Structural Fragility and Inflammatory Response of Ruptured Cerebral Aneurysms : A Comparative Study Between Ruptured and Unruptured Cerebral Aneurysms

Formation of the atherosclerotic intima must involve altered metabolism of the elastin-rich arterial extracellular matrix. Proteases potentially involved in these processes remain unclear. This study examined the expression of the potent elastases cathepsins S and K in human atheroma. Normal arteries contained little or no cathepsin K or S. In contrast, macrophages in atheroma contained abundant immunoreactive cathepsins K and S. Intimal smooth muscle cells (SMC), especially cells appearing to traverse the internal elastic laminae, also contained these enzymes. Extracts of atheromatous tissues had approximately twofold greater elastase-specific activity than extracts of uninvolved arteries, mostly due to cysteine proteases. Cultured human SMC displayed no immunoreactive cathepsins K and S and exhibited little or no elastolytic activity when incubated with insoluble elastin. SMC stimulated with the atheroma-associated cytokines IL-1beta or IFN-gamma secreted active cathepsin S and degraded substantial insoluble elastin (15-20 microg/10(6) cells/24 h). A selective inhibitor of cathepsin S blocked > 80% of this elastolytic activity. The presence of cathepsins K and S at sites of vascular matrix remodeling and the ability of SMC and macrophages to use these enzymes to degrade elastin supports a role for elastolytic cathepsins in vessel wall remodeling and identifies novel therapeutic targets in regulating plaque stability.

Immunocytochemical analysis of human saccular aneurysms, commonly referred to as berry aneurysms, was performed on formalin-fixed, paraffin-embedded sections using monoclonal antibodies with single and double staining methods. Atherosclerotic lesions were detected in all aneurysms, which ranged in size from 2 mm to 3 cm in diameter. Changes consistent with the earliest stages of atherogenesis, so-called "fatty streaks," were not detected. In the smallest aneurysms, atherosclerotic lesions were characterized by diffuse intimal thickening composed predominantly of proliferating smooth muscle cells (SMC) with a small number of macrophages and lymphocytes. Large aneurysms had advanced atherosclerotic lesions with cellular infiltrates composed mostly of macrophages, more mature looking SMC and a greater number of lymphocytes. Major histocompatibility complex (MHC) class II expression was detected predominantly in macrophages in all aneurysms. Some SMC in advanced atherosclerotic lesions, but not in diffuse intimal thickening, had MHC class II immunoreactivity. A significant number of lymphocytes and NK cells were found at the site of aneurysmal rupture. The progression of atherosclerosis within the aneurysmal sac correlated positively with aneurysmal growth, and we speculate may have contributed to aneurysmal rupture. Some evidence also suggested a possible role of atherosclerosis in the formation of berry aneurysms.