多技术联合评估缺氧性肺动脉高压小鼠模型

doi:10.12300/j.issn.1674-5817.2025.181

实验动物与比较医学 ›› 2026, Vol. 46 ›› Issue (4): 476-486.DOI: 10.12300/j.issn.1674-5817.2025.181

多技术联合评估缺氧性肺动脉高压小鼠模型

杜红枝¹(), 范瑾²^,³, 魏晓露², 王连嵋², 刘艳², 陈韡亚², 陈腾飞², 高云航², 宋玲², 张广平²()(), 侯红平²()

^1.山西省儿童医院超声科, 太原 030013
^2.中国中医科学院中药研究所, 道地药材品质保障与资源持续利用全国重点实验室, 北京 100700
^3.北京市第二医院, 北京 100031

收稿日期:2025-11-07 修回日期:2026-04-23 出版日期:2026-08-25 发布日期:2026-08-22
通讯作者: 侯红平（1988—），女，博士，副研究员，硕士生导师，主要从事慢性疾病研究。E-mail：hphou@icmm.ac.cn。ORCID：0009-0005-0371-525X；
张广平（1975—），男，博士，研究员，博士生导师，主要从事呼吸系统疾病研究。E-mail：gpzhang@icmm.ac.cn。ORCID：0000-0001-5732-7520
作者简介:杜红枝（1987—），女，硕士，主治医师，主要从事影像学检查。E-mail： 836119745@qq.com。ORCID：0009-0002-8613-6197
基金资助:
国家自然科学基金资助项目-青年科学基金“基于PINK1/Parkin介导的线粒体自噬动态平衡在痰热清干预慢阻肺的机制研究”(82104502);道地药材品质保障与资源持续利用全国重点实验室2024年度科研专项“鼻渊通窍颗粒对幼年腺样体肥大动物模型作用的药效物质基础及机制研究”(CI2023E002-Y-43)

Multimodal Assessment of a Hypoxic Pulmonary Hypertension Mouse Model

DU Hongzhi¹(), FAN Jin²^,³, WEI Xiaolu², WANG Lianmei², LIU Yan², CHEN Weiya², CHEN Tengfei², GAO Yunhang², SONG Ling², ZHANG Guangping²()(), HOU Hongping²()

^1.Department of Ultrasound, Shanxi Children's Hospital, Taiyuan 030013, China
^2.Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing 100700, China
^3.Beijing No. 2 Hospital, Beijing 100031, China

Received:2025-11-07 Revised:2026-04-23 Published:2026-08-25 Online:2026-08-22
Correspondence to: HOU Hongping (ORCID: 0009-0005-0371-525X), E-mail: hphou@icmm.ac.cn;
ZHANG Guangping (ORCID: 0000-0001 -5732-7520), E-mail: gpzhang@icmm.ac.cn

摘要/Abstract

摘要：

目的通过间歇性低氧诱导构建小鼠缺氧性肺动脉高压（hypoxic pulmonary hypertension，HPH）模型，并建立全面、可靠的HPH模型综合评估体系，为该病的机制研究及转化应用提供实验依据。方法将24只雄性SPF级BALB/c小鼠随机分为对照组和模型组，每组12只，将模型组小鼠置于低压氧舱控制系统中制备HPH模型，对照组小鼠不予任何处理。造模28 d后，综合运用一般状态评分量表、超声心动图检查、血流动力学、血气分析、血液学检测、脏器系数检测、病理学观察和ELISA检测，对各组小鼠的病理生理特点进行评估，并对超声心动图指标、肺组织中内皮素-1（endothelin-1，ET-1）和B型利尿钠肽前体的氨基末端（N-terminal pro-B-type natriuretic peptide，NT-proBNP）含量以及其他指标进行相关性分析。结果随着造模时间的延长，与对照组相比，模型组小鼠的体重、饮水量和活动状态均有所下降（P<0.05）。超声心动图显示，与对照组相比，模型组小鼠右心室各径线增大（P<0.01），右室前壁肥厚（P<0.01），主肺动脉内径增宽（P<0.01），肺动脉瓣收缩峰值流速、三尖瓣环收缩期位移及三尖瓣环收缩期峰值流速测值均明显降低（P<0.001），部分小鼠出现三尖瓣反流。血流动力学结果显示，与对照组相比，模型组小鼠右心室收缩压升高（P<0.001）。血气分析结果显示，与对照组相比，模型组小鼠pH、氧分压、血氧饱和度、实际碳酸氢根和二氧化碳总量均有所降低（P<0.01）。血液学指标显示，与对照组相比，模型组小鼠的淋巴细胞（P<0.05）和网织红细胞（P<0.001）计数均有所降低。脏器系数检测结果显示，与对照组相比，模型组小鼠心脏和肺脏的脏器系数均显著升高（P＜0.05和P＜0.001）。病理检查显示，与对照组相比，模型组右心室肥厚系数显著升高（P<0.001），右心室、肺动脉和肺血管有不同程度的受损，肺动脉壁厚度系数和肺动脉面积系数均显著升高（P<0.001）。ELISA检测结果显示，与对照组相比，模型组小鼠肺组织中ET-1和NT-proBNP显著升高（P<0.05，P<0.001）。相关性分析显示，部分超声心动图指标与HPH发展中的多项指标相关性较高（P<0.05）。结论超声心动图能够准确评估HPH的右心室结构、功能受损及肺动脉高压等一系列血流动力学改变；实验室检查不仅有助于验证模型是否构建成功，而且能深入揭示HPH的发病机制，评估干预效果，为临床转归提供科学依据；病理学检查可以进一步证实肺血管重构和右心负荷增加的改变。这种多模态分析为HPH的基础和转化研究提供了可靠的动物模型及评估模式，对探索疾病机制和开发精准治疗策略具有重要意义。

关键词: 超声心动图, 血流动力学, 间歇性低氧肺动脉高压, 病理学检查, 小鼠

Abstract:

Objective To establish a mouse model of hypoxic pulmonary hypertension (HPH) through intermittent hypoxia induction, and to develop a comprehensive and reliable evaluation system for the HPH model, thereby providing experimental evidence for mechanistic studies and translational applications related to this disease. Methods Twenty-four male specific pathogen-free (SPF) BALB/c mice were randomly divided into a control group and a model group, with 12 mice per group. Mice in the model group were placed in a hypobaric oxygen chamber control system to establish the HPH model, whereas mice in the control group received no intervention. After 28 days of modeling, a comprehensive evaluation of the pathophysiological characteristics of both groups was performed using a general condition scoring scale, echocardiography, hemodynamic measurements, blood gas analysis, hematological tests, organ coefficient determination, histopathological examination, and enzyme-linked immunosorbent assay (ELISA). In addition, correlation analyses were conducted among echocardiographic parameters, the contents of endothelin?1 (ET?1) and N?terminal pro?B?type natriuretic peptide (NT?proBNP) in lung tissue, and other measured indices. Results With prolonged modeling duration time, body weight, water intake, and activity level of mice in the model group were significantly decreased compared with the control group (P<0.05). Echocardiography showed that, compared with the control group, the model group exhibited increased right ventricular dimensions (P<0.01), right ventricular anterior wall thickening (P<0.01), and widened main pulmonary artery diameter (P<0.01), whereas the peak systolic velocity across the pulmonary valve, tricuspid annular plane systolic excursion, and peak systolic velocity of the tricuspid annulus were significantly decreased (P<0.001); tricuspid regurgitation was observed in some model animals. Hemodynamic results revealed that right ventricular systolic pressure was elevated in the model group compared with the control group (P<0.001). Blood gas analysis showed that pH, partial pressure of oxygen, oxygen saturation, actual bicarbonate, and total carbon dioxide were all decreased in the model group compared with the control group (P<0.01). Hematological indices demonstrated that lymphocyte counts (P<0.05) and reticulocyte counts (P<0.001) were decreased in the model group compared with the control group. Compared with the control group, the organ coefficients of heart and lung in the model group were significantly increased (P<0.05 and P<0.001). Pathological examination revealed that the right ventricular hypertrophy index was significantly increased in the model group (P<0.001), with varying degrees of damage to the right ventricle, pulmonary artery, and pulmonary vessels; both the pulmonary artery wall thickness percentage and the pulmonary wall area percentage were significantly elevated (P<0.001). ELISA results showed that the levels of ET?1 and NT?proBNP in lung tissues were significantly increased in the model group compared with the control group (P<0.05 and P<0.001, respectively). Correlation analysis indicated that some echocardiographic parameters were highly correlated with multiple indices in the development of HPH (P<0.05). Conclusion Echocardiography can accurately assess a series of hemodynamic changes in HPH, including right ventricular structural, functional impairment, and pulmonary hypertension. Laboratory tests not only help verify whether the model has been successfully established, but also provide deeper insights into the pathogenesis of HPH, evaluate the effects of interventions, and offer scientific evidence for clinical outcomes. Pathological examination can further confirm the alterations in pulmonary vascular remodeling and increased right heart load. This multimodal analysis provides a reliable animal model and evaluation paradigm for both basic and translational research on HPH, and is of great significance for exploring disease mechanisms and developing precision therapeutic strategies.

Key words: Echocardiography, Hemodynamics, Intermittent hypoxia-induced pulmonary hypertension, Pathological examination, Mice

中图分类号:

R-332

杜红枝,范瑾,魏晓露,等. 多技术联合评估缺氧性肺动脉高压小鼠模型[J]. 实验动物与比较医学, 2026, 46(4): 476-486. DOI: 10.12300/j.issn.1674-5817.2025.181.

DU Hongzhi,FAN Jin,WEI Xiaolu,et al. Multimodal Assessment of a Hypoxic Pulmonary Hypertension Mouse Model[J]. Laboratory Animal and Comparative Medicine, 2026, 46(4): 476-486. DOI: 10.12300/j.issn.1674-5817.2025.181.

图/表 8

表1 一般状态评分量表

Table 1 General condition scoring scale

评价维度 Evaluation dimensions	评分标准/分 Scoring criteria/points
评价维度 Evaluation dimensions	0	1	2	3
精神状态 Mental status	精神饱满，反应灵敏，受刺激（如轻触）后迅速回避	精神稍萎靡，反应较迟钝，受刺激后缓慢回避	精神萎靡，嗜睡，刺激后无明显回避反应	精神极度萎靡，处于濒死状态，对刺激无反应
毛发状态 Hair condition	毛发光洁顺滑，紧贴体表，无杂乱、脱毛	毛发略粗糙，少量杂乱，无脱毛	毛发干枯、杂乱，局部蓬松，伴少量脱毛	毛发严重干枯、蓬乱，大面积脱毛或结块
活动度 Activity level	活动频繁，自主探索活跃，笼内穿梭自如	活动减少，多静坐，偶尔穿梭走动	活动极少，仅在摄食饮水时短暂活动，大部分时间蜷缩一隅	几乎无自主活动，蜷缩不动
呼吸状态 Respiratory status	呼吸平稳，胸腹起伏均匀，无异常呼吸音	呼吸频率轻度加快，胸腹起伏略明显，无张口呼吸	呼吸急促，胸腹起伏剧烈，伴轻微张口呼吸或喘鸣	严重呼吸困难，张口呼吸，喘鸣明显，甚至出现发绀（口唇/肢端青紫）
饮食与体况 Diet and body condition	摄食、饮水正常，体重稳定增长，体形匀称	摄食、饮水量轻度下降，体重增长缓慢或无明显变化	摄食、饮水量显著下降，体重下降＞5%，体型偏瘦	几乎不进食、饮水，体重下降＞10%，体型极度消瘦，皮肤弹性差

注：n=12；与对照组相比，^*P＜0.05，^**P＜0.01，^***P＜0.001。
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图1 对照组和模型组小鼠的一般状态评分（A）和体重变化（B）

注：

n=12；与对照组相比，^*P＜0.05，^**P＜0.01，^***P＜0.001。

Figure 1 General condition scores （A） and body weight changes （B） of mice in the control and model groups

Note：

n=12； compared with the control group， ^*P＜0.05， ^**P＜0.01， ^***P＜0.001.

表2 对照组和模型组小鼠的超声参数 (n=6,

x ˉ

±s)

Table 2 Echocardiograms parameters in mice of the control and model groups

xˉ±s)
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指标 Parameters	对照组 Control group	模型组 Model group
RVWT δ/mm	0.35±0.02	0.50±0.10^**
RVAPD l/mm	1.23±0.13	1.59±0.09^***
MPAD l/mm	1.45±0.10	1.69±0.10^***
Vpa /（mm·s^-1）	694.33±41.70	579.48±41.43^***
RVTD l/mm	2.39±0.11	3.07±0.15^***
RVLD l/mm	3.29±0.29	3.87±0.30^**
TAPSV /（mm·s^-1）	63.84±9.02	38.90±8.90^***
TAPSE l/mm	1.17±0.11	0.69±0.24^***

表2 对照组和模型组小鼠的超声参数 (n=6, $x ˉ$ ±s)

Table 2 Echocardiograms parameters in mice of the control and model groups

指标 Parameters	对照组 Control group	模型组 Model group
RVWT δ/mm	0.35±0.02	0.50±0.10^**
RVAPD l/mm	1.23±0.13	1.59±0.09^***
MPAD l/mm	1.45±0.10	1.69±0.10^***
Vpa /（mm·s^-1）	694.33±41.70	579.48±41.43^***
RVTD l/mm	2.39±0.11	3.07±0.15^***
RVLD l/mm	3.29±0.29	3.87±0.30^**
TAPSV /（mm·s^-1）	63.84±9.02	38.90±8.90^***
TAPSE l/mm	1.17±0.11	0.69±0.24^***

图2 对照组和模型组小鼠的超声心动图

Figure 2 Echocardiograms of control and model mice

表3 对照组和模型组小鼠的血气和血液学指标检测结果 (n=6，

x ˉ

±s)

Table 3 Results of blood gas and hematological tests in mice of the control and model groups

xˉ±s)
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检测指标 Measured parameters		对照组 Control group	模型组 Model group
右心室收缩压 Right ventricular systolic pressure	RVSP p/mmHg	4.76±0.95	9.46±0.75^***
血气指标 Blood gas indicators	pH	7.037±0.089	6.899±0.045^**
	PCO₂p/mmHg	67.9±4.5	57.6±11.6
	PO₂p/mmHg	108.0±4.0	85.3±4.1^***
	SO₂φ/%	94.2±1.6	85.5±3.8^***
	HCO₃^-c/（mmol·L^-1）	18.0±4.0	10.8±1.7^**
	TCO₂c/(mmol·L^-1)	20.0±3.8	12.0±2.1^**
	a/A	1	1
	Lac c/(mmol·L^-1)	6.59±0.63	9.51±1.13^***
	WBC C_cell /(10⁹·L^-1)	5.12±0.26	7.11±0.81^***
血液学指标 Hematological indicators	RBC C_cell /(10¹²·L^-1)	10.46±0.29	11.31±0.40^**
	PCV φ/%	47.03±0.75	49.57±1.30^**
	HGB ρ/(g·L^-1)	157.33±1.37	169.00±3.46^***
	PLT C_cell /(10⁹·L^-1)	535.67±276.84	1 229.67±90.20^***
	RDW-SD/fL	23.4±0.5	26.1±0.2^***
	RDW-CV/%	19.3±0.3	19.9±0.3^**
	RDW φ/fL	7.53±0.51	8.17±0.40^*
	NEUT C_cell /(10⁹·L^-1)	0.83±0.07	1.46±0.32^**
	LYMPH C_cell /(10⁹·L^-1)	5.39±1.21	3.84±0.44^*
	RET C_cell /(10⁹·L^-1)	3.62±0.27	2.06±0.31^***

表3 对照组和模型组小鼠的血气和血液学指标检测结果 (n=6， $x ˉ$ ±s)

Table 3 Results of blood gas and hematological tests in mice of the control and model groups

检测指标 Measured parameters		对照组 Control group	模型组 Model group
右心室收缩压 Right ventricular systolic pressure	RVSP p/mmHg	4.76±0.95	9.46±0.75^***
血气指标 Blood gas indicators	pH	7.037±0.089	6.899±0.045^**
	PCO₂p/mmHg	67.9±4.5	57.6±11.6
	PO₂p/mmHg	108.0±4.0	85.3±4.1^***
	SO₂φ/%	94.2±1.6	85.5±3.8^***
	HCO₃^-c/（mmol·L^-1）	18.0±4.0	10.8±1.7^**
	TCO₂c/(mmol·L^-1)	20.0±3.8	12.0±2.1^**
	a/A	1	1
	Lac c/(mmol·L^-1)	6.59±0.63	9.51±1.13^***
	WBC C_cell /(10⁹·L^-1)	5.12±0.26	7.11±0.81^***
血液学指标 Hematological indicators	RBC C_cell /(10¹²·L^-1)	10.46±0.29	11.31±0.40^**
	PCV φ/%	47.03±0.75	49.57±1.30^**
	HGB ρ/(g·L^-1)	157.33±1.37	169.00±3.46^***
	PLT C_cell /(10⁹·L^-1)	535.67±276.84	1 229.67±90.20^***
	RDW-SD/fL	23.4±0.5	26.1±0.2^***
	RDW-CV/%	19.3±0.3	19.9±0.3^**
	RDW φ/fL	7.53±0.51	8.17±0.40^*
	NEUT C_cell /(10⁹·L^-1)	0.83±0.07	1.46±0.32^**
	LYMPH C_cell /(10⁹·L^-1)	5.39±1.21	3.84±0.44^*
	RET C_cell /(10⁹·L^-1)	3.62±0.27	2.06±0.31^***

注：RVHI，右心室肥厚系数；ET-1，内皮素-1；NT-proBNP，B型利尿钠肽前体的氨基末端。与对照组相比，^*P＜0.05，^***P＜0.001；n=6。
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图3 对照组和模型组小鼠的脏器系数（A）、右心室肥厚系数（B）及肺组织中内皮素-1和B型利尿钠肽前体的氨基末端含量（C～D）
注：RVHI，右心室肥厚系数；ET-1，内皮素-1；NT-proBNP，B型利尿钠肽前体的氨基末端。与对照组相比，^*P＜0.05，^***P＜0.001；n=6。

Figure 3 Organ coefficient （A）， right ventricular hypertrophy index （B） and endothelin-1 and N-terminal pro-B-type natriuretic peptide （C-D） in lung tissue of control and model mice
Note： RVHI， right ventricular hypertrophy index； ET-1， endothelin-1； NT-proBNP， N-terminal pro-B-type natriuretic peptide. Compared with the control group， ^*P＜0.05， ^***P＜0.001； n=6.

注：A，对照组和模型组小鼠心脏、肺动脉和肺组织的病理学观察结果，比例尺为50 μm；B，对照组和模型组小鼠的血管壁厚度系数（WT）和血管壁面积系数（WA）。与对照组相比，^***P＜0.001；n=6。
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图4 对照组和模型组小鼠的组织病理学观察结果和肺血管参数
注：A，对照组和模型组小鼠心脏、肺动脉和肺组织的病理学观察结果，比例尺为50 μm；B，对照组和模型组小鼠的血管壁厚度系数（WT）和血管壁面积系数（WA）。与对照组相比，^***P＜0.001；n=6。

Figure 4 Histopathological observations and pulmonary vascular parameters in mice of the control and model groups
Note： A， Histopathology of the heart， pulmonary artery， and lung tissue in the control and model groups， scale bar=50 μm； B，Wall thickness percentage （WT） and wall area percentage （WA） in the control and model groups. Compared with the control group， ^***P＜0.001； n=6.

注：A，超声心动图指标与心肺功能病理损伤指标的相关性；B，超声心动图指标与血气分析指标的相关性；C，血液学指标与心肺功能病理损伤指标的相关性；D，血气分析指标与心肺功能病理损伤指标的相关性。RVWT，右室前壁厚度；RVAPD，右心室前后径；MPAD，肺动脉主干内径；Vpa，肺动脉瓣收缩峰值流速；RVTD，右心室左右径；RVLD，右心室上下径；TAPSV，三尖瓣环收缩期峰值流速；TR，三尖瓣反流；TAPSE，三尖瓣环收缩期位移；RVSP，右心室收缩压；RVHI，右心室肥厚系数；WA，血管壁面积系数；WT，血管壁厚度系数；ET-1，内皮素-1；NT-proBNP，B型利尿钠肽前体的氨基末端；PCO₂，二氧化碳分压；PO₂，氧分压；SO₂，血氧饱和度；HCO₃^-，实际碳酸氢根；TCO₂，二氧化碳总量；Lac，乳酸；WBC，白细胞；RBC，红细胞；HGB，血红蛋白；PCV，血细胞比容；PLT，血小板；RDW-SD，红细胞体积分布宽度标准差；RDW-CV，红细胞体积分布宽度变异系数；RDW，红细胞体积分布宽度；NEUT，中性粒细胞；LYMPH，淋巴细胞；RET，网织红细胞。
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图5 模型组小鼠各指标间相关性的分析热图
注：A，超声心动图指标与心肺功能病理损伤指标的相关性；B，超声心动图指标与血气分析指标的相关性；C，血液学指标与心肺功能病理损伤指标的相关性；D，血气分析指标与心肺功能病理损伤指标的相关性。RVWT，右室前壁厚度；RVAPD，右心室前后径；MPAD，肺动脉主干内径；Vpa，肺动脉瓣收缩峰值流速；RVTD，右心室左右径；RVLD，右心室上下径；TAPSV，三尖瓣环收缩期峰值流速；TR，三尖瓣反流；TAPSE，三尖瓣环收缩期位移；RVSP，右心室收缩压；RVHI，右心室肥厚系数；WA，血管壁面积系数；WT，血管壁厚度系数；ET-1，内皮素-1；NT-proBNP，B型利尿钠肽前体的氨基末端；PCO₂，二氧化碳分压；PO₂，氧分压；SO₂，血氧饱和度；HCO₃^-，实际碳酸氢根；TCO₂，二氧化碳总量；Lac，乳酸；WBC，白细胞；RBC，红细胞；HGB，血红蛋白；PCV，血细胞比容；PLT，血小板；RDW-SD，红细胞体积分布宽度标准差；RDW-CV，红细胞体积分布宽度变异系数；RDW，红细胞体积分布宽度；NEUT，中性粒细胞；LYMPH，淋巴细胞；RET，网织红细胞。

Figure 5 Heatmap of correlation analysis among various indicators in the model group mice
Note： A， Correlation between echocardiographic indicators and indicators of pathological damage to cardiopulmonary function； B， Correlation between echocardiographic parameters and blood gas analysis indicators； C， Correlation between hematological parameters and indicators of pathological damage to cardiopulmonary function； D， Correlation between blood gas analysis indicators and indicators of pathological damage to cardiopulmonary function. RVWT， right ventricular anterior wall thickness； RVAPD， right ventricular anteroposterior diameter； MPAD， main pulmonary artery diameter； Vpa， peak systolic velocity across the pulmonary valve； RVTD， right ventricular transverse diameter； RVLD， right ventricular longitudinal diameter； TAPSV， peak systolic velocity of tricuspid annulus； TR， tricuspid regurgitation； TAPSE， tricuspid annular plane systolic excursion； RVSP， right ventricular systolic pressure； RVHI，right ventricular hypertrophy index； WA， wall area percentage； WT， wall thickness percentage； ET-1， endothelin-1； NT-proBNP， N-terminal pro-B-type natriuretic peptide； PCO₂， partial pressure of carbon dioxide； PO₂， partial pressure of oxygen； SO₂， oxygen saturation； HCO₃^-， actual bicarbonate； TCO₂， total carbon dioxide； Lac， lactic acid； WBC， white blood cell； RBC， red blood cell； HGB， hemoglobin； PCV， packed cell volume； PLT， platelet； RDW-SD， red cell volume distribution width standard deviation； RDW-CV， red cell volume distribution width coefficient of variation； RDW， red cell volume distribution width； NEUT， neutrophil； LYMPH， lymphocyte； RET， reticulocyte.

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多技术联合评估缺氧性肺动脉高压小鼠模型

Multimodal Assessment of a Hypoxic Pulmonary Hypertension Mouse Model

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