title: Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia.
abstract: Maturation of the lung extracellular matrix (ECM) plays an important role in the formation of alveolar gas exchange units. A key step in ECM maturation is cross-linking of collagen and elastin, which imparts stability and functionality to the ECM. During aberrant late lung development in bronchopulmonary dysplasia (BPD) patients and animal models of BPD, alveolarization is blocked, and the function of ECM cross-linking enzymes is deregulated, suggesting that perturbed ECM cross-linking may impact alveolarization. In a hyperoxia (85% O2)-based mouse model of BPD, blunted alveolarization was accompanied by alterations to lung collagen and elastin levels and cross-linking. Total collagen levels were increased (by 63%). The abundance of dihydroxylysinonorleucine collagen cross-links and the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio were increased by 11 and 18%, respectively, suggestive of a profibrotic state. In contrast, insoluble elastin levels and the abundance of the elastin cross-links desmosine and isodesmosine in insoluble elastin were decreased by 35, 30, and 21%, respectively. The lung collagen-to-elastin ratio was threefold increased. Treatment of hyperoxia-exposed newborn mice with the lysyl oxidase inhibitor β-aminopropionitrile partially restored normal collagen levels, normalized the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio, partially normalized desmosine and isodesmosine cross-links in insoluble elastin, and partially restored elastin foci structure in the developing septa. However, β-aminopropionitrile administration concomitant with hyperoxia exposure did not improve alveolarization, evident from unchanged alveolar surface area and alveoli number, and worsened septal thickening (increased by 12%). These data demonstrate that collagen and elastin cross-linking are perturbed during the arrested alveolarization of developing mouse lungs exposed to hyperoxia.
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;
authors.forename: Ivana
authors.initials: I
authors.lastname: Mižíková
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;
authors.forename: Jordi
authors.initials: J
authors.lastname: Ruiz-Camp
authors.affiliation: Institute of Virology and Cell Biology, University of Lübeck, Lübeck, Germany; and.
authors.forename: Heiko
authors.initials: H
authors.lastname: Steenbock
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany;
authors.forename: Alicia
authors.initials: A
authors.lastname: Madurga
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany;
authors.forename: István
authors.initials: I
authors.lastname: Vadász
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany;
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany;
authors.forename: Konstantin
authors.initials: K
authors.lastname: Mayer
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany;
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: Institute of Virology and Cell Biology, University of Lübeck, Lübeck, Germany; and Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brinckmann
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany; rory.morty@mpi-bn.mpg.de.
authors.forename: Rory E
authors.initials: RE
authors.lastname: Morty
mesh_terms: D000629:Aminopropionitrile / Q000494:pharmacology; D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism*; D004549:Elastin / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D018496:Hyperoxia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D008168:Lung / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011499:Protein Processing, Post-Translational; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000629:Aminopropionitrile; D003094:Collagen; D004549:Elastin; D008249:Protein-Lysine 6-Oxidase
keywords: alveolarization; collagen; elastin; lung development; lysyl oxidase