Chorioamnionitis induces changes in ovine pulmonary endogenous epithelial stem/progenitor cells in utero.
Journal
Pediatric research
ISSN: 1530-0447
Titre abrégé: Pediatr Res
Pays: United States
ID NLM: 0100714
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
01
04
2020
accepted:
25
09
2020
revised:
15
09
2020
pubmed:
19
10
2020
medline:
18
3
2022
entrez:
18
10
2020
Statut:
ppublish
Résumé
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. 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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 33070161
doi: 10.1038/s41390-020-01204-9
pii: 10.1038/s41390-020-01204-9
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
549-558Informations de copyright
© 2021. International Pediatric Research Foundation, Inc.
Références
Sabic, D. & Koenig, J. M. A perfect storm: fetal inflammation and the developing immune system. Pediatr. Res. 87, 319–326 (2019).
Peng, C. C. et al. Intrauterine inflammation, infection, or both (Triple I): a new concept for chorioamnionitis. Pediatr. Neonatol. 59, 231–237 (2018).
doi: 10.1016/j.pedneo.2017.09.001
Berger, A. et al. Microbial invasion of the amniotic cavity at birth is associated with adverse short-term outcome of preterm infants. J. Perinat. Med. 31, 115–121 (2003).
doi: 10.1515/JPM.2003.016
Galinsky, R. et al. The consequences of chorioamnionitis: preterm birth and effects on development. J. Pregnancy 2013, 412831 (2013).
doi: 10.1155/2013/412831
Thomas, W. & Speer, C. P. Chorioamnionitis is essential in the evolution of bronchopulmonary dysplasia–the case in favour. Paediatr. Respir. Rev. 15, 49–52 (2014).
pubmed: 24128984
Alvira, C. M. & Morty, R. E. Can we understand the pathobiology of bronchopulmonary dysplasia? J. Pediatr. 190, 27–37 (2017).
doi: 10.1016/j.jpeds.2017.08.041
Möbius, M. A. & Thébaud, B. Bronchopulmonary dysplasia: where have all the stem cells gone?: origin and (potential) function of resident lung stem cells. Chest 152, 1043–1052 (2017).
doi: 10.1016/j.chest.2017.04.173
Collins, J. J. & Thebaud, B. Progenitor cells of the distal lung and their potential role in neonatal lung disease. Birth Defects Res. A Clin. Mol. Teratol. 100, 217–226 (2014).
doi: 10.1002/bdra.23227
Stahlman, M. T., Gray, M. E. & Whitsett, J. A. Expression of thyroid transcription factor-1 (TTF-1) in fetal and neonatal human lung. J. Histochem. Cytochem. 44, 673–678 (1996).
doi: 10.1177/44.7.8675988
Yee, M. et al. Alternative progenitor lineages regenerate the adult lung depleted of alveolar epithelial type 2 cells. Am. J. Respir. Cell Mol. Biol. 56, 453–464 (2017).
doi: 10.1165/rcmb.2016-0150OC
Das, I. et al. A study of spectrum of pulmonary pathology and expression of thyroid transcription factor-1 during neonatal period. Indian J. Pathol. Microbiol. 61, 334–338 (2018).
doi: 10.4103/IJPM.IJPM_650_17
Willems, M. G. et al. Pulmonary vascular changes in extremely preterm sheep after intra-amniotic exposure to Ureaplasma parvum and lipopolysaccharide. PLoS ONE 12, e0180114 (2017).
doi: 10.1371/journal.pone.0180114
Kuypers, E. et al. Altered canonical Wingless-Int signaling in the ovine fetal lung after exposure to intra-amniotic lipopolysaccharide and antenatal betamethasone. Pediatr. Res. 75, 281–287 (2014).
doi: 10.1038/pr.2013.226
Gussenhoven, R. et al. The paradoxical effects of chronic intra-amniotic Ureaplasma parvum exposure on ovine fetal brain development. Dev. Neurosci. 39, 472–486 (2017).
doi: 10.1159/000479021
Willems, M. G. et al. Systemic interleukin-2 administration improves lung function and modulates chorioamnionitis-induced pulmonary inflammation in the ovine fetus. Am. J. Physiol. Lung Cell. Mol. Physiol. 310, L1–L7 (2016).
doi: 10.1152/ajplung.00289.2015
Leibel, S. & Post, M. Endogenous and exogenous stem/progenitor cells in the lung and their role in the pathogenesis and treatment of pediatric lung disease. Front. Pediatr. 4, 36 (2016).
doi: 10.3389/fped.2016.00036
Peake, J. L. & Pinkerton, K. E. in Comparative Biology of the Normal Lung (ed. Parent, R. A.) Ch. 3 (Elsevier, 2015).
Vaughan, A. E. et al. Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature 517, 621–625 (2015).
doi: 10.1038/nature14112
Danopoulos, S. et al. Human lung branching morphogenesis is orchestrated by the spatiotemporal distribution of ACTA2, SOX2, and SOX9. Am. J. Physiol. Lung Cell. Mol. Physiol. 314, L144–L149 (2018).
doi: 10.1152/ajplung.00379.2017
Bianco-Miotto, T. et al. Epigenetics and DOHaD: from basics to birth and beyond. J. Dev. Orig. Health Dis. 8, 513–519 (2017).
doi: 10.1017/S2040174417000733
Postma, D. S., Bush, A. & van den Berge, M. Risk factors and early origins of chronic obstructive pulmonary disease. Lancet 385, 899–909 (2015).
doi: 10.1016/S0140-6736(14)60446-3
Um-Bergstrom, P. et al. Pulmonary outcomes in adults with a history of bronchopulmonary dysplasia differ from patients with asthma. Respir. Res. 20, 102 (2019).
doi: 10.1186/s12931-019-1075-1
Borghesi, A. et al. Circulating endothelial progenitor cells in preterm infants with bronchopulmonary dysplasia. Am. J. Respir. Crit. Care Med. 180, 540–546 (2009).
doi: 10.1164/rccm.200812-1949OC
Schittny, J. C. Development of the lung. Cell Tissue Res. 367, 427–444 (2017).
doi: 10.1007/s00441-016-2545-0
Rennard, S. I. et al. Airway epithelial cells: functional roles in airway disease. Am. J. Respir. Crit. Care Med. 150, S27–S30 (1994).
doi: 10.1164/ajrccm/150.5_Pt_2.S27
Davies, D. E. Epithelial barrier function and immunity in asthma. Ann. Am. Thorac. Soc. 11, S244–S251 (2014).
doi: 10.1513/AnnalsATS.201407-304AW
Donne, M. L., Lechner, A. J. & Rock, J. R. Evidence for lung epithelial stem cell niches. BMC Dev. Biol. 15, 32 (2015).
doi: 10.1186/s12861-015-0082-9
Ota, C. et al. Linking bronchopulmonary dysplasia to adult chronic lung diseases: role of WNT signaling. Mol. Cell Pediatr. 3, 34 (2016).
doi: 10.1186/s40348-016-0062-6
Saito, A., Horie, M. & Nagase, T. TGF-beta signaling in lung health and disease. Int. J. Mol. Sci. 19, 2460 (2018).
Ahmed, A. S. et al. Effect of aging on stem cells. World J. Exp. Med. 7, 1–10 (2017).
doi: 10.5493/wjem.v7.i1.1
Meiners, S. & Hilgendorff, A. Early injury of the neonatal lung contributes to premature lung aging: a hypothesis. Mol. Cell. Pediatr. 3, 24 (2016).
doi: 10.1186/s40348-016-0052-8
Jobe, A. H. & Bancalari, E. Bronchopulmonary dysplasia. Am. J. Respir. Crit. Care Med. 163, 1723–1729 (2001).
doi: 10.1164/ajrccm.163.7.2011060
Viscardi, R. et al. Disordered pulmonary myofibroblast distribution and elastin expression in preterm infants with Ureaplasma urealyticum pneumonitis. Pediatr. Dev. Pathol. 9, 143–151 (2006).
doi: 10.2350/10-05-0112.1
Choi, C. W. et al. Protective effect of chorioamnionitis on the development of bronchopulmonary dysplasia triggered by postnatal systemic inflammation in neonatal rats. Pediatr. Res. 79, 287–294 (2016).
doi: 10.1038/pr.2015.224
Willet, K. E. et al. Antenatal endotoxin and glucocorticoid effects on lung morphometry in preterm lambs. Pediatr. Res. 48, 782–788 (2000).
doi: 10.1203/00006450-200012000-00014
Yee, M., Buczynski, B. W. & O’Reilly, M. A. Neonatal hyperoxia stimulates the expansion of alveolar epithelial type II cells. Am. J. Respir. Cell Mol. Biol. 50, 757–766 (2014).
doi: 10.1165/rcmb.2013-0207OC
Yee, M. et al. Type II epithelial cells are critical target for hyperoxia-mediated impairment of postnatal lung development. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L1101–L1111 (2006).
doi: 10.1152/ajplung.00126.2006
Deptula, N. et al. Brief mechanical ventilation causes differential epithelial repair along the airways of fetal, preterm lambs. Am. J. Physiol. Lung Cell. Mol. Physiol. 311, L412–L420 (2016).
doi: 10.1152/ajplung.00181.2016
Kemp, M. et al. The clinical use of corticosteroids in pregnancy. Hum. Reprod. Update 22, 240–259 (2015).
pubmed: 26590298
Curstedt, T., Halliday, H. L. & Speer, C. P. A unique story in neonatal research: the development of a porcine surfactant. Neonatology 107, 321–329 (2015).
doi: 10.1159/000381117