Altered canonical Wingless-Int signaling in the ovine fetal lung after exposure to intra-amniotic lipopolysaccharide and antenatal betamethasone.
BACKGROUND
Antenatal inflammation and maternal corticosteroids induce fetal lung maturation but interfere with late lung development. Canonical Wingless-Int (Wnt) signaling directs lung development and repair. We showed that intra-amniotic (IA) lipopolysaccharide (LPS) exposure disrupted developmental signaling pathways in the preterm lamb lungs. Therefore, we hypothesized that pulmonary Wnt signaling was altered by exposure to IA LPS and/or antenatal corticosteroids.


METHODS
Ovine fetuses were exposed to IA LPS, maternal intramuscular betamethasone, a control saline injection, or a combination thereof at 107 and/or 114 d gestational age (term = 150 d gestational age) before delivery at 121 d gestational age.


RESULTS
IA LPS exposure decreased the lung expression of lymphoid enhancer-binding factor 1 (LEF1), a major Wnt pathway effector. WNT1, WNT4, and downstream messenger β-catenin decreased after LPS exposure. WNT7b mRNA increased fourfold 14 d post-LPS exposure. Betamethasone treatment 7 d before LPS exposure prevented the reduction in LEF1 expression, whereas betamethasone administration after LPS normalized the LPS-induced increase in Wnt7b mRNA.


CONCLUSIONS
IA LPS exposure decreased canonical Wnt signaling in the developing lung. Antenatal corticosteroids before or after IA inflammation had different effects on pulmonary Wnt signaling. This study provides new insights into possible mechanisms by which prenatal inflammation affects lung development and how corticosteroid can be beneficial in this setting.
1] Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands [2] School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands [3] School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.
Elke
E
Kuypers
1] Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands [2] School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands [3] School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.
Monique G M
MG
Willems
1] Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands [2] School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands [3] School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands [4] Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Jennifer J P
JJ
Collins
1] Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands [2] School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands [3] School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.
Tim G A M
TG
Wolfs
1] School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia [2] The Ritchie Centre, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
Ilias
I
Nitsos
School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia.
J
J
Jane Pillow
1] School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia [2] The Ritchie Centre, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
Graeme R
GR
Polglase
School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia.
Matthew W
MW
Kemp
School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia.
John P
JP
Newnham
1] Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands [2] School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands [3] School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.
Tammo
T
Delhaas
1] School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia [2] Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
Alan H
AH
Jobe
1] School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia [2] Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
Suhas G
SG
Kallapur
1] Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands [2] School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands [3] School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands [4] School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia.
Boris W
BW
Kramer
D000818:Animals; D001623:Betamethasone / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007249:Inflammation; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000737:chemistry; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D018811:Maternal Exposure; D010766:Phosphorylation; D011247:Pregnancy; D011270:Pregnancy, Animal; D012756:Sheep; D034561:Sheep, Domestic; D013997:Time Factors; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
D008070:Lipopolysaccharides; D051821:Lymphoid Enhancer-Binding Factor 1; D051153:Wnt Proteins; D051176:beta Catenin; D001623:Betamethasone; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3