Li Jian-Ming, Eslami Mohammad H, Rohrer Michael J, Dargon Phong, Joris Isabella, Hendricks Gregory, Baker Stephen, Cutler Bruce S
Department of Surgery, Division of Vascular Surgery, University of Massachusetts Medical School, Worcester, MA 01655, USA.
J Vasc Surg. 2008 May;47(5):1048-57. doi: 10.1016/j.jvs.2007.12.005.
Interleukin 18 (IL18) is an interferon (IFN)-gamma-inducing factor and a proinflammatory and proatherogenic cytokine. IL18 binding protein (IL18-BP) functions as an IL18 inhibitor. This study was designed to investigate whether systemic administration of IL18-BP could inhibit neointimal hyperplasia and arterial lipid deposition.
New Zealand white, male rabbits were fed with a 21% fat, 0.15% cholesterol diet. The left superficial femoral artery (SFA) was de-endotheliazed with a 2F arterial embolectomy catheter. IL18-BP (5 microg, 10 microg, or 25 microg), or 0.9% saline (control) was administered by i.v. bolus during surgery. Rabbits were followed-up at 2 and 4 weeks. Intima-media (I/M) and lumen-whole artery (L/A) area ratios, and luminal areas were measured. Serum lipid levels, liver enzymes, and kidney function were evaluated. Inflammatory cells were quantified and further verified with immunohistofluorescence staining. The extent of lipid deposition in the artery wall was quantified with Oil Red O (ORO) staining employing Zeiss AxioVision 4.6.3. Image analysis software. Lipid laden cells including macrophages were evaluated by transmission electron microscopy (TEM).
Intravenous IL18-BP 5 microg, 10 microg, and 25 microg significantly reduced I/M ratios compared with the control group at both 2 and 4 weeks. There was no significant difference between the 5 microg and 10 microg dose groups. However, at 10 microg, IL18-BP significantly increased L/A ratio more than either the 5 microg IL18-BP or control groups. The high fat diet caused significant elevation of serum lipids at 4 and 6 weeks. IL18-BP had no effect on blood lipid levels. Lipid deposit in the thoracic aorta of the control group at 6 weeks was more than at 4 weeks (P = .025). Administration of IL18-BP inhibited the lipid deposition at 4 weeks (not significant) and 6 weeks (P = .012 to .008) compared with its control group. Lipid laden macrophages (foam cells), as well as endothelial cells and smooth muscle cells were seen in the descending thoracic aorta after 6 weeks of a high fat diet by ORO, immunohistofluorescence staining, and TEM. The lipid laden cells were not seen in either of IL18-BP groups. IL18-BP 10 microg significantly inhibited mono/macro adherence and infiltration in the SFA after balloon-injury at 2 weeks after surgery.
A single intravenous dose of IL18-BP significantly decreased arterial neointimal hyperplasia, improved lumen to artery ratio after balloon-injury and also prevented arteriosclerosis progression.
A single intravenous dose of IL18BP decreased neointimal hyperplasia and improved arterial L/A ratios in an atherosclerotic balloon-injury animal model. These preliminary results suggest that IL18BP may be a promising molecular approach to inhibit neointimal hyperplasia and arteriosclerosis progression following coronary and peripheral angioplasty.
白细胞介素18（IL18）是一种干扰素（IFN）-γ诱导因子，也是一种促炎和促动脉粥样硬化细胞因子。IL18结合蛋白（IL18-BP）发挥IL18抑制剂的作用。本研究旨在探讨全身性给予IL18-BP是否能抑制内膜增生和动脉脂质沉积。
给雄性新西兰白兔喂食含21%脂肪、0.15%胆固醇的饮食。用2F动脉取栓导管对左股浅动脉（SFA）进行去内皮处理。在手术期间通过静脉推注给予IL18-BP（5微克、10微克或25微克）或0.9%生理盐水（对照组）。在2周和4周时对兔子进行随访。测量内膜中层（I/M）和管腔-全动脉（L/A）面积比以及管腔面积。评估血清脂质水平、肝酶和肾功能。对炎症细胞进行定量，并通过免疫荧光染色进一步验证。采用蔡司AxioVision 4.6.3图像分析软件，用油红O（ORO）染色对动脉壁脂质沉积程度进行定量。通过透射电子显微镜（TEM）评估包括巨噬细胞在内的脂质负载细胞。
在2周和4周时，静脉注射5微克、10微克和25微克的IL18-BP与对照组相比，显著降低了I/M比。5微克和10微克剂量组之间无显著差异。然而，在10微克时，IL18-BP使L/A比显著高于5微克IL18-BP组或对照组。高脂饮食在4周和6周时导致血清脂质显著升高。IL18-BP对血脂水平无影响。对照组6周时胸主动脉中的脂质沉积多于4周时（P = 0.025）。与对照组相比，给予IL18-BP在4周时（无显著性差异）和6周时（P = 0.012至0.008）抑制了脂质沉积。高脂饮食6周后，通过ORO、免疫荧光染色和TEM在降主动脉中可见脂质负载巨噬细胞（泡沫细胞）以及内皮细胞和平滑肌细胞。在IL18-BP组中均未见到脂质负载细胞。10微克的IL18-BP在术后2周时显著抑制了球囊损伤后SFA中的单核/巨噬细胞黏附和浸润。
单次静脉注射IL18-BP可显著减少动脉内膜增生，改善球囊损伤后的管腔与动脉比值，并预防动脉粥样硬化进展。
在动脉粥样硬化球囊损伤动物模型中，单次静脉注射IL18BP可减少内膜增生并改善动脉L/A比。这些初步结果表明，IL18BP可能是一种有前景的分子方法，可抑制冠状动脉和外周血管成形术后的内膜增生和动脉粥样硬化进展。
