全氟丁烷微球介导的超声空化对大鼠急性痛风性关节炎秋水仙碱治疗的增效作用

Ultrasound stimulated perfluorobutane microbubbles cavitation enhanced the therapeutic effect of colchicine in rats with acute gouty arthritis

目的探讨超声激励全氟丁烷微球产生的空化效应能否增强秋水仙碱对大鼠急性痛风性关节炎(AGA)的治疗效果,并减少其不良反应。方法通过注射尿酸盐(MSU)晶体构建大鼠AGA模型,根据是否进行空化辐照及是否给予不同剂量的秋水仙碱将其随机分为A~F共6组,A组为空白对照组,B组为模型对照组,C组为空化组,D组为标准浓度药物组,E组为低浓度药物空化组,F组为标准浓度药物空化组。注射MSU后第7 h与第8 h对踝关节进行超声造影(CEUS)后计算曲线下面积(AUC),对比空化效应对大鼠踝关节血流灌注的影响。根据24 h踝关节肿胀程度和步态评分评估AGA的症状。采用HE染色法检测中性粒细胞的浸润,通过检测血浆中白细胞介素1β(IL-1β)的水平分析各组炎症反应情况;通过检测内皮一氧化氮合酶(eNOS)的浓度分析血管扩张情况;通过胃肠道反应评分分析各组不良反应程度。结果进行空化的三组(C、E、F组)CEUS血流灌注和AUC值明显高于未空化组(A、B、D组)(均P<0.05)。与D组相比,E组AGA大鼠的踝关节肿胀程度、步态评分、血浆IL-1β水平差异无统计学意义(均P>0.05),但血浆eNOS浓度高于D组(P<0.05),胃肠道反应的情况显著减低(P<0.05)。与D组相比,F组踝关节肿胀程度、步态评分降低,HE染色显示AGA大鼠踝关节的中性粒细胞滑膜浸润程度更轻(均P<0.05),但两组间血浆IL-1β水平及胃肠道反应的情况差异无统计学意义(均P>0.05)。结论超声激励全氟丁烷微球产生的空化作用可以增强AGA大鼠踝关节血流灌注,使局部秋水仙碱的治疗效果增强,有助于减少秋水仙碱的用量,降低其不良反应。

Objective To investigate whether cavitation induced by ultrasound stimulated perfluorobutane microbubbles can enhance the therapeutic effect of colchicine and reduce its side effects on acute gouty arthritis(AGA)in rats.Methods The AGA rat model was established by injection of monosodium urate(MSU)crystals.The rats were randomly divided into 6 groups(A:blank control group,B:model control group,C:cavitation group,D:standard concentration drug group,E:low concentration drug cavitation group,F:standard concentration drug cavitation group)according to whether they were given different doses of colchicine.The area under the curve(AUC)of contrast-enhanced ultrasound(CEUS)was calculated at 7 h and 8 h after MSU injection to compare the effect of cavitation on ankle blood perfusion.The symptoms of AGA were evaluated according to the degree of ankle swelling and gait score at 24 h.The infiltration of neutrophils was detected by HE staining,and the inflammatory response was analyzed by detecting the level of interleukin-1β(IL-1β)in plasma.Vascular dilatation was analyzed by detecting the concentration of endothelial nitric oxide synthase(eNOS).The degree of adverse reactions in each group was analyzed by gastrointestinal reaction score.Results The CEUS blood perfusion and AUC values of the three groups with cavitation(groups C,E and F)were significantly higher than those of the non-cavitation groups(groups A,B and D)(all P<0.05).Compared with group D,there were no significant differences in the degree of ankle swelling,gait score,and plasma IL-1βlevel in group E(all P>0.05),but the plasma eNOS concentration was higher and the incidence of gastrointestinal reactions was significantly lower in group E(all P<0.05).Compared with group D,the degree of ankle swelling and gait score in group F were decreased,and HE staining showed that the degree of synovial infiltration of neutrophils in the ankle joints of AGA rats in group F was lighter(all P<0.05),but there was no significant difference in plasma IL-1βlevel and the incidence of gastrointestinal reactions between group D and group F(all P>0.05).Conclusions The cavitation of perfluorobutane microspheres stimulated by ultrasound can enhance the blood perfusion of the ankle joint of AGA rats,enhance the therapeutic effect of local colchicine,and help to reduce the dosage of colchicine and its side effects.