E-015 Inflammation in murine aneurysm healing: the role of CXCL1

Introduction Cerebral aneurysms affect up to 5% of the U.S. population and can have devastating consequences. Rupture of cerebral aneurysms results in subarachnoid hemorrhage which has a mortality of up to 40%. Current prophylactic treatment options include surgical placement of a clip or use of coils or flow diverters through an endovascular approach. These options carry significant complication risks with functional disability or death occurring in up to 17.5% of patients after surgical clipping and in up to 8.4% after endovascular treatment. A significant drawback of endovascular coiling is that up to 20% of aneurysms can recur and require retreatment due to incomplete thrombus formation and insufficient fibrotic healing. This high rate of recurrence warrants investigation into the pathophysiology of aneurysm healing and development of more effective therapeutic options. As inflammatory processes appear to be the primary mechanism underlying cerebral aneurysm pathophysiology, it is critical to investigate aneurysm healing in the context of key inflammatory mediators. A more robust understanding of underlying inflammatory processes is crucial to developing novel treatments for complete resolution of unruptured cerebral aneurysms. Using a novel in vitro flow chamber model, we have identified chemokine (C-X-C) motif ligand 1 (CXCL1) as an important mediator in aneurysm pathophysiology. As there is increased expression of CXCL1 at arterial bifurcations and in aneurysms in vitro, we hypothesized that CXCL1 may be a key mediator in aneurysm healing. Methods Using our murine aneurysm healing model, aneurysms were induced in the right common carotid artery of C57BL/6 mice using elastase. Three weeks later when aneurysm formation was complete, aneurysms were implanted with either poly(lactic-co-glycolic acid)(PLGA)+CXCL1 - coated coils or PLGA only - coated coils. Three weeks after coil implantation, aneurysms were harvested for histological quantification of aneurysm healing. In a subsequent experiment, aneurysms were induced in C57BL/6 mice using the same elastase model. Three weeks after aneurysm induction, all mice underwent aneurysm coiling with PLGA-coated coils. Animals were randomly assigned to receive intraperitoneal injections of either CXCL1 neutralizing antibody or isotype-matched IgG control. Aneurysm tissue was harvested for histological quantification of aneurysm healing. Results In the first experiment, we found that animals treated with PLGA+CXCL1 - coated coils had significantly less aneurysm healing than those treated with PLGA only - coated coils (21.8% ± 3.87 versus 39.8% ± 8.02, respectively; p = 0.048). In the second experiment, animals treated with CXCL1 neutralizing antibody had significantly increased aneurysm healing compared to those treated with IgG control (63.8% ± 3.69 versus 42.4% ± 3.55, respectively; p = 0.00012). Conclusion Our findings suggest CXCL1 decreases murine aneurysm healing after coil implantation. Therapeutic intervention with CXCL1 neutralizing antibody appears to increase aneurysm healing after coil implantation. Disclosures D. Patel: None. K. Motwani: None. K. Hosaka: None. B. Hoh: None.