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Departments of R
Glucocorticoid Metabolism in the Human
Fetal Lung: Implications for Lung Development
and the Pulmonary Surfactant System
Mark R. Garbrecht a Jonathan M. Klein b Thomas J. Schmidt c Key Words
Glucocorticoid metabolism ؒ
Anatomy and Cell Biology, b Pediatrics, and c Physiology and Biophysics, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa , USA Abstract

reported the benefi
Oon 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 sur-factant 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 It has been nearly 35 years since Liggins and Howie fi rst concerning the expression and activity of the HSD en- ts of antenatal glucocorticoid (GC) zymes in the human fetal lung and contrast this to what treatment to promote the maturation of the human fetal is known about the HSD enzymes in the fetal rodent lung. lung, and nearly that long since Pasqualini et al. demon-strated 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, char-acterization of the enzymes involved in GC metabolism has greatly expanded our understanding of GC signaling in target tissues. In man, the biologically active GC (cor-tisol) and the biologically inactive GC (cortisone) are in-terconverted by the tissue-specifi c expression of the type 1 and type 2 11 ␤ -hydroxysteroid dehydrogenase en-zymes (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 Although rodents, rabbits, sheep, and several primates have been invaluable model systems for the study of fe-tal lung development, we have chosen to largely focus this review on human lung, since there are signifi cant differences in GC metabolism between humans and oth-er species. Role of Glucocorticoids in Fetal Lung
Development and Induction of the Pulmonary
Surfactant System
In 1969, Liggins [1] reported that antenatal glucocor- ticoids (GCs) accelerate the appearance of pulmonary effects of GCs in the kidney and placenta. In contrast, the surfactant in newborn lambs. Shortly thereafter, Liggins role of GC metabolism in modulating the effects of GCs and Howie [2] described the benefi ts of maternally ad- Tel. +1 319 3357738, Fax +1 319 3357198, E-Mail jeanne-snyder@uiowa.edu ministered antenatal GCs in reducing the incidence of tidylcholine [13, 14] . Dipalmitoylphosphatidylcholine is respiratory distress syndrome (RDS) in prematurely born the major component responsible for the surface-tension infants via the acceleration of fetal lung maturation. The reducing properties of surfactant [13, 14] . administration of synthetic GCs to pregnant women Pulmonary surfactant contains four SPs: SP-A, SP-B, threatening preterm delivery in an effort to accelerate fe- SP-C, and SP-D. Three of these proteins, SP-A, SP-B and tal lung maturation remained controversial and failed to SP-D, are also produced by Clara cells, which are a type gain widespread acceptance for many years until a Con- of conducting airway epithelial cell [15–17] . SP-A and sensus Development Conference was held by the Nation- SP-D are hydrophilic surfactant proteins (35 and 43 kDa al Institutes of Health (NIH) in 1994. The NIH recom- respectively) that are members of the collectin family of mended that all fetuses between 24 and 34 weeks’ gesta- innate host defense proteins [18, 19] . The hydrophobic tion at risk for preterm delivery should be considered as surfactant proteins, SP-B and SP-C, are 5- to 7-kDa pro- candidates for antenatal GC therapy [3] . In the following teins that are required for achieving the optimal surface- years, many fetuses were subjected to multiple courses of tension reducing properties of surfactant by promoting antenatal GCs, and this has precipitated concerns over the rapid adsorption of surfactant phospholipids along the safety and effi cacy of this treatment [4, 5] . Over the last three decades, the effects of antenatal GCs on fetal lung maturation and the pulmonary surfac-tant system have been a topic of intense scientifi c and Glucocorticoids and Surfactant Synthesis
clinical interest and have prompted much research. Ad-vances in biochemistry and molecular biology have led to GCs have complex effects on the production of pul- a greater understanding of how GCs exert their potent monary surfactant. Near the end of gestation, fetal plas-effects in the developing lung and other organ systems ma GC levels rise sharply, and this facilitates the fi nal [6–8] . The complex mechanisms by which GCs regulate maturation of the fetal lung and stimulates fetal lung sur- fetal lung maturation and the individual components of factant synthesis [8, 9] . In humans, GCs stimulate the pulmonary surfactant are now beginning to be appreci- synthesis of surfactant phospholipids [11] . Crucial to the ated. Many studies have focused on the mechanisms by increase in surfactant phospholipid synthesis is a GC-me- which GCs regulate the genes that encode the enzymes diated increase in the expression of fatty acid synthase, involved in the production of both the surfactant phos- an enzyme involved in the de novo synthesis of fatty acids pholipids as well as the genes encoding the surfactant-as- used in the phospholipid biosynthetic pathway [10, 21] . sociated proteins (SPs). These studies have been exten- Additionally, GCs increase the expression of SP-B, SP-C, sively reviewed elsewhere [8–11] . The focus of this review and SP-D, but decrease expression of SP-A [22–24] . GCs will be to summarize another avenue of investigation con- affect the mRNA levels of the SPs via alterations in both cerning the role of GC metabolism in the developing hu- the transcription and the stability of the transcripts en- coding these proteins. GCs increase the transcription of all of the human surfactant protein genes and this appears to be the dominant mechanism for increasing the expres- Pulmonary Surfactant and Surfactant-
sion of the SP-C and SP-D genes [23, 25, 26] . However, Associated Proteins
GCs can also have dramatic effects on mRNA stability. GCs increase the stability of SP-B mRNA and decrease A critical event in the transition to extrauterine, air the stability of SP-A mRNA, two post-transcriptional breathing life is the production of pulmonary surfactant. mechanisms which contribute signifi cantly to the overall Pulmonary surfactant is a complex mixture of phospho- increase or decrease in mRNA levels of these surfactant lipids and proteins that consists of ϳ 10% protein, ϳ 10% protein genes [25–27] . cholesterol, and ϳ 80% phospholipids [12] . Surfactant is Synthetic GCs, such as betamethasone and dexameth- produced and secreted by type II alveolar epithelial cells asone (Dex), are routinely administered to women threat- and functions to reduce surface tension at the alveolar ening premature delivery in order to accelerate fetal lung air-liquid interface, thereby preventing alveolar collapse maturation and reduce the incidence of RDS [4, 28] . The at end-expiration [12, 13] . The lipid component of pul- dose and type of synthetic steroid used, and the frequen- monary surfactant is composed largely of saturated phos- cy of administration are subjects of debate in the fi eld of phatidylcholine species, principally dipalmitoylphospha- obstetrics [3–5, 29] . A single course of GCs is very effec- tive in reducing the incidence of RDS and intracranial pothesis is supported by the observation that a decrease hemorrhage in preterm infants; however, multiple cours- in fetal lung fl uid pressure, as observed in congenital dia- es of antenatal GCs have been associated with adverse phragmatic hernia and oligohydramnios, contributes to side effects and abnormal infant development [3–5, 30] . neonatal pulmonary hypoplasia [53, 54] . GCs, in synergy with thyroid hormones, are known to be important for the development of the fl uid-absorbing phenotype re- Glucocorticoids and Fetal Lung Maturation
quired for effi cient alveolar gas exchange following birth [55] . GCs regulate Na + transport by increasing the expres- GCs can also promote fetal lung maturation by affect- sion and activity of epithelial Na + channels (ENaC) in ing structural changes in the developing lung. For exam- ple, GCs promote lung cell proliferation, the differentia- tion of type II alveolar epithelial cells, and the thinning of alveolar walls [8, 9, 31, 32] . Many of these effects are Local Metabolism of Glucocorticoids
indirect and may represent the actions of GC-regulated factors such as C/EBP ␦ [33] , transforming growth fac- In humans, GCs exist in two chemical forms that dif- tor- ␤ [34] , epidermal growth factor [35] , vascular endo- fer in the side group that occupies the 11 ␤ position of the thelial growth factor [36] , and fi broblast growth factors steroid ring. The endogenous, biologically active GC, cor- [37] . The critical role of GCs in fetal lung development tisol, has a hydroxyl group at this position, while the bio- has been highlighted in a number of studies using mouse logically inactive form of the GC, cortisone, has a ketone genetic models. Mice bearing targeted disruptions of group at this position ( fi g. 1 ). Binding of cortisol to the genes encoding corticotrophin-releasing hormone and the GR is thought to be dependent on the presence of the hy- glucocorticoid receptor (GR) display delayed lung devel- droxyl group at the 11 ␤ position [58] . Circulating plasma opment as a result of decreased endogenous GC release levels of free cortisol are approximately 100-fold lower and intracellular GR signaling, respectively than those of free cortisone, in large part because a sig- These abnormalities include decreased levels of SP-A, nifi cant amount of cortisol remains reversibly bound to SP-B, and SP-C, increased cellularity and decreased al- corticosteroid binding globulins (i.e., transcortin) and veolar septal thinning, as well as alterations in alveolar other plasma proteins [59] . epithelial cell proportions [38, 40] . However, excessive GC action in peripheral tissues is thought to be regu- exposure to GCs (as in repeated doses of antenatal syn- lated by (1) the activation/inhibition of the hypothalam- thetic GCs) has been reported to negatively affect post- ic-pituitary-adrenal (HPA) axis (i.e., physiological feed- natal lung development and alveolarization in monkeys back mechanisms regulating adrenal GC biosynthesis and rats [42, 43] . These adverse effects may be the result and release), (2) the reversible binding of cortisol to trans- of inhibition of alveolar septation or may be related to cortin, and/or (3) the differential expression of the GR. growth inhibitory effects of high levels of GCs on lung More recently, the local metabolism of GCs has been rec-epithelial cells in rats [44] . One follow-up study in humans ognized as a critical factor in regulating GC action in pe- has shown normal lung growth as measured by lung vol- ume or expiratory air fl ow in infants treated with antenatal GC metabolism is mediated by the tissue-specifi c ex- GCs when compared to untreated individuals [45] . None- pression of two enzymes: 11 ␤ -hydroxysteroid dehydroge- theless, conclusive data documenting the effects of ante- nase type 1 and type 2 (HSD1 and HSD2). Both HSD natal GCs on postnatal lung growth and alveolarization enzymes belong to the short chain alcohol dehydrogenase superfamily, and their genes have been cloned [62, 63] . GCs play an important role in the transition of the fe- HSD1 utilizes nicotinamide adenine dinucleotide phos- tal lung from a fl uid-secreting organ to a fl uid-absorbing phate (NADPH) as a cofactor in the 11 ␤ -oxidoreduction organ at term. During gestation, the fetal lung actively of inactive cortisone to active cortisol [64] . In this reac-transports Na + and Cl – into the lumen of the developing tion, HSD1 transfers an electron (in the form of hydro- lung [46] . This ion fl ux leads to the accumulation of fl uid gen) from NADPH to the 11 ␤ -ketone group of cortisone, in the lumen of the lung [47] . Positive fl uid pressure in thus generating the characteristic hydroxyl group at the the developing lung is thought to contribute to the overall F position of cortisol ( fi g. 1 ). In contrast, HSD2 uti-
growth and maturation of the lung, most likely via stimu- lizes nicotinamide adenine dinucleotide (NAD + ) in cata- lyzing the 11 ␤ -oxidation of cortisol to cortisone [65, 66] . R O (Oxidation)
O(Oxidoreduction)
Fig. 1. Cortisol metabolism by the HSD1 and HSD2 enzymes. HSD1 utilizes the cofactor NADPH to convert the
11 ␤ -ketone group of cortisone to a hydroxyl group (oxidoreduction). This reaction yields biologically active cor-
tisol from inactive cortisone. HSD2 utilizes the cofactor NAD + to convert cortisol to biologically inactive cortisone
(oxidation). In this reaction, the 11 ␤ -hydroxyl group of cortisol is oxidized to a ketone group.
In this reaction, HSD2 transfers an electron (in the form ticoids such as aldosterone, as well as GCs, increase of hydrogen) from the 11 ␤ -hydroxyl group of cortisol to ENaC subunit expression and Na + transport in lung NAD + , thus generating the 11 ␤ -ketone group character- epithelial cells [56, 57, 75] . Recently, HSD2 and MR istic of cortisone ( fi g. 1 ). While HSD2 functions to con- were found to co-localize in both adult and fetal human vert active cortisol to inactive cortisone, HSD1 functions conducting airway epithelia and adult type II alveolar to convert excess inactive cortisone to biologically active epithelial cells [69, 76] . Alterations in MR activation cortisol. HSD1 is primarily found in the liver, central affect Na + transport and fl uid reabsorption across al-nervous system, and adipose tissue, where relatively low veolar epithelia, an observation which is suggestive that levels of intracellular cortisol are amplifi ed by the conver- one of the roles of HSD2 in the lung may be to locally sion of cortisone to cortisol [67] . In contrast, HSD2 is inactivate cortisol, thereby ensuring aldosterone is the most highly expressed in aldosterone-sensitive, sodium- primary ligand for the MR for aldosterone and limiting transporting tissues such as the kidney, colon, and sali- GC-mediated increases in Na + transport [76, 77] . Thus, vary glands [68, 69] . In these tissues, HSD2 has been the human lung could be considered a sodium-trans-shown to locally inactivate cortisol, thus preventing il- porting tissue in which the proper functioning of the licit occupation of the mineralocorticoid receptor (MR) HSD system may help maintain normal organ function by cortisol, since the MR has equal affi nities for both al- dosterone and cortisol [70, 71] . Mutations in the HSD2 gene result in increased levels of cortisol in the renal epi-thelia and this leads to constitutive transactivation of the Metabolism of Synthetic Glucocorticoids
MR and the syndrome of apparent mineralocorticoid ex-cess [72] . HSD2 mutations may also contribute to essen- Several studies are suggestive that the metabolism of tial hypertension and other cardiovascular disorders [66, synthetic GCs, such as Dex, may differ from that of the natural GC, cortisol [61, 78–80] . Fluorine and methyl The human lung expresses the MR and actively trans- group substitutions in Dex limit its oxidoreduction and ports sodium across the alveolar surface in order to oxidation by HSD1 and HSD2, respectively [79, 81] . In- maintain a delicate fl uid balance in the alveolus that is terestingly, HSD2 has recently been shown to actively critical to effi cient gas exchange [69, 74] . Mineralocor- and preferentially oxidoreduce 11-dehydro Dex (the pre- O 11-dehydro dexamethasone
Fig. 2. Dexamethasone metabolism by the HSD1 and HSD2 enzymes. Fluorine and methyl group substitutions
(9- and 16- ␣ positions) not found in cortisol and cortisone (fi g. 1) render 11-dehydro Dex resistant to oxidoreduc-
tion by HSD1 and Dex resistant to oxidation by HSD2. Fluorination at the 9 ␣ position allows effi cient oxidore-
duction of 11-dehydro Dex by HSD2 such that the redox equilibrium favors the 11-hydroxy form of the steroid
in HSD2-expressing tissues.
sumably inactive 11-keto metabolite of Dex) to yield Dex, HSD Expression and Activity in the
a pathway that is the opposite of HSD2 metabolism of Developing Human Lung
natural GCs (i.e., the conversion of cortisol to inactive cortisone) ( fi g. 2 ) [78–80] . Additionally, two recent stud- ies have demonstrated that the 11-keto metabolite of Dex the fi rst direct in vivo evidence of cortisol metabolism (11-dehydro Dex) can compete for GC binding to the GR in human fetal lung tissues. In this study, the authors and act as a potent GR agonist [82, 83] . In contrast, the observed that following umbilical vein administration of 11-keto metabolite of cortisol, cortisone, is a poor ligand [ 3 H]-cortisol and [ 14 C]-cortisone, [ 3 H]-cortisone, but not for the GR and is biologically inactive [82, 84, 85] . [ 14 C]-cortisol, was detected in the harvested fetal lungs Together, these observations highlight unique and po- ( table 1 ) [86] . These fi ndings are suggestive that at mid- tentially important differences in the metabolism and gestation, the human fetal lung actively oxidizes cortisol activity of the natural GC, cortisol, versus the synthetic to cortisone, but does not convert cortisone to cortisol. In GC, Dex. This is particularly signifi cant given the wide- contrast, Smith et al. [32] subsequently observed that cul- spread clinical use of synthetic GCs in the treatment of tured human fetal lung cells actively converted cortisone diseases of the respiratory, immune, cardiovascular, ner- to cortisol, whereas oxidation of cortisol was undetectable vous, and integumentary systems. However, the dichot- omy in the metabolism of natural versus synthetic GCs In the late 1970s and early 1980s, the issue of cortisol may be unique to Dex, and not apply to all synthetic GCs. metabolism by the human fetal lung was re-examined in It has recently been reported that the 11-hydroxy form a number of in vitro studies by Murphy [89, 90] and of the synthetic GC, prednisolone, is biologically active, Abramovitz et al. [87, 88] . These studies revealed that in while its 11-keto metabolite, prednisone, is biologically intact human fetal lung explants, net inactivation of cor- inactive [85] . Thus the biological activity of the 11-hy- tisol to cortisone predominates throughout gestation, al- droxy and 11-keto metabolites of prednisolone seem to though it decreases near term [89, 90] . In subsequent parallel that of the natural GC, cortisol, and not that of studies, the metabolism of cortisol was compared in cul- Dex. Whether other synthetic GCs, such as betametha- tured human fetal lung cells versus intact human fetal sone, are also active in their 11-keto forms is currently lung explants [87, 88] . These studies confi rmed the obser- vations of Smith et al. [32] , that conversion of cortisone Table 1. Comparison of HSD activities in human versus rodent fetal lung
RModel system Net conversion References
cortisol to cortisone (oxidative), decreases near term Cultured lung cells (mainly fi broblasts) 11-dehydrocorticosterone to corticosterone Cultured lung fi broblastsHomogenized lung tissue to cortisol predominated in cultured human fetal lung tisone (results suggestive of HSD2 activity) early in gesta-cells and increased with time in culture [87, 88] . Impor- tion, and that this enzymatic activity decreases near term tantly, morphological analysis of the cultured human fetal [89] . Following the advent of more sophisticated bio- lung cells revealed that the increase in conversion of cor- chemical and molecular techniques, it was demonstrated tisone to cortisol paralleled an increase in the proportion that the human fetal lung expresses HSD2 protein in a broblasts to epithelial cells in the cultures, such that variety of epithelia in the pseudoglandular, canalicular, by the end of approximately 5 days in culture, fi broblasts and terminal sac phases of lung development [76, 91, 92] . were the only cell type detected [87, 88] . In contrast, the Surprisingly, HSD2 expression was not detected in dif- authors observed that oxidation of cortisol to cortisone ferentiated type 1 and type 2 alveolar epithelial cells of always predominated in the intact human fetal lung ex- the fetal lung [76] . However, HSD2 expression has been plants, with conversion of cortisone to cortisol either detected in epithelial cells of the trachea, bronchi, termi-barely detected or undetectable ( table 1 ) [87, 88] . Of note nal bronchioles, and in type 2 alveolar epithelial cells of was the observation that when intact human fetal lung the adult lung [69, 93] . To our knowledge, HSD1 protein explants were allowed to remain in culture longer than expression in the human fetal lung has never been re-6–7 days, some conversion of cortisone to cortisol was ported. However, HSD1 mRNA has been detected in observed; however, the predominant HSD activity re- adult human lung tissue and in cultured human lung fi - mained oxidative [87, 88] . The increase in oxidoreduc- broblasts [62, 94–96] . Reports of HSD1 protein expres- tion was attributed to fi broblast outgrowth observed in sion in adult human lung tissue have been confl icting. the human fetal lung explants cultured for long periods HSD1 protein has been detected in adult human lung tis- of time [88] . Taken together, these early studies are sug- sue by some investigators, while others have been unable gestive that in vivo, and in the intact human fetal lung to confi rm these observations [83, 93–95, 97] . The dis- explants cultured in vitro, the predominant HSD activity crepancy in the ability to detect HSD1 protein in human is oxidative (i.e., inactivation of cortisol to cortisone) [86– lung may be related to the method of lung tissue prepara- 90] . Predominant oxidoreductive activity (i.e., activation tion and/or the tissue tested. HSD1 protein has been de- of cortisone to cortisol) is only observed in cultured hu- tected by immunoblot analysis in cultured adult lung fi - man fetal lung cells which are predominantly fi broblasts broblasts and in microsome preparations of adult lung and clearly does not parallel the in vivo situation [32, tissue [94, 95] . However, HSD1 protein expression was undetectable by immunoblot analysis of total lung ho- The studies described above were conducted prior to mogenate protein and immunohistochemical analysis of the cloning and characterization of the HSD1 and HSD2 adult lung tissue [83, 93, 97] . Cultured adult and fetal lung broblasts seem to express high levels of HSD1 protein strate that the predominant metabolism of GCs in the and enzymatic activity, which are not apparent in intact human fetal lung involves the oxidation of cortisol to cor- tissue [87, 88, 94] . Additionally, detection of HSD1 pro- tein in fresh adult lung required the use of relatively large tisol observed ( table 1 ) [87–90] . The ability of the human amounts (100 ␮ g) of purifi ed microsomal protein [95] . fetal lung to oxidize cortisol appears to be dependent Despite these intriguing fi ndings, little additional re- upon gestational age, since human fetal lung tissues ob- search has been carried out to defi ne the role of HSD2 in tained closer to term have a reduced ability to oxidize human fetal lung development and the regulation of the cortisol to cortisone [89] . Net conversion of cortisone to surfactant system. In contrast, a recent study has ad- cortisol (oxidoreduction) is not observed in human fetal dressed the role of HSD2 in regulating the effects of nat- lung tissue of any gestational age [89] . Several studies ural GCs in the human adult lung. In a study by Feinstein have suggested that fi broblast-like cells in the fetal lung and Schleimer [98] , the authors observed that inhibition of a number of species, including humans, can exhibit of HSD2 activity increased the potency of the natural GC, strong HSD1 (i.e., oxidoreductive) activity, and could cortisol, in primary airway epithelial cells. be a source of locally produced cortisol or corticoste-rone [32, 87, 88, 106–108] . However, it was subsequent-ly demonstrated that at least in humans, this observa- HSD1 and HSD2 Expression in the Developing
tion is restricted to lung fi broblasts cultured in vitro, Rodent Lung
since intact human fetal lung tissue does not convert signifi cant amounts of cortisone to cortisol [87–90] . Ad- In rodents, as in humans, HSD1 catalyzes the oxido- ditionally, it has been demonstrated that in vivo , mid- reduction of the biologically inactive endogenous GC (11- gestation human fetal lung does not covert cortisone to dehydrocorticosterone in rodents) to its biologically ac- tive form (corticosterone), thereby locally increasing the In sharp contrast to observations made using human availability of active GCs [99, 100] . Rodent HSD2 cata- fetal lung tissue, oxidoreduction of 11-dehydrocortico- lyzes the oxidation of active corticosterone to the inactive sterone predominates in the fetal rodent lung. Intact fetal metabolite, 11-dehydrocorticosterone, thereby reducing rat lung tissue effi ciently oxidoreduces inactive 11-dehy-local levels of active GCs [99, 100] . In contrast to the drocorticosterone to active corticosterone, with almost no situation in the human lung, it has been reported that the oxidation of corticosterone to inactive 11-dehydrocorti- rodent lung solely expresses HSD1, although in one study costerone observed ( table 1 ) [109] . Cultures of mixed fe- HSD2 mRNA was detected in the fetal lung by in situ tal rat lung cells, isolated fetal rat lung fi broblasts, homog-hybridization [99, 101–103] . Two recent reports by Hun- enates of fetal rat lung, and homogenates of fetal mouse dertmark et al. [104, 105] have highlighted a role for pe- lung all exhibit effi cient oxidoreductase activity [104– ripheral GC metabolism in the development of the rodent 106, 109] . While some oxidation of corticosterone to in- fetal lung. Chemical inhibition of fetal HSD1 activity (via active 11-dehydrocorticosterone can occur in cultures of maternal administration of a HSD1 inhibitor) reduces mixed fetal rat lung cells and homogenates of fetal mouse the gestation-dependent accumulation of SP-A and abol- lung, the equilibrium tends to remain on the side of oxi- ishes the normal increase in the lecithin/sphingomyelin doreduction [104, 105] . Interestingly, the oxidoreduction ratio in the amniotic fl uid that occurs during gestation, of 11-dehydrocorticosterone to active corticosterone in- two independent indicators of fetal lung maturation creases in both fetal mouse and rat lungs closer to term [104] . Additionally, histological analyses revealed de- creased lamellar body content in the alveolar type 2 cells Thus, it appears that humans and rodents differ sig- of fetal rats exposed to a HSD1 inhibitor, results sugges- nifi cantly in the predominance of the type of HSD activ- tive of a critical role for HSD1 in the production of pul- ity present in the fetal lung. These observations are sur- monary surfactant in the developing rodent lung [104] . prising since the HSD enzymes in both species carry out In support of this concept, transgenic mice lacking the the same biochemical reactions and since GCs are thought HSD1 gene exhibit delayed fetal lung development [105] . to play similar roles in the development of the lung in Together, these fi ndings support the idea that HSD1 ac- humans and mice. A possible explanation for this species tivity provides an ample source of biologically active GCs dichotomy may lie in differences in the mechanisms or that are required for the normal development of the fetal timing of developmental events in the two species or in rodent lung and its associated surfactant system. differences in the GC-mediated regulation of critical mat- Intact cultures of mid-trimester human fetal lung dem- uration factors. Indeed, alveolarization in rodents occurs onstrate almost exclusive oxidation of cortisol to corti- almost exclusively in the neonatal period following birth, sone, with very little oxidoreduction of cortisone to cor- while in humans a signifi cant portion of alveolarization is completed during late gestation and continues into the ylprednisolone may be viable alternatives to the use of [110] . Additionally, GCs have been more potent synthetic GCs such as Dex and betametha- shown to increase pulmonary SP-A levels in mice, but sone [118, 119] . These alternative GCs appear to be as decrease SP-A levels in humans [24, 111, 112] . Alterna- effective as Dex in reducing oxygen dependency and tively, HSD activity in both the human and rodent fetal chronic lung disease in preterm infants, but with fewer lungs may function to increase local production of active short- and long-term side effects such as decreased so- GCs near term, albeit by different mechanisms. Indeed, matic growth, insulin resistance, hypertension, and neu- oxidation of cortisol to inactive cortisone decreases in hu- rodevelopmental disabilities [118, 119] . man fetal lungs closer to term, while oxidoreduction of Although research on the peripheral metabolism of 11-dehydrocorticosterone to active corticosterone in- GCs by the HSD system has largely focused on the me- creases in rodent lungs closer to term [89, 104, 105] . tabolism of cortisol and Dex, further research is needed to elucidate the role of these enzymes in the metabolism of other commonly used synthetic GCs. The fi nding that Use of Synthetic GCs in the Prevention of
the 11-dehydro metabolite of Dex (11-dehydro Dex) is Neonatal Lung Disease
biologically active, while the 11-dehydro metabolite of cortisol (cortisone) is not, is suggestive that additional The debate over the use of synthetic GCs for the pre- research is also needed to determine the potential bio- vention of RDS continues to be widely discussed in the logical activity of the metabolites of other clinically used fi elds of obstetrics and neonatology. Synthetic GCs are synthetic GCs [82, 83] . These studies may yield impor-typically given to women at risk for preterm delivery in tant information that could lead to the safe use of alterna- an effort to accelerate lung maturation and stimulate pul- tive GCs to more effectively prevent or treat neonatal monary surfactant production. These therapies have been lung disease and reduce the incidence of short- and long- proven to reduce the incidence of neonatal RDS O[2, 28] . term side effects that often occur with current GC treat-
However, evidence has accumulated in recent years con- cerning short- and long-term side effects of treating fe-tuses (via maternal administration of steroids) and neo-nates (postnatally) with supraphysiologic doses of GCs. Acknowledgements
Multiple courses of antenatal GCs have been associated with increased risks of neonatal sepsis, decreased birth This work was supported by the National Institutes of Health Grant RO1 HL-50050 to J.M.S. M.R.G. is supported by an Amer- weight, increased risk of severe early lung disease, pro- ican Heart Association Pre-Doctoral Fellowship. longed adrenal suppression, and altered HPA axis reac-tivity [4, 5, 29, 113] . Furthermore, postnatal GC treat-ment (to prevent and/or treat chronic lung disease) has been associated with decreased somatic growth, decreased neuromotor and cognitive function, increased risk of ce-rebral palsy, cardiac abnormalities, as well as hyperten-sion, hyperglycemia, and increased plasma urea concen-trations [114–118] . Given the widespread effects of GCs on many aspects of cellular growth, metabolism, and dif-ferentiation, it is not surprising that long-term effects of high doses of GCs administered in the developmentally critical antenatal period abound. Prenatal exposure to GCs has been linked to long-term alterations in HPA axis reactivity, hypertension, and insulin resistance [for re-view, see 113] . Despite the widespread use of Dex and betamethasone in the antenatal and postnatal period to prevent or treat lung diseases due to prematurity, the use of other GCs for this purpose is a topic that warrants further study. Indeed, two recent reports are suggestive that cortisol and meth- References
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