Document Detail


ADRB3 adrenergic receptor is a key regulator of human myometrial apoptosis and inflammation during chorioamnionitis.
MedLine Citation:
PMID:  17989355     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The pathophysiology underlying preterm labor triggered by inflammatory conditions such as chorioamnionitis remains largely unclear. It has already been suggested that beta-3 adrenergic (ADRB3) agonists might be of interest in the pharmacological management of preterm labor. Although there is evidence implicating ADRB receptors in the control of inflammation, there are minimal data relating specifically to ADRB3. To explore the cellular consequences of chorioamnionitis and detect apoptosis, we first performed immunostaining and Western blot experiments on human myometrial samples obtained from women with confirmed chorioamnionitis. We then developed an in vitro model of chorioamnionitis by incubating the myometrial samples obtained from uncomplicated pregnancies with Escherichia coli lipopolysaccharide (LPS). We observed that chorioamnionitis was associated with a significant increase in cleaved CASP3 protein expression, as well as chromatin condensation, which were reproduced experimentally by LPS stimulation (10 microg/ml, 48 h). Lipopolysaccharide stimulation of normal human myometrium also induced CASP3 transcripts, increased the proapoptotic marker BAX, and decreased the antiapoptotic marker BCL2. Lipopolysaccharide-induced apoptosis was antagonized by neutralization of secreted tumor necrosis factor by a specific antibody. Furthermore, LPS stimulation increased medium culture levels of proinflammatory cytokines interleukin 6 (IL6) and IL8. Lipopolysaccharide-induced apoptosis and cytokine production were prevented by the new and potent ADRB3 agonist SAR150640 in a concentration-dependent manner. SAR150640 by itself did not exhibit any effect on apoptosis or cytokine production in control tissues. This study shows that chorioamnionitis is associated with apoptosis of human myometrial cells. It emphasizes the potential therapeutic interest of ADRB3 agonists in the field of preterm labor and other inflammatory conditions.
Authors:
Fréderic Lirussi; Zo Rakotoniaina; Siham Madani; Françoise Goirand; Michelle Breuiller-Fouché; Marie-Josèphe Leroy; Paul Sagot; John J Morrison; Monique Dumas; Marc Bardou
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-11-07
Journal Detail:
Title:  Biology of reproduction     Volume:  78     ISSN:  0006-3363     ISO Abbreviation:  Biol. Reprod.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-02-27     Completed Date:  2008-05-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0207224     Medline TA:  Biol Reprod     Country:  United States    
Other Details:
Languages:  eng     Pagination:  497-505     Citation Subset:  IM    
Affiliation:
Laboratoire de Physiologie et Pharmacologie Cardiovasculaires Expérimentales (LPPCE, EA279, IFR Santé-STIC), Faculté de Médecine, Université de Bourgogne, Dijon, France.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis* / genetics
Benzoates / pharmacology
Chorioamnionitis / etiology*,  genetics,  pathology
Cytokines / metabolism
Female
Humans
Inflammation* / genetics,  metabolism,  pathology
Lipopolysaccharides / pharmacology
Myometrium / drug effects,  metabolism,  pathology*
Pregnancy
Pregnancy Trimester, Third / metabolism
Receptors, Adrenergic, beta-3 / agonists,  metabolism,  physiology*
Sulfonamides / pharmacology
Chemical
Reg. No./Substance:
0/Benzoates; 0/Cytokines; 0/Lipopolysaccharides; 0/Receptors, Adrenergic, beta-3; 0/Sulfonamides; 0/ethyl 4-(4-((2-hydroxy-3-(4-hydroxy-3-((methylsulfonyl)amino)phenoxy)propyl)amino)cyclohexyl)benzoate

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