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

胡聪; 李攀; 王志刚; 江德鹏

doi:10.16016/j.1000-5404.201801166

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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

基础医学 | 更新时间：2026-01-09

- 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
- Anti-ICAM targeted liposomes loaded with imatinib and liquid fluorocarbon treat ALI/ARDS mouse model induced by LPS
- 第三军医大学学报 2018年40卷第15期页码：1357-1363
- 作者机构：
  
  1.400010 重庆, 重庆医科大学:附属第二医院呼吸内科
  2.400010 重庆, 重庆医科大学:超声分子影像重庆市重点实验室
- 作者简介：
  
  [ 江德鹏, 电话:(023)63693094, E-mail:depengjiang@163.com JIANG Depeng,电话:(023)63693094, E-mail:depengjiang@163.com
- 基金信息：
  
  国家自然科学基金应急管理项目(81650003)
- DOI：10.16016/j.1000-5404.201801166
  中图分类号： R-332;R563.8;R944.9
- 收稿：2018-02-01，
  
  修回：2018-03-29，
  
  纸质出版：2018-08-15
- 稿件说明：
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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.

Cong HU, Pan LI, Zhigang WANG, et al. Anti-ICAM targeted liposomes loaded with imatinib and liquid fluorocarbon treat ALI/ARDS mouse model induced by LPS[J]. Journal of Third Military Medical University, 2018, 40(15): 1357-1363.
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. DOI： 10.16016/j.1000-5404.201801166.

Cong HU, Pan LI, Zhigang WANG, et al. Anti-ICAM targeted liposomes loaded with imatinib and liquid fluorocarbon treat ALI/ARDS mouse model induced by LPS[J]. Journal of Third Military Medical University, 2018, 40(15): 1357-1363. DOI： 10.16016/j.1000-5404.201801166.

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（

0.01），炎症因子IL-6，IL-8，TNF-α增加（

0.01），IL-10减少（

0.05）。湿干重比（W/D）增高（

0.01），而小鼠肺泡液体清除率（alveolar fluid clearance，AFC）明显减弱（

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（

0.05），炎症因子IL-6，IL-8，TNF-α减少（

0.05），IL-10增加（

0.05）。肺湿干重比下降（

0.05），而小鼠肺泡液体清除率好转（

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 (

=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 (

0.01)

elevated IL-8

IL-6 and TNF-α levels (

0.01) while reduced IL-10 level (

0.05)

and increased W/D ratio (

0.01) and decreased AFC (

0.01). ICAM-1 targeted liposomes treatment obviously attenuated the lung injury

decreased pathological score (

0.05) and IL-8

IL-6 and TNF-α levels (

0.05)

but increased IL-10 level (

0.05)

reduced the W/D ratio of the lung (

0.05)

and improved AFC (

0.05).

Conclusion

ICAM-1 targeted liposomes loaded with IM and LF have obvious therapeutic effect on LPS-induced ALI/ARDS mice.

关键词

Keywords

references

BERNARD G R, ARTIGAS A, BRIGHAM K L, et al . The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination[J ] . Am J Respir Crit Care Med, 1994, 149(3 Pt 1):818-824. DOI:10.1164/ajrccm.149.3.7509706.

WARE L B, MATTHAY M A. The acute respiratory distress syndrome[J]. N Engl J Med, 2000, 342(18):1334-1349. DOI:10.1056/NEJM200005043421806.

CHISLOCK E M, RING C, PENDERGAST A M. Abl kinases are required for vascular function, Tie2 expression, and angiopoietin-1-mediated survival[J]. Proc Natl Acad Sci USA, 2013, 110(30):12432-12437.DOI:10.1073/pnas.1304188110.

GREUBER E K, SMITH-PEARSON P, WANG J, et al . Role of ABL family kinases in cancer:from leukaemia to solid tumours[J ] . Nat Rev Cancer, 2013, 13(8):559-571. DOI:10.1038/nrc3563 .

MOEN M D, MCKEAGE K, PLOSKER G L, et al . Imatinib:a review of its use in chronic myeloid leukaemia[J ] . Drugs, 2007, 67(2):299-320. DOI:10.2165/00003495-200767020-00010.

RHEE C K, LEE S H, YOON H K, et al . Effect of nilotinib on bleomycin-induced acute lung injury and pulmonary fibrosis in mice[J ] . Respiration, 2011, 82(3):273-287. DOI:10.1159/000327719.

AMAN J, PETERS M J, WEENINK C, et al . Reversal of vascular leak with imatinib[J ] . Am J Respir Crit Care Med, 2013, 188(9):1171-1173.DOI:10.1164/rccm.201301-0136LE.

DOS SANTOS L V, LIMA J P, ABDALLA K C, et al . Imatinib-induced bone edema:case report and review of literature[J ] . J Natl Compr Canc Netw, 2013, 11(10):1187-1191. DOI:10.6004/jnccn.2013.0140.

DRUKER B J, TALPAZ M, RESTA DJ, et al . Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia[J ] . N Engl J Med, 2001, 344(14):1031-1037. DOI:10.1056/NEJM200104053441401.

WANG Q, ZHENG X, CHENG Y, et al . Resolvin D1 stimulates alveolar fluid clearance through alveolar epithelial sodium channel, Na, K-ATPase via ALX/cAMP/PI3K pathway in lipopolysaccharide-induced acute lung injury[J ] . J Immunol, 2014, 192(8):3765-3777. DOI:10.4049/jimmunol.1302421.

刘俊彦, 吕学军, 赵维, 等.Sirt1通过去乙酰化NF-κB/p65减轻小鼠肺泡Ⅱ型上皮细胞脂多糖损伤[J].第三军医大学学报, 2017, 39(14):1415-1421.DOI:10.16016/j.1000-5404.201611089.

LIUJ Y, LYU X J, ZHAO W, et al .Sirt1 alleviated lipopolysaccharide damage in alveolar type Ⅱ epithelial cells by deacetylated NF-kappa B/p65 in[J ] .J Third Mil Med Univ, 2017, 39(14):1415-1421.DOI:10.16016/j.1000-5404.201611089.

梁家宁, 周倩倩, 张天相, 等.TNF-α和IL-1β在急性呼吸窘迫综合征小鼠肺组织表达的变化及评价[J].细胞与分子免疫学杂志, 2017, 33(2):159-163. DOI:10.13423/j.cnki.cjcmi.008006.

LIANGJ N, ZHOU Q Q, ZHANG T X, et al . Changes of TNF-alpha and IL-1 beta in lung tissues of mice with acute respiratory distress syndrome and evaluation of[J ] . Cell Mol Immunol, 2017, 33(2):159-163. DOI:10.13423/j.cnki.cjcmi.008006.

王川江, 徐昉.过度自噬对白介素-1β在急性呼吸窘迫综合征中失控性炎症的调节作用研究[J].重庆医科大学学报, 2017, 42(1):15-20.DOI:10.13406/j.cnki.cyxb.001144.

WANGC J, XU F. Excessive autophagy on interleukin-1 beta in acute respiratory distresssyndrome in the comprehensive regulation of inflammatory effect[J]. J Chongqing Med Univ, 2017, 42(1):15-20.DOI:10.13406/j.cnki.cyxb.001144.

LETSIOU E, RIZZO A N, SAMMANI S, et al . Differential and opposing effects of imatinib on LPS-and ventilator-induced lung injury[J ] . Am J Physiol Lung Cell Mol Physiol, 2015, 308(3):L259-L269. DOI:10.1152/ajplung.00323.2014.

CHANDEL N S, BUDINGER G R, MUTLU G M, et al . Keratinocyte growth factor expression is suppressed in early acute lung injury/acute respiratory distress syndrome by smad and c-Abl pathways[J ] . Crit Care Med, 2009, 37(5):1678-1684. DOI:10.1097/CCM.0b013e 31819fc81a.

MITSOPOULOS P, OMRI A, ALIPOUR M, et al . Effectiveness of liposomal-N-acetylcysteine against LPS-induced lung injuries in rodents[J ] . Int J Pharm, 2008, 363(1/2):106-111.DOI:10.1016/j.ijpharm.2008.07.015.

STEIMBACH L M, TONIN F S, VIRTUOSO S, et al . Efficacy and safety of amphotericin B lipid-based formulations-A systematic review and meta-analysis[J ] . Mycoses, 2017, 60(3):146-154. DOI:10.1111/myc.12585.

OLIVIER K N, GRIFFITH D E, EAG LE G, et al . Randomized trial of liposomal amikacin for inhalation in nontuberculous Mycobacterial lung disease[J ] . Am J Respir Crit Care Med, 2017, 195(6):814-823. DOI:10.1164/rccm.201604-0700OC.

MUZYKANTOV V R, CHRISTOFIDOU-SOLOMIDOU M, BALYASNIKOVA I, et al . Streptavidin facilitates internalization and pulmonary targeting of an anti-endothelial cell antibody (platelet-endothelial cell adhesion molecule 1):a strategy for vascular immunotargeting of drugs[J ] . Proc Natl Acad Sci USA, 1999, 96(5):2379-2384. DOI:10.1073/pnas.96.5.2379.

BRENNER J S, BHAMIDIPATI K, GLASSMAN P M, et al . Mechanisms that determine nanocarrier targeting to healthy versus inflamed lung regions[J ] . Nanomedicine, 2017, 13(4):1495-1506.DOI:10.1016/j.nano.2016.12.019.

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