The long-term goal of this proposal is to elucidate the pathophysiological mechanisms underlying abdominal aortic aneurysm (AAA) formation and progression. AAA is a common and potentially fatal vascular condition affecting up to 9% of individiuals age 65 and older. AAA is a complex disease associated with male gender, hypertension, atherosclerosis, coronary artery disease, and cigarette smoking. It is among the top twenty leading causes of death in the United States, accounting for approximately 15,000 deaths per year. It is estimated that as many as 1 in 20 U.S. veterans over the age of 50 have AAA. Treatment option for AAA is currently limited to surgical intervention. Open surgical repair of large AAA (greater than 5.5 cm in diameter) is an effective option in preventing death from ruptures. Although effective, open surgical repair can be associated with high post-operative mortality (up to 6%). Given the limited treatment options, the advanced age of patients with AAA-which may preclude them from undergoing surgery- medical treatment to slow progression thus represents an attractive alternative. The objective of this application is to further the understanding of immune-mediated pathways involved in AAA. Increasing evidence suggests that AAA is an inflammatory, immune-mediated disease. Using an elastase-induced AAA mouse model that recapitulates many key features of human AAA, we previously established that an autoantibody directs aneurysm development through complement activation. We subsequently cloned a pathogenic IgG autoantibody specific for fibrinogen that binds to elastase-perfused aortic wall tissues in the mouse, activates the complement lectin pathway (LP) upstream of the alternative pathway (AP), and induces AAA formation. Additionally we demonstrate that, in human AAA tissues, fibrinogen colocalizes with mannan-binding lectin (MBL), an essential component of the LP, suggesting that recognition of fibrinogen may initiate complement activation in humans as well. Moreover, we found that circulating autoantibodies in a subset of individuals with AAA react against purified fibrinogen in vitro and fibrinogen- associated epitopes in human aneurysmal tissues, further enhancing the relevance of our experimental findings. Complement activation leads to the generation of anaphylatoxins (C3a and C5a) that attract neutrophils to the aortic wall. Once recruited neutrophils release neutrophil extracellular traps (NETs) that likely modulate the adaptive (T cell) response. Lastly, we established that CD8+ T cells are critically involved in aneurysm genesis downstream of neutrophil recruitment. Several outstanding questions remain: 1) what is the mechanism that triggers autoimmunity against a protein (fibrinogen) abundantly found in the circulation; 2) what are the events that link neutrophils and NETs to the chronic, adaptive immune (T cell) responses, and 3) how do T cells propagate the inflammatory cascade that leads to the eventual aneurysmal dilatation. We posit that a thorough investigation of the immune processes in AAA will provide new insights into mechanisms that govern aneurysm genesis and identify potential therapeutic targets for immune-based medical therapies.
Abdominal aortic aneurysm (AAA) is among the top 20 leading causes of death in the U.S., accounting for ~15,000 deaths per year. Previous studies indicate that as many as 1 in 20 U.S. veterans over the age of 50 have AAA. Open surgical repair of large AAA (greater than 5.5 cm in diameter) is effective in preventing death from ruptured aneurysm. Of the 35,000 operations performed each year to repair AAA 1,200 were performed by the Department of Veterans Affairs according to one study. Although effective, open surgical repair can be associated with high post-operative mortality (up to 6%). Endovascular repair carries lower post-operative mortality risk but does not lead to increased long-term survival among older patients who make up a large percentage of the veterans population. Given the limited treatment options, the advanced age of patients with AAA-which may preclude them from undergoing major surgery-and the uncertainties that still pertain to endovascular repair, there is a need to develop medical treatment approaches that halt disease progression.
| Yan, Huimin; Zhou, Hui-Fang; Akk, Antonina et al. (2016) Neutrophil Proteases Promote Experimental Abdominal Aortic Aneurysm via Extracellular Trap Release and Plasmacytoid Dendritic Cell Activation. Arterioscler Thromb Vasc Biol 36:1660-1669 |
