title: Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development.
abstract: The highly orchestrated interactions between the epithelium and mesenchyme required for normal lung development can be disrupted by perinatal inflammation in preterm infants, although the mechanisms are incompletely understood. We used transgenic (inhibitory κB kinase β transactivated) mice that conditionally express an activator of the NF-κB pathway in airway epithelium to investigate the impact of epithelial-derived inflammation during lung development. Epithelial NF-κB activation selectively impaired saccular stage lung development, with a phenotype comprising rapidly progressive distal airspace dilation, impaired gas exchange, and perinatal lethality. Epithelial-derived inflammation resulted in disrupted elastic fiber organization and down-regulation of elastin assembly components, including fibulins 4 and 5, lysyl oxidase like-1, and fibrillin-1. Fibulin-5 expression by saccular stage lung fibroblasts was consistently inhibited by treatment with bronchoalveolar lavage fluid from inhibitory κB kinase β transactivated mice, Escherichia coli lipopolysaccharide, or tracheal aspirates from preterm infants exposed to chorioamnionitis. Expression of a dominant NF-κB inhibitor in fibroblasts restored fibulin-5 expression after lipopolysaccharide treatment, whereas reconstitution of fibulin-5 rescued extracellular elastin assembly by saccular stage lung fibroblasts. Elastin organization was disrupted in saccular stage lungs of preterm infants exposed to systemic inflammation. Our study reveals a critical window for elastin assembly during the saccular stage that is disrupted by inflammatory signaling and could be amenable to interventions that restore elastic fiber assembly in the developing lung.
authors.affiliation: Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: john.benjamin@vanderbilt.edu.
authors.forename: John T
authors.initials: JT
authors.lastname: Benjamin
authors.affiliation: Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Riet
authors.initials: R
authors.lastname: van der Meer
authors.affiliation: Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Im
authors.affiliation: Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Plosa
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Rinat
authors.initials: R
authors.lastname: Zaynagetdinov
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Ankita
authors.initials: A
authors.lastname: Burman
authors.affiliation: Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Madeline E
authors.initials: ME
authors.lastname: Havrilla
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Gleaves
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Vasiliy V
authors.initials: VV
authors.lastname: Polosukhin
authors.affiliation: Department of Pathology, Seattle Children's Hospital, Seattle, Washington.
authors.forename: Gail H
authors.initials: GH
authors.lastname: Deutsch
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yanagisawa
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Davidson
authors.affiliation: Department of Pediatrics, Division of Neonatology, University of California-San Diego, San Diego, California.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Prince
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pediatrics, Division of Pulmonary Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Young
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee; Nashville Veterans Affairs Medical Center, Nashville, Tennessee.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004549:Elastin / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism*; D047109:Fetal Development; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D007234:Infant, Premature; D007249:Inflammation / Q000150:complications* / Q000378:metabolism; D008168:Lung / Q000196:embryology*; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D023421:Models, Animal; D016328:NF-kappa B / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016328:NF-kappa B; D004549:Elastin