Single Administration Of Ultra-low-dose Lipopolysaccharide In Rat Early Pregnancy Induces TLR4 Activation In The Placenta Contributing To Preeclampsia

Balanced immune responses are essential for the maintenance of successful pregnancy.Aberrant responses of maternal immune system during pregnancy increase the risk of preeclampsia.Toll-like receptor 4(TLR4)plays a crucial role in the activation of immune system at the maternal-fetal interface.This study aimed to generate a rat model of preeclampsia by 0.5 μg/kg lipopolysaccharide(LPS,a TLR4 agonist)administration on gestational day(GD)5 as rats are subjected to placentation immediately after implantation between GDs 4 and 5,and to assess the contribution of TLR4 signaling to the development of preeclampsia.Single administration of 0.5 μg/kg LPS significantly increased blood pressure of pregnant rats since GD 6(systolic blood pressure,124.89 ± 1.79 mm Hg vs.119.02 ± 1.80 mm Hg,P < 0.05)and urinary protein level since GD 9(2.02 ± 0.29 mg vs.1.11 ± 0.18 mg,P < 0.01),but barely affected blood pressure or proteinuria of virgin rats compared with those of saline-treated pregnant rats.This was accompanied with adverse pregnancy outcomes including fetal growth restriction,fetal resorption and placenta abruption.The expression of TLR4 and NF-κB p65 were both increased in the placenta but not the kidney from LPS-treated pregnant rats,with deficient trophoblast invasion and spiral artery remodeling.Furthermore,the levels of inflammatory cytokines were elevated systemically and locally in the placenta from pregnant rats treated with LPS.TLR4 signaling in the placenta was activated,to which that in the placenta of humans with preeclampsia changed similarly.In vitro studies showed that LPS stimulation provoked an enhanced expression of NF-κB P-p65 but not p65 time-dependently and dose-dependently,a decreased migration of HTR-8/SVneo cells,and an increased secretion of inflammatory cytokines time-dependently and dose-dependently.In conclusion,LPS administration to pregnant rats in early pregnancy could elicit TLR4-mediated immune response at the maternal-fetal interface contributing to poor early placentation that may culminate in the preeclampsia-like syndrome.