Inflammatory Mediators in the Pathogenesis of Vascular Disease

Abstract

This thesis explores the role of inflammation in vascular disease in human subjects. Three disparate models of vascular disease have been explored: atherosclerotic vascular disease, which examined the common carotid artery, was compared to two forms of hereditary thoracic aortic aneurysm, one of purely hereditary origin, Marfan syndrome (MFS), and the other of a combined hereditary and haemodynamic stress aetiology, bicuspid aortic valve (BAV)-associated thoracic aortic aneurysm. Inflammation was found to be an important contributor to the pathogenesis in all cases. To examine inflammation in these three diseases, we chose to determine the expression levels of a range of inflammatory markers. In the case of atherosclerosis, where there is an extensive literature on the involvement of inflammation, we chose to analyse four novel cytokines that have been recently examined in the context of a range of inflammatory diseases, but which had not been analysed in atherosclerosis. On the other hand, due to the almost complete paucity of literature on the role of inflammation in heritable thoracic aortic aneurysm, we chose to examine both basic and novel inflammatory cytokines, in addition to markers of specific inflammatory cell types. The study that examined atherosclerotic plaque revealed for the first time that the novel, pro-inflammatory cytokines, IL-31, IL-32 and IL-34, are substantially upregulated in clinically symptomatic plaques when compared to asymptomatic plaques, suggesting that these inflammatory mediators contribute to the severity of the disease. Moreover, we found that these mediators also correlated with both clinical symptoms and a clinical intervention, namely the used of lipid-lowering statins. On the other hand, the anti- inflammatory cytokine IL-33 was significantly upregulated in asymptomatic patients with stable atherosclerotic plaque, suggesting an active role of IL-33 in maintaining a stable plaque phenotype. Overall, these data imply that such mediators might be used as prediction markers to monitoring the severity of plaque formation and may also be potential therapeutic targets for preventing plaque progression. In the studies that examined the contribution of inflammation to the formation of thoracic aneurysms in the two hereditary forms of thoracic aortopathy, we examined a set of basic inflammatory markers (IL-10, IL-17, MPO and CD3) and several novel inflammatory markers (IL-36, and γ, IL-37 and IL-38). We found that inflammation is present within the aortic wall in both of these diseases, and that the level of inflammation in BAV-associated thoracic aortopathy is higher than in MFS. These data are consistent with the aetiology of these two diseases, namely, that MFS is a “purely” inherited disease, while BAV-associated aneurysm also has a substantial contribution from haemodynamic stress.