Glucocorticoid Metabolism in the Human Fetal Lung: Implications for Lung Development and the Pulmonary Surfactant System

Abstract

It has been nearly 35 years since Liggins and Howie first reported the benefits of antenatal glucocorticoid (GC) treatment to promote the maturation of the human fetal lung, and nearly that long since Pasqualini and colleagues demonstrated that the human fetal lung actively metabolizes GCs. Since that time, our understanding of the effects of GCs on fetal lung maturation and pulmonary surfactant production has increased dramatically. Similarly, characterization of the enzymes involved in GC metabolism has greatly expanded our understanding of GC signaling in target tissues. In man, the biologically active GC (cortisol) and the biologically inactive GC (cortisone) are interconverted by the tissue-specific expression of the type 1 and type 2 11β-hydroxysteroid dehydrogenase enzymes (HSD1 and HSD2). Much of the research on GC metabolism in peripheral target tissues has focused on the role of HSD1 in amplifying the effects of GCs in liver and adipose tissue or on the role of HSD2 in blocking the effects of GCs in the kidney and placenta. In contrast, the role of GC metabolism in modulating the effects of GCs on fetal lung maturation and the pulmonary surfactant system in humans is less understood. The goal of this review article is to present a brief overview of the role of GCs in human fetal lung maturation and pulmonary surfactant production, and to familiarize the reader with the biochemistry of the metabolism of natural and synthetic GCs by the HSD enzymes. In addition, we will review data concerning the expression and activity of the HSD enzymes in the human fetal lung and contrast this to what is known about the HSD enzymes in the fetal rodent lung. Although rodents, rabbits, sheep, and several primates have been invaluable model systems for the study of fetal lung development, we have chosen to largely focus this review on human lung, since there are significant differences in GC metabolism between humans and other species.

LGL1, a novel branching morphogen in developing kidney, is induced by retinoic acid

“…We confirm that Lgl1 mRNA expression is stimulated by GC in kidney cells as it is in the lung. This is, at first, puzzling since glucocorticoids stimulate alveolarization of lung bud branches but are reported to inhibit lung bud branching (7,18). Similarly, we noted reduced UB branching in fetal kidney explants exposed to cortisol (10 Ϫ7 M).…”

“…Similarly, we noted reduced UB branching in fetal kidney explants exposed to cortisol (10 Ϫ7 M). However, fetal GC levels rise sharply toward the end of gestation, coinciding with stimulation of surfactant synthesis (7). At an earlier stage, both the lung and kidney undergo a phase of rapid branching morphogenesis, LGL1 then drives branching morphogenesis in developing lung and kidney.…”

“…Two important molecules that regulate lung development are retinoids and glucocorticoids (GC). RA stimulates initial lung branching of the primary lung bud (16,29), while GC stimulates terminal maturation and differentiation of the alveoli (7).…”

Lung Disease and Brain Development

“…Over the last three decades, the effects of antenatal glucocorticoids (GCs) on fetal lung maturation and the pulmonary surfactant system have been a topic of intense scientifi c and clinical interest [50,51] . In humans GCs primarily stimulate the synthesis of surfactant phospholipids by inducing de novo synthesis of fatty acids.…”

Prenatal Corticosteroids: Pretermer Outcomes, Stress, Schizophrenia, Multiple Sclerosis and the Developmental Role of Melatonin and Vitamin D3

“…1 This seems crucial to increase the likelihood of survival of pretermers. 2 However, a number of side effects are known to arise from such antenatal corticosteroids.…”