title: Prostaglandins are essential for cervical ripening in LPS-mediated preterm birth but not term or antiprogestin-driven preterm ripening.
abstract: Globally, an estimated 13 million preterm babies are born each year. These babies are at increased risk of infant mortality and life-long health complications. Interventions to prevent preterm birth (PTB) require an understanding of processes driving parturition. Prostaglandins (PGs) have diverse functions in parturition, including regulation of uterine contractility and tissue remodeling. Our studies on cervical remodeling in mice suggest that although local synthesis of PGs are not increased in term ripening, transcripts encoding PG-endoperoxide synthase 2 (Ptgs2) are induced in lipopolysaccharide (LPS)-mediated premature ripening. This study provides evidence for two distinct pathways of cervical ripening: one dependent on PGs derived from paracrine or endocrine sources and the other independent of PG actions. Cervical PG levels are increased in LPS-treated mice, a model of infection-mediated PTB, consistent with increases in PG synthesizing enzymes and reduction in PG-metabolizing enzymes. Administration of SC-236, a PTGS2 inhibitor, along with LPS attenuated cervical softening, consistent with the essential role of PGs in LPS-induced ripening. In contrast, during term and preterm ripening mediated by the antiprogestin, mifepristone, cervical PG levels, and expression of PG synthetic and catabolic enzymes did not change in a manner that supports a role for PGs. These findings in mice, supported by correlative studies in women, suggest PGs do not regulate all aspects of the parturition process. Additionally, it suggests a need to refocus current strategies toward developing therapies for the prevention of PTB that target early, pathway-specific processes rather than focusing on common late end point mediators of PTB.
authors.affiliation: Department of Obstetrics and Gynecology and Green Center for Reproductive Biology Sciences (B.C.T., M.L.A., D.M., M.M.), University of Texas Southwestern Medical Center, Dallas, Texas 75235; Department of Pediatrics, Cell, and Developmental Biology (J.R., N.E., B.C.P.) and Eicosanoid Core Laboratory (G.L.M.), Vanderbilt University, Nashville, Tennessee 37221; Department of Mechanical Engineering (S.S.), Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307; Department of Internal Medicine (R.J.A.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Obstetrics and Gynecology (M.H.), Tufts Medical Center, Boston, Massachusetts 02111.
authors.forename: Brenda C
authors.initials: BC
authors.lastname: Timmons
authors.forename: Jeff
authors.initials: J
authors.lastname: Reese
authors.forename: Simona
authors.initials: S
authors.lastname: Socrate
authors.forename: Noah
authors.initials: N
authors.lastname: Ehinger
authors.forename: Bibhash C
authors.initials: BC
authors.lastname: Paria
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.forename: Meredith L
authors.initials: ML
authors.lastname: Akins
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Auchus
authors.forename: Don
authors.initials: D
authors.lastname: McIntire
authors.forename: Michael
authors.initials: M
authors.lastname: House
authors.forename: Mala
authors.initials: M
authors.lastname: Mahendroo
mesh_terms: D000818:Animals; D020070:Cervical Ripening / Q000378:metabolism*; D002584:Cervix Uteri / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D008070:Lipopolysaccharides / Q000378:metabolism*; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D016595:Misoprostol / Q000494:pharmacology; D007752:Obstetric Labor, Premature; D011247:Pregnancy; D011270:Pregnancy, Animal; D047928:Premature Birth; D011372:Progestins / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism*; D011720:Pyrazoles / Q000737:chemistry; D013256:Steroids / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry; D047929:Term Birth; D000096926:Benzenesulfonamides
chemical_list: D008070:Lipopolysaccharides; D015735:Mifepristone; D016595:Misoprostol; D011372:Progestins; D011453:Prostaglandins; D011720:Pyrazoles; D013256:Steroids; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides