title: Transglutaminase 2: a new player in bronchopulmonary dysplasia?
abstract: Aberrant remodelling of the extracellular matrix in the developing lung may underlie arrested alveolarisation associated with bronchopulmonary dysplasia (BPD). Transglutaminases are regulators of extracellular matrix remodelling. Therefore, the expression and activity of transglutaminases were assessed in lungs from human neonates with BPD and in a rodent model of BPD. Transglutaminase expression and localisation were assessed by RT-PCR, immunoblotting, activity assay and immunohistochemical analyses of human and mouse lung tissues. Transglutaminase regulation by transforming growth factor (TGF)-β was investigated in lung cells by luciferase-based reporter assay and RT-PCR. TGF-β signalling was neutralised in vivo in an animal model of BPD, to determine whether TGF-β mediated the hyperoxia-induced changes in transglutaminase expression. Transglutaminase 2 expression was upregulated in the lungs of preterm infants with BPD and in the lungs of hyperoxia-exposed mouse pups, where lung development was arrested. Transglutaminase 2 localised to the developing alveolar septa. TGF-β was identified as a regulator of transglutaminase 2 expression in human and mouse lung epithelial cells. In vivo neutralisation of TGF-β signalling partially restored normal lung structure and normalised lung transglutaminase 2 mRNA expression. Our data point to a role for perturbed transglutaminase 2 activity in the arrested alveolarisation associated with BPD.
authors.affiliation: Dept of Internal Medicine, University of Giessen and Marburg Lung Center, Giessen.
authors.forename: Thilo J
authors.initials: TJ
authors.lastname: Witsch
authors.affiliation: Dept of Internal Medicine, University of Giessen and Marburg Lung Center, Giessen Dept of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Gero
authors.initials: G
authors.lastname: Niess
authors.affiliation: Dept of Internal Medicine, University of Giessen and Marburg Lung Center, Giessen Dept of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Elpidoforos
authors.initials: E
authors.lastname: Sakkas
authors.affiliation: Dept of Internal Medicine, University of Giessen and Marburg Lung Center, Giessen Dept of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Likhoshvay
authors.affiliation: Dept of Internal Medicine, University of Giessen and Marburg Lung Center, Giessen Dept of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Becker
authors.affiliation: Dept of Internal Medicine, University of Giessen and Marburg Lung Center, Giessen.
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.affiliation: Dept of Internal Medicine, University of Giessen and Marburg Lung Center, Giessen.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Mayer
authors.affiliation: Dept of Internal Medicine, University of Giessen and Marburg Lung Center, Giessen.
authors.forename: István
authors.initials: I
authors.lastname: Vadász
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Roberts
authors.affiliation: Dept of Internal Medicine, University of Giessen and Marburg Lung Center, Giessen Dept of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: Dept of Internal Medicine, University of Giessen and Marburg Lung Center, Giessen Dept of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany rory.morty@mpi-bn.mpg.de.
authors.forename: Rory E
authors.initials: RE
authors.lastname: Morty
mesh_terms: D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000378:metabolism* / Q000401:mortality; D004847:Epithelial Cells / Q000166:cytology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D018496:Hyperoxia / Q000378:metabolism; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011650:Pulmonary Alveoli / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins