Foetal Lung Maturation in 11β-Hydroxysteroid Dehydrogenase Type 1 Knockout Mice

Abstract

Glucocorticoids (GCs) induce surfactant synthesis in the late foetal lung. Deficient GC action causes respiratory distress syndrome (RDS). 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inert cortisone (11-dehydrocorticosterone in rodents) into active cortisol (corticosterone), thus amplifying intracellular GC action. Reduction or loss of pulmonary 11β-HSD1 activity in glycyrrhetinic acid-treated rats substantially impaired foetal lung maturation (Hundertmark et al., Horm Metab Res, this issue). To test these data, we investigated 11β-HSD1 activity and lung maturity in the late foetal lung using 11β-HSD1 knockout mice. Control foetal mice showed high 11β-HSD activity in the late foetal lung and levels of plasma 11-dehydrocorticosterone were high. Lungs from 11β-HSD1 -/- mice had lower surfactant protein-A (mRNA and protein) levels and significant depletion of lung surfactant according to both light and electron microscopy, and also had reduced amniotic fluid lecithin/sphingomyelin ratios. These results support the previous experiments with glycyrrhetinic acid and emphasize the importance of 11β-HSD1 in foetal lung maturation.

Key words

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

References

• 1 Hundertmark S, Dill A, Bühler H, Stevens P, Loomann K, Ragosch V, Seckl J R, Lipka C. 11β-hydroxysteroid dehydrogenase type 1: a new regulator of fetal lung maturation.  Horm Met Res. 2002;  34 537-544
• 2 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. 11beta-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
• 3 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
• 4 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-L440
• 5 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
• 6 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
• 7 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
• 8 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 foetal lung.  Endocrinology. 1995;  136 2573-2578
• 9 Tye L M, Burton A F. Variation in the pattern of metabolism of corticosteroids in foetal mouse tissues.  Life Sci. 1980;  26 35-39
• 10 Abramovitz M, Carriero R, Murphy B E. Investigation of factors influencing 11 beta-hydroxysteroid dehydrogenase (EC 1.1.1.146) activity in midgestational human foetal lung monolayer and explant cultures.  J Steroid Biochem. 1984;  21 677-683
• 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
• 12 Mantovani A, Ricciardi C, Stazi A V, Macri C, Piccioni A, Badellino E, De Vincenzi M, Caiola S, Patriarca M. Teratogenicity study of ammonium glycyrrhizinate in the Sprague-Dawley rat.  Food Chem Toxicol. 1988;  26 435-440
• 13 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
• 14 Zimmermann B. Lung organoid culture.  Differentiation. 1987;  36 86-109