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Updated: Jul 20, 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 induced TGF-beta1 but suppressed CTGF in preterm lungs
Steffen Kunzmann1, Christian P Speer, Alan H Jobe
1Department of Pediatrics, Academisch ziekenhuis Maastricht, Postbus 5800, 6202 AZ Maastricht, The Netherlands.
Insights
Antenatal inflammation from chorioamnionitis increases transforming growth factor (TGF)-beta1 in preterm lamb lungs, potentially impairing lung development and contributing to bronchopulmonary dysplasia (BPD). This inflammation also decreases connective tissue growth factor (CTGF).
Area of Science:
- Neonatal research
- Pulmonary medicine
- Developmental biology
Background:
- Chorioamnionitis is linked to preterm birth and bronchopulmonary dysplasia (BPD).
- Transforming growth factor (TGF)-beta1 and connective tissue growth factor (CTGF) are crucial in lung development and inflammation.
- TGF-beta1 signaling pathways are implicated in BPD pathogenesis.
Purpose of the Study:
- To investigate the effects of chorioamnionitis-induced antenatal inflammation on TGF-beta1, its signaling pathway, and CTGF in preterm lamb lungs.
- To understand the molecular mechanisms linking antenatal inflammation to BPD development.
Main Methods:
- Fetal sheep were exposed to intra-amniotic endotoxin or saline.
- Preterm delivery was performed at 125 days gestation.
- Lung tissue was analyzed for TGF-beta1, phosphorylated Smad2, CTGF, and TNF-alpha expression.
Main Results:
- Intra-amniotic endotoxin increased lung TGF-beta1 mRNA and protein expression.
- Elevated TGF-beta1 correlated with increased phosphorylation of Smad2.
- CTGF expression in lung endothelial cells decreased significantly, while TNF-alpha protein increased.
Conclusions:
- Antenatal inflammation upregulates TGF-beta1 and Smad signaling in fetal lamb lungs, potentially contributing to impaired alveolarization and reduced inflammation.
- Decreased CTGF expression may hinder vascular development and limit lung fibrosis, impacting alveolar and pulmonary vascular development characteristic of BPD.
Abstract:
Chorioamnionitis is frequently associated with preterm birth and increases the risk of adverse outcomes such as bronchopulmonary dysplasia (BPD). Transforming growth factor (TGF)-beta1 is a key regulator of lung development, airway remodeling, lung fibrosis, and regulation of inflammation, and all these processes contribute to the development of BPD. Connective tissue growth factor (CTGF) is a downstream mediator of some of the profibrotic effects of TGF-beta1, vascular remodeling, and angiogenesis. TGF-beta1-induced CTGF expression can be blocked by TNF-alpha. We asked whether chorioamnionitis-associated antenatal inflammation would regulate TGF-beta1, the TGF-beta1 signaling pathway, and CTGF in preterm lamb lungs. Fetal sheep were exposed to 4 mg of intra-amniotic endotoxin or saline for 5 h, 24 h, 72 h, or 7 days before preterm delivery at 125 days gestation (full term = 150 days). Intra-amniotic endotoxin increased lung TGF-beta1 mRNA and protein expression. Elevated TGF-beta1 levels were associated with TGF-beta1-induced phosphorylation of Smad2. CTGF was selectively expressed in lung endothelial cells in control lungs, and intra-amniotic endotoxin caused CTGF expression to decrease to 30% of control values and TNF-alpha protein to increase. The antenatal inflammation-induced TGF-beta1 expression and Smad signaling in the fetal lamb lung may contribute to impaired lung alveolarization and reduced lung inflammation. Decreased CTGF expression may inhibit vascular development or remodeling and limit lung fibrosis during remodeling. These effects may contribute to the impaired alveolar and pulmonary vascular development that is the hallmark of the new form of BPD.
