Ovine fetal thymus response to lipopolysaccharide-induced chorioamnionitis and antenatal corticosteroids.
BACKGROUND
Chorioamnionitis is associated with preterm delivery and involution of the fetal thymus. Women at risk of preterm delivery receive antenatal corticosteroids which accelerate fetal lung maturation and improve neonatal outcome. However, the effects of antenatal corticosteroids on the fetal thymus in the settings of chorioamnionitis are largely unknown. We hypothesized that intra-amniotic exposure to lipopolysaccharide (LPS) causes involution of the fetal thymus resulting in persistent effects on thymic structure and cell populations. We also hypothesized that antenatal corticosteroids may modulate the effects of LPS on thymic development.


METHODS
Time-mated ewes with singleton fetuses received an intra-amniotic injection of LPS 7 or 14 days before preterm delivery at 120 days gestational age (term = 150 days). LPS and corticosteroid treatment groups received intra-amniotic LPS either preceding or following maternal intra-muscular betamethasone. Gestation matched controls received intra-amniotic and maternal intra-muscular saline. The fetal intra-thoracic thymus was evaluated.


RESULTS
Intra-amniotic LPS decreased the cortico-medullary (C/M) ratio of the thymus and increased Toll-like receptor (TLR) 4 mRNA and CD3 expression indicating involution and activation of the fetal thymus. Increased TLR4 and CD3 expression persisted for 14 days but Foxp3 expression decreased suggesting a change in regulatory T-cells. Sonic hedgehog and bone morphogenetic protein 4 mRNA, which are negative regulators of T-cell development, decreased in response to intra-amniotic LPS. Betamethasone treatment before LPS exposure attenuated some of the LPS-induced thymic responses but increased cleaved caspase-3 expression and decreased the C/M ratio. Betamethasone treatment after LPS exposure did not prevent the LPS-induced thymic changes.


CONCLUSIONS
Intra-amniotic exposure to LPS activated the fetal thymus which was accompanied by structural changes. Treatment with antenatal corticosteroids before LPS partially attenuated the LPS-induced effects but increased apoptosis in the fetal thymus. Corticosteroid administration after the inflammatory stimulus did not inhibit the LPS effects on the fetal thymus.
Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands.
Elke
E
Kuypers
Jennifer J P
JJ
Collins
Reint K
RK
Jellema
Tim G A M
TG
Wolfs
Matthew W
MW
Kemp
Ilias
I
Nitsos
J Jane
JJ
Pillow
Graeme R
GR
Polglase
John P
JP
Newnham
Wilfred T V
WT
Germeraad
Suhas G
SG
Kallapur
Alan H
AH
Jobe
Boris W
BW
Kramer
D000305:Adrenal Cortex Hormones / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002821:Chorioamnionitis / Q000139:chemically induced* / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D011247:Pregnancy; D012756:Sheep / Q000196:embryology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013950:Thymus Gland / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D013997:Time Factors; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism
D000305:Adrenal Cortex Hormones; D055415:Bone Morphogenetic Protein 4; D017252:CD3 Complex; D051858:Forkhead Transcription Factors; D053823:Hedgehog Proteins; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors