Department of Women's Health, Hartford Hospital, Hartford, CT, USA.
Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT, USA.
Am J Reprod Immunol. 2021 Aug;86(2):e13424. doi: 10.1111/aji.13424. Epub 2021 Apr 6.
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.
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.
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.
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.
胎膜早破与所有早产的 30%有关。羊膜的弱化与基质金属蛋白酶（MMPs）的增加以及其抑制剂组织金属蛋白酶抑制剂（TIMPs）的减少有关。此外，粒细胞-巨噬细胞集落刺激因子（GM-CSF）已被证明可在体外削弱胎儿膜。我们假设，用 GM-CSF 治疗的孕妇会导致 MMPs：TIMP 增加，从而导致膜破裂和早产。
妊娠第 17 天的 CD-1 小鼠接受宫内 GM-CSF 注射或载体对照。另一组小鼠接受宫内脂多糖注射，并接受抗小鼠 GM-CSF 或对照抗体治疗。评估小鼠胎膜破裂和/或早产情况，并收集子宫、羊水和血清进行分析。
87.5%的 GM-CSF 小鼠出现膜破裂或早产的证据，而对照组小鼠为 0%（p<.001）。GM-CSF 治疗降低了 TNFα 的表达（p<.05），同时增加了 MMP2：TIMP1 的比值（p<.05）、MMP2：TIMP2 的比值（p<.05）、MMP2：TIMP3 的比值（p<.001）、MMP9：TIMP1 的比值（p<.01）、MMP9：TIMP2 的比值（p<.05）、MMP9：TIMP3 的比值（p<.001）和 MMP10：TIMP1 的比值（p<.05）。用 LPS 和 GM-CSF 抗体治疗的小鼠与对照组相比，MMP2：TIMP1 的比值降低（p<.0001）。
这些研究表明，GM-CSF 通过增加我们动物模型中 MMPs：TIMP 的比值，导致膜破裂和早产。通过增加对 GM-CSF 相关分子途径的理解，我们或许能够开发出预防早产和降低新生儿发病率的未来疗法。
