title: Repeated intrauterine exposures to inflammatory stimuli attenuated transforming growth factor-β signaling in the ovine fetal lung.
abstract: BACKGROUND
  Bronchopulmonary dysplasia (BPD) is one of the most common complications after preterm birth and is associated with intrauterine exposure to bacteria. Transforming growth factor-β (TGFβ) is implicated in the development of BPD.
  
  
  OBJECTIVE
  We hypothesized that different and/or multiple bacterial signals could elicit divergent TGFβ signaling responses in the developing lung.
  
  
  METHODS
  Time-mated pregnant Merino ewes received an intra-amniotic injection of lipopolysaccharide (LPS) and/or Ureaplasma parvum serovar 3 (UP) at 117 days' and/or 121/122 days' gestational age (GA). Controls received an equivalent injection of saline and or media. Lambs were euthanized at 124 days' GA (term = 150 days' GA). TGFβ1, TGFβ2, TGFβ3, TGFβ receptor (R)1 and TGFβR2 protein levels, Smad2 phosphorylation and elastin deposition were evaluated in lung tissue.
  
  
  RESULTS
  Total TGFβ1 and TGFβ2 decreased by 24 and 51% after combined UP+LPS exposure, whereas total TGFβ1 increased by 31% after 7 days' LPS exposure but not after double exposures. Alveolar expression of TGFβR2 decreased 75% after UP, but remained unaltered after double exposures. Decreased focal elastin deposition after single LPS exposure was prevented by double exposures.
  
  
  CONCLUSIONS
  TGFβ signaling components and elastin responded differently to intrauterine LPS and UP exposure. Multiple bacterial exposures attenuated TGFβ signaling and normalized elastin deposition.
authors.affiliation: Department of Pediatrics, School of Oncology and Developmental Biology, School of Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Jennifer J P
authors.initials: JJ
authors.lastname: Collins
authors.forename: Suhas G
authors.initials: SG
authors.lastname: Kallapur
authors.forename: Christine L
authors.initials: CL
authors.lastname: Knox
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Kemp
authors.forename: Elke
authors.initials: E
authors.lastname: Kuypers
authors.forename: Luc J I
authors.initials: LJ
authors.lastname: Zimmermann
authors.forename: John P
authors.initials: JP
authors.lastname: Newnham
authors.forename: Alan H
authors.initials: AH
authors.lastname: Jobe
authors.forename: Boris W
authors.initials: BW
authors.lastname: Kramer
mesh_terms: D000650:Amnion / Q000187:drug effects; D000818:Animals; D002821:Chorioamnionitis; D004195:Disease Models, Animal; D004549:Elastin / Q000032:analysis; D005260:Female; D005865:Gestational Age; D007249:Inflammation / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008168:Lung / Q000737:chemistry / Q000196:embryology*; D010766:Phosphorylation; D011247:Pregnancy; D011248:Pregnancy Complications / Q000503:physiopathology*; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis; D012756:Sheep / Q000196:embryology*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000032:analysis; D053781:Transforming Growth Factor beta2 / Q000032:analysis; D053782:Transforming Growth Factor beta3 / Q000032:analysis; D014509:Ureaplasma
chemical_list: D008070:Lipopolysaccharides; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; D004549:Elastin