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Vol. 104, No. 1, 2013
Issue release date: July 2013
Neonatology 2013;104:49-55

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

Collins J.J.P. · Kallapur S.G. · Knox C.L. · Kemp M.W. · Kuypers E. · Zimmermann L.J.I. · Newnham J.P. · Jobe A.H. · Kramer B.W.
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

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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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  1. Jobe AH, Bancalari E: Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-1729.
  2. Speer CP: Inflammation and bronchopulmonary dysplasia. Semin Neonatol 2003;8:29-38.
  3. DiGiulio DB, Romero R, Kusanovic JP, Gomez R, Kim CJ, Seok KS, Gotsch F, Mazaki-Tovi S, Vaisbuch E, Sanders K, Bik EM, Chaiworapongsa T, Oyarzun E, Relman DA: Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes. Am J Reprod Immunol 2010;64:38-57.
  4. Yoon BH, Romero R, Park JS, Chang JW, Kim YA, Kim JC, Kim KS: Microbial invasion of the amniotic cavity with Ureaplasma urealyticum is associated with a robust host response in fetal, amniotic, and maternal compartments. Am J Obstet Gynecol 1998;179:1254-1260.
  5. Onderdonk AB, Delaney ML, DuBois AM, Allred EN, Leviton A: Detection of bacteria in placental tissues obtained from extremely low gestational age neonates. Am J Obstet Gynecol 2008;198:110.e1-e7.
  6. Collins JJ, Kallapur SG, Knox CL, Nitsos I, Polglase GR, Pillow JJ, Kuypers E, Newnham JP, Jobe AH, Kramer BW: Inflammation in fetal sheep from intra-amniotic injection of Ureaplasma parvum. Am J Physiol Lung Cell Mol Physiol 2010;299:L852-L860.
  7. Novy MJ, Duffy L, Axthelm MK, Sadowsky DW, Witkin SS, Gravett MG, Cassell GH, Waites KB: Ureaplasma parvum or Mycoplasma hominis as sole pathogens cause chorioamnionitis, preterm delivery, and fetal pneumonia in rhesus macaques. Reprod Sci 2009;16:56-70.
  8. Viscardi RM, Atamas SP, Luzina IG, Hasday JD, He JR, Sime PJ, Coalson JJ, Yoder BA: Antenatal Ureaplasma urealyticum respiratory tract infection stimulates proinflammatory, profibrotic responses in the preterm baboon lung. Pediatr Res 2006;60:141-146.
  9. Kramer BW, Moss TJ, Willet KE, Newnham JP, Sly PD, Kallapur SG, Ikegami M, Jobe AH: Dose and time response after intra-amniotic endotoxin in preterm lambs. Am J Respir Crit Care Med 2001;164:982-988.
  10. Kramer BW, Kallapur SG, Moss TJ, Nitsos I, Newnham JP, Jobe AH: Intra-amniotic LPS modulation of TLR signaling in lung and blood monocytes of fetal sheep. Innate Immun 2009;15:101-107.
  11. Kallapur SG, Kramer BW, Knox CL, Berry CA, Collins JJ, Kemp MW, Nitsos I, Polglase GR, Robinson J, Hillman NH, Newnham JP, Chougnet C, Jobe AH: Chronic fetal exposure to Ureaplasma parvum suppresses innate immune responses in sheep. J Immunol 2011;187:2688-2695.
  12. Elgert KD: Immunology: Understanding the Immune System, ed 2. Hoboken/NJ, Wiley-Blackwell, 2009.
  13. Shimizu T, Kida Y, Kuwano K: Ureaplasma parvum lipoproteins, including MB antigen, activate NF-κB through TLR1, TLR2 and TLR6. Microbiology 2008;154:1318-1325.
  14. Bartram U, Speer CP: The role of transforming growth factor-β in lung development and disease. Chest 2004;125:754-765.
  15. Kallapur SG, Jobe AH, Ball MK, Nitsos I, Moss TJ, Hillman NH, Newnham JP, Kramer BW: Pulmonary and systemic endotoxin tolerance in preterm fetal sheep exposed to chorioamnionitis. J Immunol 2007;179:8491-8499.

    External Resources

  16. Burri PH: Structural aspects of postnatal lung development - alveolar formation and growth. Biol Neonate 2006;89:313-322.
  17. Lee AJ, Lambermont VA, Pillow JJ, Polglase GR, Nitsos I, Newnham JP, Beilharz MW, Kallapur SG, Jobe AH, Kramer BW: Fetal responses to lipopolysaccharide-induced chorioamnionitis alter immune and airway responses in 7-week-old sheep. Am J Obstet Gynecol 2011;204:364 e317-e324.
  18. Hartling L, Liang Y, Lacaze-Masmonteil T: Chorioamnionitis as a risk factor for bronchopulmonary dysplasia: A systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2012;97:F8-F17.
  19. Masterson JC, Molloy EL, Gilbert JL, McCormack N, Adams A, O'Dea S: Bone morphogenetic protein signalling in airway epithelial cells during regeneration. Cell Signal 2011;23:398-406.
  20. Been JV, Debeer A, van Iwaarden JF, Kloosterboer N, Passos VL, Naulaers G, Zimmermann LJ: Early alterations of growth factor patterns in bronchoalveolar lavage fluid from preterm infants developing bronchopulmonary dysplasia. Pediatr Res 2010;67:83-89.
  21. Ichiba H, Saito M, Yamano T: Amniotic fluid transforming growth factor-β1 and the risk for the development of neonatal bronchopulmonary dysplasia. Neonatology 2009;96:156-161.
  22. Lahra MM, Beeby PJ, Jeffery HE: Intrauterine inflammation, neonatal sepsis, and chronic lung disease: a 13-year hospital cohort study. Pediatrics 2009;123:1314-1319.
  23. Kramer BW, Joshi SN, Moss TJ, Newnham JP, Sindelar R, Jobe AH, Kallapur SG: Endotoxin-induced maturation of monocytes in preterm fetal sheep lung. Am J Physiol Lung Cell Mol Physiol 2007;293:L345-L353.
  24. Azizia M, Lloyd J, Allen M, Klein N, Peebles D: Immune status in very preterm neonates. Pediatrics 2012;129:e967-e974.
  25. Van Marter LJ, Dammann O, Allred EN, Leviton A, Pagano M, Moore M, Martin C: Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants. J Pediatr 2002;140:171-176.

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