The serotonin reuptake inhibitor fluoxetine induces human fetal membrane sterile inflammation through p38 MAPK activation.

Serotonin Reuptake Inhibitors (SRIs) are often used as first line therapy for depression and other psychiatric disorders. SRI use during pregnancy is associated with preterm premature rupture of membranes (PPROM) and subsequent preterm birth. The objective of this study was to investigate the mechanism(s) responsible for SRI-associated PPROM. Putative mechanisms underlying PPROM include fetal membrane (FM) inflammation, increased apoptosis, and/or accelerated senescence, the later which may be reversed by statins. Human FM explants from normal term deliveries without labor, infection, or antidepressant use were treated with or without the SRI, fluoxetine (FLX), either alone or in the presence of a p38 MAPK inhibitor or the statins, simvastatin or rosuvastatin. FMs were also collected from women either unexposed or exposed to FLX during pregnancy. FLX significantly increased FM p38 MAPK activity and secretion of inflammatory IL-6. Inhibition of p38 MAPK reduced FM IL-6 secretion in response to FLX. Statins did not reduce the SRI-induced FM IL-6 production. FMs from women exposed to FLX during pregnancy expressed elevated levels of p38 MAPK activity compared to matched unexposed women. FMs exposed to FLX did not exhibit signs of increased apoptosis and/or accelerated senescence. These results indicate that the SRI, FLX, may induce sterile FM inflammation during pregnancy through activation of the p38 MAPK pathway, and in the absence of apoptosis and senescence. These findings may better inform clinicians and patients as they weigh the risks and benefits of SRI antidepressant treatment during pregnancy.

Propranolol Targets Hemangioma Stem Cells via cAMP and Mitogen-Activated Protein Kinase Regulation.

UNLABELLED: Infantile hemangiomas (IHs) are the most common vascular tumor and arise from a hemangioma stem cell (HemSC). Propranolol has proved efficacious for problematic IHs. Propranolol is a nonselective ß-adrenergic receptor (ßAR) antagonist that can lower cAMP levels and activate the mitogen-activated protein kinase (MAPK) pathway downstream of ßARs. We found that HemSCs express ß1AR and ß2AR in proliferating IHs and determined the role of these ßARs and the downstream pathways in mediating propranolol's effects. In isolated HemSCs, propranolol suppressed cAMP levels and activated extracellular signal-regulated kinase (ERK)1/2 in a dose-dependent fashion. Propranolol, used at doses of <10(-4) M, reduced cAMP levels and decreased HemSC proliferation and viability. Propranolol at ≥10(-5) M reduced cAMP levels and activated ERK1/2, and this correlated with HemSC apoptosis and cytotoxicity at ≥10(-4) M. Stimulation with a ßAR agonist, isoprenaline, promoted HemSC proliferation and rescued the antiproliferative effects of propranolol, suggesting that propranolol inhibits ßAR signaling in HemSCs. Treatment with a cAMP analog or a MAPK inhibitor partially rescued the HemSC cell viability suppressed by propranolol. A selective ß2AR antagonist mirrored propranolol's effects on HemSCs in a dose-dependent fashion, and a selective ß1AR antagonist had no effect, supporting a role for ß2AR signaling in IH pathobiology. In a mouse model of IH, propranolol reduced the vessel caliber and blood flow assessed by ultrasound Doppler and increased activation of ERK1/2 in IH cells. We have thus demonstrated that propranolol acts on HemSCs in IH to suppress proliferation and promote apoptosis in a dose-dependent fashion via ß2AR perturbation, resulting in reduced cAMP and MAPK activation. SIGNIFICANCE: The present study investigated the action of propranolol in infantile hemangiomas (IHs). IHs are the most common vascular tumor in children and have been proposed to arise from a hemangioma stem cell (HemSC). Propranolol, a nonselective ß-adrenergic receptor (ßAR) antagonist, has proven efficacy; however, understanding of its mechanism of action on HemSCs is limited. The presented data demonstrate that propranolol, via ßAR perturbation, dose dependently suppresses cAMP levels and activated extracellular signal-regulated kinase 1/2. Furthermore, propranolol acts via perturbation of ß2AR, and not ß1AR, although both receptors are expressed in HemSCs. These results provide important insight into propranolol's action in IHs and can be used to guide the development of more targeted therapy.