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
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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.
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Importantly, we demonstrate that these essential alterations can already be initiated before birth. So far, stem/progenitor dysfunction has only been shown postnatally.
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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.
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Acknowledgements
We would like to thank Nico Kloosterboer and Lilian Kessels for their excellent technical assistance. This work was supported by a National Institutes of Health (Bethesda, MD, USA) grant (HD 57869) and by the Dutch Lung Foundation (Longfonds, Grant no. 6.1.16.088 to T.G.A.M.W., N.L.R., and P.G.J.N.).
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H.W., T.G.A.M.W., and N.L.R. contributed to the conception and design of the research; H.W., A.J.C.N.v.L., M.W.K., M.S.P., A.H.J., M.S., H.U., J.P.N., and B.W.K. participated in conduction of experiments, acquirement, and analysis of data; H.W., D.R.M.G.O., P.G.J.N., C.A.H.S.-R., V.L.S.L., B.W.K., T.D., T.G.A.M.W., and N.L.R. drafted, edited, and revised the manuscript. All the authors approved the final version of the manuscript.
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Widowski, H., Ophelders, D.R.M.G., van Leeuwen, A.J.C.N. et al. Chorioamnionitis induces changes in ovine pulmonary endogenous epithelial stem/progenitor cells in utero. Pediatr Res 90, 549–558 (2021). https://doi.org/10.1038/s41390-020-01204-9
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DOI: https://doi.org/10.1038/s41390-020-01204-9
