Inhibition of cyclooxygenase-2 prevents inflammation-mediated preterm labor in the mouse.
Prostaglandins (PGs) have proven important during parturition, but inhibition of PG production treating preterm labor (PTL) results in significant maternal and fetal side effects. We hypothesize that specific inhibition of either cyclooxygenase (COX)-1 or -2 may result in separation of therapeutic and toxic effects. We demonstrate that COX-2, but not COX-1, is induced during inflammation-mediated PTL caused by lipopolysaccharide (LPS) administration. A two- to threefold increase in uterine and ovarian PG concentrations coincides with this induction of COX-2. The COX-2-selective inhibitor SC-236 proved effective in stopping preterm delivery and the increases in PGs. The COX-1-selective inhibitor SC-560 also attenuated uterine and ovarian PG production after LPS but did not inhibit PTL as efficiently as SC-236. COX-1-deficient mice, which show delay in the onset of term labor, exhibited no delay in onset of PTL after LPS. These findings suggest that the mechanisms for initiation of inflammation-mediated PTL and term labor differ and that selective COX-2 inhibition may provide a means of stopping inflammation-induced PTL in humans.
Gross
G
G
Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Imamura
T
T
Vogt
S K
SK
Wozniak
D F
DF
Nelson
D M
DM
Sadovsky
Y
Y
Muglia
L J
LJ
D000818:Animals; D015152:Blotting, Northern; D002118:Calcium / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D007213:Indomethacin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology; D007743:Labor, Obstetric / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D007752:Obstetric Labor, Premature / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control*; D010053:Ovary / Q000201:enzymology; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology*; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000494:pharmacology; D011453:Prostaglandins / Q000276:immunology; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D013449:Sulfonamides / Q000494:pharmacology; D014599:Uterus / Q000201:enzymology; D000096926:Benzenesulfonamides
D002118:Calcium; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007213:Indomethacin; D007476:Ionophores; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D011453:Prostaglandins; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C115461:SC 560; C496512:Ptgs1 protein, mouse