Sven Hundertmark

Gestational age dependence of 11β-hydroxysteroid dehydrogenase and its relationship to the enzymes of phosphatidylcholine synthesis in lung and liver of fetal rat

Increase in fetal surfactant synthesis and lung maturity is caused by the glucocorticoidal induction of enzymes required for phosphatidylcholine (PC) synthesis towards the end of gestation. The regulation of gestational age-dependent induction of PC synthesis by glucocorticoids is still unclear. Since 11-beta-hydroxysteroid dehydrogenase (11 beta-HSD) activity and its metabolising capacity for glucocorticoids have been suggested to play a central role in this regulation, we measured the gestational age-dependent changes in 11 beta-HSD and PC synthesizing enzymes in lung and liver of fetal rat. The activity of cholinephosphate cytidyltransferase (CCT; key enzyme in PC synthesis), choline phosphotransferase (CPT) and lysolecithin acyltransferase (LAT) were found to increase gradually in the lung towards the end of gestation, reached peak values at term followed by a decrease of activity reaching finally adult levels. Only CK activity exhibited constant levels until term followed by a slight increase after the birth. In comparison with the lung, the liver enzymes followed a similar pattern, but at a higher rate of activity except for CCT which was higher in the lung. The activity of 11 beta-HSD in fetal lung microsomes was detectable from day 20 and increased towards the end of gestation in the lung and liver of the rat. Oxidase activity was always found to exceed the reductase activity. The activity of 11 beta-HSD continued to increase after delivery and reached peak levels in adult animals in both organs. In order to test the hypothesis, whether 11 beta-HSD activity and PC synthesis are induced by increasing endogenous glucocorticoidal levels, we examined on day 19 of gestation the effect of dexamethasone (DEXA) on enzymatic activities (11 beta-HSD, CCT) and on [14C]choline incorporation in phosphatidylcholine in fetal lung organoid cultures. Additionally, changes in CCT activity in fetal lungs after maternal administration of DEXA were measured. DEXA accelerated 11 beta-HSD and CCT activities as well as [14C]choline incorporation. We conclude, that endogenous glucocorticoids induce PC synthesis as well as 11 beta-HSD activity in lung and liver of the fetal rat. Fetal PC synthesis is not altered by increasing 11 beta-HSD levels, because the increase of free serum corticosterone levels apparently exceeds the metabolising capacity of 11 beta-HSD towards term.

11-Beta-hydroxysteroid dehydrogenase of rat lung : enzyme kinetic, oxidase-reductase ratio, electrolyte and trace element dependence

The modulation of the intracellular glucocorticoidal effect on surfactant synthesis of the fetal lung by the metabolic capacity of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) could be an important factor in lung maturation. The kinetic properties of microsomal 11 beta-HSD of the rat lung are characterized with respect to product inhibition, substrate specificity, effect of electrolytes or trace elements, and the dependence of the oxidase reductase (OR) ratio on incubation conditions. With NADP+ product inhibition of the reductase was demonstrated. The most common trace elements and electrolytes exhibited no effect on the activity of 11 beta-HSD. It is shown that the OR ratio was strongly dependent on assay conditions. With optimal assay conditions oxidase activity exceeds reductase activity in adult and fetal rat lung microsomes (OR ratio > 1). Thus, glucocorticoids are mainly metabolized to their inactive forms. The enzyme activity in the adult is about 10 times higher than in the fetal lung. The low enzyme activity in fetal lungs could be the reason why the glucocorticoidal effects on surfactant synthesis are not suppressed despite the predominance of oxidase activity.

Die imminente Frühgeburt als Notfall

ZusammenfassungEtwa 2/3 der Neonatalsterblichkeit ist Folge der Frühgeburtlichkeit. Ein wesentlicher bisher wenig beachteter Faktor ist die Notwendigkeit der Qualitätssicherung für die Erkennung und Erstbehandlung der imminenten Frühgeburt.Ärzte, die im Rahmen der Primärversorgung von Schwangeren mit fraglichen Frühgeburtsbestrebungen die Entscheidung zwischen rechtzeitiger intrauteriner Verlegung oder Möglichkeit der weiterer Betreuung zu treffen haben, nehmen eine große Verantwortung auf sich. Die zu großzügige Verlegung in Zentren ist mit unnötigen Kosten und Verängstigung der Schwangeren verbunden. Eine zu zurückhaltende Verlegungspraxis kann zu Notsituationen führen, die die Prognose der Kinder verschlechtern.Allgemeingültige Handlungsrichtlinien für eine sinnvolle diagnostische und therapeutische Kaskade in dieser Situation sind schwierig zu erstellen. Ein individuell erstellter Notfallplan ist hier sinnvoll, wobei die wichtigste Maßnahme bei tatsächlich drohender Frühgeburt eine zügig organisierte ärztlich begleitete Verlegung der Schwangeren in ein Krankenhaus der Maximalversorgung ist. Die Durchführung weiterer Basismaßnahmen (Lungenreifeinduktion, Tokolyse, Antibiotika, evtl. Entbindung vor Ort unter Hinzuziehung eines Neonatologen) ist abhängig vom Befund, dem Schwangerschaftsalter und den lokalen Möglichkeiten individuell für die Situation zu indizieren.Auf der Basis der aktuellen Erkenntnisse werden nachfolgend Empfehlung für diese Maßnahmen gegeben.AbstractApproximately two-thirds of neonatal mortalities are due to premature birth. An essential factor that has thus far received inadequate attention is the necessity to perform quality monitoring for the recognition and first treatment of imminent premature birth.Physicians accept great responsibility when called upon to decide between timely intrauterine transfer and continued care in the primary management of pregnant women with signs of premature labor. Overly liberal transfer to level III centers involves unnecessary costs and adds to the anxiety of the expectant mothers. A too restrictive transfer practice can lead to emergency situations that worsen the prognosis of the children. It is difficult to establish universally valid guidelines for a meaningful diagnostic and therapeutic cascade in this situation.An individual emergency plan makes sense here, the most important measure being a quick, medically supervised transfer to a level III hospital in cases of imminent premature birth. The indication for further basic procedures (e.g., lung maturity induction, tocolysis, antibiotics, on-the-spot delivery with neonatological consultation) should be individually established according to the results, the gestational age, and the local facilities. Recommendations for these procedures are based on the current state of the art.