Abstract 16106: Novel Small Molecule Agonists of Integrin Cd11b/cd18 Reduce Leukocyte Migration and Post Injury Neointimal Hyperplasia
Background: Leukocyte recruitment precedes neointimal hyperplasia after percutaneous transluminal coronary angioplasty and stenting. While blocking integrin-mediated leukocyte adhesion provides benefit in inflammatory diseases, the consequences of increased leukocyte adhesivity in vascular remodeling are less well understood. This study hypothesizes that increased leukocyte adhesion by novel compounds, termed leukadherins, prevents cell mobilization, inflammation and neointimal hyperplasia in an experimental model of vascular injury.
Material and Methods: Two compounds, leukadherins 1 and 3 (LA1 and LA3) were selected after screening a library of >100,000 small molecules with a cell-based high throughput assay. These compounds specifically bound to and allosterically increased CD11b/CD18 dependent cell-adhesion. Compound treatment significantly reduced neutrophil chemotaxis in vitro and decreased neutrophil recruitment upon acute thioglycollate-induced peritonitis in wild type mice. Next, to demonstrate the consequences of increasing leukocyte adhesion in post- injury neointimal hyperplasia, we used the rat balloon injury model. Vascular injury was inflicted in the right iliac artery of Fisher male rats with a 2 French Fogarty balloon catheter connected to an angiography kit. Leukadherins and vehicle control (DMSO) were intra-muscularly administered (100μg/kg) to rats 30 min prior to vascular injury and then every other day until the end of the experiments at 3 wks post surgery. Injured arteries of the LA1 and LA3 treated groups developed significantly reduced neointimas compared to those from control animals (neointima to media ratio of 0.16 ± 1 and 0.15 ± 1 vs. 0.22 ± 1 p<0.05). Leukadherin treatment also led to a reduction in the number of medial macrophages in LA1 and LA3 treated (16 ± 1 and 15 ± 1, respectively (p<0.05)) over DMSO treated animals (16 ± 1) as determined by immunohistochemistry analysis with an anti-CD68 antibody
Conclusion: Leukadherin treatment leads to reduced accumulation of leukocytes at the site of vascular injury and a subsequent decrease in neointimal thickening. Our results suggest that pharmacological activation of CD11b/CD18 offers a novel approach for modulating inflammatory diseases.
- © 2010 by American Heart Association, Inc.