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Updated: Jun 2, 2026
A Murine Model of Fetal Exposure to Maternal Inflammation to Study the Effects of Acute Chorioamnionitis on Newborn Intestinal Development
Published on: June 24, 2020
Antenatal inflammation reduces expression of caveolin-1 and influences multiple signaling pathways in preterm fetal
Steffen Kunzmann1, Jennifer J P Collins, Yang Yang
1University Children's Hospital, University of Würzburg, Germany. kunzmann_s@kinderklinik.uni-wuerzburg.de
Insights
Antenatal inflammation from chorioamnionitis reduces caveolin-1 (Cav-1) expression in preterm fetal lungs, impacting lung development and potentially contributing to bronchopulmonary dysplasia (BPD). This decrease is linked to specific molecular pathway activations and increased heme oxygenase-1 (HO-1).
Area of Science:
- Neonatal Physiology
- Pulmonary Medicine
- Molecular Biology
Background:
- Bronchopulmonary dysplasia (BPD) is a chronic lung disease in preterm infants, often linked to chorioamnionitis and characterized by disrupted lung development and injury.
- Caveolins (Cavs), particularly Cav-1, are crucial in lung injury and repair, but their role in the developing, injured lung remains understudied.
Purpose of the Study:
- To investigate the hypothesis that chorioamnionitis-induced antenatal lung inflammation decreases caveolin-1 (Cav-1) expression in preterm fetal lungs.
- To examine associated changes in Smad and Stat transcription factors, acid-sphingomyelinase (a-SMase) activity, ceramide generation, and heme oxygenase-1 (HO-1) expression.
Main Methods:
- Fetal sheep were exposed to intra-amniotic endotoxin or saline, followed by preterm delivery at 124 days of gestation.
- Lung tissue analysis included real-time PCR, Western blotting, immunohistochemistry for Cav-1 and HO-1, and Smad/Stat phosphorylation.
- Acid-sphingomyelinase (a-SMase) activity and ceramide concentrations were measured.
Main Results:
- Intra-amniotic endotoxin significantly decreased both Cav-1 mRNA and protein expression in fetal sheep lungs.
- Reduced Cav-1 levels correlated with increased phosphorylation of Smad2/3, Stat3, and Stat1, but not Smad1/5.
- Heme oxygenase-1 (HO-1) expression, a-SMase activity, and ceramide concentrations were elevated.
Conclusions:
- Antenatal inflammation associated with chorioamnionitis leads to decreased Cav-1 expression in the preterm fetal lung.
- The reduction in Cav-1 is associated with the activation of Smad2/3, Stat signaling, and the a-SMase/ceramide pathway, alongside increased HO-1.
- These molecular changes may play a role in the pathogenesis of bronchopulmonary dysplasia (BPD).
Abstract:
Bronchopulmonary dysplasia (BPD), associated with chorioamnionitis, results from the simultaneous effects of disrupted lung development, lung injury, and repair superimposed on the developing lung. Caveolins (Cavs) are implicated as major modulators of lung injury and remodeling by multiple signaling pathways, although Cavs have been minimally studied in the injured developing lung. We hypothesized that chorioamnionitis-associated antenatal lung inflammation would decrease the expression of Cav-1 in preterm fetal lungs. We tested whether changes occurred in the transcription factors Smad2/3, Smad1/5, Stat3, and Stat1, and we also studied the activation of acid-sphingomyelinase (a-SMase) with the generation of ceramide, along with changes in the expression of heme oxygenase-1 (HO-1) as indicators of possible Cav-1-mediated effects. Fetal sheep were exposed to 10 mg of intra-amniotic endotoxin or saline for 2, 7, or 2 + 7 days before preterm delivery at 124 days of gestation. The expression of Cav-1 and HO-1 and the phosphorylation of Smad and Stat were evaluated by real-time PCR, Western blotting, and/or immunohistochemistry. The activity of a-SMase and the concentrations of ceramide were measured. Intra-amniotic endotoxin decreased Cav-1 mRNA and protein expression in the lungs, with a maximum reduction of Cav-1 mRNA to 50% ± 7% of the control value (P < 0.05), and of Cav-1 protein expression to 20% ± 5% of the control value (P < 0.05). Decreased concentrations of Cav-1 were associated with the elevated phosphorylation of Smad2/3, Stat3, and Stat1, but not of Smad1/5. The expression of HO-1, a-SMase activity, and ceramide increased. Antenatal inflammation decreased the expression of Cav-1 in the preterm fetal lung. The decreased expression of Cav-1 was associated with the activation of the Smad2/3, Stat, and a-SMase/ceramide pathways, and with the increased expression of HO-1. The decreased concentrations of Cav-1 and changes in other signaling pathways may contribute to BPD.
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