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

Xue P, Zheng M, Gong P, Lin C, Zhou J, Li Y, Shen L, Diao Z, Yan G, Sun H, Hu Y - PLoS ONE (2015)

Bottom Line: Balanced immune responses are essential for the maintenance of successful pregnancy.Toll-like receptor 4 (TLR4) plays a crucial role in the activation of immune system at the maternal-fetal interface.This was accompanied with adverse pregnancy outcomes including fetal growth restriction.

View Article: PubMed Central - PubMed

Affiliation: Drum Tower Clinical Medical College, Nanjing Medical University, Nanjing, China.

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.

No MeSH data available.


Related in: MedlinePlus

Expression of TLR4 and NF-κB p65 in the kidney of different pregnant groups.Immunohistochemistry for TLR4 (A) and NF-κB p65 (B) in paraffin-embedded renal tissue sections (4 μm) from the saline-treated and LPS-treated pregnant rats. Corresponding concentrations of anti-IgG served as non-specific controls (C). Data are expressed as mean ± SEM, N = 1 kidney for 10 rats/group, N.S. means P > 0.05. Magnification 400 ×. Bar 100 μm.
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pone.0124001.g005: Expression of TLR4 and NF-κB p65 in the kidney of different pregnant groups.Immunohistochemistry for TLR4 (A) and NF-κB p65 (B) in paraffin-embedded renal tissue sections (4 μm) from the saline-treated and LPS-treated pregnant rats. Corresponding concentrations of anti-IgG served as non-specific controls (C). Data are expressed as mean ± SEM, N = 1 kidney for 10 rats/group, N.S. means P > 0.05. Magnification 400 ×. Bar 100 μm.

Mentions: Histological examination of the kidney showed that LPS administration to rats in early pregnancy caused glomerular endothelial swelling with occlusion of capillary loops and urinary space (Fig 4). To determine whether renal morphological alterations were associated with the immune response of the kidney per se, the expression and location of TLR4 and its downstream target NF-κB p65 in the kidney were assessed by immunostaining (Fig 5). Predominantly expressed by tubular epithelial cell in the kidney, TLR4 had similar expression in the pregnant groups (Fig 5A). Similarly, the expression of NF-κB p65 was not significantly different in the kidney of the pregnant groups (Fig 5B).


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

Xue P, Zheng M, Gong P, Lin C, Zhou J, Li Y, Shen L, Diao Z, Yan G, Sun H, Hu Y - PLoS ONE (2015)

Expression of TLR4 and NF-κB p65 in the kidney of different pregnant groups.Immunohistochemistry for TLR4 (A) and NF-κB p65 (B) in paraffin-embedded renal tissue sections (4 μm) from the saline-treated and LPS-treated pregnant rats. Corresponding concentrations of anti-IgG served as non-specific controls (C). Data are expressed as mean ± SEM, N = 1 kidney for 10 rats/group, N.S. means P > 0.05. Magnification 400 ×. Bar 100 μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390151&req=5

pone.0124001.g005: Expression of TLR4 and NF-κB p65 in the kidney of different pregnant groups.Immunohistochemistry for TLR4 (A) and NF-κB p65 (B) in paraffin-embedded renal tissue sections (4 μm) from the saline-treated and LPS-treated pregnant rats. Corresponding concentrations of anti-IgG served as non-specific controls (C). Data are expressed as mean ± SEM, N = 1 kidney for 10 rats/group, N.S. means P > 0.05. Magnification 400 ×. Bar 100 μm.
Mentions: Histological examination of the kidney showed that LPS administration to rats in early pregnancy caused glomerular endothelial swelling with occlusion of capillary loops and urinary space (Fig 4). To determine whether renal morphological alterations were associated with the immune response of the kidney per se, the expression and location of TLR4 and its downstream target NF-κB p65 in the kidney were assessed by immunostaining (Fig 5). Predominantly expressed by tubular epithelial cell in the kidney, TLR4 had similar expression in the pregnant groups (Fig 5A). Similarly, the expression of NF-κB p65 was not significantly different in the kidney of the pregnant groups (Fig 5B).

Bottom Line: Balanced immune responses are essential for the maintenance of successful pregnancy.Toll-like receptor 4 (TLR4) plays a crucial role in the activation of immune system at the maternal-fetal interface.This was accompanied with adverse pregnancy outcomes including fetal growth restriction.

View Article: PubMed Central - PubMed

Affiliation: Drum Tower Clinical Medical College, Nanjing Medical University, Nanjing, China.

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.

No MeSH data available.


Related in: MedlinePlus