The Physiologic Significance of 11beta-hydroxysteroid Dehydrogenase Type 1 in Fetal Lung Development Redux

Hundertmark et al. [1] recently reported that 11-oxo steroids, like their 11-hydroxy isoforms, can stimulate fetal lung maturation due to the expression of 11β-hydroxysteroid dehydrogenase Type 1 (11β HSD 1), the enzyme that converts (inactive) cortisone to (active) cortisol [2]. In a subsequent study, this group has shown that knocking out the 11β HSD 1 gene inhibits lung maturation and surfactant synthesis [3], confirming the biological significance of 11β HSD 1 in lung development. A series of studies performed by my collaborators and myself beginning more than 30 years ago had previously demonstrated the biological activity and significance of 11β HSD 1 in fetal human, rabbit and rat lung development. These studies were the first to elucidate the physiologic role of glucocorticoids in normal fetal lung development [4]. I would like to relate these studies, which were overlooked in the Hundertmark publications.

Our laboratory at McGill University was the first to discover why the placenta is a ‘barrier’ to steroids. Hillman and Giroud [5] demonstrated that the placenta quantitatively oxidizes cortisol to cortisone as it passes through from mother to fetus. This was thought to be protective since glucocorticoids are classically considered to be catabolic. By contrast, Burton demonstrated that fetal mouse liver had the capacity to convert 11-dehydrocorticosterone to corticosterone [6] [7], setting a precedent for the local tissue activation of glucocorticoids in specific fetal tissues. The discovery by Liggins that glucocorticoids stimulate fetal lung development and reduce the morbidity and mortality of preterm birth catalyzed the then burgeoning interest in fetal steroid metabolism [8]. The presence of 11β HSD 1 activity in human fetal lung cells was first reported by Smith, Torday and Giroud in 1973 [9]. In a subsequent study [10], we showed that cortisol could directly affect fetal rabbit lung cell surfactant phospholipid synthesis, and that cortisol stimulated 11β HSD 1 activity by fetal rabbit lung cells [11]. To determine whether 11β HSD 1 could actively generate cortisol from cortisone in the intact fetal lung, we perfused fetal rabbit lung via the pulmonary artery with ³H-cortisone, and demonstrated quantitative secretion of ³H-cortisol from the pulmonary vein [12]; we also reported that 11β HSD 1 activity increased significantly from 23 to 29 days gestation (day 31 = term).

The physiological significance of 11β HSD 1 activation by fetal lung fibroblasts was elucidated by in-depth studies on the cell-molecular mechanism of glucocorticoid action on lung maturation. Smith [13] discovered that cortisol stimulated lung fibroblast synthesis of a low molecular-weight paracrine factor he termed fibroblast-pneumonocyte factor (FPF), which was secreted into the extracellular milieu and stimulated surfactant phospholipid synthesis by the alveolar type II cell [14]. My laboratory pursued these observations by demonstrating that the hormone-dependent sex difference in fetal lung development was due to the differential expression of FPF in male and female fetal lung fibroblasts. The male-female difference in FPF expression by these cells was shown to be due in part to a sex difference in the expression of 11β HSD 1, both in vivo and in vitro [15]. This androgen-dependent mechanism was subsequently shown to be mediated by transforming growth factor β [16] [17].

My laboratory has more recently discovered that fetal rat lung fibroblasts express and secrete leptin, which binds to its cognate receptor on the fetal type II cell, stimulating surfactant phospholipid and protein synthesis [18] [19]. Leptin has many of the same characteristics as FPF: 1) its molecular weight (16,000 D) is within the molecular weight range (10 - 20,000 D) previously reported for FPF [14]; 2) its expression is stimulated by glucocorticoids [14] and inhibited by both androgens [15] and transforming growth factor β [15]. These similarities between leptin and FPF are further borne out by their common cellular origins - leptin is produced by mature adipocytes [20], which lung lipofibroblasts bear a strong resemblance to, both structurally and functionally [21]. Lipofibroblasts are located adjacent to epithelial type II cells [22], and it is these specific fibroblasts which also have been shown to produce FPF [23]. Therefore, leptin may be the long-sought-after FPF.

The recent report of 11β HSD 1’s role in fetal lung development by Hundertmark [1] [2] has confirmed our earlier findings using contemporary techniques. The observation that knocking out the 11β HSD 1 gene gives a lung phenotype consistent with its role in fetal lung maturation and pulmonary surfactant production [3] is further confirmation of the earlier series of studies of its role in this critical process of fetal transition and viability cited in this commentary. I thank Dr. Hundertmark and his colleagues for allowing me to reprise these studies in the light of their important contribution to this literature.

References

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