SAR150640, a selective beta3-adrenoceptor agonist, prevents human myometrial remodelling and activation of matrix metalloproteinase in an in vitro model of chorioamnionitis.
OBJECTIVE
The uterine pathophysiology underlying inflammatory conditions such as chorioamnionitis remains largely unclear. As we have shown that beta(3)-adrenoceptors act as regulators of myometrial inflammation, we wanted to investigate the potential role of beta(3)-adrenoceptors in preventing uterine remodelling induced by inflammation.


METHODS
The consequences of human chorioamnionitis on myometrial remodelling were characterized by Sirius Red staining and metalloproteinase (MMP) expression, and compared with the effects of incubating human myometrial samples with Escherichia coli lipopolysaccharide (LPS) in vitro. We also assessed the effect of SAR150640, a selective beta(3)-adrenoceptor agonist, on the production and activity of MMPs.


RESULTS
Chorioamnionitis was associated with a 46% decrease in total collagen, as well as over-expression of MMP2 (+61%) and MMP9 (+84%); both effects were reproduced by incubation with LPS (10 microg x mL(-1), 48 h). LPS-induced over-expression of MMP2 and MMP9 in normal human myometrium was paralleled by an overactivity of the proteins. Both over-expression and overactivity were prevented by the beta(3)-adrenoceptor agonist SAR150640 in a concentration-dependent manner. SAR150640, by itself, did not exhibit any effect on MMP production in control tissues.


CONCLUSIONS
This study shows that inflammation was associated with an intense remodelling of human myometrium, a process likely to be explained by MMP activation. Our study emphasizes the potential therapeutic relevance of beta(3)-adrenoceptor agonists to the treatment of preterm labour and other uterine inflammatory conditions.
Centre d'Investigations Cliniques plurithématique 803 (INSERM CIC-P 803), Dijon, France.
F
F
Lirussi
M
M
O'Brien
M
M
Wendremaire
F
F
Goirand
P
P
Sagot
M
M
Dumas
J J
JJ
Morrison
M
M
Bardou
D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D002821:Chorioamnionitis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000378:metabolism*; D008954:Models, Biological; D009215:Myometrium / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011433:Propranolol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D001565:Benzoates; D008070:Lipopolysaccharides; D013449:Sulfonamides; C521336:ethyl 4-(4-((2-hydroxy-3-(4-hydroxy-3-((methylsulfonyl)amino)phenoxy)propyl)amino)cyclohexyl)benzoate; C482199:lipopolysaccharide, E coli O55-B5; D011433:Propranolol; D020782:Matrix Metalloproteinases