Inhibition of prostaglandin E-2 synthesis in abdominal aortic aneurysms - Implications for smooth muscle cell viability, inflammatory processes, and the expansion of abdominal aortic aneurysms

Background-There is no treatment proven to limit the growth of abdominal ao rtic aneurysms, in which the histological hallmarks include inflammation an d medial atrophy, with apoptosis of smooth muscle cells and destruction of elastin. Methods and Results-Aneurysm biopsies were used for explant cultures, the p reparation of smooth muscle cell cultures, and isolation of macrophages. Ti ssue macrophages stained strongly for cyclooxygenase 2. Prostaglandin E-2 ( PGE(2)) concentrations in aneurysm tissue homogenates, conditioned medium f rom explants, and isolated macrophages were 49 +/- 22 ng/g, 319 +/- 38 ng/m L, and 22 +/- 21 ng/mL, respectively. PGE(2) inhibited DNA synthesis and pr oliferation in normal aortic smooth muscle cells (IC50, 23.2 +/- 3.8 and 23 .6 +/- 4.5 ng/mL, respectively). In smooth muscle cells derived from aneury smal aorta, PGE(2) also caused cell death, with generation of oligonucleoso mes. Conditioned medium from the mixed smooth muscle and monocyte cultures derived from explants also had potent growth-inhibitory effects, and fracti onation of this medium showed that the growth-inhibitory molecule(s) coelut ed with PGE(2). In explants, indomethacin 10 mu mol/L or mefenamic acid 10 mu mol/L abolished PGE(2) secretion and significantly reduced LL-1 beta and IL-6 secretion. In a separate case-control study, the expansion of abdomin al aortic aneurysms was compared in 15 patients taking nonsteroidal anti-in flammatory drugs and 63 control subjects; median growth rates were 1.5 and 3.2 mm/y, respectively, P = 0.001. Conclusions The adverse effects of PGE(2) on aortic smooth muscle cell viab ility and cytokine secretion in vitro and the apparent effect of anti-infla mmatory drugs to lower aneurysm growth rates suggest that selective inhibit ion of PGE(2) synthesis could be an effective treatment to curtail aneurysm expansion.