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Repeated Intrauterine Exposures to Inflammatory Stimuli Attenuated Transforming Growth Factor-β Signaling in the Ovine Fetal LungCollins J.J.P.a · Kallapur S.G.b, c · Knox C.L.d · Kemp M.W.c · Kuypers E.a · Zimmermann L.J.I.a · Newnham J.P.c · Jobe A.H.b, c · Kramer B.W.a
aDepartment of Pediatrics, School of Oncology and Developmental Biology, School of Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands; bCincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA; cSchool of Women's and Infant's Health, The University of Western Australia, Perth, W.A., and dInstitute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology, Brisbane, Qld., Australia
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. Objectives: 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.
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