D-半乳糖誘導(dǎo)的衰老大鼠膿毒癥模型的初步研究
發(fā)布時(shí)間：2019-04-19 03:49
【摘要】：背景:隨著人口老齡化日趨嚴(yán)重,老年人群中膿毒癥患者在逐年增加,發(fā)病率及死亡率也隨著年齡的升高顯著上升。盡管做了大量的臨床試驗(yàn)和基礎(chǔ)研究,但目前仍沒(méi)有有效治療老年嚴(yán)重膿毒癥患者的方法。臨床與基礎(chǔ)研究的分歧主要在于用于基礎(chǔ)研究的試驗(yàn)動(dòng)物過(guò)于年輕不能真實(shí)反映老年膿毒癥患者的特點(diǎn)。近年來(lái),利用D-半乳糖(D-galactose, D-gal)制備的亞急性衰老模型已應(yīng)用于多種老年性疾病的研究當(dāng)中并且取得了良好的效果,但關(guān)于其相關(guān)的老年膿毒癥模型研究較少。因此,利用D-gal誘導(dǎo)的衰老大鼠建立膿毒癥模型將為老年膿毒癥的基礎(chǔ)與臨床研究提供新的思路。目的:1、觀察D-gal誘導(dǎo)的衰老大鼠膿毒癥模型死亡率、炎癥細(xì)胞因子、器官功能及生命體征的變化;2、探討在老年膿毒癥研究中的應(yīng)用價(jià)值。方法:本研究由兩部分組成。第一部分采用D-gal皮下注射的方法建立大鼠衰老模型,將 12 周雄性 Sprague-Dawley (SD)大鼠分為低劑量(low-dose)誘導(dǎo)組(LD-galgroup,誘導(dǎo)劑量 125mg/kg/d)、高劑量(high-dose)誘導(dǎo)組(HD-galgroup,誘導(dǎo)劑量 500mg/kg/d)和對(duì)照組(controlgroup,皮下注射同等劑量0.9%NaCl),6周后測(cè)量血清丙二醇(MDA)和超氧化物歧化酶(SOD)含量并觀察腎功能及生命體征變化。第二部分采用盲腸結(jié)扎穿孔(CLP)的方法在已建立的大鼠衰老模型的基礎(chǔ)上建立膿毒癥模型。實(shí)驗(yàn)分組同前,觀察各組間CLP術(shù)后12h及24h死亡率、炎癥因子、腎功能、MicroRNA-155及生命體征的變化。結(jié)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 術(shù)后 1 周的死亡率分別是 73.3% (HD-gal)、40% (LD-gal)和 33.3% (control); 3、與對(duì)照組相比,高劑量誘導(dǎo)組在CLP術(shù)后的血清肌酐、尿素氮、中性粒細(xì)胞明膠酶相關(guān)脂質(zhì)運(yùn)載蛋白、白介素-6、白介素-10、腫瘤壞死因子-α以及MicroRNA-155水平明顯升高(P0.05);4、根據(jù)腎損傷RIFLE分級(jí),CLP術(shù)后24小時(shí)發(fā)生嚴(yán)重急性腎損傷(RIFLE-F)的可能分別是 80% (HD-gal)、43% (LD-gal)和 43% (control); 5、高劑量誘導(dǎo)組在 CLP術(shù)后更易出現(xiàn)心率、收縮壓和體溫的降低。結(jié)論:與青年SD大鼠膿毒癥模型相比,在高劑量D-gal誘導(dǎo)的衰老大鼠上建立的膿毒癥模型死亡率高,這可能與炎癥反應(yīng)的增加和嚴(yán)重的急性腎損傷相關(guān)。并且高劑量誘導(dǎo)組更易出現(xiàn)嚴(yán)重的感染性休克和低體溫。因此,使用高劑量D-gal誘導(dǎo)的衰老大鼠膿毒癥模型進(jìn)行臨床前研究可以為老年患者的膿毒癥治療提供更有價(jià)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-偽 (TNF-偽) and tumor necrosis factor-偽 (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.
【學(xué)位授予單位】：中國(guó)人民解放軍醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R459.7;R-332
本文編號(hào)：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-偽 (TNF-偽) and tumor necrosis factor-偽 (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.
【學(xué)位授予單位】：中國(guó)人民解放軍醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R459.7;R-332
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