ErbB receptors in fetal lung development
Final Report Abstract
Prenatal glucocorticoids and postnatal surfactant replacement therapy have decreased mortality from respiratory distress syndrome (RDS), but these therapies have not affected the incidence of bronchopulmonary dyslasia (BPD), the long-term pulmonary sequelae. BPD results in an alveolar and vascular dysfunction. An understanding of the mechanisms of normal lung development and how these are altered in the dysfunctional lung development of BPD would help to prevent BPD. Neuregulin1 (NRG1) and its receptor ErbB4 play a major role in the develpoing lung. While ErbB4 seems to play a prominent role in normal fetal lung development, inflammation and glucocorticoids, two aspects of lung injury in the setting of preterm birth, seem to shift ErbB receptor orchestration towards a prominent involvement of ErbB2. Both are known stimulators of fetal surfactant synthesis, but there is growing evidence that both have inhibitory effects on alveolar development, a major pathogenetic characteristic of BPD. Our data showed that a similar alveolar simplification occurs with pulmonary ErbB4 deletion, suggesting this as being involved in inflammation induced disturbance of alveolarisation. Also, ErbB4 regulates Sftpb and Sftpd expression and nuclear transport of ErbB4 is critical for it. Our overall hypothesis was that ErbB4 and ErbB2 signaling is involved not only in regulating fetal lung development, but also in fetal lung injury leading to the clinical pictures of RDS and the long term disability, BPD.
Publications
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ErbB4 deletion leads to changes in lung function and structure similar to bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2008 Mar;294(3):L516-22
Purevdorj E, Zscheppang K, Hoymann HG, Braun A, von Mayersbach D, Brinkhaus M, Schmiedl A, Dammann CEL
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Fetal ErbB4 deletion delays functional and structural lung development. BBA 2010 Jul;1803(7):832- 9
Liu W, Purevdorj E, Zscheppang E, von Mayersbach D, Brinkhaus M-J, Schmiedl A, Dammann CEL
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Neuregulin-1, the fetal endothelium, and brain damage in preterm newborns. Brain Behavior, and Immunity 2010; 24(5) 784-91
Hoffmann I, Bueter W, Zscheppang K, Brinkhaus M, Liese A, Riemke R, Dörk T, Dammann O, and Dammann CEL
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Estrogen-induced upregulation of Sftpb requires transcriptional control of neuregulin receptor ErbB4 in mouse lung type II epithelial cells. Biochim Biophys Acta. 2011 Oct;1813(10):1717-27
Zscheppang K, Konrad M, Zischka M, Huhn V, Dammann CE
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Lipopolysaccharide-induced injury is more pronounced in fetal transgenic ErbB4-deleted lungs. Am J Physiol Lung Cell Mol Physiol. 2011 Oct;301(4):L490-9
Schmiedl A, Behrens J, Zscheppang K, Purevdorj E, von Mayersbach D, Liese A, Dammann CE
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Neuregulin receptor ErbB4 functions as a transcriptional cofactor for the expression of surfactant protein B in the fetal lung. Am J Respir Cell Mol Biol. 2011 Oct;45(4):761-7
Zscheppang K, Dörk T, Schmiedl A, Jones A, Dammann CEL
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Presenilin-1 processing of ErbB4 in fetal type II cells is necessary for control of fetal lung maturation. Biochim Biophys Acta. 2011 Mar;1813(3):480-91
Hoeing K, Zscheppang K, Mujahid S, Murray S, Volpe MV, Dammann CE, Nielsen HC
