Regulation of postnatal lung development and homeostasis by estrogen receptor beta.
Estrogens have well-documented effects on lung development and physiology. However, the classical estrogen receptor alpha (ERalpha) 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 ERbeta is abundantly expressed and biologically active in the lung. Comparisons of lungs from wild-type mice and mice with an inactivated ERbeta gene (ERbeta(-/-)) revealed decreased numbers of alveoli in adult female ERbeta(-/-) 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 ERbeta(-/-) mice, and direct transcriptional regulation of these genes by ERbeta was demonstrated. This suggests that estrogens act via ERbeta 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 ERbeta as a previously unknown regulator of postnatal lung development and homeostasis.
Patrone
Cesare
C
Department of Medical Nutrition, Karolinska Institute, NOVUM, Huddinge University Hospital, SE14186 Huddinge, Sweden.
Cassel
Tobias N
TN
Pettersson
Katarina
K
Piao
Yun-Shang
YS
Cheng
Guojun
G
Ciana
Paolo
P
Maggi
Adriana
A
Warner
Margaret
M
Gustafsson
Jan-Ake
JA
Nord
Magnus
M
D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D047629:Estrogen Receptor beta; D005260:Female; D018507:Gene Expression Regulation, Developmental; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D066298:In Vitro Techniques; D008168:Lung / Q000002:abnormalities / Q000254:growth & development* / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000378:metabolism; D011960:Receptors, Estrogen / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic
D047629:Estrogen Receptor beta; D010982:Platelet-Derived Growth Factor; D011663:Pulmonary Surfactants; D011960:Receptors, Estrogen; C075278:platelet-derived growth factor A; D004958:Estradiol; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004247:DNA