Sar150640, a selective β3-adrenoceptor agonist, prevents human myometrial remodelling and activation of matrix metalloproteinase in an in vitro model of chorioamnionitis

Background and purpose: 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. Experimental approach: 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. Key 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 mu g center dot 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 and implications: 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

Beta3 adrenergic receptor stimulation in human macrophages inhibits NADPHoxidase activity and induces catalase expression via PPARγ activation

IF 4.521International audienceThe beta3 adrenergic receptor (β3-AR) stimulation plays a protective role against preterm labor by blocking myometrial contraction, cytokine production, remodeling and apoptosis. We previously demonstrated that macrophage-induced ROS production in the myometrium was a key element leading to the induction of all these labor-associated features. We thus aimed to investigate if the β3-AR could be expressed in human macrophages and could trigger its protective role in the myometrium by directly inhibiting ROS production. Using lipopolysaccharide (LPS)-stimulated myometrial samples and cell co-culture experiments, we demonstrated that β3-AR stimulation inhibits the activation of the NADPH oxidase, leading to the subsequent inhibition of ROS production by macrophages. This antioxidant effect was associated with a potent anti-inflammatory response in macrophages. Furthermore, we observed that β3-AR leads to the expression of catalase not only in macrophages but also in myometrial cells, thereby preventing the transactivation of myometrial cells by hydrogen peroxide. Pharmacological experiments allowed us to demonstrate that these effects were driven by an Erk1/2-mediated activation of the antioxidant transcription factor PPARγ. These results suggest that β3-AR protective effects in the myometrium could be due to its dual antioxidant properties. Further, the effects observed in a macrophage could highlight new applications in chronic inflammatory diseases

A pivotal role for the IL-1β and the inflammasome in preterm labor

Abstract During labor, monocytes infiltrate massively the myometrium and differentiate into macrophages secreting high levels of reactive oxygen species and of pro-inflammatory cytokines (i.e. IL-1β), leading to myometrial contraction. Although IL-1β is clearly implicated in labor, its function and that of the inflammasome complex that cleaves the cytokine in its active form, has never been studied on steps preceding contraction. In this work, we used our model of lipopolysaccharide-induced preterm labor to highlight their role. We demonstrated that IL-1β was secreted by the human myometrium during labor or in presence of infection and was essential for myometrial efficient contractions as its blockage with an IL-1 receptor antagonist (Anakinra) or a neutralizing antibody completely inhibited the induced contractions. We evaluated the implication of the inflammasome on myometrial contractions and differentiation stages of labor onset. We showed that the effects of macrophage-released IL-1β in myometrial cell transactivation were blocked by inhibition of the inflammasome, suggesting that the inflammasome by producing IL-1β was essential in macrophage/myocyte crosstalk during labor. These findings provide novel innovative approaches in the management of preterm labor, specifically the use of an inflammasome inhibitor to block the precursor stages of labor before the acquisition of the contractile phenotype

Improved stability of lipiodol-drug emulsion for transarterial chemoembolisation of hepatocellular carcinoma results in improved pharmacokinetic profile: Proof of concept using idarubicin.

OBJECTIVES: To investigate the relationship between the improved stability of an anticancer drug-lipiodol emulsion and pharmacokinetic (PK) profile for transarterial chemoembolisation (TACE) of hepatocellular carcinoma (HCC). METHODS: The stability of four doxorubicin- or idarubicin-lipiodol emulsions was evaluated over 7 days. PK and clinical data were recorded after TACE with the most stable emulsion in eight unresectable HCC patients, after institutional review board approval. RESULTS: The most stable emulsion was the one that combined idarubicin and lipiodol (1:2 v:v). At 7 days, the percentages of aqueous, persisting emulsion and oily phases were 50-0-50, 33-0-67, 31-39-30, and 10-90-0 for the doxorubicin-lipiodol (1:1 v:v), doxorubicin-lipiodol (1:2 v:v), idarubicin-lipiodol (1:1 v:v), and the idarubicin-lipiodol (1:2 v:v) emulsion, respectively. After TACE, mean idarubicin Cmax and AUC0-24h were 12.5 ± 9.4 ng/mL and 52 ± 16 ng/mL*h. Within 24 h after injection, 40% of the idarubicin was in the liver, either in vessels, tumours, or hepatocytes. During the 2 months after TACE, no clinical grade >3 adverse events occurred. One complete response, five partial responses, one stabilisation, and one progression were observed at 2 months. CONCLUSION: This study showed a promising and favourable PK and safety profile for the idarubicin-lipiodol (1:2 v:v) emulsion for TACE. KEY POINTS: • Transarterial chemoembolisation (TACE) regimens that improve survival in hepatocellular carcinoma are needed. • Improved emulsion stability for TACE resulted in a favourable pharmacokinetic profile. • Preliminary safety and efficacy data for the idarubicin-lipiodol emulsion for TACE were encouraging

Improved stability of lipiodol-drug emulsion for transarterial chemoembolisation of hepatocellular carcinoma results in improved pharmacokinetic profile: Proof of concept using idarubicin

To investigate the relationship between the improved stability of an anticancer drug-lipiodol emulsion and pharmacokinetic (PK) profile for transarterial chemoembolisation (TACE) of hepatocellular carcinoma (HCC). The stability of four doxorubicin- or idarubicin-lipiodol emulsions was evaluated over 7 days. PK and clinical data were recorded after TACE with the most stable emulsion in eight unresectable HCC patients, after institutional review board approval. The most stable emulsion was the one that combined idarubicin and lipiodol (1:2 v:v). At 7 days, the percentages of aqueous, persisting emulsion and oily phases were 50-0-50, 33-0-67, 31-39-30, and 10-90-0 for the doxorubicin-lipiodol (1:1 v:v), doxorubicin-lipiodol (1:2 v:v), idarubicin-lipiodol (1:1 v:v), and the idarubicin-lipiodol (1:2 v:v) emulsion, respectively. After TACE, mean idarubicin C-max and AUC(0-24h) were 12.5 +/- 9.4 ng/mL and 52 +/- 16 ng/mL*h. Within 24 h after injection, 40 % of the idarubicin was in the liver, either in vessels, tumours, or hepatocytes. During the 2 months after TACE, no clinical grade > 3 adverse events occurred. One complete response, five partial responses, one stabilisation, and one progression were observed at 2 months. This study showed a promising and favourable PK and safety profile for the idarubicin-lipiodol (1:2 v:v) emulsion for TACE. aEuro cent Transarterial chemoembolisation (TACE) regimens that improve survival in hepatocellular carcinoma are needed. aEuro cent Improved emulsion stability for TACE resulted in a favourable pharmacokinetic profile. aEuro cent Preliminary safety and efficacy data for the idarubicin-lipiodol emulsion for TACE were encouraging