Fetal lung development and the influence of glucocorticoids on pulmonary surfactant.

Abstract The fetal lung undergoes extensive anatomic and histologic differentiation during gestation in preparation for its role as an organ for gas exchange in the neonate. To successfully adapt to the air breathing state, it must also mature physiologically and biochemically and develop the capacity to produce essential pulmonary surfactants. The surfactants are composed primarily of phospholipids, especially lecithins, and serve the vital function of maintaining alveolar stability on expiration. This role is demonstrated experimentally with the classical pressure-volume apparatus. It has been observed that when a fetal lung is inflated with air, a threshold pressure of approximately 15 cm water is required to increase lung volume, and that maximum inflation is achieved between approximately 30 and 35 cm water. During the deflation phase, an immature lung will readily collapse, whereas a mature lung will show resistance to collapse when the pressure is lowered. With advancing gestation, progressively improved deflation stability is achieved, signalling the presence of adequate pulmonary surfactant in the fetal airway. Biochemical approaches to the study of lung development depend on assessment of phospholipid synthesis by determination of enzyme activities, pathway rates, and the concentration of phospholipid products. The attention of investigators has centered specifically on the biosynthesis of lung lecithin. There are two pathways for de novo formation of lecithin: the choline incorporation pathway (I) and phosphatidylethanolamine methylation (II). Recent studies with isotopic techniques have demonstrated that pathway I is the predominant mechanism. There are three enzymes in this pathway, each of which shows significantly increased activity during late gestation in fetal rats. Shortly after the rise in enzyme activity, an increase in overall choline pathway rate has been identified, and subsequently, the concentration of lung lecithin is likewise increased. Hormonal regulation of fetal lung development has been studied with a number of techniques in several species of lower animals. Using the anatomic approach, investigators have demonstrated that 48–72 h following administration of glucocorticoids, increased potential air space and greater “alveolarization” is apparent. Physiologic evidence of enhanced maturation following corticosteroid administration to fetal animals includes greater distensibility, greater deflation stability, and an earlier appearance of surface active material in lung extracts. The biochemical effects of glucocorticoids with respect to lung development are an increased synthesis of lecithin, an enhanced rate of choline incorporation, and increased activities of various enzymes. The net biochemical effect is to enhance the capacity of the fetal lung to produce the surface active phospholipids of the alveolar lining layer. Because of exogenous corticosteroid, this capacity is developed at an earlier time in gestation than would normally be found. The hormone therefore acts as a stimulus capable of changing the timing of lung development such that the maturation process is accelerated.