【摘要】：目的:探討血管內(nèi)介入治療、射頻消融治療以及抗血管生成治療肝泡狀棘球蚴病的治療效果。方法:Wistar大鼠復(fù)制肝泡球蚴動(dòng)物模型。血管內(nèi)介入治療分為5組,模型對照組、口服組、靜脈注射組、肝動(dòng)脈組、門靜脈組。分別觀察阿苯達(dá)唑納米微球治療后泡球蚴組織濕重、病理學(xué)變化、HIF-1α、VEGF-A、VEGF-C、微血管密度、微淋巴管密度的變化。射頻消融治療分為兩組,模型對照組及射頻實(shí)驗(yàn)組,觀察射頻消融治療后泡球蚴組織濕重、病理學(xué)變化、血清HIF-1α、血清及組織VEGF、微血管密度、微淋巴管密度的變化�？寡苌芍委煼譃閮山M,模型對照組和肝動(dòng)脈灌注貝伐單抗實(shí)驗(yàn)組,觀察給予抗血管藥物治療后病理學(xué)變化、VEGF、微淋巴管密度、Fox P3+Treg細(xì)胞的動(dòng)態(tài)變化。結(jié)果:血管介入治療對大鼠白細(xì)胞及ALT/AST的五個(gè)分組的不同時(shí)間點(diǎn)的資料進(jìn)行重復(fù)資料的方差分析,不同時(shí)間點(diǎn)的測量的白細(xì)胞水平具有統(tǒng)計(jì)學(xué)差異(P0.05),白細(xì)胞一過性升高,肝功能一過性損傷。泡球蚴組織濕重5組差異無統(tǒng)計(jì)學(xué)意義(P0.05)。病理學(xué)改變門靜脈組、肝動(dòng)脈組與口服組之間比較具有統(tǒng)計(jì)學(xué)差異(P0.05),以變性、壞死為主。血管內(nèi)介入治療的兩組肝臟的局部的阿苯達(dá)唑亞砜藥物濃度最高,相對于血漿和泡球蚴囊具有統(tǒng)計(jì)學(xué)差異(P0.05)。血管內(nèi)介入治療組VEGF-a/VEGF-c、HIF-1α、微血管密度、微淋巴管密度明顯高于模型對照組。射頻消融治療后,不同時(shí)間點(diǎn)的測量的白細(xì)胞及肝功能水平具有統(tǒng)計(jì)學(xué)差異(P0.05),白細(xì)胞一過性升高,肝功能一過性損傷。泡球蚴濕重較前明顯下降趨勢(P0.05),減重率為32.16%。病理學(xué)變化以壞死為主。血清VEGF值有下降趨勢,差異有統(tǒng)計(jì)學(xué)意義(P0.05);缺氧誘導(dǎo)因子有上升趨勢,差異有統(tǒng)計(jì)學(xué)意義(P0.05)。泡球蚴邊緣帶微血管計(jì)數(shù)、及微淋巴管計(jì)數(shù)均較術(shù)前有明顯下降,且具有統(tǒng)計(jì)學(xué)差異(P0.05)。在抗血管生成治療的實(shí)驗(yàn)中,藥物灌注組及生理鹽水灌注組,兩組在試驗(yàn)后的轉(zhuǎn)氨酶變化曲線基本一致,無明顯統(tǒng)計(jì)學(xué)差異(P0.05),但均有一過性的轉(zhuǎn)氨酶升高。病理學(xué)觀察無明顯改變�？寡苌芍委熀�,VEGF變化呈下降再上升曲線,術(shù)后第7天VEGF明顯降低(P0.05),術(shù)后第14天血清VEGF降至最低(P0.05),術(shù)后第28天血清VEGF升高至對照組水平(P0.05)。泡球蚴組織邊緣帶VEGF-a的檢測結(jié)果與血清VEGF在體內(nèi)的變化趨勢一致。Fox P3+Treg細(xì)胞呈下降趨勢,而微淋巴管密度無明顯變化。結(jié)論:血管內(nèi)介入治療雖然對肝功能造成一過性損傷,通過檢測阿苯達(dá)唑亞砜濃度、HIF1-α、VEGF、微血管密度計(jì)數(shù)、微淋巴管密度,以及病理學(xué)及超微結(jié)構(gòu)觀察證明了血管內(nèi)介入治療有其獨(dú)特優(yōu)勢,具有更為優(yōu)異的肝臟靶向性和泡球蚴囊的阿苯達(dá)唑亞砜濃度,治療效果優(yōu)于與口服、靜脈治療。肝泡狀棘球蚴病的射頻消融治療,著重在于大鼠泡球蚴射頻消融的方法的探索與建立。射頻消融的熱能損傷通過病理學(xué)觀察、血管內(nèi)皮生長因子、缺氧誘導(dǎo)因子對比分析等,認(rèn)為能夠直接殺滅泡狀棘球蚴,是一種有效的治療方法�？寡苌芍委熦惙慰垢蝿�(dòng)脈灌注后,可有效抑制局部VEGF誘導(dǎo)的血管生成,并使泡球蚴組織邊緣區(qū)域微血管、微淋巴管的正常化,以及抑制Fox P3+Treg表達(dá),逆轉(zhuǎn)免疫耐受,從而調(diào)動(dòng)機(jī)體免疫殺傷作用。
[Abstract]:Objective: To investigate the therapeutic effects of endovascular interventional therapy, radiofrequency ablation and anti-angiogenesis on hepatic alveolar echinococcosis.Methods: Wistar rats were used to reproduce the animal model of hepatic alveolar echinococcosis.Intravascular interventional therapy was divided into five groups: model control group, oral group, intravenous injection group, hepatic artery group and portal vein group. The changes of wet weight, pathological changes, HIF-1a, VEGF-A, VEGF-C, microvessel density and microlymphatic vessel density of alveolar echinococcus after microsphere ablation were divided into two groups: model control group and experimental group. Antiangiogenic therapy was divided into two groups: model control group and hepatic artery infusion with bevacizumab group. Pathological changes, vascular endothelial growth factor, microlymphatic density and Fox P3 + Treg cell dynamic changes were observed after antiangiogenic therapy. Results: Interventional therapy was performed in five groups of leukocytes and ALT / AST in rats. There was no significant difference in the wet weight of alveolar echinococcus between the 5 groups (P 0.05). Pathological changes in portal vein group, hepatic artery group and oral group were compared. There was significant difference between the two groups (P 0.05). The local concentration of albendazole sulfoxide in the liver of the two groups was the highest, which was significantly higher than that of plasma and alveolar cysts (P 0.05). The levels of VEGF-a/VEGF-c, HIF-1a, microvessel density and microlymphatic vessel density in the treatment group were significantly higher than those in the model group. After radiofrequency ablation, the leucocyte and liver function levels measured at different time points were statistically different (P 0.05). Leucocyte transient elevation and liver function transient injury. The wet weight of alveolar echinococcus decreased significantly (P 0.05) and the weight loss rate was 32.16%. Pathological changes were mainly necrosis. The serum VEGF value had a downward trend, the difference was significant. There was statistical significance (P 0.05); hypoxia inducible factor had an upward trend, the difference was statistically significant (P 0.05). Microvessel count and microlymphatic vessel count of alveolar hydatid marginal zone were significantly decreased compared with those before operation, and the difference was statistically significant (P 0.05). In the experiment of anti-angiogenesis therapy, drug perfusion group and normal saline perfusion group, two groups were in the experiment. After anti-angiogenesis treatment, the change of VEGF showed a descending and rising curve, and it decreased significantly on the 7th day after operation (P 0.05). On the 14th day after operation, the level of serum VEGF decreased to the lowest level (P 0.05), and on the 28th day after operation. The results of detection of VEGF-a in the marginal zone of alveolar echinococcus tissue were consistent with that of serum VEGF in vivo. Fox P3 + Treg cells showed a downward trend, while the density of microlymphatic vessels did not change significantly. Conclusion: Although intravascular interventional therapy caused transient damage to liver function, the concentration of albendazole sulfoxide could be detected. Endovascular interventional therapy has its unique advantages, with better liver targeting and albendazole sulfoxide concentration in alveolar cysts. The therapeutic effect is superior to oral and intravenous therapy. Radiofrequency ablation of hepatic alveolar echinococcosis Radiofrequency ablation of alveolar echinococcus in rats is an effective method for the treatment of alveolar echinococcus. Antiangiogenic therapy of bevacizumab hepatic artery perfusion is an effective method for the treatment of alveolar echinococcus. After injection, it can effectively inhibit angiogenesis induced by local vascular endothelial growth factor, normalize microvasculature and microlymphatic vessels in the marginal region of alveolar hydatid tissue, inhibit the expression of Fox P3+Treg, reverse the immune tolerance, and thus mobilize the body's immune killing effect.
【學(xué)位授予單位】：新疆醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R532.32

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