -20° angle relative to the ground to simulate unloading for 30 days (24 hours a day). Data on body weight, blood volume, and blood biochemistry indicators were collected at different time points for statistical analysis of basic physiological changes. After the experiment, the miniature pigs were euthanized and tissue samples were collected for histopathological observation of the cardiovascular, skeletal and muscle systems HE and Masson staining. Statistical analysis was also conducted on the thickness of arterial vessels and the diameter of skeletal muscle fibers. Additionally, western blotting was employed to detect the expression levels of skeletal muscle atrophy-related proteins, including muscle-specific RING finger protein 1 (MuRf-1) and muscle atrophy F-box (MAFbx, as known as Atrogin-1), while immunohistochemistry was used to detect the expression of glial fibrillary acidic protein (GFAP), an indicator of astrocyte activation in the brain, reflecting the pathophysiological functional changes across systems. Results After hindlimb unloading, the experimental group showed significant decreases in body weight (P<0.001) and blood volume (P<0.01). During the experiment, hemoglobin, hematocrit, and red blood cell count levels significantly decreased (P<0.05) but gradually recovered. The expression levels of alanine aminotransferase and γ-glutamyltransferase initially decreased (P<0.05) before rebounding, while albumin significantly decreased (P<0.001) and globulin significantly increased (P<0.01). Creatinine significantly decreased (P<0.05). The average diameter of gastrocnemius muscle fibers in the experimental group significantly shortened (P<0.05), with a leftward shift in the distribution of muscle fiber diameters and an increase in small-diameter muscle fibers. Simultaneously, Atrogin-1 expression in the gastrocnemius and paravertebral muscles significantly increased (P<0.05). These changes are generally consistent with the effects of weightlessness on humans and animals in space. Furthermore, degenerative changes were observed in some neurons of the cortical parietal lobe, frontal lobe, and hippocampal regions of the experimental group, with a slight reduction in the number of Purkinje cells in the cerebellar region, and a significant enhancement of GFAP-positive signals in the hippocampal area (P<0.05). Conclusion Miniature pigs subjected to a -20° angle hind limb unloading for 30 days maybe serve as a new animal model for simulating weightlessness, applicable to related aerospace research.

Key words: Simulated weightlessness, Miniature pig, Animal model, Hindlimb unloading

中图分类号:

R-332

涂颖欣,纪依澜,王菲,等. 小型猪后肢去负荷模拟失重模型的建立与组织损伤研究[J]. 实验动物与比较医学, 2024, 44(5): 475-486. DOI: 10.12300/j.issn.1674-5817.2024.038.

TU Yingxin,JI Yilan,WANG Fei,et al. Evaluation of Simulated Weightlessness Model of Hindlimb Unloading Miniature Pigs and Their Tissue Damage[J]. Laboratory Animal and Comparative Medicine, 2024, 44(5): 475-486. DOI: 10.12300/j.issn.1674-5817.2024.038.

图/表 6

图1 后肢去负荷模拟失重实验中用定制金属笼固定实验组小型猪

Figure 1 Experimental group miniature pigs fixed in a customized metal cage for hindlimb unloading simulated weightlessness experiment

注：实验组小型猪（n=7）使用定制金属笼固定，并用帆布吊带悬挂，使其后肢离地去负荷，身体与地面呈-20°角。对照组小型猪（n=2）使用金属笼中饲养而不悬挂固定。A，体重变化（^***实验期间实验组体重变化与对照组相比具有显著差异）；B，血液红细胞（RBC）计数变化；C，血液血红蛋白（HGB）变化；D，血液红细胞比容（HCT）变化；E，血容量的变化（△PV为血浆容量变化量，^**实验第8天的实验组△PV与对照组相比具有显著差异）；F，血清丙氨酸氨基转移酶（ALT）变化；G，血清γ-谷氨酰转移酶（γ-GT）变化；H，血清白蛋白（ALB）变化；I，血清球蛋白（GLB）变化；J，肌酐（Cr）变化。^*P<0.05，^**P<0.01，^***P<0.001。
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图 2 后肢去负荷模拟失重实验期间实验组和对照组小型猪的部分基础体征指标变化
注：实验组小型猪（n=7）使用定制金属笼固定，并用帆布吊带悬挂，使其后肢离地去负荷，身体与地面呈-20°角。对照组小型猪（n=2）使用金属笼中饲养而不悬挂固定。A，体重变化（^***实验期间实验组体重变化与对照组相比具有显著差异）；B，血液红细胞（RBC）计数变化；C，血液血红蛋白（HGB）变化；D，血液红细胞比容（HCT）变化；E，血容量的变化（△PV为血浆容量变化量，^**实验第8天的实验组△PV与对照组相比具有显著差异）；F，血清丙氨酸氨基转移酶（ALT）变化；G，血清γ-谷氨酰转移酶（γ-GT）变化；H，血清白蛋白（ALB）变化；I，血清球蛋白（GLB）变化；J，肌酐（Cr）变化。^*P<0.05，^**P<0.01，^***P<0.001。

Figure 2 Changes in selected basic physical indicators of miniature pigs in the experimental and control groups during hindlimb unloading simulated weightlessness experiment
Note：Miniature pigs in the experimental group (n=7) were immobilized using customized metal cages and suspended from canvas slings so that their hind limbs were off the ground to unload and their bodies were at a -20° angle to the ground. Control group miniature pigs (n=2) were housed in metal cages without suspension immobilization. A, Changes in body weight during the experiment (^*** the body weight change of the experimental group is significantly different from the control group）; B, Changes in red blood cell count (RBC) during the experiment; C, Changes in hemoglobin（HGB） during the experiment; D, Changes in hematocrit (HCT) during the experiment; E, Changes in plasma volume change (△PV) during the experiment (^** the ΔPV of experimental group is significantly higher than the control group at the 8th day); F, Changes in serum alanine aminotransferase (ALT) during the experiment; G, Changes in serum γ-glutamyl transferase (γ-GT) during the experiment; H, Changes in serum albumin (ALB) during the experiment; I, Changes in serum globulin (GLB) during the experiment; J, Changes in creatinine (Cr) during the experiment. ^*P<0.05， ^**P<0.01， ^***P<0.001.

注：实验组小型猪（n=7）使用定制金属笼固定，并用帆布吊带悬挂，使其后肢离地去负荷，身体与地面呈-20°角。对照组小型猪（n=2）使用金属笼中饲养而不悬挂固定。A，各动脉血管的HE染色图（比例尺大小为100 μm）；B，各动脉血管的Masson染色图（比例尺大小为100 μm）；C，各动脉血管内-中膜厚度的统计分析结果。
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图3 后肢去负荷模拟失重实验结束后小型猪动脉血管组织病理学及厚度变化
注：实验组小型猪（n=7）使用定制金属笼固定，并用帆布吊带悬挂，使其后肢离地去负荷，身体与地面呈-20°角。对照组小型猪（n=2）使用金属笼中饲养而不悬挂固定。A，各动脉血管的HE染色图（比例尺大小为100 μm）；B，各动脉血管的Masson染色图（比例尺大小为100 μm）；C，各动脉血管内-中膜厚度的统计分析结果。

Figure 3 Histopathology and thickness changes of arterial blood vessels in miniature pigs after the hindlimb unloading simulated weightlessness experiment
Note：Miniature pigs in the experimental group (n=7) were immobilized using customized metal cages and suspended from canvas slings so that their hind limbs were off the ground to unload and their bodies were at a -20° angle to the ground. Control group miniature pigs (n=2) were housed in metal cages without suspension immobilization. A, HE staining of each artery (the scale size is 100 μm); B, Masson staining of each artery (the scale size is 100 μm); C, Statistical analysis of intima-media thickness in each artery.

注：实验组小型猪（n=7）使用定制金属笼固定，并用帆布吊带悬挂，使其后肢离地去负荷，身体与地面呈-20°角。对照组小型猪（n=2）使用金属笼中饲养而不悬挂固定。A、B、C，分别是各骨骼肌组织（腓肠肌、比目鱼肌、椎旁肌肉和前肢肌肉）的HE染色图（低倍镜及高倍镜视野下比例尺大小分别为100 μm和20 μm）、肌纤维直径统计图和肌纤维直径分布图。^*P<0.05。
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图4 后肢去负荷模拟失重实验结束后小型猪骨骼肌结构和肌纤维直径变化
注：实验组小型猪（n=7）使用定制金属笼固定，并用帆布吊带悬挂，使其后肢离地去负荷，身体与地面呈-20°角。对照组小型猪（n=2）使用金属笼中饲养而不悬挂固定。A、B、C，分别是各骨骼肌组织（腓肠肌、比目鱼肌、椎旁肌肉和前肢肌肉）的HE染色图（低倍镜及高倍镜视野下比例尺大小分别为100 μm和20 μm）、肌纤维直径统计图和肌纤维直径分布图。^*P<0.05。

Figure 4 Changes in skeletal muscle structure and muscle fiber diameter of miniature pigs after the hindlimb unloading simulated weightlessness experiment
Note：Miniature pigs in the experimental group (n=7) were immobilized using customized metal cages and suspended from canvas slings so that their hind limbs were off the ground to unload and their bodies were at a -20° angle to the ground. Control group miniature pigs (n=2) were housed in metal cages without suspension immobilization. Figures A, B, and C represent the HE staining images (the scale size is 100 μm or 20 μm by low and high magnification) , the statistical chart of muscle fiber diameters, and the distribution chart of muscle fiber diameters for various skeletal muscle tissues (gastrocnemius muscle, soleus muscle, paravertebral muscle, and forelimb muscle),respectively. ^*P<0.05.

注：实验组小型猪（n=7）使用定制金属笼固定，并用帆布吊带悬挂，使其后肢离地去负荷，身体与地面呈-20°角。对照组小型猪（n=2）使用金属笼中饲养而不悬挂固定。A，蛋白质印迹法检测比目鱼肌和腓肠肌中MuRf-1和Atrogin-1的表达量；B，蛋白质印迹法检测椎旁肌肉和前肢肌肉中MuRf-1和Atrogin-1的表达量。^*P<0.05，^**P<0.01。
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图5 后肢去负荷模拟失重实验结束后小型猪的肌肉萎缩相关蛋白表达量变化
注：实验组小型猪（n=7）使用定制金属笼固定，并用帆布吊带悬挂，使其后肢离地去负荷，身体与地面呈-20°角。对照组小型猪（n=2）使用金属笼中饲养而不悬挂固定。A，蛋白质印迹法检测比目鱼肌和腓肠肌中MuRf-1和Atrogin-1的表达量；B，蛋白质印迹法检测椎旁肌肉和前肢肌肉中MuRf-1和Atrogin-1的表达量。^*P<0.05，^**P<0.01。

Figure 5 Changes in expression levels of muscle atrophy proteins MuRf-1 and Atrogin-1 in miniature pigs after the hindlimb unloading simulated weightlessness experiment
Note：Miniature pigs in the experimental group (n=7) were immobilized using customized metal cages and suspended from canvas slings so that their hind limbs were off the ground to unload and their bodies were at a -20° angle to the ground. Control group miniature pigs (n=2) were housed in metal cages without suspension immobilization. A, Expression levels of MuRf-1 and Atrogin-1 in soleus muscle and gastrocnemius muscle detected using western blotting; B, Expression levels of MuRf-1 and Atrogin-1 in paravertebral muscle and forelimb muscle detected using western blotting. ^*P<0.05， ^**P<0.01.

注：实验组小型猪（n=7）使用定制金属笼固定，并用帆布吊带悬挂，使其后肢离地去负荷，身体与地面呈-20°角。对照组小型猪（n=2）使用金属笼中饲养而不悬挂固定。A，各脑区的HE染色（比例尺大小为20 μm），箭头示变性的神经元；B，各脑区神经胶质原纤维酸性蛋白（GFAP）免疫组织化学染色结果（比例尺大小为50 μm）；C，各脑区GFAP表达定量分析（IOD，累积光密度）。^**P<0.01。
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图6 后肢去负荷模拟失重实验结束后小型猪各脑区的组织病理学及相关蛋白表达变化
注：实验组小型猪（n=7）使用定制金属笼固定，并用帆布吊带悬挂，使其后肢离地去负荷，身体与地面呈-20°角。对照组小型猪（n=2）使用金属笼中饲养而不悬挂固定。A，各脑区的HE染色（比例尺大小为20 μm），箭头示变性的神经元；B，各脑区神经胶质原纤维酸性蛋白（GFAP）免疫组织化学染色结果（比例尺大小为50 μm）；C，各脑区GFAP表达定量分析（IOD，累积光密度）。^**P<0.01。

Figure 6 Changes in histopathology and related protein expression in each brain region of miniature pigs after the hindlimb unloading simulated weightlessness experiment
Note：Miniature pigs in the experimental group (n=7) were immobilized using customized metal cages and suspended from canvas slings so that their hind limbs were off the ground to unload and their bodies were at a -20° angle to the ground. Control group miniature pigs (n=2) were housed in metal cages without suspension immobilization. A, HE staining of each brain region (the scale size is 20 μm), the arrow indicates the degenerating neuron; B, Glial fibrillary acidic protein (GFAP) immunohistochemistry staining of each brain region (the scale size is 50 μm); C, Quantitative analysis of GFAP expression in each brain region (IOD, integrated optical density).^**P<0.01.

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小型猪后肢去负荷模拟失重模型的建立与组织损伤研究

Evaluation of Simulated Weightlessness Model of Hindlimb Unloading Miniature Pigs and Their Tissue Damage

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