The influence of indomethacin on the metabolism and cytokine secretion of human aneurysmal aorta.
BACKGROUND
inflammation and proteolysis are important processes in the development of abdominal aortic aneurysms (AAAs). Prostaglandin E2 (PGE2) (a product of cyclo-oxygenase 2), other inflammatory mediators and proteolytic enzymes are produced in high quantities in the aneurysm wall. We developed an explant culture system for AAA tissue to assess the effects of potential drug therapies.


METHODS
full thickness biopsies of human AAA were established in culture in the presence or absence of indomethacin (a cyclo-oxygenase-2 inhibitor). The conditioned medium was collected at 48 h intervals and analysed for products of collagen breakdown, matrix metalloproteinases, PGE2 and inflammatory cytokines. Explant viability was assessed by histology, glucose consumption, lactate dehydrogenase release and demonstration of protein synthesis in the tissue.


RESULTS
nuclear morphology was maintained for 4 or more days and this, together with biochemical assays, indicated that AAA explants were viable in short-term culture. Indomethacin (10 microM) markedly reduced AAA explant production of prostaglandin E2 from 320 ng/ml to 3.3 ng/ml (p=0.028, n=6). Indomethacin also reduced the release of interleukin-1beta (IL-1beta) (from 166 pg/ml to 9.8 pg/ml, p =0.04, n=5) and interleukin-6 (IL-6) (from 119 ng/ml to 57 ng/ml, p=0.028, n=6), but had no effect on monocyte chemotactic protein 1 or matrix metalloproteinase-9 secretion.


CONCLUSIONS
short-term explants of AAA are a novel method to assess the effects of drugs on aneurysm tissue. Indomethacin reduces the production of PGE2, IL-1beta and IL-6, suggesting that cyclo-oxygenase-2 inhibitors may control the inflammation in the aneurysm wall and potentially limit AAA growth.
Franklin
I J
IJ
Imperial College School of Medicine at Charing Cross, London, U.K.
Walton
L J
LJ
Greenhalgh
R M
RM
Powell
J T
JT
D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism*; D046508:Culture Techniques; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007213:Indomethacin / Q000494:pharmacology* / Q000627:therapeutic use; D007375:Interleukin-1 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008565:Membrane Proteins; D008666:Metalloendopeptidases / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D014176:Protein Biosynthesis
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; D007527:Isoenzymes; D008565:Membrane Proteins; D007770:L-Lactate Dehydrogenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D008666:Metalloendopeptidases; D005947:Glucose; D015232:Dinoprostone; D007213:Indomethacin