Helene Widowski1,2,3, Daan R M G Ophelders1,3, Anaïs J C N van Leeuwen1, Peter G J Nikkels4, Carmen A H Severens-Rijvers5, Vanessa L S LaPointe6, Jack P M Cleutjens5,7, Matthias C Hütten8,9, Matthew W Kemp10, Matthew S Payne10, Masatoshi Saito10,11, Haruo Usuda10,11, John P Newnham10, Alan H Jobe10,12, Boris W Kramer1,3,13, Tammo Delhaas2,7, Tim G A M Wolfs1,3, Niki L Reynaert14,15. 1. Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands. 2. Department of BioMedical Engineering, Maastricht University Medical Center, Maastricht, The Netherlands. 3. GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands. 4. Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. 5. Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands. 6. Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands. 7. CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, The Netherlands. 8. Neonatology, Pediatrics Department, Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Center, Maastricht, The Netherlands. 9. University Children's Hospital Würzburg, University of Würzburg, Würzburg, Germany. 10. Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, WA, Australia. 11. Tohoku University Centre for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan. 12. Perinatal Institute Cincinnati Children's Hospital Medical Centre, Cincinnati, OH, USA. 13. School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands. 14. Department of Respiratory Medicine, Maastricht University, Maastricht, The Netherlands. n.reynaert@maastrichtuniversity.nl. 15. NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands. n.reynaert@maastrichtuniversity.nl.
Abstract
BACKGROUND: Chorioamnionitis, an intrauterine infection of the placenta and fetal membranes, is a common risk factor for adverse pulmonary outcomes in premature infants including BPD, which is characterized by an arrest in alveolar development. As endogenous epithelial stem/progenitor cells are crucial for organogenesis and tissue repair, we examined whether intrauterine inflammation negatively affects these essential progenitor pools. METHODS: In an ovine chorioamnionitis model, fetuses were intra-amniotically exposed to LPS, 2d or 7d (acute inflammation) before preterm delivery at 125d of gestation, or to intra-amniotic Ureaplasma parvum for 42d (chronic inflammation). Lung function, pulmonary endogenous epithelial stem/progenitor pools, and downstream functional markers were studied. RESULTS: Lung function was improved in the 7d LPS and 42d Ureaplasma groups. However, intrauterine inflammation caused a loss of P63+ basal cells in proximal airways and reduced SOX-9 expression and TTF-1+ Club cells in distal airways. Attenuated type-2 cell numbers were associated with lower proliferation and reduced type-1 cell marker Aqp5 expression, indicative for impaired progenitor function. Chronic Ureaplasma infection only affected distal airways, whereas acute inflammation affected stem/progenitor populations throughout the lungs. CONCLUSIONS: Acute and chronic prenatal inflammation improve lung function at the expense of stem/progenitor alterations that potentially disrupt normal lung development, thereby predisposing to adverse postnatal outcomes. IMPACT: In this study, prenatal inflammation improved lung function at the expense of stem/progenitor alterations that potentially disrupt normal lung development, thereby predisposing to adverse postnatal outcomes. Importantly, we demonstrate that these essential alterations can already be initiated before birth. So far, stem/progenitor dysfunction has only been shown postnatally. This study indicates that clinical protocols to target the consequences of perinatal inflammatory stress for the immature lungs should be initiated as early as possible and ideally in utero. Within this context, our data suggest that interventions, which promote function or repair of endogenous stem cells in the lungs, hold great promise.
BACKGROUND: Chorioamnionitis, an intrauterine infection of the placenta and fetal membranes, is a common risk factor for adverse pulmonary outcomes in premature infants including BPD, which is characterized by an arrest in alveolar development. As endogenous epithelial stem/progenitor cells are crucial for organogenesis and tissue repair, we examined whether intrauterine inflammation negatively affects these essential progenitor pools. METHODS: In an ovine chorioamnionitis model, fetuses were intra-amniotically exposed to LPS, 2d or 7d (acute inflammation) before preterm delivery at 125d of gestation, or to intra-amniotic Ureaplasma parvum for 42d (chronic inflammation). Lung function, pulmonary endogenous epithelial stem/progenitor pools, and downstream functional markers were studied. RESULTS: Lung function was improved in the 7d LPS and 42d Ureaplasma groups. However, intrauterine inflammation caused a loss of P63+ basal cells in proximal airways and reduced SOX-9 expression and TTF-1+ Club cells in distal airways. Attenuated type-2 cell numbers were associated with lower proliferation and reduced type-1 cell marker Aqp5 expression, indicative for impaired progenitor function. Chronic Ureaplasma infection only affected distal airways, whereas acute inflammation affected stem/progenitor populations throughout the lungs. CONCLUSIONS: Acute and chronic prenatal inflammation improve lung function at the expense of stem/progenitor alterations that potentially disrupt normal lung development, thereby predisposing to adverse postnatal outcomes. IMPACT: In this study, prenatal inflammation improved lung function at the expense of stem/progenitor alterations that potentially disrupt normal lung development, thereby predisposing to adverse postnatal outcomes. Importantly, we demonstrate that these essential alterations can already be initiated before birth. So far, stem/progenitor dysfunction has only been shown postnatally. This study indicates that clinical protocols to target the consequences of perinatal inflammatory stress for the immature lungs should be initiated as early as possible and ideally in utero. Within this context, our data suggest that interventions, which promote function or repair of endogenous stem cells in the lungs, hold great promise.