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Updated: Nov 11, 2025
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
Granulocyte-macrophage colony-stimulating factor initiates amniotic membrane rupture and preterm birth in a mouse
Christopher Nold1,2, Kristyn Esteves3, Todd Jensen2
1Department of Women's Health, Hartford Hospital, Hartford, CT, USA.
Objective:
Preterm premature rupture of membranes is associated with 30% of all preterm births. The weakening of amniotic membranes is associated with an increase in matrix metallopeptidases (MMPs) along with a decrease in their inhibitors, tissue inhibitor metallopeptidases (TIMPs). Additionally, granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to weaken fetal membranes in-vitro. We hypothesize pregnant mice treated with GM-CSF lead to increased MMPs:TIMPs resulting in membrane rupture and preterm birth.
Study Design:
Pregnant CD-1 mice on gestational day 17 received either an intrauterine injection of GM-CSF or vehicle control. A second series of mice were administered an intrauterine injection of Lipopolysaccharide along with either anti-mouse GM-CSF or control antibody. Mice were evaluated for rupture of membranes and/or preterm birth and the uterus, amniotic fluid, and serum were collected for analysis.
Results:
87.5% of GM-CSF mice exhibited evidence of membrane rupture or preterm birth, compared with 0% in control mice (p < .001). Treatment with GM-CSF decreased the expression of TNFα (p < .05) while increasing the ratio of MMP2:TIMP1 (p < .05), MMP2:TIMP2 (p < .05), MMP2:TIMP3 (p < .001), MMP9:TIMP1 (p < .01), MMP9:TIMP2 (p < .05), MMP9:TIMP3 (p < .001), and MMP10:TIMP1 (p < .05). Mice treated with LPS and the GM-CSF antibody resulted in a decrease in the ratio of MMP2:TIMP1 (p < .0001) compared with controls.
Conclusion:
These studies demonstrate GM-CSF will result in membrane rupture and preterm birth by increasing the ratio MMPs:TIMPs in our animal model. By increasing our understanding of the molecular pathways associated with GM-CSF, we may be able to develop future therapies to prevent preterm birth and reduce neonatal morbidity.
Insights
Granulocyte-macrophage colony-stimulating factor (GM-CSF) causes preterm birth in mice by increasing matrix metallopeptidases (MMPs) to tissue inhibitor metallopeptidases (TIMPs) ratios. This research may lead to new therapies for preventing preterm birth and reducing infant complications.
Area of Science:
- Reproductive biology
- Molecular biology
- Obstetrics
Background:
- Preterm premature rupture of membranes accounts for 30% of preterm births.
- Weakening of amniotic membranes is linked to increased matrix metallopeptidases (MMPs) and decreased tissue inhibitor metallopeptidases (TIMPs).
- Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to weaken fetal membranes in vitro.
Purpose of the Study:
- To investigate the effect of GM-CSF on pregnant mice.
- To determine if GM-CSF induces membrane rupture and preterm birth.
- To analyze the impact of GM-CSF on MMPs and TIMPs ratios in the context of preterm birth.
Main Methods:
- Pregnant CD-1 mice on gestational day 17 received intrauterine injections of GM-CSF or a vehicle control.
- A separate group of mice received lipopolysaccharide (LPS) with either anti-mouse GM-CSF or a control antibody.
- Mice were monitored for membrane rupture and preterm birth; uterine, amniotic fluid, and serum samples were collected for analysis.
Main Results:
- 87.5% of mice treated with GM-CSF experienced membrane rupture or preterm birth, versus 0% in controls (p < .001).
- GM-CSF treatment increased MMPs:TIMPs ratios, including MMP2:TIMP1, MMP2:TIMP2, MMP2:TIMP3, MMP9:TIMP1, MMP9:TIMP2, MMP9:TIMP3, and MMP10:TIMP1.
- Mice treated with LPS and the GM-CSF antibody showed a significant decrease in the MMP2:TIMP1 ratio compared to controls (p < .0001).
Conclusions:
- GM-CSF administration leads to membrane rupture and preterm birth in a mouse model.
- This effect is mediated by an increased ratio of MMPs to TIMPs.
- Understanding these molecular pathways could inform future therapies to prevent preterm birth and reduce neonatal morbidity.
