Abstract 63: CXCL8 Signaling Pathways and the Aortic Abdominal Aneurysm: The Oral CXCR2 Antagonist DF2156A Fully Abrogates Aneurysm Formation
An aneurysm of the abdominal aorta (AAA) is part of the atherososclerotic spectrum of diseases. The disease is characterized by a localized dilatation of the infrarenal artery and rupture of the weakened segment is now responsible for more than 15.000 annual deaths in the US alone. The pathology of AAA is complex and poorly understood. It is generally conceived that AAA is characterized by a localized general pro-inflammatory response and an accompanying protease imbalance that is held responsible for the progressive weakening of the aortic wall. The exact inflammatory pathways that drive aneurysm progression and that distinguish AAA from occlusive atherosclerotic disease have not yet been identified. We previously reported a 21-fold increase in CXCL8 mRNA expression and an approx. 300-fold increase in CXCL8 protein levels in human AAA, as compared to human occlusive atherosclerotic disease (p<0.001); suggesting that activation of the CXCL8/CXCR1-2 axis is a distinctive feature of AAA.
We now performed a histological and protein analysis of human AAA and human occlusive atherosoclerotic disease, showing abundant presence of the CXCL8 receptors CXCR1 and 2 as well as increased ERK phosphorylation in AAA. Evaluation on cellular level identified abundant neutrophils (fully absent in atherosoclerosis) as well as increased neovascularization as clear distinctive features of AAA, a finding that is consistent with increased CXCL8 signaling. To test a putative role of CXCL8/CXCR1-2 system in AAA we next tested whether the oral CXCR2 antagonist DF2156A prevents aneurysm formation in the elastase model, a well established model of the disease. This study showed that a once daily dose of 15mg/kg DF2156A fully abrogates aneurysm formation in the elastase model (71.86% aortic diameter growth in 14 days (SEM 4.88) in untreated animals vs. 17.66% growth (SEM 1.71) in animals treated with DF2156A) (p<0.001).
In conclusion, these studies identify activation of the CXCL8/CXCR1-2 pathway as a distinctive feature of AAA and characterize this pathway as a potential target for the stabilization of AAA.
- © 2012 by American Heart Association, Inc.