Granulocyte-Macrophage Colony-Stimulating Factor Initiates Amniotic Membrane Rupture And Preterm Birth In A Mouse Model

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 TNF alpha (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.