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LPS-induced chorioamnionitis and antenatal corticosteroids modulate Shh signaling in the ovine fetal lung.

ABSTRACT: Chorioamnionitis and antenatal corticosteroids mature the fetal lung functionally but disrupt late-gestation lung development. Because Sonic Hedgehog (Shh) signaling is a major pathway directing lung development, we hypothesized that chorioamnionitis and antenatal corticosteroids modulated Shh signaling, resulting in an altered fetal lung structure. Time-mated ewes with singleton ovine fetuses received an intra-amniotic injection of lipopolysaccharide (LPS) and/or maternal intramuscular betamethasone 7 and/or 14 days before delivery at 120 days gestational age (GA) (term = 150 days GA). Intra-amniotic LPS exposure decreased Shh mRNA levels and Gli1 protein expression, which was counteracted by both betamethasone pre- or posttreatment. mRNA and protein levels of fibroblast growth factor 10 and bone morphogenetic protein 4, which are important mediators of lung development, increased 2-fold and 3.5-fold, respectively, 14 days after LPS exposure. Both 7-day and 14-day exposure to LPS changed the mRNA levels of elastin (ELN) and collagen type I alpha 1 (Col1A1) and 2 (Col1A2), which resulted in fewer elastin foci and increased collagen type I deposition in the alveolar septa. Corticosteroid posttreatment prevented the decrease in ELN mRNA and increased elastin foci and decreased collagen type I deposition in the fetal lung. In conclusion, fetal lung exposure to LPS was accompanied by changes in key modulators of lung development resulting in abnormal lung structure. Betamethasone treatment partially prevented the changes in developmental processes and lung structure. This study provides new insights into clinically relevant prenatal exposures and fetal lung development.

SUBMITTER: Collins JJ

PROVIDER: S-EPMC3517680 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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LPS-induced chorioamnionitis and antenatal corticosteroids modulate Shh signaling in the ovine fetal lung.

Collins Jennifer J P JJ Kuypers Elke E Nitsos Ilias I Jane Pillow J J Polglase Graeme R GR Kemp Matthew W MW Newnham John P JP Cleutjens Jack P JP Frints Suzanna G M SG Kallapur Suhas G SG Jobe Alan H AH Kramer Boris W BW

American journal of physiology. Lung cellular and molecular physiology 20120907 9

Chorioamnionitis and antenatal corticosteroids mature the fetal lung functionally but disrupt late-gestation lung development. Because Sonic Hedgehog (Shh) signaling is a major pathway directing lung development, we hypothesized that chorioamnionitis and antenatal corticosteroids modulated Shh signaling, resulting in an altered fetal lung structure. Time-mated ewes with singleton ovine fetuses received an intra-amniotic injection of lipopolysaccharide (LPS) and/or maternal intramuscular betameth ...[more]

PMID: 22962010

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Project description: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.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.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.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.

Project description:OBJECTIVE:To investigate the regulatory role of classical Shh signaling pathway in the development of the epithelium and mesenchyme (bronchial cartilage and smooth muscles) during lung development in fetal mice. METHODS:Immunohistochemical technique was used to detect the expression of Shh signaling pathway receptor Smo and Pdgfr-? in murine fetal lungs to explore the spatial and temporal characteristics of their expression. Based on the interstitial specificity of Pdgfr-? expression, we constructed a Pdgfr-?-cre to establish a E12.5 - E16.5 transgenic mice with specific knockout of the key Shh signaling molecule Smo in the pulmonary interstitium with tamoxifen induction. Immunofluorescence technique was used to observe the epithelium and mesenchyme (bronchial cartilage and smooth muscle) during fetal lung development in the transgenic mice to assess the role of Shh signaling pathway in the epithelial-to-mesenchymal (EMT) transition during the lung development. RESULTS:Smo was highly expressed in the epithelial and stromal lung tissues in the pseudoglandular stage and was gradually lowered over time with its distribution mainly in the interstitial tissues. Pdgfr-? was enriched in the distal lung epithelial and mesenchy tissues in early embryonic lungs and gradually migrated to the proximal stroma until becoming concentrated around the main bronchial proximal stroma. We successfully specific established mouse models of specific mesenchymal Smo knockout. Compared with the control group, the transgenic mice during E12.5-E16.5 showed significantly reduced lung the volume and bronchial branching with also decreased expression of the proximal epithelial P63 (P<0.05). The transgenic mice exhibited alterations in the expression of ?-smooth muscle actin with delayed bronchial cartilage development and decreased expression of mucoprotein. CONCLUSION:The temporospatial specific expression of Shh signaling pathway plays an important role in developmental regulation of mouse embryonic lung epithelium and mesenchyme (bronchial cartilage and smooth muscle).

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LPS-induced chorioamnionitis and antenatal corticosteroids modulate Shh signaling in the ovine fetal lung.

Publications

LPS-induced chorioamnionitis and antenatal corticosteroids modulate Shh signaling in the ovine fetal lung.

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