title: Deregulation of the lysyl hydroxylase matrix cross-linking system in experimental and clinical bronchopulmonary dysplasia.
abstract: Bronchopulmonary dysplasia (BPD) is a common and serious complication of premature birth, characterized by a pronounced arrest of alveolar development. The underlying pathophysiological mechanisms are poorly understood although perturbations to the maturation and remodeling of the extracellular matrix (ECM) are emerging as candidate disease pathomechanisms. In this study, the expression and regulation of three members of the lysyl hydroxylase family of ECM remodeling enzymes (Plod1, Plod2, and Plod3) in clinical BPD, as well as in an experimental animal model of BPD, were addressed. All three enzymes were localized to the septal walls in developing mouse lungs, with Plod1 also expressed in the vessel walls of the developing lung and Plod3 expressed uniquely at the base of developing septa. The expression of plod1, plod2, and plod3 was upregulated in the lungs of mouse pups exposed to 85% O2, an experimental animal model of BPD. Transforming growth factor (TGF)-β increased plod2 mRNA levels and activated the plod2 promoter in vitro in lung epithelial cells and in lung fibroblasts. Using in vivo neutralization of TGF-β signaling in the experimental animal model of BPD, TGF-β was identified as the regulator of aberrant plod2 expression. PLOD2 mRNA expression was also elevated in human neonates who died with BPD or at risk for BPD, compared with neonates matched for gestational age at birth or chronological age at death. These data point to potential roles for lysyl hydroxylases in normal lung development, as well as in perturbed late lung development associated with BPD.
authors.affiliation: Dept. of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Parkstrasse 1, D-61231 Bad Nauheim, Germany. rory.morty@mpi-bn.mpg.de.
authors.forename: Thilo J
authors.initials: TJ
authors.lastname: Witsch
authors.forename: Pawel
authors.initials: P
authors.lastname: Turowski
authors.forename: Elpidoforos
authors.initials: E
authors.lastname: Sakkas
authors.forename: Gero
authors.initials: G
authors.lastname: Niess
authors.forename: Simone
authors.initials: S
authors.lastname: Becker
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.forename: Konstantin
authors.initials: K
authors.lastname: Mayer
authors.forename: István
authors.initials: I
authors.lastname: Vadász
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Roberts
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Rory E
authors.initials: RE
authors.lastname: Morty
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D018496:Hyperoxia / Q000503:physiopathology; D007231:Infant, Newborn; D008168:Lung / Q000196:embryology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D016212:Transforming Growth Factor beta; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; C582419:lysyl hydroxylase 2, mouse
keywords: bronchopulmonary dysplasia; extracellular matrix; lung development; lysyl hydroxylase