The Therapeutic Effect Of LXA4and Its Analogue BML-111on Preeclampsia Rat Model Miniced By Low-dose Lipopolysaccharide Administration And Its Possible Mechanism

Background: Preeclampsia is a pregnancy-specific syndrome which is characterizedby hypertension and proteinuria1. It affects about5%-8%of pregnant women in theUnited States2. But the exact etiology and pathogenesis of PE is still unclear, deliveryis still the only effective treatment. Many reports suggested that low dose ofendotoxin exposure could minic pre-eclampsia in humans3,4,5and nitric oxide (NO)and NO-derived species play a important role in reproducing the clinical features ofpre-eclampisa in the proposed animal model5. Clinical data showed that the level ofoxidative stress was elevated in preeclamptic women6. Meanwhile, lipoxins,discoveried by Serhan in1984, is an first endogennous anti-inflammatory andpro-resolving arachidonic acid. It has been recently reported that LXs could inhibitthe occurence and development of oxidative stress7. At the same time lipoxinsconcentration in the plasma of PE patients is very low, so we thought that lipoxinsmight relieve the symptoms of PE through inhibiting the effect of inflammation oroxidative stress on the placenta.Objective：Investigate the therapeutic effect of LXA4and its analogue BML-111on Pre-eclampsia rat model miniced by low-dose lipopolysaccharide administration andits possible mechanism.Methods: Pregnant rats were infused with1μg/kg LPS on day14of pregnancy,which could minic PE.20rats were randomly divided into3groups: control, LPS andLPS+BML-111group. The blood pressures were measured continuously from day7through day19of pregnancy;24h-urinary albumin excretion was detected by theBCA protein assay kit; the morphological changes of placenta and kidney wereexamined by hematoxylin and eosin staining. Human first-trimester extravilloustrophoblast cell line (TEV-1) was applied in vitro experiment, which was divided into4groups: control, LPS, LPS+LXA4and LPS+LXA4+BOC-2group. The vitalityof TEV-1cells was measured by MTT assay and the apoptosis rates of TEV-1cellswere analyzed through FACS assay. In placental tissues, serum specimens and TEV-1cells, the MDA concentration was examined with TBARS assay kit; the mRNAexpression of SOD, GPx and HO-1were tested by RT-PCR; the protein expression ofp-Erk and NF-κB were tested by western blotting.Results:(1) In LPS group the blood pressure and24h-urinary albumin excretion ofpregnant rats significantly increased on day15,17and19of pregnacy and themorphological changes of placenta and kidney were characterized by thickening theplacenta vessel walls and accumulating lymphocytes in glomerular endothelial cells(compared with control group, p <0.05). BML-111could effectively alleviate theinjury induced by LPS (compared with LPS group, p <0.05).(2)In LPS group MDA concentration significantly increased in placenta tissues andserum specimens; the mRNA expressions of SOD, GPx and HO-1weredownregulated and the protein expressions of p-Erk and NF-κB wereupregulated(compared with control group, p <0.05). BML-111could effectivelyreverse these changes (compared with LPS group, p <0.05).(3) In LPS group the vitality of TEV-1cells decreased and the apoptosis ratessignificantly increased (p <0.05); LXA4could promote the proliferation and inhibitthe apoptosis of LPS-stimulated TEV-1cells (compared with LPS group, p <0.05); LXA4receptor antagonist (Boc-2) could partially blocked the protection effect ofLXA4(compared with LPS+LXA4group, p <0.05).(4) In LPS group the content of MDA significantly increased in TEV-1cells, themRNA expressions of SOD, GPx and HO-1were downregulated and the proteinexpressions of p-Erk and NF-κB were upregulated(compared with control group, p <0.05). LXA4could effectively reverse these changes (compared with LPS group, p <0.05), Boc-2could partially blocked the effect of LXA4(compared with LPS+LXA4group, p <0.05).Conclusions：Pregnant rats were infused with low dose of LPS on day14ofpregnancy, which could minic PE. LXA4could effectively alleviate the symptoms ofPE, the possible mechanism was that LXA4suppressed the activity of ERK to inhibitthe oxidation-sensitive transcription factor NF-κB, leading to increase the expressionof antioxidant enzymes(SOD, GPx and HO-1).