D-半乳糖诱导的衰老大鼠脓毒症模型的初步研究
发布时间：2019-04-19 03:49
【摘要】：背景:随着人口老龄化日趋严重,老年人群中脓毒症患者在逐年增加,发病率及死亡率也随着年龄的升高显著上升。尽管做了大量的临床试验和基础研究,但目前仍没有有效治疗老年严重脓毒症患者的方法。临床与基础研究的分歧主要在于用于基础研究的试验动物过于年轻不能真实反映老年脓毒症患者的特点。近年来,利用D-半乳糖(D-galactose, D-gal)制备的亚急性衰老模型已应用于多种老年性疾病的研究当中并且取得了良好的效果,但关于其相关的老年脓毒症模型研究较少。因此,利用D-gal诱导的衰老大鼠建立脓毒症模型将为老年脓毒症的基础与临床研究提供新的思路。目的:1、观察D-gal诱导的衰老大鼠脓毒症模型死亡率、炎症细胞因子、器官功能及生命体征的变化;2、探讨在老年脓毒症研究中的应用价值。方法:本研究由两部分组成。第一部分采用D-gal皮下注射的方法建立大鼠衰老模型,将 12 周雄性 Sprague-Dawley (SD)大鼠分为低剂量(low-dose)诱导组(LD-galgroup,诱导剂量 125mg/kg/d)、高剂量(high-dose)诱导组(HD-galgroup,诱导剂量 500mg/kg/d)和对照组(controlgroup,皮下注射同等剂量0.9%NaCl),6周后测量血清丙二醇(MDA)和超氧化物歧化酶(SOD)含量并观察肾功能及生命体征变化。第二部分采用盲肠结扎穿孔(CLP)的方法在已建立的大鼠衰老模型的基础上建立脓毒症模型。实验分组同前,观察各组间CLP术后12h及24h死亡率、炎症因子、肾功能、MicroRNA-155及生命体征的变化。结果:1、D-半乳糖皮下注射6周后,大鼠血清MDA含量升高SOD活性下降(H D-gal vs. control, P0.01 for MDA and SOD; L D-gal vs. control, P0.01 for MDA and SOD; H D-gal vs. L D-gal, P=0.017 for MDA, P=0.034 for SOD); 2、CLP 术后 1 周的死亡率分别是 73.3% (HD-gal)、40% (LD-gal)和 33.3% (control); 3、与对照组相比,高剂量诱导组在CLP术后的血清肌酐、尿素氮、中性粒细胞明胶酶相关脂质运载蛋白、白介素-6、白介素-10、肿瘤坏死因子-α以及MicroRNA-155水平明显升高(P0.05);4、根据肾损伤RIFLE分级,CLP术后24小时发生严重急性肾损伤(RIFLE-F)的可能分别是 80% (HD-gal)、43% (LD-gal)和 43% (control); 5、高剂量诱导组在 CLP术后更易出现心率、收缩压和体温的降低。结论:与青年SD大鼠脓毒症模型相比,在高剂量D-gal诱导的衰老大鼠上建立的脓毒症模型死亡率高,这可能与炎症反应的增加和严重的急性肾损伤相关。并且高剂量诱导组更易出现严重的感染性休克和低体温。因此,使用高剂量D-gal诱导的衰老大鼠脓毒症模型进行临床前研究可以为老年患者的脓毒症治疗提供更有价值的信息。
[Abstract]:Background: with the aging of the population, sepsis patients in the elderly population are increasing year by year, and the morbidity and mortality also increase with the increase of age. Although a large number of clinical trials and basic research have been done, there is still no effective treatment for elderly patients with severe sepsis. The differences between clinical and basic research mainly lie in the fact that the experimental animals used for basic research are too young to reflect the characteristics of elderly sepsis patients. In recent years, the subacute aging model prepared by D-galactose (D-gal) has been applied to the study of many senile diseases and has achieved good results, but there are few researches on the related senile sepsis models. Therefore, the establishment of sepsis model in aging rats induced by D-gal will provide a new idea for the basic and clinical research of senile sepsis. Aim: 1. To observe the mortality, inflammatory cytokines, organ function and vital signs of aging rats sepsis induced by D-gal, and to explore the application value in the study of senile sepsis. 2. Methods: this study consists of two parts. In the first part, the aging model of rats was established by subcutaneous injection of D-gal. The 12-week male Sprague-Dawley (SD) rats were divided into low-dose (low-dose)-induced group (LD-galgroup,-induced dose 125mg/kg/d). High dose (high-dose) induction group (HD-galgroup, induced dose 500mg/kg/d) and control group (controlgroup, subcutaneously injected with the same dose of 0.9%NaCl). After 6 weeks, the levels of serum propanediol (MDA) and superoxide dismutase (SOD) were measured and the changes of renal function and vital signs were observed. In the second part, the sepsis model was established on the basis of the aging model of rats by cecal ligation and perforation of (CLP). The changes of mortality, inflammatory factors, renal function, MicroRNA-155 and vital signs at 12 and 24 hours after CLP were observed in each group. Results: 1. After subcutaneous injection of D-galactose for 6 weeks, the content of serum MDA increased and the activity of SOD decreased (H D-gal vs. control, P0.01 for MDA and SOD; L D-gal vs. control, P0.01 for MDA and SOD;). HD-gal vs. LD-gal, P0. 017 for MDA, P0. 034 for SOD); 2, 1-week mortality were 73. 3% (HD-gal), 40% (LD-gal) and 33. 3% (control);, respectively. 3, compared with the control group, the serum creatinine, urea nitrogen, neutrophil gelatinase-associated lipid transport protein, interleukin-6, interleukin-10 in the high-dose induction group after CLP. Tumor necrosis factor-伪 (TNF-伪) and tumor necrosis factor-伪 (MicroRNA-155) were significantly increased (P0.05). 4. According to the RIFLE grade of renal injury, the possible occurrence of severe acute renal injury (RIFLE-F) 24 hours after CLP was 80% (HD-gal), 43% (LD-gal) and 43% (control);, respectively. 5. Heart rate, systolic blood pressure and body temperature were more likely to decrease in the high dose induced group after CLP. Conclusion: compared with the model of sepsis in young SD rats, the mortality of sepsis model induced by high dose of D-gal in aging rats is higher than that in young rats, which may be related to the increase of inflammatory reaction and severe acute renal injury. High dose induction group was more likely to develop severe septic shock and hypothermia. Therefore, pre-clinical studies using high-dose D-gal-induced sepsis model in aging rats can provide more valuable information for the treatment of sepsis in elderly patients.
【学位授予单位】：中国人民解放军医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R459.7;R-332
本文编号：2460572
[Abstract]:Background: with the aging of the population, sepsis patients in the elderly population are increasing year by year, and the morbidity and mortality also increase with the increase of age. Although a large number of clinical trials and basic research have been done, there is still no effective treatment for elderly patients with severe sepsis. The differences between clinical and basic research mainly lie in the fact that the experimental animals used for basic research are too young to reflect the characteristics of elderly sepsis patients. In recent years, the subacute aging model prepared by D-galactose (D-gal) has been applied to the study of many senile diseases and has achieved good results, but there are few researches on the related senile sepsis models. Therefore, the establishment of sepsis model in aging rats induced by D-gal will provide a new idea for the basic and clinical research of senile sepsis. Aim: 1. To observe the mortality, inflammatory cytokines, organ function and vital signs of aging rats sepsis induced by D-gal, and to explore the application value in the study of senile sepsis. 2. Methods: this study consists of two parts. In the first part, the aging model of rats was established by subcutaneous injection of D-gal. The 12-week male Sprague-Dawley (SD) rats were divided into low-dose (low-dose)-induced group (LD-galgroup,-induced dose 125mg/kg/d). High dose (high-dose) induction group (HD-galgroup, induced dose 500mg/kg/d) and control group (controlgroup, subcutaneously injected with the same dose of 0.9%NaCl). After 6 weeks, the levels of serum propanediol (MDA) and superoxide dismutase (SOD) were measured and the changes of renal function and vital signs were observed. In the second part, the sepsis model was established on the basis of the aging model of rats by cecal ligation and perforation of (CLP). The changes of mortality, inflammatory factors, renal function, MicroRNA-155 and vital signs at 12 and 24 hours after CLP were observed in each group. Results: 1. After subcutaneous injection of D-galactose for 6 weeks, the content of serum MDA increased and the activity of SOD decreased (H D-gal vs. control, P0.01 for MDA and SOD; L D-gal vs. control, P0.01 for MDA and SOD;). HD-gal vs. LD-gal, P0. 017 for MDA, P0. 034 for SOD); 2, 1-week mortality were 73. 3% (HD-gal), 40% (LD-gal) and 33. 3% (control);, respectively. 3, compared with the control group, the serum creatinine, urea nitrogen, neutrophil gelatinase-associated lipid transport protein, interleukin-6, interleukin-10 in the high-dose induction group after CLP. Tumor necrosis factor-伪 (TNF-伪) and tumor necrosis factor-伪 (MicroRNA-155) were significantly increased (P0.05). 4. According to the RIFLE grade of renal injury, the possible occurrence of severe acute renal injury (RIFLE-F) 24 hours after CLP was 80% (HD-gal), 43% (LD-gal) and 43% (control);, respectively. 5. Heart rate, systolic blood pressure and body temperature were more likely to decrease in the high dose induced group after CLP. Conclusion: compared with the model of sepsis in young SD rats, the mortality of sepsis model induced by high dose of D-gal in aging rats is higher than that in young rats, which may be related to the increase of inflammatory reaction and severe acute renal injury. High dose induction group was more likely to develop severe septic shock and hypothermia. Therefore, pre-clinical studies using high-dose D-gal-induced sepsis model in aging rats can provide more valuable information for the treatment of sepsis in elderly patients.
【学位授予单位】：中国人民解放军医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R459.7;R-332
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