Altered canonical Wingless-Int signaling in the ovine fetal lung after exposure to intra-amniotic lipopolysaccharide and antenatal betamethasone

Abstract

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 intraamniotic (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. conclusion: 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.

Selection of Reference Genes for Gene Expression Studies related to lung injury in a preterm lamb model

“…Our choice of reference genes analyzed was limited to five potential candidate genes. Other reference genes, including 60S ribosomal protein (L32) 26 31 , or ribosomal protein subunit 15 (RPS15) 25 32 33 34 , have been used in a small number of lamb lung studies and may warrant consideration in the future. Furthermore, due to the developmental plasticity of the model and the geographic tissue response observed within the lung, the results of this study may not be applicable to other ovine or organ models.…”

Linking bronchopulmonary dysplasia to adult chronic lung diseases: role of WNT signaling

“…Antenatal inflammation of chorioamniotic membranes causes premature birth and adversely affects lung development [ 59 ]. Intra-amniotic lipopolysaccharide (LPS) exposure, which mimics amniotic bacterial infection, decreases the expression of Lef-1 , Wnt1 , Wnt4 , and β-catenin in the canalicular stage of lung development [ 60 ]. Similarly, in adult mice, acute lung injury caused by intra-tracheal application of LPS and followed by high tidal volume mechanical ventilation results in the activation of DKK1 and the subsequent down-regulation of active β-catenin in the lung alveolar epithelium.…”

Avoiding the prenatal programming effects of glucocorticoids: are there alternative treatments for the induction of antenatal lung maturation?

“…Pro-inflammatory cytokines, including IL-a, IL-6, IL-8 and TNF-alpha, directly affected fetal type II pneumocytes [47,148] , and that NF-κ B led to thickened lung interstitium, reduced branching, and a BPD-like phenotype [16,71] . The exact mechanism by which interleukins activate maturation processes is still not fully understood [75] .…”