title: Fgf10 deficiency is causative for lethality in a mouse model of bronchopulmonary dysplasia.
abstract: Inflammation-induced FGF10 protein deficiency is associated with bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurely born infants characterized by arrested alveolar development. So far, experimental evidence for a direct role of FGF10 in lung disease is lacking. Using the hyperoxia-induced neonatal lung injury as a mouse model of BPD, the impact of Fgf10 deficiency in Fgf10+/-versus Fgf10+/+pups was investigated. In normoxia, no lethality of Fgf10+/+or Fgf10+/-pups was observed. By contrast, all Fgf10+/-pups died within 8 days of hyperoxic injury, with lethality starting at day 5, whereas Fgf10+/+pups were all alive. Lungs of pups from the two genotypes were collected on postnatal day 3 following normoxia or hyperoxia exposure for further analysis. In hyperoxia, Fgf10+/-lungs exhibited increased hypoalveolarization. Analysis by FACS of the Fgf10+/-versus control lungs in normoxia revealed a decreased ratio of alveolar epithelial type II (AECII) cells over total Epcam-positive cells. In addition, gene array analysis indicated reduced AECII and increased AECI transcriptome signatures in isolated AECII cells from Fgf10+/-lungs. Such an imbalance in differentiation is also seen in hyperoxia and is associated with reduced mature surfactant protein B and C expression. Attenuation of the activity of Fgfr2b ligands postnatally in the context of hyperoxia also led to increased lethality with decreased surfactant expression. In summary, decreased Fgf10 mRNA levels lead to congenital lung defects, which are compatible with postnatal survival, but which compromise the ability of the lungs to cope with sub-lethal hyperoxic injury. Fgf10 deficiency affects quantitatively and qualitatively the formation of AECII cells. In addition, Fgfr2b ligands are also important for repair after hyperoxia exposure in neonates. Deficient AECII cells could be an additional complication for patients with BPD. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors: Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Aulweg 130, 35392, Giessen, Germany.|University Children's Hospital Gießen, Division of General Pediatrics and Neonatology, Justus-Liebig-University, Member of the German Lung Center (DZL), Gießen, Germany.
authors: Cho-Ming
authors: CM
authors: Chao
authors: Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Aulweg 130, 35392, Giessen, Germany.
authors: Faady
authors: F
authors: Yahya
authors: Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Aulweg 130, 35392, Giessen, Germany.
authors: Alena
authors: A
authors: Moiseenko
authors: Division of Neonatology, Department of Pediatrics, Columbia University, New York, NY, USA.
authors: Caterina
authors: C
authors: Tiozzo
authors: Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Aulweg 130, 35392, Giessen, Germany.
authors: Amit
authors: A
authors: Shrestha
authors: Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Aulweg 130, 35392, Giessen, Germany.
authors: Negah
authors: N
authors: Ahmadvand
authors: Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Aulweg 130, 35392, Giessen, Germany.
authors: Elie
authors: E
authors: El Agha
authors: Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Aulweg 130, 35392, Giessen, Germany.
authors: Jennifer
authors: J
authors: Quantius
authors: Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Aulweg 130, 35392, Giessen, Germany.
authors: Salma
authors: S
authors: Dilai
authors: Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Aulweg 130, 35392, Giessen, Germany.
authors: Vahid
authors: V
authors: Kheirollahi
authors: Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Aulweg 130, 35392, Giessen, Germany.
authors: Matthew
authors: M
authors: Jones
authors: Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Aulweg 130, 35392, Giessen, Germany.
authors: Jochen
authors: J
authors: Wilhem
authors: Departments of Medicine and Biomedical Sciences, Lung and Regenerative Medicine Institutes, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
authors: Gianni
authors: G
authors: Carraro
authors: University Children's Hospital Gießen, Division of General Pediatrics and Neonatology, Justus-Liebig-University, Member of the German Lung Center (DZL), Gießen, Germany.
authors: Harald
authors: H
authors: Ehrhardt
authors: University Children's Hospital Gießen, Division of General Pediatrics and Neonatology, Justus-Liebig-University, Member of the German Lung Center (DZL), Gießen, Germany.
authors: Klaus-Peter
authors: KP
authors: Zimmer
authors: LOEWE Research Group, Lung Cancer Epigenetic, Max Planck Institute for Heart and Lung Research, Member of the German Lung Center (DZL), 61231, Bad Nauheim, Germany.
authors: Guillermo
authors: G
authors: Barreto
authors: Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Member of the German Lung Center (DZL), 61231, Bad Nauheim, Germany.
authors: Katrin
authors: K
authors: Ahlbrecht
authors: Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Member of the German Lung Center (DZL), 61231, Bad Nauheim, Germany.
authors: Rory E
authors: RE
authors: Morty
authors: Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Aulweg 130, 35392, Giessen, Germany.
authors: Susanne
authors: S
authors: Herold
authors: Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA.
authors: Rosanna G
authors: RG
authors: Abellar
authors: Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Aulweg 130, 35392, Giessen, Germany.|Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Member of the German Lung Center (DZL), 61231, Bad Nauheim, Germany.
authors: Werner
authors: W
authors: Seeger
authors: Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Aulweg 130, 35392, Giessen, Germany.
authors: Ralph
authors: R
authors: Schermuly
authors: College of Life and Environmental Sciences, Wenzhou University, Wenzhou, Zhejiang, 325027, PR China.
authors: Jin-San
authors: JS
authors: Zhang
authors: Department of Pediatrics, Division of Newborn Medicine, University of Southern California, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA.
authors: Parviz
authors: P
authors: Minoo
authors: Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Aulweg 130, 35392, Giessen, Germany.|College of Life and Environmental Sciences, Wenzhou University, Wenzhou, Zhejiang, 325027, PR China.|Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Children's Hospital Los Angeles and University of Southern California, Los Angeles, CA, 90027, USA.
authors: Saverio
authors: S
authors: Bellusci
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D051526:Fibroblast Growth Factor 10 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D018496:Hyperoxia / Q000150:complications / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011663:Pulmonary Surfactants / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism
chemical_list: C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D051497:Receptor, Fibroblast Growth Factor, Type 2
keywords: AECII; bronchopulmonary dysplasia; differentiation; fibroblast growth factor 10; surfactant