The influence of indomethacin on the metabolism and cytokine secretion of human aneurysmal aorta

Introduction: inflammation and proteolysis are important processes in the d evelopment of abdominal aortic aneurysms (AAAs). Prostaglandin E2 (PGE2) (a product of cyclo-oxygenase 2), other inflammatory mediators and proteolyti c enzymes are produced in high quantifies in the aneurysm wall. We develope d an explant culture system for AAA tissue to assess the effects of potenti al drug therapies. Methods: full thickness biopsies of human AAA were established in culture i n the presence or absence of indomethacin (a cyclo-oxygenase-2 inhibitor). The conditioned medium was collected at 48 h intervals and analysed for pro ducts of collagen breakdown, matrix metalloproteinases, PGE2 and inflammato ry cytokines. Explant viability was assessed by histology, glucose consumpt ion, lactate dehydrogenase release and demonstration of protein synthesis i n the tissue. Results: nuclear morphology was maintained for 4 or more days and this, tog ether with biochemical assays, indicated that AAA explants were viable in s hort-term culture. Indomethacin (10 mu M) markedly reduced AAA explant prod uction of prostaglandin E2 from 320 ng/ml to 3.3 ng/ml (p = 0.028, n = 6). Indomethacin also reduced the release of interleukin-1 beta (IL-1 beta) (fr om 166 pg/ml to 9.8 pg/ml, p = 0.04, n=5) and interleukin-6 (IL-6) (from 11 9 ng/ml to 57 ng/ml, p = 0.028, n = 6), but had no effect on monocyte chemo tactic protein 1 or matrix metalloproteinase-9 secretion. Conclusions: short-term explants of AAA are a novel method to assess the ef fects of drugs on aneurysm tissue. Indomethacin reduces the production of P GE2, IL-1 beta and IL-6, suggesting that cyclo-oxygenase-2 inhibitors may c ontrol the inflammation in the aneurysm wall and potentially limit AAA grow th.