title: Statins prevent cervical remodeling, myometrial contractions and preterm labor through a mechanism that involves hemoxygenase-1 and complement inhibition.
abstract: Preterm birth (PTB) is a major public health problem, with a global prevalence of 9.6% and over a million annual neonatal deaths. In a mouse model of preterm labor (PTL) induced by intravaginal administration of a subclinical dose of lipopolysaccharide (LPS), we previously demonstrated that LPS ascends to the cervix, inducing complement activation, cervical remodeling and PTL. Here we show that complement activation also plays a role in myometrial contractions during PTL in this model. Increased levels of C5a were detected in the myometrium of LPS-treated mice but not in age-matched control or term myometrium. Human and mouse myometrium incubated with C5a showed increased frequency of contractions and expression of connexin 43, suggesting that C5a is an uterotonic molecule. Statins, which showed beneficial effects in preventing complement-mediated pregnancy complications, prevented cervical remodeling, myometrial contractions and PTL in the LPS model. The protective effects of statins in PTL were associated with increased synthesis, expression and activity of heme oxygenase (HO-1) in myometrium and cervix. Coadministration of HO-1 inhibitor tin-protoporphyrin-IX with pravastatin abrogated the protective effects of pravastatin on cervical remodeling and myometrial contractions leading to PTB. In addition, pravastatin inhibited complement activation in the cervix by increasing the synthesis and expression of complement inhibitor decay-accelerating factor. This study in mice suggests that statins might be useful to prevent PTL in humans. Clinical trials in humans are needed and if these results are confirmed, they may form the basis for a new clinical approach to prevent PTB.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, CA 94117, USA.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Gonzalez
authors.affiliation: MRC Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK Clinical Sciences, Imperial College London, London W12 0NN, UK.
authors.forename: Silvia M A
authors.initials: SM
authors.lastname: Pedroni
authors.affiliation: MRC Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK MRC Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK King's College London, St Thomas' Hospital, London SE1 7EH, UK guillermina.girardi@kcl.ac.uk guillerminagirardi@gmail.com.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Girardi
mesh_terms: D000328:Adult; D000818:Animals; D018958:CD55 Antigens / Q000235:genetics / Q000378:metabolism; D002584:Cervix Uteri / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D015936:Complement C5a / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009215:Myometrium / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007752:Obstetric Labor, Premature / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D017035:Pravastatin / Q000494:pharmacology*; D011247:Pregnancy; D011524:Protoporphyrins / Q000494:pharmacology; D014590:Uterine Contraction / Q000187:drug effects
chemical_list: D018958:CD55 Antigens; D018031:Connexin 43; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D008665:Metalloporphyrins; D011524:Protoporphyrins; D015936:Complement C5a; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1; D017035:Pravastatin
keywords: cervix; complement; myometrium; preterm labor; statins