Dynamic Regulation of GH–IGF1 Signaling in Injury and Recovery in Hyperoxia-Induced Neonatal Lung Injury

Prematurely born infants often require supplemental oxygen that impairs lung growth and results in arrest of alveolarization and bronchopulmonary dysplasia (BPD). The growth hormone (GH)- and insulin-like growth factor (IGF)1 systems regulate cell homeostasis and organ development. Since IGF1 is dec...

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Autores principales:	Christina Vohlen, Jasmine Mohr, Alexey Fomenko, Celien Kuiper-Makris, Tiffany Grzembke, Rabia Aydogmus, Rebecca Wilke, Dharmesh Hirani, Jörg Dötsch, Miguel A. Alejandre Alcazar
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	neonatal hyperoxia and bronchopulmonary dysplasia growth hormone and IGF1 lung injury and regeneration alveolar epithelial type II cell neonatal lung fibroblast Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/39bb3e8cd3114a7ab345772480ea95e9
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spelling	oai:doaj.org-article:39bb3e8cd3114a7ab345772480ea95e92021-11-25T17:09:36ZDynamic Regulation of GH–IGF1 Signaling in Injury and Recovery in Hyperoxia-Induced Neonatal Lung Injury10.3390/cells101129472073-4409https://doaj.org/article/39bb3e8cd3114a7ab345772480ea95e92021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2947https://doaj.org/toc/2073-4409Prematurely born infants often require supplemental oxygen that impairs lung growth and results in arrest of alveolarization and bronchopulmonary dysplasia (BPD). The growth hormone (GH)- and insulin-like growth factor (IGF)1 systems regulate cell homeostasis and organ development. Since IGF1 is decreased in preterm infants, we investigated the GH- and IGF1 signaling (1) in newborn mice with acute and prolonged exposure to hyperoxia as well as after recovery in room air; and (2) in cultured murine lung epithelial cells (MLE-12) and primary neonatal lung fibroblasts (pLFs) after treatment with GH, IGF1, and IGF1-receptor (IGF1-R) inhibitor or silencing of GH-receptor (<i>Ghr</i>) and <i>Igf1r</i> using the siRNA technique. We found that (1) early postnatal hyperoxia caused an arrest of alveolarization that persisted until adulthood. Both short-term and prolonged hyperoxia reduced GH-receptor expression and STAT5 signaling, whereas <i>Igf1</i> mRNA and pAKT signaling were increased. These findings were related to a loss of epithelial cell markers (SFTPC, AQP5) and proliferation of myofibroblasts (αSMA<sup>+</sup> cells). After recovery, GH-R-expression and STAT5 signaling were activated, <i>Igf1r</i> mRNA reduced, and SFTPC protein significantly increased. Cell culture studies showed that IGF1 induced expression of mesenchymal (e.g., <i>Col1a1</i>, <i>Col4a4</i>) and alveolar epithelial cell type I (<i>Hopx</i>, <i>Igfbp2</i>) markers, whereas inhibition of IGF1 increased SFTPC and reduced AQP5 in MLE-12. GH increased <i>Il6</i> mRNA and reduced proliferation of pLFs, whereas IGF1 exhibited the opposite effect. In summary, our data demonstrate an opposite regulation of GH- and IGF1- signaling during short-term/prolonged hyperoxia-induced lung injury and recovery, affecting alveolar epithelial cell differentiation, inflammatory activation of fibroblasts, and a possible uncoupling of the GH-IGF1 axis in lungs after hyperoxia.Christina VohlenJasmine MohrAlexey FomenkoCelien Kuiper-MakrisTiffany GrzembkeRabia AydogmusRebecca WilkeDharmesh HiraniJörg DötschMiguel A. Alejandre AlcazarMDPI AGarticleneonatal hyperoxia and bronchopulmonary dysplasiagrowth hormone and IGF1lung injury and regenerationalveolar epithelial type II cellneonatal lung fibroblastBiology (General)QH301-705.5ENCells, Vol 10, Iss 2947, p 2947 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	neonatal hyperoxia and bronchopulmonary dysplasia growth hormone and IGF1 lung injury and regeneration alveolar epithelial type II cell neonatal lung fibroblast Biology (General) QH301-705.5
spellingShingle	neonatal hyperoxia and bronchopulmonary dysplasia growth hormone and IGF1 lung injury and regeneration alveolar epithelial type II cell neonatal lung fibroblast Biology (General) QH301-705.5 Christina Vohlen Jasmine Mohr Alexey Fomenko Celien Kuiper-Makris Tiffany Grzembke Rabia Aydogmus Rebecca Wilke Dharmesh Hirani Jörg Dötsch Miguel A. Alejandre Alcazar Dynamic Regulation of GH–IGF1 Signaling in Injury and Recovery in Hyperoxia-Induced Neonatal Lung Injury
description	Prematurely born infants often require supplemental oxygen that impairs lung growth and results in arrest of alveolarization and bronchopulmonary dysplasia (BPD). The growth hormone (GH)- and insulin-like growth factor (IGF)1 systems regulate cell homeostasis and organ development. Since IGF1 is decreased in preterm infants, we investigated the GH- and IGF1 signaling (1) in newborn mice with acute and prolonged exposure to hyperoxia as well as after recovery in room air; and (2) in cultured murine lung epithelial cells (MLE-12) and primary neonatal lung fibroblasts (pLFs) after treatment with GH, IGF1, and IGF1-receptor (IGF1-R) inhibitor or silencing of GH-receptor (<i>Ghr</i>) and <i>Igf1r</i> using the siRNA technique. We found that (1) early postnatal hyperoxia caused an arrest of alveolarization that persisted until adulthood. Both short-term and prolonged hyperoxia reduced GH-receptor expression and STAT5 signaling, whereas <i>Igf1</i> mRNA and pAKT signaling were increased. These findings were related to a loss of epithelial cell markers (SFTPC, AQP5) and proliferation of myofibroblasts (αSMA<sup>+</sup> cells). After recovery, GH-R-expression and STAT5 signaling were activated, <i>Igf1r</i> mRNA reduced, and SFTPC protein significantly increased. Cell culture studies showed that IGF1 induced expression of mesenchymal (e.g., <i>Col1a1</i>, <i>Col4a4</i>) and alveolar epithelial cell type I (<i>Hopx</i>, <i>Igfbp2</i>) markers, whereas inhibition of IGF1 increased SFTPC and reduced AQP5 in MLE-12. GH increased <i>Il6</i> mRNA and reduced proliferation of pLFs, whereas IGF1 exhibited the opposite effect. In summary, our data demonstrate an opposite regulation of GH- and IGF1- signaling during short-term/prolonged hyperoxia-induced lung injury and recovery, affecting alveolar epithelial cell differentiation, inflammatory activation of fibroblasts, and a possible uncoupling of the GH-IGF1 axis in lungs after hyperoxia.
format	article
author	Christina Vohlen Jasmine Mohr Alexey Fomenko Celien Kuiper-Makris Tiffany Grzembke Rabia Aydogmus Rebecca Wilke Dharmesh Hirani Jörg Dötsch Miguel A. Alejandre Alcazar
author_facet	Christina Vohlen Jasmine Mohr Alexey Fomenko Celien Kuiper-Makris Tiffany Grzembke Rabia Aydogmus Rebecca Wilke Dharmesh Hirani Jörg Dötsch Miguel A. Alejandre Alcazar
author_sort	Christina Vohlen
title	Dynamic Regulation of GH–IGF1 Signaling in Injury and Recovery in Hyperoxia-Induced Neonatal Lung Injury
title_short	Dynamic Regulation of GH–IGF1 Signaling in Injury and Recovery in Hyperoxia-Induced Neonatal Lung Injury
title_full	Dynamic Regulation of GH–IGF1 Signaling in Injury and Recovery in Hyperoxia-Induced Neonatal Lung Injury
title_fullStr	Dynamic Regulation of GH–IGF1 Signaling in Injury and Recovery in Hyperoxia-Induced Neonatal Lung Injury
title_full_unstemmed	Dynamic Regulation of GH–IGF1 Signaling in Injury and Recovery in Hyperoxia-Induced Neonatal Lung Injury
title_sort	dynamic regulation of gh–igf1 signaling in injury and recovery in hyperoxia-induced neonatal lung injury
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/39bb3e8cd3114a7ab345772480ea95e9
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Dynamic Regulation of GH–IGF1 Signaling in Injury and Recovery in Hyperoxia-Induced Neonatal Lung Injury

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