肝泡状棘球蚴病综合介入治疗的实验研究

发布时间：2018-08-11 19:20

【摘要】：目的:探讨血管内介入治疗、射频消融治疗以及抗血管生成治疗肝泡状棘球蚴病的治疗效果。方法:Wistar大鼠复制肝泡球蚴动物模型。血管内介入治疗分为5组,模型对照组、口服组、静脉注射组、肝动脉组、门静脉组。分别观察阿苯达唑纳米微球治疗后泡球蚴组织湿重、病理学变化、HIF-1α、VEGF-A、VEGF-C、微血管密度、微淋巴管密度的变化。射频消融治疗分为两组,模型对照组及射频实验组,观察射频消融治疗后泡球蚴组织湿重、病理学变化、血清HIF-1α、血清及组织VEGF、微血管密度、微淋巴管密度的变化。抗血管生成治疗分为两组,模型对照组和肝动脉灌注贝伐单抗实验组,观察给予抗血管药物治疗后病理学变化、VEGF、微淋巴管密度、Fox P3+Treg细胞的动态变化。结果:血管介入治疗对大鼠白细胞及ALT/AST的五个分组的不同时间点的资料进行重复资料的方差分析,不同时间点的测量的白细胞水平具有统计学差异(P0.05),白细胞一过性升高,肝功能一过性损伤。泡球蚴组织湿重5组差异无统计学意义(P0.05)。病理学改变门静脉组、肝动脉组与口服组之间比较具有统计学差异(P0.05),以变性、坏死为主。血管内介入治疗的两组肝脏的局部的阿苯达唑亚砜药物浓度最高,相对于血浆和泡球蚴囊具有统计学差异(P0.05)。血管内介入治疗组VEGF-a/VEGF-c、HIF-1α、微血管密度、微淋巴管密度明显高于模型对照组。射频消融治疗后,不同时间点的测量的白细胞及肝功能水平具有统计学差异(P0.05),白细胞一过性升高,肝功能一过性损伤。泡球蚴湿重较前明显下降趋势(P0.05),减重率为32.16%。病理学变化以坏死为主。血清VEGF值有下降趋势,差异有统计学意义(P0.05);缺氧诱导因子有上升趋势,差异有统计学意义(P0.05)。泡球蚴边缘带微血管计数、及微淋巴管计数均较术前有明显下降,且具有统计学差异(P0.05)。在抗血管生成治疗的实验中,药物灌注组及生理盐水灌注组,两组在试验后的转氨酶变化曲线基本一致,无明显统计学差异(P0.05),但均有一过性的转氨酶升高。病理学观察无明显改变。抗血管生成治疗后,VEGF变化呈下降再上升曲线,术后第7天VEGF明显降低(P0.05),术后第14天血清VEGF降至最低(P0.05),术后第28天血清VEGF升高至对照组水平(P0.05)。泡球蚴组织边缘带VEGF-a的检测结果与血清VEGF在体内的变化趋势一致。Fox P3+Treg细胞呈下降趋势,而微淋巴管密度无明显变化。结论:血管内介入治疗虽然对肝功能造成一过性损伤,通过检测阿苯达唑亚砜浓度、HIF1-α、VEGF、微血管密度计数、微淋巴管密度,以及病理学及超微结构观察证明了血管内介入治疗有其独特优势,具有更为优异的肝脏靶向性和泡球蚴囊的阿苯达唑亚砜浓度,治疗效果优于与口服、静脉治疗。肝泡状棘球蚴病的射频消融治疗,着重在于大鼠泡球蚴射频消融的方法的探索与建立。射频消融的热能损伤通过病理学观察、血管内皮生长因子、缺氧诱导因子对比分析等,认为能够直接杀灭泡状棘球蚴,是一种有效的治疗方法。抗血管生成治疗贝伐单抗肝动脉灌注后,可有效抑制局部VEGF诱导的血管生成,并使泡球蚴组织边缘区域微血管、微淋巴管的正常化,以及抑制Fox P3+Treg表达,逆转免疫耐受,从而调动机体免疫杀伤作用。
[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.
【学位授予单位】：新疆医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R532.32

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