fluprostenol and Disease-Models--Animal

Selective activation or blockade of the prostaglandin (PG) F2α receptor (FP receptor) affects ectopic endometrial tissue growth and endometriosis development.. FP receptor antagonists might represent a promising approach for the treatment of peritoneal endometriosis.. Eutopic and ectopic endometrium from women with endometriosis exhibit higher expression of key enzymes involved in the PGF2α biosynthetic pathway. It has also been shown that the PGF2α-FP receptor interaction induces angiogenesis in human endometrial adenocarcinoma.. For this study, a mouse model of endometriosis was developed by inoculating human endometrial biopsies into the peritoneal cavity of nude mouse (n = 15). Mice were treated with AL8810 (FP receptor antagonist), Fluprostenol (FP receptor agonist) or PBS. Endometriosis-like lesions were collected and analysed for set of markers for angiogenesis, tissue remodelling, apoptosis, cell proliferation and capillary formation using qPCR and immunohistochemistry.. We found that selective inhibition of the FP receptor with a specific antagonist, AL8810, led to a significant decline in the number (P < 0.01) and size of endometriosis-like lesions (P < 0.001), down-regulated the expression of key mediators of tissue remodelling (MMP9, P < 0.05) and angiogenesis (VEGF, P < 0.01) and up-regulated the pro-apoptotic factor (Bax, P < 0.01) as compared with controls. Immunohistochemical analyses further showed a marked decrease in cell proliferation and capillary formation in endometrial implants from AL8810-treated mice, as determined by proliferating cell nuclear antigen (PCNA) and von Willebrand factor (vWF) immunostaining, respectively. Moreover, Fluprostenol, a selective FP receptor agonist, showed the opposite effects.. We carried out this study in nude mice, which have low levels of endogenous estrogens which may affect the lesion growth. Caution is required when interpreting these results to women.. This study extends the role of PG signalling in endometriosis pathogenesis and points towards the possible relevance of selective FP receptor antagonism as a targeted treatment for endometriosis.. Not Applicable.. This work was supported by grant MOP-123259 to the late Dr Ali Akoum from the Canadian Institutes for Health Research. The authors have no conflict of interest.

Topics: Animals; Apoptosis; Dinoprost; Dinoprostone; Disease Models, Animal; Disease Progression; Endometriosis; Female; Humans; Luteolytic Agents; Mice; Mice, Nude; Prostaglandins F, Synthetic; Xenograft Model Antitumor Assays

Prostanoid-modulatory approaches in heart failure patients have displayed effects which may seem to be mutually incompatible. Both treatment with prostanoids and inhibition of prostanoid synthesis have resulted in increased mortality in heart failure patients. Currently, it is unknown if prostanoids mediate contractile effects in failing human heart and if this can explain some of the clinical effects seen after prostanoid modulatory treatments. Therefore, the objectives of this study were to determine if prostanoids could elicit direct inotropic responses in human ventricle, and if so to determine if they are modified in failing ventricle. Contractile force was measured in left ventricular strips from non-failing or failing human and rat hearts. The ratio of phosphorylated to non-phosphorylated myosin light chain 2 (MLC-2) was measured by Western blotting in myocardial strips, and the levels of prostanoid FP receptor mRNA and protein were measured in rat by real-time RT-PCR and receptor binding assays. In non-failing human hearts, prostanoids evoked a positive inotropic effect and an increase of MLC-2 phosphorylation which was absent in failing human hearts. In failing rat heart, the prostanoid FP receptor-mediated inotropic response and prostanoid FP receptor-density was reduced by ~40-50% compared to non-failing rat heart. Prostanoids mediate a sustained positive inotropic response in non-failing heart, which appears to be down regulated in failing heart. The pathophysiological significance of changes in prostanoid-mediated inotropic support in the failing heart remains to be determined.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alprostadil; Animals; Cardiac Myosins; Child; Disease Models, Animal; Female; Heart Failure; Heart Ventricles; Humans; Iloprost; Male; Middle Aged; Myocardial Contraction; Myosin Light Chains; Prostaglandins F, Synthetic; Rats; Receptors, Prostaglandin; Ventricular Function