A mAb to the β2-leukocyte integrin Mac-1 (CD11b/CD18) reduces intimal thickening after angioplasty or stent implantation in rabbits
A mAb to the β2-leukocyte integrin Mac-1 (CD11b/CD18) reduces intimal thickening after angioplasty or stent implantation in rabbits
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DOI：
10.1073/pnas.95.17.10134
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发表时间：
1998-08-18
影响因子：
11.1
通讯作者：
Simon, DI
中科院分区：
文献类型：
--
作者：
Rogers, C;Edelman, ER;Simon, DI
白细胞在实验性损伤的血管中早期大量募集，与细胞增殖和内膜生长成正比。活化的循环白细胞和Mac-1（CD 11b/CD 18，alpha（M）beta（2））表达是血管成形术患者再狭窄风险的标志物。由于血管成形术的血管缺乏内皮，但有广泛的纤维蛋白（原）和血小板沉积，我们假设Mac-1依赖性粘附纤维蛋白（原）是白细胞募集和功能的重要决定因素，这可能反过来促进内膜生长。为了研究这一假设，我们将M1/70，一种抗CD 11b阻断mAb，给予兔（1 mg/kg i，v.）在髂动脉球囊剥脱或更深支架诱导损伤之前即刻和之后每48小时持续3、6或14天。M1/70，结合到分离的兔单核细胞和剂量依赖性抑制Mac-1介导的纤维蛋白原结合在体外，减少白细胞募集超过2倍3，6，和14天后损伤。损伤后14天的新生内膜生长通过M1/70治疗显著减弱（球囊损伤后内膜面积为0.12 +/- 0.09 mm（2），与溶剂处理对照组的0.32 +/- 0.08 mm（2）相比，P < 0.01，IgG处理对照组的0.38 +/- 0.08 mm（2）相比，P < 0.005;支架损伤后的内膜面积为0.56 +/- 0.16 mm（2），而溶剂处理对照组为0.84 +/- 0.13 mm（2），P < 0.05，IgG处理对照组为0.90 +/- 0.15 mm（2），P < 0.02）。Mac-1阻断减少实验性新生内膜增厚，表明白细胞募集和浸润损伤动脉可能是预防内膜增生的有效靶点。
Leukocytes are recruited early and abundantly to experimentally injured vessels, in direct proportion to cell proliferation and intimal growth. Activated circulating leukocytes and Mac-1 (CD11b/CD18, alpha(M)beta(2)) expression are markers of restenosis risk in patients undergoing angioplasty. As angioplastied vessels lack endothelium but have extensive fibrin(ogen) and platelet deposition, we hypothesized that Mac-1-dependent adhesion to fibrin(ogen) is an important determinant of leukocyte recruitment and function, which may in turn promote intimal growth. To study this hypothesis we administered M1/70, an anti-CD11b blocking mAb, to rabbits (1 mg/kg i,v.) immediately before, and every 48 hr for 3, 6, or 14 days after, iliac artery balloon denudation or deeper stent-induced injury. M1/70, which bound to isolated rabbit monocytes and dose-dependently inhibited Mac-1-mediated fibrinogen binding in vitro, reduced leukocyte recruitment more than 2-fold 3, 6, and 14 days after injury. Neointimal growth 14 days after injury was markedly attenuated by treatment with M1/70 (intimal area after balloon injury, 0.12 +/- 0.09 mm(2), compared with 0.32 +/- 0.08 mm(2) in vehicle-treated controls, P < 0.01, and 0.38 +/- 0.08 mm(2) in IgG-treated controls, P < 0.005; intimal area after stent injury, 0.56 +/- 0.16 mm(2), compared with 0.84 +/- 0.13 mm(2) in vehicle-treated controls, P < 0.05, and 0.90 +/- 0.15 mm(2) in IgG-treated controls, P < 0.02). Mac-1 blockade reduces experimental neointimal thickening, suggesting that leukocyte recruitment to and infiltration of injured arteries may be a valid target for preventing intimal hyperplasia.