The pathophysiology of abdominal aortic aneurysm growth: Corresponding and discordant inflammatory and proteolytic processes in abdominal aortic and popliteal artery aneurysms

ObjectiveThere is remarkable controversy over the processes driving abdominal aneurysm growth. The inherent limitations of animal and human studies hamper elucidation of the key inflammatory and proteolytic processes. Human data are largely derived from surgical specimens that typically reflect the final stages of the disease process and thus do not allow distinction between primary and secondary processes. Clear epidemiologic and genetic associations between abdominal aortic aneurysm (AAA) and popliteal artery aneurysms (PAA) suggest that that these two pathologies share common grounds. On this basis, we reasoned that information of corresponding and discordant processes in these aneurysms might provide critical clues on the processes that are crucial for aneurysm progression.MethodsMessenger RNA (semi-quantitative real-time polymerase chain reaction) and protein analysis (enzyme-linked immunosorbent assay, multiplex, Western blotting), and histology were performed on aneurysm wall samples obtained during elective PAA and AAA repair. Nonaneurysmal aorta tissue from organ donors was included as reference.ResultsMessenger RNA and protein analysis showed that PAA and AAA are both characterized by a marked activation of nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) proinflammatory transcription factors, and hyperexpression of interleukin (IL)-6 and IL-8. Discordant findings were found for other inflammatory markers such as interferon-γ, interferon-inducible protein 10, tumor necrosis factor-α, monocyte chemotactic protein-1, and macrophage inflammatory protein 1α and β, which were all lower in PAA. On the cellular level, both pathologies exhibited profuse infiltration of macrophages, neutrophils, and T-helper cells. Results for B cells, plasma cells, and cytotoxic T cells were discordant, with minimal infiltration of these cell types in PAA. Evaluation of protease expression and activation showed that both conditions are dominated by increased matrix metalloproteinase 8 and 9, and cathepsin K, L and S expression and activation.ConclusionThis explorative study characterizes degenerative aneurysmal disease general inflammatory conditions that are dominated by profound activation of the NF-κB and AP-1 pathways, hyperexpression of IL-6 and IL-8, and neutrophil involvement. Discordant findings for interferon γ, cytotoxic T cells, B cells, and plasma cells challenge a critical role for these factors in the process of aneurysm growth. Pharmaceutic strategies targeting the common components in AAA and PAA may prove effective for the stabilization of AAA.

Clinical RelevanceAn understanding of the processes driving aneurysm growth is critical for the development of new therapeutic strategies. Studies in animals and those using human material have helped to identify a variety of molecular candidates for intervention. Yet, interpretation of the data is complicated by the limited validity of animal models and because human tissue is generally obtained during surgical abdominal aortic aneurysm repair and thus represents the final stages of the disease. Strong genetic and epidemiologic associations between abdominal aortic aneurysm and popliteal aneurysms suggest that these aneurysms share a common ground. We therefore reasoned that information on parallel and incongruent pathways in these aneurysms may provide critical information on the key processes driving aneurysmal growth. Results of this study help to identify pathways that are essential to aneurysm growth.