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Potential Role of Prenatal Inflammation in the Impairment of Lung Development Following Mechanical Ventilation of Preterm Lambs

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Abstract

Background

Our objective was to determine the effects of severe fetal inflammation, associated with an increase in the number and activation state of fetal polymorphonuclear leukocytes (PMNLs), on postnatal lung development in mechanically ventilated preterm lambs.

Methods

Four groups of preterm fetal sheep (0.85 term) were surgically prepared: (1) a granulocyte-colony stimulating factor (GCSF) group received intravenous GCSF to increase fetal PMNL count, (2) a lipopolysaccharide (LPS) group received intra-amniotic LPS to activate the fetal PMNLs, (3) a GCSF + LPS group received both GCSF and LPS, and (4) a control group received saline. After 10-day mechanical ventilation following preterm delivery, the lungs were examined histologically and analyzed morphometrically.

Results

Compared to the control group, the GCSF + LPS group exhibited necrotizing funisitis, lower surface density of alveolar walls, lower numerical density of alveoli, greater alveolar radius, and lower volume density of secondary septal crests (all P <.05). There was no evidence of tissue destruction, or elastin fragmentation or thick deposits of elastin, in the alveolar walls in any of the 4 groups.

Conclusion

The mechanical ventilation following severe prenatal inflammation did not lead to overt lung injury or degradation of elastin but resulted in arrested alveolarization in the lungs of preterm lambs.

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References

  1. Fanaroff AA, Stoll BJ, Wright LL, et al.; NICHD Neonatal Research Network. Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol. 2007;196(2):147e 1-147e8.

    Article  Google Scholar 

  2. Kusuda S, Fujimura M, Uchiyama A, Totsu S, Matsunami K,; Neonatal Research Network, Japan. Trends in morbidity and mortality among very-low-birth-weight infants from 2003 to 2008 in Japan. Pediatr Res. 2012;72(5):531–538.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Stoll BJ, Hansen NI, Bell EF, et al.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. 2010;126(3):443–456.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Latini G, De Felice C, Giannuzzi R, Del Vecchio A. Survival rate and prevalence of bronchopulmonary dysplasia in extremely low birth weight infants. Early Hum Dev. 2013;89(suppl 1):S69–S73.

    Article  PubMed  Google Scholar 

  5. Eriksson L, Haglund B, Ewald U, Odlind V, Kieler H. Short and long-term effects of antenatal corticosteroids assessed in a cohort of 7,827 children born preterm. Acta Obstet Gynecol Scand. 2009;88(8):933–938.

    Article  CAS  PubMed  Google Scholar 

  6. Ahn HM, Park EA, Cho SJ, Kim YJ, Park HS. The association of histological chorioamnionitis and antenatal steroids on neonatal outcome in preterm infants born at less than thirty-four weeks’ gestation. Neonatology. 2012;102(4):259–264.

    Article  CAS  PubMed  Google Scholar 

  7. Stevens TP, Harrington EW, Blennow W, Soll RF. Early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants with or at risk for respiratory distress syndrome. Cochrane Database Syst Rev. 2007;(4):CD003063. doi:10.1002/14651858.

    Google Scholar 

  8. Cools F, Henderson-Smart DJ, Offringa M, Askie LM. Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants. Cochrane Database Syst Rev. 2010;(3):CD000104. doi:10.1002/14651858.

    Google Scholar 

  9. Yoder BA, Harrison M, Clark RH. Time-related changes in steroid use and bronchopulmonary dysplasia in preterm infants. Pediatrics. 2009;124(2):673–679.

    Article  PubMed  Google Scholar 

  10. Vom Hove M, Prenzel F, Uhlig HH, Robel-Tillig E. Pulmonary outcome in former preterm, very low birth weight children with bronchopulmonary dysplasia: a case-control follow-up at school age. J Pediatr. 2014;164(1):40–45.

    Article  PubMed  Google Scholar 

  11. Vollsæter M, Røksund OD, Eide GE, Markestad T, Halvorsen T. Lung function after preterm birth: development from mid-childhood to adulthood. Thorax. 2013;68(8):767–776.

    Article  PubMed  Google Scholar 

  12. Doyle LW, Faber B, Callanan C, Freezer N, Ford GW, Davis NM. Bronchopulmonary dysplasia in very low birth weight subjects and lung function in late adolescence. Pediatrics. 2006;118(1):108–113.

    Article  PubMed  Google Scholar 

  13. Jensen EA, Schmidt B. Epidemiology of bronchopulmonary dysplasia. Birth Defects Res A Clin Mol Teratol. 2014;100(3):145–157.

    Article  CAS  PubMed  Google Scholar 

  14. Soraisham AS, Singhal N, McMillan DD, Sauve RS, Lee SK; Canadian Neonatal Network. A multicenter study on the clinical outcome of chorioamnionitis in preterm infants. Am J Obstet Gynecol. 2009;200(4):372 e1-e6.

    Article  PubMed  Google Scholar 

  15. Kramer BW, Ladenburger A, Kunzmann S, et al. Intravenous lipopolysaccharide-induced pulmonary maturation and structural changes in fetal sheep. Am J Obstet Gynecol. 2009;200(2):195. e1-e10.

    Article  PubMed  Google Scholar 

  16. Moss TJ, Nitsos I, Kramer BW, Ikegami M, Newnham JP, Jobe AH. Intra-amniotic endotoxin induces lung maturation by direct effects on the developing respiratory tract in preterm sheep. Am J Obstet Gynecol. 2002;187(4):1059–1065.

    Article  CAS  PubMed  Google Scholar 

  17. Jobe AH. Effects of chorioamnionitis on the fetal lung. Clin Perinatol. 2012;39(3):441–457.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lahra MM, Beeby PJ, Jeffery HE. Maternal versus fetal inflammation and respiratory distress syndrome: a 10-year hospital cohort study. Arch Dis Child Fetal Neonatal Ed. 2009;94(1):F13–F16.

    Article  CAS  PubMed  Google Scholar 

  19. Matsuda T, Nakajima T, Hattori S, et al. Necrotizing funisitis: clinical significance and association with chronic lung disease in premature infants. Am J Obstet Gynecol. 1997;177(6):1402–1407.

    Article  CAS  PubMed  Google Scholar 

  20. Park CW, Yoon BH, Park JS, Jun JK. A fetal and an intra-amniotic inflammatory response is more severe in preterm labor than in preterm PROM in the context of funisitis: unexpected observation in human gestations. PLoS One. 2013;8(5):e62521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Watanabe T, Matsuda T, Hanita T, et al. Induction of necrotizing funisitis by fetal administration of intravenous granulocyte-colony stimulating factor and intra-amniotic endotoxin in premature fetal sheep. Pediatr Res. 2007;62(6):670–673.

    Article  CAS  PubMed  Google Scholar 

  22. Lauweryns JM. “Hyaline membrane disease” in newborn infants. Macroscopic, radiographic, and light and electron microscopic studies. Hum Pathol. 1970;1(2):175–204.

    Article  CAS  PubMed  Google Scholar 

  23. Askin FB. Pulmonary interstitial air and pneumothorax in the neonate. In: Stocker JT, ed. Pediatric Pulmonary Disease. New York, NY: Hemisphere; 1989:165–174.

  24. Northway WH, Jr Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med. 1967;276(7):357–368.

    Article  PubMed  Google Scholar 

  25. Thurlbeck WM. Morphologic aspects of bronchopulmonary dysplasia. J Pediatr. 1979;95(5 pt 2):842–843.

    Article  CAS  PubMed  Google Scholar 

  26. Jobe AJ. The new BPD: an arrest of lung development. Pediatr Res. 1999;46(6):641–643.

    Article  CAS  PubMed  Google Scholar 

  27. Pierce RA, Albertine KH, Starcher BC, Bohnsack JF, Carlton DP, Bland RD. Chronic lung injury in preterm lambs: disordered pulmonary elastin deposition. Am J Physiol. 1997;272(3 pt 1):L452–L460.

    CAS  PubMed  Google Scholar 

  28. Okajima S, Matsuda T, Cho K, Matsumoto Y, Kobayashi Y, Fujimoto S. Antenatal dexamethasone administration impairs normal postnatal lung growth in rats. Pediatr Res. 2001;49(6):777–781.

    Article  CAS  PubMed  Google Scholar 

  29. Weibel ER, Gomez DM. A principle for counting tissue structures on random sections. J Appl Physiol. 1962;17:343–348.

    Article  CAS  PubMed  Google Scholar 

  30. Benirschke K, Kaufmann P. Infectious diseases. In: Elston CW, Fox H, eds. Pathology of the Human Placenta. 3rd ed. New York, NY: Springer-Verlag; 1995:537–623.

  31. Janoff A, White R, Carp H, Harel S, Dearing R, Lee D. Lung injury induced by leukocytic proteases. Am J Pathol. 1979;97(1):111–136.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Fujimura M, Kitajima H, Nakayama M. Increased leukocyte elastase of the tracheal aspirate at birth and neonatal pulmonary emphysema. Pediatrics. 1993;92(4):564–569.

    CAS  PubMed  Google Scholar 

  33. Galinsky R, Moss TJ, Polglase GR, Hooper SB. Intrauterine inflammation alters cardiopulmonary but not cerebral hemodynamics during open endotracheal tube suction in preterm lambs. Pediatr Res. 2013;74(1):48–53.

    Article  CAS  PubMed  Google Scholar 

  34. Hodgman J. Relationship between Wilson-Mikity syndrome and the new bronchopulmonary dysplasia. Pediatrics. 2003;112(6 pt 1):1414–1415.

    Article  PubMed  Google Scholar 

  35. Kallapur SG, Jobe AH, Ball MK, et al. Pulmonary and systemic endotoxin tolerance in preterm fetal sheep exposed to chorioamnionitis. J Immunol. 2007;179(12):8491–8499.

    Article  CAS  PubMed  Google Scholar 

  36. Kramer BW, Moss TJ, Willet KE, et al. Dose and time response after intraamniotic endotoxin in preterm lambs. Am J Respir Crit Care Med. 2001;164(6):982–988.

    Article  CAS  PubMed  Google Scholar 

  37. Ueda K, Cho K, Matsuda T, et al. A rat model for arrest of alveolarization induced by antenatal endotoxin administration. Pediatr Res. 2006;59(3):396–400.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Center for Perinatal and Neonatal Care, Tohoku University Hospital, Sendai, Miyagi, Japan

    Takushi Hanita MD, Tadashi Matsuda MD, PhD, Masatoshi Saito MD, PhD & Ryuta Kitanishi MD

  2. Department of Anatomy and Developmental Biology, Monash University, Victoria, Australia

    Takushi Hanita MD & Richard Harding DSc

  3. Department of Obstetrics and Gynecology, Hokkaido University Hospital, Sapporo, Japan

    Kazutoshi Cho MD, PhD

  4. Department of Veterinary Pathology, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan

    Yoshiyasu Kobayashi PhD

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  1. Takushi Hanita MD
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  2. Tadashi Matsuda MD, PhD
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  3. Masatoshi Saito MD, PhD
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Correspondence to Tadashi Matsuda MD, PhD.

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Hanita, T., Matsuda, T., Saito, M. et al. Potential Role of Prenatal Inflammation in the Impairment of Lung Development Following Mechanical Ventilation of Preterm Lambs. Reprod. Sci. 24, 478–487 (2017). https://doi.org/10.1177/1933719116660846

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