Laboratory Animal and Comparative Medicine ›› 2024, Vol. 44 ›› Issue (6): 636-644.DOI: 10.12300/j.issn.1674-5817.2024.087
• Animal Models of Human Diseases • Previous Articles Next Articles
YANG Jiahao1(), DING Chunlei1, QIAN Fenghua2, SUN Qi1, JIANG Xusheng2, CHEN Wen2, SHEN Mengwen1(
)(
)
Received:
2024-06-21
Revised:
2024-10-09
Online:
2024-12-25
Published:
2025-01-04
Contact:
SHEN Mengwen
CLC Number:
YANG Jiahao,DING Chunlei,QIAN Fenghua,et al. Research Progress on Animal Models of Sepsis-Related Organ Injury[J]. Laboratory Animal and Comparative Medicine, 2024, 44(6): 636-644. DOI: 10.12300/j.issn.1674-5817.2024.087.
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URL: https://www.slarc.org.cn/dwyx/EN/10.12300/j.issn.1674-5817.2024.087
给药途径 Routes of administration | 优点 Advantages | 局限 Limitations |
---|---|---|
腹腔注射 Intraperitoneal injection | 操作简便,适用于快速诱导脓毒症模型 | 可引起腹膜炎等多种并发症,无法造成目标脏器损伤;无法完全模拟临床脓毒症多菌性感染 |
静脉注射 Intravenous injection | 接近临床细菌及毒素入血情况,适用于研究循环中的炎症反应 | 易损伤血管;对药物剂量及浓度要求高 |
气管内给药 Intratracheal administration | 可模拟肺部感染引起的脓毒症,适合建立急性肺损伤模型 | 操作复杂、易对气管造成损伤;对药物剂量及浓度要求高 |
Table 1 Common routes of drug administration for modeling and their advantages and limitations
给药途径 Routes of administration | 优点 Advantages | 局限 Limitations |
---|---|---|
腹腔注射 Intraperitoneal injection | 操作简便,适用于快速诱导脓毒症模型 | 可引起腹膜炎等多种并发症,无法造成目标脏器损伤;无法完全模拟临床脓毒症多菌性感染 |
静脉注射 Intravenous injection | 接近临床细菌及毒素入血情况,适用于研究循环中的炎症反应 | 易损伤血管;对药物剂量及浓度要求高 |
气管内给药 Intratracheal administration | 可模拟肺部感染引起的脓毒症,适合建立急性肺损伤模型 | 操作复杂、易对气管造成损伤;对药物剂量及浓度要求高 |
方法 Methods | 具体技术 Specific techniques | 优点 Advantages | 局限 Limitations |
---|---|---|---|
破坏肠道屏障组织完整性 Disrupting the integrity of intestinal barrier tissue | CLP[ | 脓毒症造模“金标准”最接近人类脓毒症发病过程;可重复性高;可模拟多菌性感染 | 手术难度大、死亡率及疾病严重程度难以控制 |
CASP[ | 接近人类脓毒症发病过程;可重复性高;可控制脓毒症严重程度 | 手术难度大、操作复杂 | |
CLI[ | 与CLP模式相同,可持续释放病原体,模拟临床腹腔感染致脓毒症 | 代谢组学、血流动力学以及免疫反应的研究尚未成熟 | |
植入病原体/毒性药物 Introducing pathogens/ toxic drugs | 脂多糖、酵母聚糖、肽聚糖[ | 易操作、低侵入性;可激活宿主免疫系统用于研究脓毒症相关免疫反应 | 无法模拟脓毒症的多菌性感染 |
大肠杆菌、金黄色葡萄球菌、肺炎克雷伯菌[ | 易操作、低侵入性;适用研究宿主对特定病原体的反应机制 | 无法模拟脓毒症的多菌性感染,有细菌使用的实验室等级要求 | |
载有病原体的纤维蛋白凝块[ | 可重复性高;使病原体缓慢释放,造成持久感染而不影响最终死亡率 | 纤维蛋白凝块制作难度大 | |
粪便溶液、盲肠匀浆[ | 易操作、低侵入性;可模拟多菌性感染 | 免疫反应过于强烈,易导致早期死亡或早期完全康复,浓度难以控制 |
Table 2 Common methods for establishing animal models of sepsis and their advantages and limitations
方法 Methods | 具体技术 Specific techniques | 优点 Advantages | 局限 Limitations |
---|---|---|---|
破坏肠道屏障组织完整性 Disrupting the integrity of intestinal barrier tissue | CLP[ | 脓毒症造模“金标准”最接近人类脓毒症发病过程;可重复性高;可模拟多菌性感染 | 手术难度大、死亡率及疾病严重程度难以控制 |
CASP[ | 接近人类脓毒症发病过程;可重复性高;可控制脓毒症严重程度 | 手术难度大、操作复杂 | |
CLI[ | 与CLP模式相同,可持续释放病原体,模拟临床腹腔感染致脓毒症 | 代谢组学、血流动力学以及免疫反应的研究尚未成熟 | |
植入病原体/毒性药物 Introducing pathogens/ toxic drugs | 脂多糖、酵母聚糖、肽聚糖[ | 易操作、低侵入性;可激活宿主免疫系统用于研究脓毒症相关免疫反应 | 无法模拟脓毒症的多菌性感染 |
大肠杆菌、金黄色葡萄球菌、肺炎克雷伯菌[ | 易操作、低侵入性;适用研究宿主对特定病原体的反应机制 | 无法模拟脓毒症的多菌性感染,有细菌使用的实验室等级要求 | |
载有病原体的纤维蛋白凝块[ | 可重复性高;使病原体缓慢释放,造成持久感染而不影响最终死亡率 | 纤维蛋白凝块制作难度大 | |
粪便溶液、盲肠匀浆[ | 易操作、低侵入性;可模拟多菌性感染 | 免疫反应过于强烈,易导致早期死亡或早期完全康复,浓度难以控制 |
脏器损伤 Organ damage | 方式 Method | 时间 Time | 优势 Advantages | 局限 Limitations | 检测指标 Testing indexes |
---|---|---|---|---|---|
脓毒症致心肌病 Sepsis-induced myocardial injury, SIMI | LPS腹腔注射[ 器官损伤情况观察剂量: 5~10 mg/kg 生存情况观察剂量:20 mg/kg | 造模后 12、24 h | 易操作、低侵入性、可快速诱导脓毒症;可通过调节剂量控制疾病严重程度 | 不能完全模拟脓毒症致心肌病的临床情况 | 超声心动图、心肌损伤标志物、心脏病理切片[ |
CLP[ | 造模后 12、24 h | 更接近临床脓毒症致心肌病的病理变化 | 操作复杂、创伤大、无法同时间点里在保证相对均一性的情况下大量造模 | ||
脓毒症致急性肺 损伤 Sepsis-induced acute lung injury, SALI | LPS腹腔注射:5~10 mg/kg[ LPS静脉注射:10~20 mg/kg[ LPS气管内滴注:10~20 mg/kg[ | 造模后4、12、24 h | 易操作、侵入性低、可快速诱导脓毒症;可通过调节剂量及注射方式控制疾病严重程度 | 难以模拟多菌性脓毒症致急性肺损伤 | 过氧化酶活性、肺干湿重比、BALF液及血清中炎症因子及蛋白水平[ |
气管内注射生物发光铜绿假单胞菌溶液(5×104 CFU/只)[ | 造模后 24 h | 可直观检测感染部位、感染严重程度 | 操作复杂、生物安全等级高、仪器要求高 | ||
粪便溶液腹腔注射:浓度75 mg/mL; 剂量1 g/kg[ | 造模后 24 h | 易操作,更接临床多菌性脓毒症致急性肺损伤的病理变化 | 粪便溶液的制备难度高、均一性差 | ||
CLP[ | 造模后 12、24 h | 更接近临床脓毒症致急性肺损伤的病理变化;模型使用成熟,易于参考 | 操作复杂、创伤大、无法同时间点里在保证相对均一性的情况下大量造模 | ||
脓毒症致急性肾 损伤 Sepsis-induced acute kidney injury, SA-AKI | LPS腹腔注射:10~15 mg/kg[ | 造模后 12 h | 易操作、侵入性低、易重复、可快速诱导脓毒症,利于肾损伤的观察 | 无法模拟多菌性或特定菌种脓毒症急性肾损伤的病理情况 | 血尿肌酐、尿素氮、肾脏病理切片[ |
盲肠匀浆腹腔注射+亚胺培南 (1.5 mg/只, bid)抗感染[ | 造模后 24 h | 接近临床脓毒症致急性肾损伤的病理情况、延长了实验动物的存活时间 | 盲肠匀浆制备难度高、均一性差 | ||
CLP+气管内滴注假单胞菌的 二次打击(107/只)[ | 造模后 24 h | 可快速诱导更为严重的脓毒症致急性肾损伤、相关肾损伤指标水平更高 | 操作复杂、死亡率高 | ||
脓毒症致急性肝 损伤 Sepsis-induced acute liver injury, SI-ALI | LPS腹腔注射:10 mg/kg[ | 造模后 6 h | 易操作、侵入性低 | 难以模拟临床上多菌性脓毒症致急性肝损伤的病理情况 | 血清ALT、AST、肝脏匀浆中细胞因子水平、肝组织病理切片[ |
LPS(100 μg/kg)+半乳糖胺 (700 mg/kg)腹腔注射[ | 造模后 1、6 h | LPS联合半乳糖胺可较好的模拟临床脓毒症致急性肝损伤、减少LPS的用量 | 对药物浓度、剂量准确度要求较高 | ||
CLP[ | 造模后 24 h | 更接近临床脓毒症致急性肝损伤的病理变化 | 操作复杂、创伤大、无法同时间点里在保证相对均一性的情况下大量造模 | ||
脓毒症相关脑病 Sepsis-associated encephalopathy, SAE | LPS腹腔注射:5~10 mg/kg[ | 造模后 3 h | 可快速诱导脓毒症相关脑病、对全身炎症反应以及免疫应答进行研究 | 难以模拟临床上多菌性脓毒症致脑病的病理情况 | 伊文思蓝染色评估血-脑脊液屏障通透性、水迷宫试验评估动物学习及记忆能力、测定脑组织样本中细胞因子水平、脑组织病理切片[ |
LPS双侧颅内注射:50 μg溶于 10 μL脑脊液[ | 造模后 24 h | 可引起慢性炎症并导致脑功能障碍 | 操作复杂、使用少难以参考 | ||
CLP[ | 造模后 24 h | 更接近临床脓毒症相关脑病的病理变化 | 操作复杂、创伤大、无法同时间点里在保证相对均一性的情况下大量造模 |
Table 3 Experimental animal modeling of sepsis-induced organ injury and the advantages and limitations of these methods
脏器损伤 Organ damage | 方式 Method | 时间 Time | 优势 Advantages | 局限 Limitations | 检测指标 Testing indexes |
---|---|---|---|---|---|
脓毒症致心肌病 Sepsis-induced myocardial injury, SIMI | LPS腹腔注射[ 器官损伤情况观察剂量: 5~10 mg/kg 生存情况观察剂量:20 mg/kg | 造模后 12、24 h | 易操作、低侵入性、可快速诱导脓毒症;可通过调节剂量控制疾病严重程度 | 不能完全模拟脓毒症致心肌病的临床情况 | 超声心动图、心肌损伤标志物、心脏病理切片[ |
CLP[ | 造模后 12、24 h | 更接近临床脓毒症致心肌病的病理变化 | 操作复杂、创伤大、无法同时间点里在保证相对均一性的情况下大量造模 | ||
脓毒症致急性肺 损伤 Sepsis-induced acute lung injury, SALI | LPS腹腔注射:5~10 mg/kg[ LPS静脉注射:10~20 mg/kg[ LPS气管内滴注:10~20 mg/kg[ | 造模后4、12、24 h | 易操作、侵入性低、可快速诱导脓毒症;可通过调节剂量及注射方式控制疾病严重程度 | 难以模拟多菌性脓毒症致急性肺损伤 | 过氧化酶活性、肺干湿重比、BALF液及血清中炎症因子及蛋白水平[ |
气管内注射生物发光铜绿假单胞菌溶液(5×104 CFU/只)[ | 造模后 24 h | 可直观检测感染部位、感染严重程度 | 操作复杂、生物安全等级高、仪器要求高 | ||
粪便溶液腹腔注射:浓度75 mg/mL; 剂量1 g/kg[ | 造模后 24 h | 易操作,更接临床多菌性脓毒症致急性肺损伤的病理变化 | 粪便溶液的制备难度高、均一性差 | ||
CLP[ | 造模后 12、24 h | 更接近临床脓毒症致急性肺损伤的病理变化;模型使用成熟,易于参考 | 操作复杂、创伤大、无法同时间点里在保证相对均一性的情况下大量造模 | ||
脓毒症致急性肾 损伤 Sepsis-induced acute kidney injury, SA-AKI | LPS腹腔注射:10~15 mg/kg[ | 造模后 12 h | 易操作、侵入性低、易重复、可快速诱导脓毒症,利于肾损伤的观察 | 无法模拟多菌性或特定菌种脓毒症急性肾损伤的病理情况 | 血尿肌酐、尿素氮、肾脏病理切片[ |
盲肠匀浆腹腔注射+亚胺培南 (1.5 mg/只, bid)抗感染[ | 造模后 24 h | 接近临床脓毒症致急性肾损伤的病理情况、延长了实验动物的存活时间 | 盲肠匀浆制备难度高、均一性差 | ||
CLP+气管内滴注假单胞菌的 二次打击(107/只)[ | 造模后 24 h | 可快速诱导更为严重的脓毒症致急性肾损伤、相关肾损伤指标水平更高 | 操作复杂、死亡率高 | ||
脓毒症致急性肝 损伤 Sepsis-induced acute liver injury, SI-ALI | LPS腹腔注射:10 mg/kg[ | 造模后 6 h | 易操作、侵入性低 | 难以模拟临床上多菌性脓毒症致急性肝损伤的病理情况 | 血清ALT、AST、肝脏匀浆中细胞因子水平、肝组织病理切片[ |
LPS(100 μg/kg)+半乳糖胺 (700 mg/kg)腹腔注射[ | 造模后 1、6 h | LPS联合半乳糖胺可较好的模拟临床脓毒症致急性肝损伤、减少LPS的用量 | 对药物浓度、剂量准确度要求较高 | ||
CLP[ | 造模后 24 h | 更接近临床脓毒症致急性肝损伤的病理变化 | 操作复杂、创伤大、无法同时间点里在保证相对均一性的情况下大量造模 | ||
脓毒症相关脑病 Sepsis-associated encephalopathy, SAE | LPS腹腔注射:5~10 mg/kg[ | 造模后 3 h | 可快速诱导脓毒症相关脑病、对全身炎症反应以及免疫应答进行研究 | 难以模拟临床上多菌性脓毒症致脑病的病理情况 | 伊文思蓝染色评估血-脑脊液屏障通透性、水迷宫试验评估动物学习及记忆能力、测定脑组织样本中细胞因子水平、脑组织病理切片[ |
LPS双侧颅内注射:50 μg溶于 10 μL脑脊液[ | 造模后 24 h | 可引起慢性炎症并导致脑功能障碍 | 操作复杂、使用少难以参考 | ||
CLP[ | 造模后 24 h | 更接近临床脓毒症相关脑病的病理变化 | 操作复杂、创伤大、无法同时间点里在保证相对均一性的情况下大量造模 |
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