Repeated Intrauterine Exposures to Inflammatory Stimuli Attenuated Transforming Growth Factor-beta Signaling in the Ovine Fetal Lung

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-beta (TGF beta) is implicated in the development of BPD. Objectives: We hypothesized that different and/or multiple bacterial signals could elicit divergent TGF beta 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). TGF beta 1, TGF beta 2, TGF beta 3, TGF beta receptor (R) 1 and TGF beta R2 protein levels, Smad2 phosphorylation and elastin deposition were evaluated in lung tissue. Results: Total TGF beta 1 and TGF beta 2 decreased by 24 and 51% after combined UP+LPS exposure, whereas total TGF beta 1 increased by 31% after 7 days' LPS exposure but not after double exposures. Alveolar expression of TGF beta R2 decreased 75% after UP, but remained unaltered after double exposures. Decreased focal elastin deposition after single LPS exposure was prevented by double exposures. Conclusions: TGF beta signaling components and elastin responded differently to intrauterine LPS and UP exposure. Multiple bacterial exposures attenuated TGF beta signaling and normalized elastin deposition.