Poster Presentation & Flash Talk 46th Annual Meeting of the Fetal and Neonatal Physiological Society 2019

Intra-uterine inflammation negatively affects endogenous epithelial stem/progenitor cell populations - improved function at the expense of development?  (#103)

Helene Widowski 1 2 , Daan Ophelders 1 2 , Anais van Leeuwen 1 , Peter Nikkels 3 , Carmen Severens-Rijvers 4 , Vanessa LaPointe 5 , Jack Cleutjens 3 , Matthew Kemp 6 , John Newnham 6 , Boris Kramer 1 2 , Tammo Delhaas 7 , Tim Wolfs 1 2 , Niki Reynaert 8 9
  1. Department of Pediatrics, Maastricht University Medical Center, Maastricht, Netherlands
  2. GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
  3. Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands
  4. Department of Pathology, Maastricht University Medical Center, Maastricht, Netherlands
  5. Department of Complex Tissue Regeneration, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, Netherlands
  6. School of Women's and Infants' Health, The University of Western Australia, Perth, WA, Australia
  7. Department of Biomedical Engineering, Maastricht University Medical Center, Maastricht, Netherlands
  8. Department of Respiratory Medicine, Maastricht University, Maastricht, Netherlands
  9. NUTRIM School of Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, Netherlands

Introduction

Chorioamnionitis is a common risk factor for adverse lung outcomes in premature infants. Underlying causes for aberrant lung development are still poorly understood, but evidence has been provided that alterations in endogenous pulmonary stem/progenitor pools play an essential role in postnatal neonatal morbidities. However, studies explicitly addressing these disturbances in the context of prenatal inflammatory stress are lacking. In the current study, we hypothesized that prenatal inflammation leads to alterations in endogenous epithelial stem/progenitor pools, potentially contributing to postnatal adverse lung development.

Methods

Ovine fetuses were intra-amniotically exposed to chronic Ureaplasma parvum (UP) at 42 days  and/or to lipopolysaccharide 7 or 2d before preterm delivery at 122d (term 147d). Lung function was recorded and lung tissues were assessed for endogenous epithelial stem/progenitor numbers and surfactant proteins.

Results and discussion

Reduced numbers of Club and alveolar type 2 cells were found in the distal airways and alveolar airspaces following both, chronic and acute intrauterine inflammatory triggers. These findings were associated with downstream changes including lower proliferation (KI67), reduced expression of the alveolar type 1 cell marker Aquaporin 5 and increased SP-C mRNA levels with concomitant improved lung function.

Conclusion

Intrauterine inflammation induces changes in epithelial stem/progenitor cells that might pave the way for postnatal adverse lung outcomes. We propose that intrauterine inflammation leads to an increase in surfactant mRNA levels, and therefore might cause a shift in AEC2 cell function, resulting in a diminished proliferation and differentiation potential of AEC2 cells.  Therefore, improved lung function occurred at the expense of maintaining appropriate lung development.

We suggest that these developmental problems should be addressed as early as possible, being in utero, to prevent the exacerbation of structural changes and diminish the incidence of adverse pulmonary outcomes postnatally.