[1]胡聪,李攀,王志刚,等.靶向抗ICAM-1的载伊马替尼和液态氟碳脂质体对内毒素诱导的急性肺损伤/急性呼吸窘迫综合征模型小鼠的治疗研究[J].第三军医大学学报,2018,40(15):1357-1363.
 HU Cong,LI Pan,WANG Zhigang,et al.Anti-ICAM targeted liposomes loaded with imatinib and liquid fluorocarbon treat ALI/ARDS mouse model induced by LPS[J].J Third Mil Med Univ,2018,40(15):1357-1363.
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靶向抗ICAM-1的载伊马替尼和液态氟碳脂质体对内毒素诱导的急性肺损伤/急性呼吸窘迫综合征模型小鼠的治疗研究(/HTML )
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《第三军医大学学报》[ISSN:1000-5404/CN:51-1095/R]

卷:
40卷
期数:
2018年第15期
页码:
1357-1363
栏目:
基础医学
出版日期:
2018-08-15

文章信息/Info

Title:
Anti-ICAM targeted liposomes loaded with imatinib and liquid fluorocarbon treat ALI/ARDS mouse model induced by LPS
作者:
胡聪李攀王志刚江德鹏
重庆医科大学:附属第二医院呼吸内科,超声分子影像重庆市重点实验室
Author(s):
HU Cong LI Pan WANG Zhigang JIANG Depeng

Department of Respiratory Diseases, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010; Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing Medical University, Chongqing, 400010, China

关键词:
急性肺损伤急性呼吸窘迫综合征伊马替尼脂质体细胞间黏附分子-1
Keywords:
acute lung injury acute respiratory distress syndrome imatinib liposomes  intercellular cell adhesion molecule-1
分类号:
R-332; R563.8; R944.9
文献标志码:
A
摘要:

目的    探讨靶向抗细胞间黏附分子-1(intercellular cell adhesion molecule1,ICAM-1)的载伊马替尼(imatinib mesylate,IM)和液态氟碳(liquid fluorocarbon,LF)脂质体对内毒素(lipopolysaccharides, LPS)诱导的急性肺损伤/急性呼吸窘迫综合征(acute lung injury/acute respiratory distress syndrome, ALI/ARDS)模型小鼠的治疗效果。方法    用旋转蒸发法制备靶向抗ICAM1的载伊马替尼和液态氟碳脂质体,用马尔文粒径仪器检测其粒径,透射电镜下观察脂质体内部载药情况。光镜下观察其形态,置于37.5 ℃恒温加热板上观察其相变情况。体外模拟体内药物释放环境,观察脂质体内包载的伊马替尼药物的释放。6~8周大小30只C57BL/6小鼠按随机数字表法分为:对照组,LPS造模组,靶向抗ICAM-1脂质体治疗组,每组10只。治疗结束1 d后观察肺石蜡切片HE染色和肺石蜡切片免疫荧光ICAM-1的分布情况,肺组织提取mRNA,用qRT-PCR检测IL-6,IL-8,IL-10,TNF-α表达情况,同时对比肺的病理切片,小鼠肺湿干重比和小鼠肺泡液体清除率。靶向抗ICAM-1脂质体和非靶向脂质体分别尾静脉注射入ALI/ARDS小鼠体内,各个器官做冰冻切片,共聚焦激光显微镜下观察两组脂质体在小鼠体内各个器官的分布。结果    成功制备靶向抗ICAM-1的载伊马替尼和液态氟碳脂质体,其粒径为(320.8±58.7)nm,透射电镜下观察其内部成功包载药物,光镜下看到脂质体大小均匀,在37.5 ℃恒温板发生相变形成微泡。12 h脂质体药物释放达到高峰,绘出脂质体药物的释放曲线。与对照组相比,LPS造模组有典型的ALI/ARDS病理特征,肺损伤明显,病理切片评分增加(P<0.01),炎症因子IL-6,IL-8,TNF-α增加(P<0.01),IL-10减少(P<0.05)。湿干重比(W/D)增高(P<0.01),而小鼠肺泡液体清除率(alveolar fluid clearance,AFC)明显减弱(P<0.01)。靶向抗ICAM1脂质体治疗组肺损伤减缓,病理切片评分下降(P<0.05),炎症因子IL-6, IL-8, TNF-α减少(P<0.05),IL-10增加(P<0.05)。肺湿干重比下降(P<0.05),而小鼠肺泡液体清除率好转(P<0.05)。结论    靶向抗ICAM-1载伊马替尼和液态氟碳脂质体对LPS诱导的小鼠ALI/ARDS有明显的治疗作用。

Abstract:

Objective     To determine the therapeutic effect of intercellular cell adhesion molecule-1 (ICAM-1) targeted liposomes loaded with imatinib (IM) and liquid fluorocarbon (LF) on the treatment of lipopolysaccharides (LPS)induced mouse model of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Methods    The anti-ICAM-1 liposomes were prepared by rotary evaporation to load IM and LF, and the particle size was detected by Malvin particle size analyzer. Transmission electron microscopy was used to observe the loading of drugs in the liposomes, while under light microscopy for the shape of the prepared liposomes. Phase transformation was observed at constant temperature heating plate at 37.5 ℃, and release rate of the drugs from the liposomes was observed in vitro. A total of 30, 6~8-week-old C57BL/6 mice were randomly divided into control group, LPS model group, and targeting ICAM-1 liposomes treatment group (n=10). In 1 d after the end of treatment, HE staining and immunofluorescence assay were employed to observe the morphology and distribution of ICAM-1 in the lung paraffin sections respectively. The mRNA levels of IL-6, IL-8, IL-10 and TNF-α in the lung tissue were detected by qRT-PCR. Pathological changes, wet-to-dry (W/D) lung weight ratio, and alveolar fluid clearance (AFC) were compared in the different groups. ICAM-1 targeted liposomes and non-targeted liposomes were injected into ALI/ARDS mice by tail vein. All organs were collected for frozen sections, and the distributions of the liposomes in various organs were observed under confocal laser microscope. Results     ICAM-1 targeted liposomes loaded with IM and LF were successfully prepared, with a particle size of 320.8±58.7 nm. Transmission electron microscopy displayed the drugs were successfully encapsulated inside them, while light microscopy showed the liposomes were uniform in size, and gradually formed into microbubbles at 37.5 ℃. The release of liposomes reached peak at 12 h, and the release curve of drugs was plotted. Compared with the control group, the mice of the LPS group presented typical pathological features of ALI/ARDS and obvious lung injury, and had increased pathological score (P<0.01), elevated IL-8, IL-6 and TNF-α levels (P<0.01) while reduced IL-10 level (P<0.05), and increased W/D ratio (P<0.01) and decreased AFC (P<0.01). ICAM1 targeted liposomes treatment obviously attenuated the lung injury, decreased pathological score (P<0.05) and IL-8, IL-6 and TNF-α levels (P<0.05), but increased IL-10 level (P<0.05), reduced the W/D ratio of the lung (P<0.05), and improved AFC (P<0.05). Conclusion    ICAM-1 targeted liposomes loaded with IM and LF have obvious therapeutic effect on LPS-induced ALI/ARDS mice.

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更新日期/Last Update: 2018-08-19