Inhibition of caspase-dependent spontaneous apoptosis via a cAMP-protein kinase A dependent pathway in neutrophils from sickle cell disease patients.

Sickle cell disease (SCD) is a chronic inflammatory condition characterized by high leucocyte counts, altered cytokine levels and endothelial cell injury. As the removal of inflammatory cells by apoptosis is fundamental for the resolution of inflammation, we aimed to determine whether the leucocyte apoptotic process is altered in SCD. Neutrophils from SCD individuals showed an inhibition of spontaneous apoptosis when cultured in vitro, in the presence of autologous serum for 20 h. Intracellular cyclic adenosine monophosphate (cAMP) levels were approximately twofold increased in SCD neutrophils; possible cAMP-upregulating factors present in SCD serum include interleukin-8, granulocyte-macrophage colony-stimulating factor and prostaglandin. Accordingly, co-incubation of SCD neutrophils with KT5720, a cAMP-dependent protein kinase (PKA) inhibitor, abrogated increased SCD neutrophil survival. Caspase-3 activity was also significantly diminished in SCD neutrophils cultured for 16 h and this activity was restored when cells were co-incubated with KT5720. BIRC2 (encoding cellular inhibitor of apoptosis protein 1, cIAP(1)), MCL1 and BAX expression were unaltered in SCD neutrophils; however, BIRC3 (encoding the caspase inhibitor, cIAP(2)), was expressed at significantly higher levels. Thus, we report an inhibition of spontaneous SCD neutrophil apoptosis that appears to be mediated by upregulated cAMP-PKA signalling and decreased caspase activity. Increased neutrophil survival may have significant consequences in SCD; contributing to leucocytosis, tissue damage and exacerbation of the chronic inflammatory state.

[PGE and PGF2-alpha levels in the umbilical cord vessels. Relationship to acid-base equilibrium in the umbilical artery]. / Niveles de PGE y PGF2-alfa en los vasos del cordón umbilical. Su relación con el equilibrio ácido-base de la arteria umbilical.

To asses the possible role of prostaglandins in the fetoplacental circulation during delivery PGE and PGF2-alfa plasma levels were measured in the umbilical vessels of term newborns. The levels of PGF2-alfa in blood from the umbilical vein are significantly higher and more variable than in the umbilical artery; 83.38 +/- 78.05 pg/ml versus 43.28 +/- 5.32 pg/ml. PGE levels are also higher in the vein 114.73 +/- 25.16 pg/ml than in the artery 83.63 +/- 9.22 pg/ml. There was a statistically significant negative correlation between the arterial pH and PGE in the umbilical vein these results support the idea that the plasmatic umbilical prostaglandins are synthetized by the placenta the variability in the values obtained in venous umbilical blood may reflect the different times of ligation of the umbilical cord. A decrease in fetal pH may be the stimulus for the prostaglandin synthesis by the placenta.

Effects of aspirin-like drugs on Walker 256 tumor growth and cachexia in rats.

Several studies have shown the relationship between prostaglandins (PGs) and cell proliferation. Some PGs may trigger cell division or are involved in this process. This study analyzes the effect of PG biosynthesis inhibitors on tumor growth in vivo and cachexia in Walker 256 tumor-bearing rats. Indomethacin markedly inhibited tumor growth (95.5%) while ibuprofen and aspirin reduced tumor growth by 73.9% and 59.4%, respectively. In addition, all drug-treated rats partially recovered body weight and food intake as compared to the saline-treated group. These findings suggest that PG synthesis inhibitors improve cancer cachexia.

Diuresis and respiratory distress syndrome: physiologic mechanisms and therapeutic implications.

Previous studies have suggested that spontaneous diuresis may be important to the recovery from respiratory distress syndrome in preterm infants. Daily quantification of fluid intake (1) and urine output (O) were recorded, and O/I and alveolar-arterial oxygen gradients (AaDO2) were determined for sequential eight-hour periods in 10 inborn premature infants with RDS. Sequential timed-urine-plasma collections were obtained during the first four days of life to evaluate the role of hormonal and vasoactive factors in the acute phase of RDS. Diuresis (O/I greater than 0.80) occurred at 25 to 32 hours, preceded any significant improvement in AaDO2 (which occurred at 57 to 64 hours), and was associated with a 6.2 +/- 1.4% decrease in body weight. Although there was no significant change in glomerular filtration rate, plasma AVP concentrations, or urinary excretion of AVP in the infants, there were significant decreases in both plasma concentrations and urinary excretion of 6-keto-PGF1 alpha (stable metabolite of prostacyclin) in sequential studies. These results suggest that changes in renal function or AVP may not be of primary importance in the diuresis associated with RDS, and that decreasing levels of prostacyclin, a prostaglandin that increases vascular permeability and lowers blood pressure, may have an important physiologic role.

Effect of gestational age on ductus arteriosus response to circulating prostaglandin E2.

Premature newborn lambs with a patent ductus arteriosus have higher plasma prostaglandin E2 concentrations than near-term newborn lambs with a contricted ductus arteriosus. To see whether these concentrations of PGE2 could produce patency of the ductus arteriosus, we studied eight near-term lambs (with constricted ductuses) delivered by cesarean section, paralyzed, and mechanically ventilated. After ductus arteriosus resistance and plasma PGE2 concentrations had stabilized, a continuous PGE2 infusion into the superior vena cava was started to determine threshold concentrations needed to dilate the ductus in vivo. By two hours after birth, circulating PGE2 concentrations in near-term lambs were considerably less then the threshold concentration, and the ductuses were constricted. In five premature newborn lambs, significantly lower concentrations of PGE2 were required to dilate the ductus: threshold and ED50 concentrations were one sixth and one third, respectively. In these premature lambs during the first two hours after birth, circulating PGE2 concentrations were twice as high as the calculated in vivo threshold level. Therefore, circulating PGE2 concentrations probably played a significant role in the patency of the ductus arteriosus in these premature lambs.

Serum inhibitor of phytohemagglutinin-induced lymphocyte proliferation in Bartter syndrome.

Serum from four patients with Bartter syndrome inhibited the response to phytohemagglutinin of autologous and homologous (healthy donor) lymphocytes. The abnormal response was normalized in three patients by the administration of indomethacin (2 mg/kg/day), a known inhibitor of prostaglandin synthesis. The serum prostaglandin E2 concentration of these patients before indomethacin therapy was significantly increased (P less than 0.02), as compared with that in controls. The serum PGE2 concentration measured in two of three patients undergoing indomethacin therapy was normal. Because PGE2 is known to inhibit the response of lymphocytes to phytohemagglutinin, we postulate that PGE2 may mediate the reduced blastogenic response observed in patients with Bartter syndrome.

Increased prostaglandin synthesis in childhood diabetes mellitus.

Prostaglandins are synthesized from the fatty acids, linoleic and arachidonic acids, and are associated with increased platelet aggregation as has been found in blood from patients with diabetes mellitus. In the present study blood was obtained from 40 children with diabetes and from 20 control children for measurements of fatty acid and PGE1, PGE2, and PGF2alpha levels. The production of PGE2 and PGF2alpha was significantly elevated in blood from the children with diabetes at all times measured. The mean quantitative plasma linoleic acid levels were also higher in the patients. The increased PG synthesis may be related to the vascular problems that occur in patients with diabetes.

Plasma prostaglandin E concentrations from birth through childhood.

The prostaglandins are synthesized in a variety of tissues and participate in an extensive number of physiologic processes. As prostaglandin concentrations have not been reported in infants and children, we measured PGE levels from birth through childhood. PGE levels in cord blood were significantly higher than those in adults. By 48 to 72 hours of age, however, they had fallen to levels that were significantly lower than those in adults. Although PGE concentrations increased with age, they remained significantly lower than did adult levels. These low levels may be related to some of the functional pecularities of the immature kidney.