低氧敏感和低氧耐受型Wistar大鼠筛选及其G1代的低氧敏感性初探

doi:10.12300/j.issn.1674-5817.2024.017

实验动物与比较医学 ›› 2024, Vol. 44 ›› Issue (4): 374-383.DOI: 10.12300/j.issn.1674-5817.2024.017

低氧敏感和低氧耐受型Wistar大鼠筛选及其G₁代的低氧敏感性初探

肖攀¹^,², 王红义¹^,², 陆璐¹^,², 张梅¹^,², 陈克明¹^,², 申栋帅¹^,²()(), 牛廷献¹^,²()()

^1.中国人民解放军联勤保障部队第九四〇医院基础医学实验室, 兰州 730050
^2.甘肃省干细胞与基因药物重点实验室, 兰州 730050

收稿日期:2024-01-30 修回日期:2024-05-30 出版日期:2024-09-06 发布日期:2024-08-25
通讯作者: 申栋帅（1992—），男，博士，技师，研究方向：人类疾病模型的构建及发病机制研究。E-mail： shends1992@163.com。ORCID： 0009-0002-7796-058X；
牛廷献（1966—），男，博士，主任技师，研究方向：人类疾病模型的构建及发病机制研究。E-mail： E–mail：ntx10000@163.com。ORCID： 0009-0000-5803-2150；
作者简介:肖攀（1991—），男，本科，主管技师，研究方向：人类疾病动物模型研制和应用研究。E-mail: 997078955@qq.com
牛廷献，男，主任技师，博士，中国人民解放军联勤保障部队第九四〇医院医疗保障中心基础医学实验室副主任、实验动物学学科带头人。长期从事实验动物饲养、繁育、质量控制与人类疾病动物模型的构建及机制研究工作，主要研究方向为高原病及高原战创伤的防治。兼任全军医学科学技术委员会实验动物学专业委员会常务委员，全军实验动物管理委员会专家库专家、专家委员会委员，甘肃省实验动物专家委员会专家库专家，甘肃省实验动物产业技术创新战略联盟副理事长，甘肃省实验动物地方标准委员会副主任。曾主持或参与完成军队和省（部）级科研课题12项，目前主持全军实验动物专项面上项目和全军实验动物平台建设项目各1项；先后以第一作者或通讯作者发表学术论文43篇，主编或参编学术著作2部；获甘肃省科技进步奖3项、军队科技进步奖2项，获国家实用新型专利2项。(ORCID: 0009-0000-5803-2150), E–mail: ntx10000@163.com
基金资助:
军队实验动物专项科研课题“高原低氧敏感型大鼠的筛选及培育”(SYDW〔2018〕12);“模拟高原低压舱与高原实地实验室共同实验差异性研究”(SYDW〔2020〕27);甘肃省科技计划项目-自然科学基金实验动物专项“高原实地与模拟高原环境大鼠肺水肿模型的建立及差异性分析”(22JR5RA023);“高原肺动脉高压大鼠模型的建立及自噬研究”(23JRRA536);“低氧敏感大鼠F4-F5代的培育及鉴定”(24JRRA010)

Screening of Hypoxia-Sensitive and Hypoxia-Tolerant Wistar Rats and Preliminary Exploration of Hypoxia Sensitivity in Their G₁Generation

XIAO Pan¹^,², WANG Hongyi¹^,², LU Lu¹^,², ZHANG Mei¹^,², CHEN Keming¹^,², SHEN Dongshuai¹^,²()(), NIU Tingxian¹^,²()()

^1.Basic Medicine Laboratory, the 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou 730050, China
^2.Gansu Key Laboratory of Stem Cells and Genetic Drug, Lanzhou 730050, China

Received:2024-01-30 Revised:2024-05-30 Published:2024-08-25 Online:2024-09-06
Contact: SHEN Dongshuai (ORCID: 0009-0002-7796-058X), E–mail: shends1992@163.com;
NIU Tingxian (ORCID: 0009-0000-5803-2150), E–mail: ntx10000@163.com;

摘要/Abstract

摘要：

目的将G₀代普通型Wistar大鼠筛选并传代，分别得到低氧敏感型和低氧耐受型G₁代大鼠，初步探讨G₁代大鼠和普通型大鼠的低氧敏感性差异。方法取200只Wistar大鼠（雌雄各半）作为G₀代，置于氧浓度控制系统中，记录G₀代大鼠在3%氧气体积分数下从放入至濒死的时间（即耐低氧时间）。挑选耐低氧时间最短的30只大鼠（雌雄各半）进行交配传代，得到G₁代低氧敏感型大鼠；挑选耐低氧时间最长的30只大鼠（雌雄各半）进行交配传代，得到G₁代低氧耐受型大鼠。另取24只普通型Wistar大鼠随机分为空白对照组和模型对照组，每组12只（雌雄各半）。空白对照组大鼠置于常氧环境，模型对照组大鼠、G₁代低氧敏感型大鼠（即G₁敏感组）和G₁代低氧耐受型大鼠（即G₁耐受组）一同置入低压低氧实验舱（模拟海拔5 000 m环境），12 h后检测或观察血气、血常规、血生化、病理切片和低氧相关基因等指标，比较4组动物的低氧敏感性差异。结果与G₀代普通型大鼠相比，G₁代耐受型大鼠的耐低氧时间显著延长（P<0.01）。相比于模型对照组，G₁耐受组大鼠的氧饱和度（oxygen saturation，SatO₂）显著升高（P<0.05）；G₁敏感组大鼠的白细胞计数（white blood cell，WBC）、中性粒细胞计数（neutrophil，NEUT）、血红蛋白浓度（hemoglobin，HGB）、红细胞比容（hematocrit，HCT）、红细胞分布宽度（red blood cell distribution width，RDW）、血小板计数（platelet count，PLT）和肌酐（creatinine，Cr）水平显著升高（P<0.05或P<0.01），实际碳酸氢盐（actual bicarbonate，AB）含量显著降低（P<0.05），脑系数和肺系数显著升高（P<0.05）。此外，病理切片结果显示模型对照组、G₁敏感组和G₁耐受组大鼠的脑组织和肺组织均受到明显损伤，且3组大鼠脑组织中低氧诱导因子-1α（hypoxia-inducible factor-1α，HIF-1α）和血管内皮生长因子A（vascular endothelial growth factor A，VEGFA）基因的表达水平无显著差异（P>0.05）。结论相比普通型大鼠，G₁代低氧敏感型/耐受型大鼠表现出良好的低氧敏感/耐受性状趋势，但仍需通过不断近交筛选传代来纯化并稳固性状。

关键词: Wistar大鼠, 低氧敏感, 低氧耐受, 血气分析, 血液指标

Abstract:

Objective By screening and passaging G₀ generation Wistar rats, we obtained hypoxia-sensitive and hypoxia-tolerant G₁ generation rats, and then the differences in hypoxia sensitivity among these rats were preliminarily explored. Methods 200 Wistar rats (half male and half female) were selected as G₀ generation and placed in a controlled oxygen concentration system. The hypoxia tolerance time, which refers to the time from placement to near death, was recorded for the G₀ generation rats at an oxygen volume fraction of 3%. 30 rats (half male and half female) with the shortest hypoxia tolerance time were selected for mating and passage to obtain G₁ generation hypoxia-sensitive rats. Similarly, 30 rats (half male and half female) with the longest hypoxia tolerance time were selected for mating and passage to obtain G₁ generation hypoxia-tolerant rats. An additional 24 standard Wistar rats were randomly divided into two groups: a control group and a model group, with 12 rats in each group (half male and half female). The control group was kept in a normoxic environment, while the model group, along with the G₁ generation hypoxia-sensitive rats (G₁sensitive group) and G₁ generation hypoxia-tolerant rats (G₁ tolerant group), were placed in a hypobaric hypoxia chamber (simulating an altitude of 5 000 m). After 12 hours, various indicators, including blood gas, complete blood count, blood biochemistry, pathological sections, and hypoxia-related genes were detected or observed to compare the differences in hypoxia sensitivity among the 4 groups. Results Compared with the G₀ generation standard rats, the hypoxia tolerance time of G₁ generation rats was significantly prolonged (P<0.01). Compared with the model group, the oxygen saturation (SatO₂) in G₁ tolerant group was significantly higher (P<0.05). In the G₁ sensitive group, the levels of white blood cell (WBC) count, neutrophil (NEUT) count, hemoglobin (HGB) concentration, hematocrit (HCT), red blood cell distribution width (RDW), platelet (PLT), and creatinine (Cr) significantly increased (P<0.05 or P<0.01), while actual bicarbonate (AB) content significantly decreased (P<0.05), and the brain and lung coefficients were significantly elevated (P<0.05). In addition, pathological section results showed that the brain and lung tissues in the model group, G₁ sensitive group, and G₁ tolerant group all suffered from significant damage, with no evident differences in the gene expression levels of hypoxia-inducible factor-1 α (HIF-1α) and vascular endothelial growth factor A (VEGFA) in brain tissues among the three groups (P>0.05). Conclusion Compared with standard rats, G₁ generation hypoxia-sensitive/tolerant rats exhibit good signs of hypoxia sensitivity/tolerance traits, but further screening and passage are still needed to purify them.

Key words: Wistar rats, Hypoxia-sensitive, Hypoxia-tolerant, Blood gas analysis, Blood indicators

中图分类号:

R-332

肖攀,王红义,陆璐,等. 低氧敏感和低氧耐受型Wistar大鼠筛选及其G₁代的低氧敏感性初探[J]. 实验动物与比较医学, 2024, 44(4): 374-383. DOI: 10.12300/j.issn.1674-5817.2024.017.

XIAO Pan,WANG Hongyi,LU Lu,et al. Screening of Hypoxia-Sensitive and Hypoxia-Tolerant Wistar Rats and Preliminary Exploration of Hypoxia Sensitivity in Their G₁Generation[J]. Laboratory Animal and Comparative Medicine, 2024, 44(4): 374-383. DOI: 10.12300/j.issn.1674-5817.2024.017.

图/表 6

表1 G0代和G1代大鼠的耐低氧时间 (t/s)

Table 1 Hypoxia tolerance time of G0 and G1 generation rats

遗传代数及低氧敏感性 Genetic algebra and hypoxia sensitivity	雄性Male				雌性Female
遗传代数及低氧敏感性 Genetic algebra and hypoxia sensitivity	n	$x ¯$ ±s		范围Range	n	$x ¯$ ±s	范围Range
G₀代 G₀ generation	100	928.18±524.06	232～2 965		100	976.98±738.53	151～3 280
G₁代敏感型 G₁hypoxia-sensitive type	232	832.15±486.19	165～2 838		251	1 171.68±399.67^acc	355～1 921
G₁代耐受型 G₁hypoxia-tolerant type	266	1 300.59±712.44^aabbcc	295～3 121		283	1 748.69±932.60^aabbccdd	384～3 621

表1 G0代和G1代大鼠的耐低氧时间 (t/s)

Table 1 Hypoxia tolerance time of G0 and G1 generation rats

遗传代数及低氧敏感性 Genetic algebra and hypoxia sensitivity	雄性Male				雌性Female
遗传代数及低氧敏感性 Genetic algebra and hypoxia sensitivity	n	$x ¯$ ±s		范围Range	n	$x ¯$ ±s	范围Range
G₀代 G₀ generation	100	928.18±524.06	232～2 965		100	976.98±738.53	151～3 280
G₁代敏感型 G₁hypoxia-sensitive type	232	832.15±486.19	165～2 838		251	1 171.68±399.67^acc	355～1 921
G₁代耐受型 G₁hypoxia-tolerant type	266	1 300.59±712.44^aabbcc	295～3 121		283	1 748.69±932.60^aabbccdd	384～3 621

表2 大鼠血气指标测定结果 (xˉ±s)

Table 2 Measurement results of blood gas indicators in rats

组别 Group	酸碱度 pH	二氧化碳分压/mmHg PaCO₂/mmHg	氧分压/mmHg PaO₂/mmHg	氧饱和度/% SatO₂/%	标准碳酸氢盐c/(mmol·L^-1) SB c/(mmol·L^-1)	实际碳酸氢盐c/(mmol·L^-1) AB c/(mmol·L^-1)
空白对照组 Control group	7.36±0.05	49.65±6.85	84.05±6.26	92.50±2.07	25.80±1.23	26.10±2.23
模型对照组 Model group	7.30±0.04^a	45.43±7.04	78.29±9.59	85.29±2.69^aa	21.29±1.80^aa	21.86±1.77^aa
G₁敏感组 G₁sensitive group	7.30±0.02^a	42.57±1.99^a	76.29±3.15^a	84.00±2.16^aa	20.43±2.30^aa	19.29±2.50^aab
G₁耐受组 G₁tolerant group	7.31±0.03^a	46.86±1.07	79.43±1.81	88.86±5.34^abc	22.86±2.97^ac	21.58±11.51^aac

表3 大鼠血常规指标测定 (xˉ±s)

Table 3 Measurement results of complete blood count indicators in rats

检测指标 Detection index	空白对照组 Control group	模型对照组 Model group	G₁敏感组 G₁ sensitive group	G₁耐受组 G₁tolerant group
白细胞计数, ×10⁹/L WBC, ×10⁹/L	4.03±1.13	4.55±0.47	5.58±1.50^aab	4.33±0.46
中性粒细胞数, ×10⁹/L NEUT, ×10⁹/L	0.92±0.24	1.09±0.16	1.59±0.54^aabb	0.94±0.13^cc
淋巴细胞数, ×10⁹/L LYMPH, ×10⁹/L	2.95±0.84	3.75±1.78	3.82±0.87	3.47±1.57
中性粒细胞百分比/% NEUT%	22.99±2.20	29.81±14.58	30.79±7.38	27.31±11.20
红细胞计数, ×10¹²/L RBC, ×10¹²/L	7.77±0.31	9.09±0.64^aa	9.49±0.63^aa	8.59±0.26^aacc
血红蛋白 ρ/(g·L^-1) HGB ρ/(g·L^-1)	141.86±3.29	165.00±9.47^aa	175.71±10.00^aabb	156.00±3.02^aabcc
血细胞比容/% HCT/%	43.79±1.44	47.78±3.09^aa	50.66±3.17^aab	44.96±1.17^bcc
红细胞分布宽度百分比/% RDW/%	15.10±0.40	24.70±0.85^aa	27.29±1.44^aabb	24.70±0.85^aacc
血小板计数, ×10⁹/L PLT, ×10⁹/L	775.00±77.59	1 085.00±82.85^aa	1 183.71±64.17^aab	994.50±75.40^aabcc
血小板分布宽度/% PDW/%	15.03±0.13	14.66±0.15^aa	14.70±0.08^aa	14.66±0.15^aa

表4 大鼠血生化指标和脏器系数测定 (xˉ±s)

Table 4 Measurement of biochemical indicators and organ coefficients in rats

组别 Group	肌酐z/(U·L^-1) Cr z/(U·L^-1)	天冬氨酸转氨酶 z/(U·L^-1) AST z/(U·L^-1)	丙氨酸转氨酶 c/(μmol·L^-1) ALT c/(μmol·L^-1)	总胆红素 c/(mmol·L^-1) TBIL c/(mmol·L^-1)	肺系数/% Lung coefficient/%	脑系数/% Brain coefficient/%	心系数/% Heart coefficient/%
空白对照组 Control group	36.00±3.43	91.60±12.89	38.20±4.98	0.04±0.74	0.52±0.08	0.60±0.05	0.32±0.02
模型对照组 Model group	39.71±3.59	121.43±25.2	39.86±9.48	0.34±0.31	0.56±0.05	0.66±0.03^aa	0.33±0.03
G₁敏感组 G₁ sensitive group	48.38±8.53^aabb	166.25±87.16^aa	40.87±7.22	0.39±0.28	0.62±0.05^aab	0.71±0.05^aab	0.34±0.02
G₁耐受组 G₁ tolerant group	44.75±6.50^aa	132.75±33.94	39.75±11.85	0.26±0.26	0.55±0.04^c	0.64±0.04^acc	0.33±0.03

图1 大鼠心脏、肺脏和大脑组织切片的HE染色（×40）注：图中比例尺大小为0.1 mm，肺部切片中黑色箭头代表该处肺泡壁增厚明显或炎性细胞浸润，脑部切片中黑色箭头代表该处海马细胞排列轻微紊乱或细胞空泡化。

Figure 1 HE staining results of heart, lung, and brain tissue sections in rats (×40)Note： The scale bar in this figure is 0.1 mm. Black arrows in the sections of lung represent significant thickening in alveolar walls or infiltration with inflammatory cells. Black arrows in the sections of brain represent a slight disorder in the arrangement of hippocampal cells or cellular vacuolization.

图2 实时荧光定量PCR检测大鼠大脑组织中HIF-1 α （A）和VEGFA（B）基因表达水平注：HIF-1α，低氧诱导因子-1α；VEGFA，血管内皮生长因子A。与空白对照组相比，****P<0.000 1。

Figure 2 Expression levels of HIF-1 α gene （A） and VEGFA gene （B） in the brain of rats detected by real-time fluorescent quantitative PCRNote：HIF-1α, hypoxia-inducible factor-1α; VEGFA, vascular endothelial growth factor A. Compared with control group, ****P<0.000 1.

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低氧敏感和低氧耐受型Wistar大鼠筛选及其G₁代的低氧敏感性初探

Screening of Hypoxia-Sensitive and Hypoxia-Tolerant Wistar Rats and Preliminary Exploration of Hypoxia Sensitivity in Their G₁Generation

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