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Molecular and Cellular Biology, December 2003, p. 8542-8552, Vol. 23, No. 23
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.23.8542-8552.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Regulation of Postnatal Lung Development and Homeostasis by Estrogen Receptor ß

Cesare Patrone,1 Tobias N. Cassel,1 Katarina Pettersson,1 Yun-Shang Piao,1 Guojun Cheng,1 Paolo Ciana,2 Adriana Maggi,2 Margaret Warner,1 Jan-Åke Gustafsson,1 and Magnus Nord1*

Department of Medical Nutrition, Karolinska Institute, NOVUM, Huddinge University Hospital, SE14186 Huddinge, Sweden,1 Center MPL, Department of Pharmacological Sciences, University of Milan, 20129 Milan, Italy2

Received 28 February 2003/ Returned for modification 28 May 2003/ Accepted 3 September 2003

Estrogens have well-documented effects on lung development and physiology. However, the classical estrogen receptor {alpha} (ER{alpha}) is undetectable in the lung, and this has left many unanswered questions about the mechanism of estrogen action in this organ. Here we show, both in vivo and in vitro, that ERß is abundantly expressed and biologically active in the lung. Comparisons of lungs from wild-type mice and mice with an inactivated ERß gene (ERß-/-) revealed decreased numbers of alveoli in adult female ERß-/- mice and findings suggesting deficient alveolar formation as well as evidence of surfactant accumulation. Platelet-derived growth factor A (PDGF-A) and granulocyte-macrophage colony-stimulating factor (GM-CSF), key regulators of alveolar formation and surfactant homeostasis, respectively, were decreased in lungs of adult female ERß-/- mice, and direct transcriptional regulation of these genes by ERß was demonstrated. This suggests that estrogens act via ERß in the lung to modify PDGF-A and GM-CSF expression. These results provide a potential molecular mechanism for the gender differences in alveolar structure observed in the adult lung and establish ERß as a previously unknown regulator of postnatal lung development and homeostasis.

* Corresponding author. Mailing address: Department of Medical Nutrition, Karolinska Institute, NOVUM, Huddinge University Hospital, SE-141 86 Huddinge, Sweden. Phone: 46-8-5858 37 25. Fax: 46-8-711 66 59. E-mail: magnus.nord{at}mednut.ki.se.

Molecular and Cellular Biology, December 2003, p. 8542-8552, Vol. 23, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.23.8542-8552.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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