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Since glucocorticoids decrease and protein kinase C (PKC) activators increase amniotic PGE2 production, the possibility that they regulate the activity of prostaglandin endoperoxide H synthase (PGHS), the rate-limiting enzyme of prostaglandin synthesis from arachidonate, was investigated. Glucocorticoids inhibited the production of PGE2 from exogenous arachidonate specifically and in a concentration dependent fashion. Furthermore, cortisol decreased PGHS activity and the amount of PGHS protein in amnion microsomes, and reduced the rate of recovery of PGHS after acetylsalicylic acid (ASA) pretreatment. Actinomycin D blocked the inhibition of PGHS recovery by cortisol, but did not suppress the spontaneous recovery of the enzyme, indicating that the glucocorticoid induced a post-transcriptional inhibitor of PGHS synthesis. PKC-activating phorbol esters, such as 12-tetradecanoyl phorbol 13-acetate (TPA) increased the synthesis of PGE2 from exogenous arachidonate, also in a specific and concentration dependent manner. PGHS recovery after ASA treatment was enhanced by TPA. PGHS activity and protein concentrations were increased by phorbol ester treatment; however, this was apparent only in tissues in which the concentrations of PGHS were initially low. These results show that the synthesis of PGHS is positively and negatively regulated in the human amnion by PKC and glucocorticoids, respectively, and suggest that effectors using these pathways may regulate the enzyme in vivo.

The phrenic nerve at the pericardial level was examined postmortem in 17 children, ages 3 days to 8 years. Detailed macroscopic and histologic examination of the central nervous system in all patients disclosed no abnormalities. Quantitative developmental studies demonstrated that myelinated axons doubled in number from birth to age 1 year when a plateau was reached. The main period of growth in diameter of myelinated axons also corresponded to the first year when median diameters increased from 1.75 microns at 3 days of age to 3.0 microns by 8 months of age. Unmyelinated axons also grew significantly in the first 11 months when median diameters reached 1.4 microns. There was no significant increase in axonal diameter at later ages. The slope of the regression line for the number of myelin lamellae on axonal diameters increased with age until 6 months of age, whereas the dispersion around the regression lines decreased in the same period. This finding suggests a direct relationship between myelination and axonal growth. Significant maturation of the phrenic nerve occurs during the first year of life.

The fibroblast of the fetal and neonatal lung is intimately involved with lung development and function. Additionally, the perinatal rat lung fibroblast is a significant source of prostaglandins (PG) I2 and E2, which in turn affect lung development and function. Their effects may be mediated by cAMP. We, therefore, tested both the relative effectiveness of PG and the beta-adrenergic agonist, isoproterenol, and the developmental age sensitivity to these agonists on rat perinatal lung fibroblast cAMP accumulation. Confluent monolayer cultures of 3rd-passage fibroblasts (greater than 95% purity) from d-3 newborn rats responded in a concentration-dependent fashion to several PG (10(-8)-10(-4) M) and isoproterenol (10(-7)-2 x 10(-6) M) by increasing cAMP accumulation. The rank order of responsiveness, in terms of maximum accumulated cAMP, were carba PGI2 greater than PGE1 = PGI2 Na salt = PGI2 methyl ester much greater than PGE2 greater than isoproterenol. At the 3 developmental d tested [d 20 fetus, d 1 newborn, and d 3 newborn (term = d 22)], PGE2, carba PGI2, and isoproterenol each elicited concentration-dependent increases in cAMP accumulation. Unstimulated cAMP levels were 2-5 fmol/micrograms protein/15 min at all three ages. On d 20 of gestation, the highest accumulation achieved at the highest concentration tested was 30-70 fmol/micrograms protein/15 min for each agonist. There was no age-dependent change in responsiveness to PGE2. Carba PGI2-stimulated cAMP accumulation increased from d 20 of gestation with each advancing age tested to approximately 15-fold by d 3 newborn.(ABSTRACT TRUNCATED AT 250 WORDS)