Single administration of ultra-low-dose lipopolysaccharide in rat early pregnancy induces TLR4 activation in the placenta contributing to preeclampsia.

Pingping Xue,Ping Gong,Guijun Yan,Yali Hu,Jianjun Zhou,Mingming Zheng,Haixiang Sun,Caimei Lin,Yujing Li,Li Shen,Zhenyu Diao,Haibin Wang

doi:10.1371/journal.pone.0124001

Abstract

Balanced immune responses are essential for the maintenance of successful pregnancy. Aberrant responses of 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 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 mmHg versus 119.02 ± 1.80 mmHg, P < 0.05) and urinary protein level since GD 9 (2.02 ± 0.29 mg versus 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. 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 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.

Highlights

Preeclampsia, as a pregnancy-specific disorder complicating 2–8% of pregnancy, is a leading cause of maternal and perinatal morbidity and mortality worldwide [1]
LPS administration to rats in early pregnancy induced a preeclampsialike syndrome By administrating pregnant rats with 0.5 μg/kg LPS on gestational day (GD) 5, a novel rat model of preeclampsia was established, which exhibited significant and characteristic hypertension, proteinuria and adverse pregnancy outcomes compared to the control pregnant group did
We found that LPS triggered an immediate high blood pressure and remained the status until to the end of gestation in pregnant, but not in non-pregnant rats

Summary

Introduction

Preeclampsia, as a pregnancy-specific disorder complicating 2–8% of pregnancy, is a leading cause of maternal and perinatal morbidity and mortality worldwide [1]. Aberrant responses of immune system during pregnancy are suggested to play an important role in the pathogenesis of pregnancy disorders with impaired placentation/remodeling, such as recurrent miscarriage, preeclampsia, and fetal growth restriction (FGR) [4,5,6]. Numerous animal studies revealed that administration of LPS to pregnant rats induced preeclampsia-like symptoms [16,17,18,19]. Interventions in these animal studies were generally applied around gestational day (GD) 14 that have missed the early stage of placental development, which appears to be a pivotal time point in the development of preeclampsia [1,2,3]

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