RESUMEN
Group B streptococci (GBS) cause fatal sepsis in newborns. Strong activation of thromboxane synthesis is assumed to correlate with severe pulmonary hypertension. In this study we compared the impact of indomethacin versus parecoxib on hemodynamics and outcome and investigated the pharmacological effects on thromboxane synthesis and EP-3 receptor gene expression. Whereas both parecoxib and indometacin reduced expression of thromboxane synthase and EP-3 receptor in infected lung tissue, parecoxib did not suppress urine levels of thromboxane like indometacin. We presume that COX-2 inhibition in GBS sepsis is associated with enhanced thrombogenicity.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2/farmacología , Isoxazoles/farmacología , Sepsis/metabolismo , Infecciones Estreptocócicas/metabolismo , Streptococcus agalactiae , Tromboxanos/biosíntesis , Animales , Animales Recién Nacidos , Dinoprostona/orina , Epoprostenol/metabolismo , Epoprostenol/orina , Regulación de la Expresión Génica/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Indometacina/farmacología , Inflamación/metabolismo , Inflamación/patología , Inflamación/orina , Pulmón/efectos de los fármacos , Pulmón/patología , Recuento de Plaquetas , Receptores de Prostaglandina E/metabolismo , Sepsis/patología , Sepsis/fisiopatología , Sepsis/orina , Infecciones Estreptocócicas/microbiología , Infecciones Estreptocócicas/patología , Infecciones Estreptocócicas/orina , Porcinos , Tromboxanos/metabolismo , Tromboxanos/orinaRESUMEN
OBJECTIVE: The F-box protein Fbxw8 is a cofactor of Cullin 7 (Cul7), which regulates protein transfer to the proteasome and cell growth. Cul7 or Fbxw8 deficiency is associated with intrauterine growth restriction (IUGR) due to abnormal placental development leading to poor oxygen supply to the fetus. We studied the role of hypoxia for Fbxw8 and Cul7 expression in trophoblastic cells. METHODS: Immunomagnetic bead-separated extravillous trophoblast (EVT) and villous trophoblast (VT) and trophoblast cell lines were incubated with 1 or 8% O(2). Fbxw8 and Cul7 expression was determined in IUGR versus matched control placentas. RESULTS: Fbxw8 was expressed uniformly in trophoblasts, whereas Cul7 expression was most prominent in trophoblast cell lines. Hypoxia reduced expression of Cul7 and Fbxw8 in all trophoblastic cells, except for villous trophoblasts. In vivo, Cul7 and Fbxw8 were detected in syncytiotrophoblast cells, VT, and EVT cells. Although no significant changes in expression levels of Fbxw8 or Cul7 were noted in IUGR compared with control placentas, Fbxw8 expression correlated negatively with gestational age in the control, but not in the IUGR group. CONCLUSION: Fbxw8 and Cul7 expression reveals a complex regulation in trophoblastic cells. Our findings suggest that dysregulation of Cul7 and Fbxw8 expression might affect trophoblast turnover in IUGR.