Download PDF
Horm Metab Res 2002; 34(10): 537-544
DOI: 10.1055/s-2002-35424
Original Basic
© Georg Thieme Verlag Stuttgart · New York

11β-Hydroxysteroid Dehydrogenase Type 1: A New Regulator of Fetal Lung Maturation

S.  Hundertmark 1 , A.  Dill 1 , H.  Bühler 2 , P.  Stevens 3 , K.  Looman 3 , V.  Ragosch 1 , J.  R.  Seckl 4 , C.  Lipka 1
  • 1Laboratory for Experimental Gynecology, Department of Obstetrics and Gynecology, Klinikum Benjamin Franklin, Freie Universität Berlin, Germany
  • 2Laboratory for Molecular Oncology, Department of Obstetrics and Gynecology, Marienhospital Herne, Universitätsklinik, Ruhr-Universität Bochum, Germany
  • 3Clinic of Neonatology, Charité Campus Mitte, Humboldt Universität Berlin, Germany
  • 4Molecular Medicine Centre, University of Edinburgh, UK
Further Information

Publication History

Received: 11 December 2001

Accepted after revision: 25 July 2002

Publication Date:
19 November 2002 (online)

Also available at
    Permissions and Reprints

Abstract

Glucocorticoids (GCs) induce surfactant synthesis in the late fetal lung. Deficient GC action causes respiratory distress syndrome. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inert cortisone (11-dehydrocorticosterone in rodents) into active cortisol (corticosterone), thus amplifying intracellular GC action. We investigated 11β-HSD1 in the late fetal lung using the licorice-derived inhibitor, glycyrrhetinic acid (GE), in pregnant rats (day 13 of gestation until term). Control fetal mice and rats showed high 11β-HSD activity in the late fetal lung; levels of plasma 11-dehydrocorticosterone were also high. Reduction/loss of pulmonary 11β-HSD1 activity in GE-treated rats substantially impaired fetal lung maturation. Lungs from GE-exposed rats had lower surfactant protein-A (mRNA and protein) levels and reduced amniotic fluid lecithin/sphingomyelin ratios. There was a marked depletion of lung surfactant before and after birth, as detected by both light and electron microscopy. The data emphasize the importance of 11β-HSD1 in amplifying key GC-dependent maturational processes in the late fetal lung.

Key words

11β-Hydroxysteroid Dehydrogenase - EC - 1.1.1.146 - Lung Maturation - Pulmonary Surfactant

References

  • 1 Lorenz U, Jurgens S, Ragosch V, Kipper-Kreissl B, Weitzel H. Medical prevention of respiratory distress syndrome.  Gynäkologe. 1991;  24 223-227
    PubMedGoogle Scholar
  • 2 Ballard P L, Ballard R A. Scientific basis and therapeutic regimens for use of antenatal glucocorticoids.  Am J Obstet Gynecol. 1995;  173 254-262
    CrossrefPubMedGoogle Scholar
  • 3 Liggins G C. Fetal lung maturation.  Aust N Z J Obstet Gynaecol. 1994;  34 247-250
    PubMedGoogle Scholar
  • 4 Rooney S A, Young S L, Mendelson C R. Molecular and cellular processing of lung surfactant.  FASEB J. 1994;  8 957-967
    PubMedGoogle Scholar
  • 5 Mendelson C R, Boggara V. Hormonal control of the surfactant system in fetal lung.  Ann Rev Physol. 1991;  53 415-440
    PubMedGoogle Scholar
  • 6 Gross I. Regulation of fetal lung maturation.  Am J Physiol. 1990;  259 L337-344
    PubMedGoogle Scholar
  • 7 Cole T J, Blendy J A, Monaghan A P, Krieglstein K, Schmid W, Aguzzi A, Fantuzzi G, Hummler E, Unsicker K, Schutz G. Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation.  Genes Dev. 1995;  9 1608-1621
    CrossrefPubMedGoogle Scholar
  • 8 White P C, Mune T, Agarwal A K. 11 beta-hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess.  Endocr Rev. 1997;  18 135-156
    CrossrefPubMedGoogle Scholar
  • 9 Diaz R, Brown R W, Seckl J R. Distinct ontogeny of glucocorticoid and mineralocorticoid receptor and 11 beta-hydroxysteroid dehydrogenase types I and II mRNAs in the fetal rat brain suggest a complex control of glucocorticoid actions.  J Neurosci. 1998;  18 2570-2580
    PubMedGoogle Scholar
  • 10 Jamieson P M, Chapman K E, Edwards C R, Seckl J R. 11 beta-hydroxysteroid dehydrogenase is an exclusive 11 beta-reductase in primary cultures of rat hepatocytes: effect of physicochemical and hormonal manipulations.  Endocrinology. 1995;  136 4754-4761
    CrossrefPubMedGoogle Scholar
  • 11 Rajan V, Chapman K E, Lyons V, Jamieson P, Mullins J J, Edwards C R, Seckl J R. Cloning, sequencing and tissue-distribution of mouse 11 beta-hydroxysteroid dehydrogenase-1 cDNA.  J Steroid Biochem Mol Biol. 1995;  52 141-147
    CrossrefPubMedGoogle Scholar
  • 12 Hundertmark S, Buhler H, Ragosch V, Dinkelborg L, Arabin B, Weitzel H K. Correlation of surfactant phosphatidylcholine synthesis and 11 beta- hydroxysteroid dehydrogenase in the fetal lung.  Endocrinology. 1995;  136 2573-2578
    CrossrefPubMedGoogle Scholar
  • 13 Funder J W, Pearce P T, Smith R, Smith A I. Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated.  Science. 1988;  242 583-585
    CrossrefPubMedGoogle Scholar
  • 14 Albiston A L, Obeyesekere V R, Smith R E, Krozowski Z S. Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme.  Mol Cell Endocrinol. 1994;  105 R11-17
    CrossrefPubMedGoogle Scholar
  • 15 Brown R W, Chapman K E, Kotelevtsev Y, Yau J L, Lindsay R S, Brett L, Leckie C, Murad P, Lyons V, Mullins J J, Edwards C R, Seckl J R. Cloning and production of antisera to human placental 11 beta-hydroxysteroid dehydrogenase type 2.  Biochem J. 1996;  313 1007-1017
    PubMedGoogle Scholar
  • 16 Brown R W, Diaz R, Robson A C, Kotelevtsev Y V, Mullins J J, Kaufman M H, Seckl J R. The ontogeny of 11 beta-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor gene expression reveal intricate control of glucocorticoid action in development.  Endocrinology. 1996;  137 794-797
    CrossrefPubMedGoogle Scholar
  • 17 Hundertmark S, Ragosch V, Schein B, Buhler H, Lorenz U, Fromm M, Weitzel H K. Gestational age dependence of 11 beta-hydroxysteroid dehydrogenase and its relationship to the enzymes of phosphatidylcholine synthesis in lung and liver of fetal rat.  Biochim Biophys Acta. 1994;  1210 348-354
    PubMedGoogle Scholar
  • 18 Kotelevtsev Y, Holmes M C, Burchell A, Houston P M, Schmoll D, Jamieson P, Best R, Brown R, Edwards C R, Seckl J R, Mullins J J. 11-beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress.  Proc Natl Acad Sci USA. 1997;  94 14 924-14 929
    PubMedGoogle Scholar
  • 19 Monder C, Stewart P M, Lakshmi V, Valentino R, Burt D, Edwards C R. Licorice inhibits corticosteroid 11 beta-dehydrogenase of rat kidney and liver: in vivo and in vitro studies.  Endocrinology. 1989;  125 1046-1053
    CrossrefPubMedGoogle Scholar
  • 20 Lonka L, Smith R. How liquorice works.  Lancet. 1987;  2 1206-1207
    PubMedGoogle Scholar
  • 21 Stewart P M, Wallace A M, Valentino R, Burt D, Shackleton C H, Edwards C R. Mineralocorticoid activity of liquorice: 11-beta-hydroxysteroid dehydrogenase deficiency comes of age.  Lancet. 1987;  2 821-824
    PubMedGoogle Scholar
  • 22 Connelly I H, Hammond G L, Harding P G, Possmayer F. Levels of surfactant-associated protein messenger ribonucleic acids in rabbit lung during perinatal development and after hormonal treatment.  Endocrinology. 1991;  129 2583-2591
    PubMedGoogle Scholar
  • 23 Schoneshofer M, Weber B, Oelkers W, Nahoul K, Mantero F. Urinary excretion rates of 15 free steroids: potential utility in differential diagnosis of Cushing’s syndrome.  Clin Chem. 1986;  32 93-96
    PubMedGoogle Scholar
  • 24 Heilmann P, Heide J, Schoneshofer M. Determination of 18 beta-glycyrrhetinic acid in human serum using the fully automated ALCA-system.  Eur J Clin Chem Clin Biochem. 1997;  35 539-543
    PubMedGoogle Scholar
  • 25 Gluck L, Kulovich M V, Borer R C, Brenner P H, Anderson G G, Spellacy W N. Diagnosis of the respiratory distress syndrome by amniocentesis.  Am J Obstet Gynecol. 1971;  173 629-635
    PubMedGoogle Scholar
  • 26 Ragosch V, Jurgens S, Lorenz U, Stolowsky C, Arabin B, Weitzel H K. Prediction of RDS by amniotic fluid analysis: a comparison of the prognostic value of traditional and recent methods.  J Perinat Med. 1992;  20 351-360
    PubMedGoogle Scholar
  • 27 Bakewell W E, Viviano C J, Dixon D, Smith G J, Hook G E. Confocal laser scanning immunofluorescence microscopy of lamellar bodies and pulmonary surfactant protein A in isolated alveolar type II cells.  Lab Invest. 1991;  65 87-95
    PubMedGoogle Scholar
  • 28 Zimmermann B. Lung organoid culture.  Differentiation. 1987;  36 86-109
    PubMedGoogle Scholar
  • 29 Tadera J V. Control of lung differentiation in vitro.  Dev Biol. 1967;  2 489-512
    PubMedGoogle Scholar
  • 30 Zimmermann B. Influence of corticosteroids and thyroxine on lung development in vitro.  Acta Endocrinol. 1985;  2 35-36
    PubMedGoogle Scholar
  • 31 Wissel H, Looman A C, Fritzsche I, Rustow B, Stevens P A. SP-A-binding protein BP55 is involved in surfactant endocytosis by type II pneumocytes.  Am J Physiol. 1996;  271 L432-440
    PubMedGoogle Scholar
  • 32 Paine R, Ben-Ze’ev A, Farmer S R, Brody J S. The pattern of cytokeratin synthesis is a marker of type 2 cell differentiation in adult and maturing fetal lung alveolar cells.  Dev Biol. 1988;  129 505-515
    CrossrefPubMedGoogle Scholar
  • 33 Endo H, Oka T. Histological and immunohistochemical analysis of lung development, with particular reference to lung hypoplasia.  Early Hum Dev. 1995;  43 233-244
    CrossrefPubMedGoogle Scholar
  • 34 Sano K, Fisher J, Mason R J, Kuroki Y, Schilling J, Benson B, Voelker D. Isolation and sequence of a cDNA clone for the rat pulmonary surfactant-associated protein (PSP-A).  Biochem Biophys Res Commun. 1987;  144 367-374
    CrossrefPubMedGoogle Scholar
  • 35 Korfhagen T R, Bruno M D, Glasser S W, Ciraolo P J, Whitsett J A, Lattier D L, Wikenheiser K A, Clark J C. Murine pulmonary surfactant SP-A gene: cloning, sequence, and transcriptional activity.  Am J Physiol. 1992;  263 L546-554
    PubMedGoogle Scholar
  • 36 Nudel U, Zakut R, Shani M, Neuman S, Levy Z, Yaffe D. The nucleotide sequence of the rat cytoplasmic beta-actin gene.  Nucleic Acids Res. 1983;  11 1759-1771
    PubMedGoogle Scholar
  • 37 Tye L M, Burton A F. Variation in the pattern of metabolism of corticosteroids in fetal mouse tissues.  Life Sci. 1980;  26 35-39
    PubMedGoogle Scholar
  • 38 Abramovitz M, Carriero R, Murphy B E. Investigation of factors influencing 11 beta-hydroxysteroid dehydrogenase (EC 1.1.1.146) activity in midgestational human fetal lung monolayer and explant cultures.  J Steroid Biochem. 1984;  21 677-683
    CrossrefPubMedGoogle Scholar
  • 39 Lucier G W, Sonawane B R, McDaniel O S. Glucuronidation and deglucuronidation reactions in hepatic and extrahepatic tissues during perinatal development.  Drug Metab Dispos. 1977;  5 279-287
    PubMedGoogle Scholar
  • 40 Mantovani A, Ricciardi C, Stazi A V, Macri C, Piccioni A, Barellino E, de Vincenti M, Caiola S, Patriarca M. Teratogenicity study of ammonium glycyrrhizinate in the Sprague-Dawley rat.  Food Chem Toxicol. 1988;  26 435-440
    PubMedGoogle Scholar
  • 41 Edwards C R, Benediktsson R, Lindsay R S, Seckl J R. Dysfunction of placental glucocorticoid barrier: link between fetal environment and adult hypertension?.  Lancet. 1993;  341 355-357
    CrossrefPubMedGoogle Scholar
  • 42 Benediktsson R, Calder A A, Edwards C R, Seckl J R. Placental 11 beta-hydroxysteroid dehydrogenase: a key regulator of fetal glucocorticoid exposure.  Clin Endocrinol. 1997;  46 161-166
    CrossrefPubMedGoogle Scholar
  • 43 Burton P J, Waddell B J. 11 beta-Hydroxysteroid dehydrogenase in the rat placenta: developmental changes and the effects of altered glucocorticoid exposure.  J Endocrinol. 1994;  143 505-513
    PubMedGoogle Scholar
  • 44 Barlow S M, Morrison P J, Sullivan F M. Plasma corticosterone levels during pregnancy in the mouse.  Br J Pharmacol. 1973;  48 346P
    PubMedGoogle Scholar
  • 45 Cohen A. Plasma corticosterone concentration in the foetal rat.  Horm Metab Res. 1973;  5 66
    PubMedGoogle Scholar
  • 46 Nicholas T E, Lugg M A. The physiological significance of 11 beta-hydroxysteroid dehydrogenase in the rat lung.  J Steroid Biochem. 1982;  17 113-118
    CrossrefPubMedGoogle Scholar
  • 47 Spinks E A, Fenwick G R. The determination of glycyrrhizin in selected UK liquorice products.  Food Addit Contam. 1990;  7 769-778
    PubMedGoogle Scholar
  • 48 Stormer F C, Reistad R, Alexander J. Glycyrrhizic acid in liquorice - evaluation of health hazard.  Food Chem Toxicol. 1993;  31 303-312
    PubMedGoogle Scholar
  • 49 Seckl J R. Glucocorticoids, feto-placental 11 beta-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease.  Steroids. 1997;  62 89-94
    Google Scholar

PD Dr. S. Hundertmark

Allgemeines Krankenhaus Altona

Paul-Ehrlich-Str. 1 · 22763 Hamburg · Germany

Phone: + 49 (30) 84 45-25 93

Fax: + 49 (30) 84 45-44 77

Email: sven.hundertmark@ak-altona.lbk-hh.de

      >