【摘要】：貧血是臨床最常見的表現(xiàn)之一,癥狀的輕重與貧血發(fā)生的程度及進(jìn)展速度有關(guān),急性重度貧血可導(dǎo)致組織缺氧性損傷甚至死亡,輸入血液或血液制品是臨床治療急性貧血的主要方法。但由于血液感染風(fēng)險(xiǎn)、血液短缺、血液誤輸以及保存方式等因素,尋求合適的血液替代品成為必然趨勢。血紅蛋白氧載體(Hemoglobin-based oxygen carriers,HBOCs)是以血紅蛋白為基礎(chǔ)的一類能夠代替血液部分功能的化合物。戊二醛聚合豬血紅蛋白(polymerized porcine hemoglobin, pPolyHb)是由戊二醛交聯(lián)聚合豬血紅蛋白制備的一種新型的HBOCs,其前期在失血性休克、100%換血等動(dòng)物模型中,從血流動(dòng)力學(xué),酸堿代謝,氧供等多方面證明該產(chǎn)品具有良好的擴(kuò)容及攜氧釋氧能力,可以保證實(shí)驗(yàn)動(dòng)物正常組織灌注及血流動(dòng)力學(xué)穩(wěn)定,可有效替代紅細(xì)胞發(fā)揮作用。本實(shí)驗(yàn)通過探討pPolyHb在大鼠和犬急性貧血模型中的復(fù)蘇效果及其對(duì)肝腎等組織的影響進(jìn)一步證明pPolyHb的有效性。首先探討pPolyHb在大鼠急性貧血/治療中對(duì)機(jī)體血壓及動(dòng)脈血?dú)庵笜?biāo)、肝腎損傷因子以及不同液體復(fù)蘇組織病理損傷情況。建立大鼠等容血液稀釋模型,將大鼠血紅蛋白含量稀釋至4±0.5g/dl或5±0.5g/dl,模擬臨床術(shù)中貧血,稀釋后,通過靜脈以0.3mL/min速率輸入pPolyHb或紅細(xì)胞(RBC),至血紅蛋白含量大于7g/dl,control組不進(jìn)行復(fù)蘇;監(jiān)控血壓和動(dòng)脈血?dú)庵笜?biāo),術(shù)后7d檢測血清中丙氨酸氨基轉(zhuǎn)移酶(ALT)、天冬氨酸轉(zhuǎn)移酶(AST)等肝腎損傷因子含量,處死解剖后通過腎組織HE染色檢測病理變化;pPolyHb組和RBC組復(fù)蘇后血壓能夠恢復(fù)到基礎(chǔ)水平,同對(duì)照組相比,復(fù)蘇后pPolyHb組無氧代謝得到顯著性改善,有效的糾正了組織酸中毒現(xiàn)象,與紅細(xì)胞組復(fù)蘇效果類似,pPolyHb組肝腎損傷因子及腎臟病理組織HE染色結(jié)果與sham組沒有顯著性差異,并優(yōu)于紅細(xì)胞組;以上結(jié)果表明pPolyHb可以改善大鼠血流動(dòng)力學(xué)參數(shù),減輕代謝性酸中毒,并且可以降低肝腎損傷因子的活性,其治療效果與RBC相當(dāng),顯著地優(yōu)于control組。在犬等容血液稀釋模型中,用同樣的方法模擬急性貧血狀態(tài),研究RBC不可獲得的情況下pPolyHb的作用效果。血液稀釋后犬隨機(jī)分為兩組,實(shí)驗(yàn)組輸入3g/kg pPolyHb,對(duì)照組以肺動(dòng)脈楔壓(PAWP)為參照,輸入生理鹽水;監(jiān)測實(shí)驗(yàn)過程中血流動(dòng)力學(xué)參數(shù)、血?dú)庵笜?biāo)、氧供氧耗參數(shù)和凝血狀態(tài),術(shù)后7d檢測血清中肝腎損傷因子含量,解剖后觀察肝、腎組織HE染色結(jié)果;pPolyHb在無RBC制品情況下使用對(duì)血流動(dòng)力學(xué)穩(wěn)定的維持較晶體液有一定優(yōu)勢,對(duì)組織的氧供有一定改善,并且可以降低肝腎損傷因子的活性,在7天后未造成明顯特異性的組織損傷。實(shí)驗(yàn)表明pPolyHb能夠顯著的改善犬由于等容血液稀釋引起的急性貧血狀態(tài)。
[Abstract]:Anemia is one of the most common clinical manifestations. The severity of symptoms is related to the degree of anemia and the rate of progression. Acute severe anemia can lead to tissue hypoxia injury or even death. Transfusion of blood or blood products is the main clinical treatment of acute anemia. However, due to the risk of blood infection, blood shortage, blood miscarriage and preservation, it is an inevitable trend to seek suitable blood substitutes. Hemoglobin oxygen carrier (Hemoglobin-based oxygen carriers,HBOCs) is a kind of hemoglobin-based compounds which can replace the partial function of blood. Glutaraldehyde polymerized porcine hemoglobin (polymerized porcine hemoglobin, pPolyHb) is a new type of HBOCs, prepared from glutaraldehyde crosslinked polymerized porcine hemoglobin. Oxygen supply and other aspects have proved that the product has a good capacity to expand and carry oxygen, which can ensure the normal tissue perfusion and hemodynamic stability of experimental animals, and can effectively replace the role of red blood cells. The effect of pPolyHb on liver and kidney tissues in acute anemia model of rats and dogs was studied to further prove the effectiveness of pPolyHb. To investigate the effects of pPolyHb on blood pressure, arterial blood gas, liver and kidney injury factors and pathological injury of different fluid resuscitation tissues in acute anemia / treatment of rats. An isovolumetric hemodilution model was established in rats. The hemoglobin content was diluted to 4 鹵0.5g/dl or 5 鹵0.5 g / dl. after hemodilution, the hemoglobin content was injected into pPolyHb or erythrocyte (RBC), via vein at 0.3mL/min rate. When the hemoglobin content was more than 7 g / dll control group, no resuscitation was carried out. Blood pressure and arterial blood gas were monitored. Serum alanine aminotransferase (ALT), aspartate transferase (AST) and other liver and kidney injury factors were detected 7 days after operation. Pathological changes were detected by HE staining in renal tissue after death. The blood pressure of pPolyHb group and RBC group could recover to the basic level after resuscitation. Compared with the control group, the anaerobic metabolism in pPolyHb group was significantly improved after resuscitation, which effectively corrected the phenomenon of tissue acidosis, which was similar to that in the erythrocyte group. There was no significant difference in liver and kidney injury factor and HE staining between pPolyHb group and sham group, and it was superior to erythrocyte group. These results suggest that pPolyHb can improve hemodynamic parameters, alleviate metabolic acidosis and decrease the activity of liver and kidney injury factors in rats. The therapeutic effect of pPolyHb is similar to that of RBC and is significantly better than that of control group. In canine isovolumetric hemodilution model, the same method was used to simulate the acute anemia and to study the effect of pPolyHb on the condition that RBC was not available. The dogs were randomly divided into two groups after hemodilution. The experimental group was given 3g/kg pPolyHb, as the control group and the pulmonary artery wedge pressure (PAWP) as the reference. The hemodynamic parameters, blood gas index, oxygen supply oxygen consumption parameter and coagulation state were monitored. The serum levels of liver and kidney injury factors were measured 7 days after operation. The results of HE staining in liver and kidney tissues were observed after dissection. In the absence of RBC products, pPolyHb has some advantages over crystal liquid in maintaining hemodynamic stability, improving the oxygen supply of tissues, and reducing the activity of liver and kidney injury factors. No specific tissue damage was caused after 7 days. Experimental results show that pPolyHb can significantly improve the acute anemia caused by isovolumetric hemodilution in dogs.
【學(xué)位授予單位】：西北大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R556

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