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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

Trophoblast invasion and SA remodeling in different pregnant groups.Representative PAS staining of fibrinoid (solid arrows), cytokeratin staining of trophoblast invasion (solid arrowheads), and α-SMA staining of VSMC (hollow arrows) in the SA of mesometrial triangle. The percentages of fibrinoid (A), trophoblast (B) and VSMC (C) of total SA contour length were determined. Corresponding concentrations of anti-IgG served as non-specific controls (D).Data are mean ± SEM, 2–3 SAs measured from 1–2 implantation sites per rat, N = 10 rats per group. **P<0.01 vs. saline-treated pregnant group. Magnification 200 ×. Bar 100 μm.
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pone.0124001.g003: Trophoblast invasion and SA remodeling in different pregnant groups.Representative PAS staining of fibrinoid (solid arrows), cytokeratin staining of trophoblast invasion (solid arrowheads), and α-SMA staining of VSMC (hollow arrows) in the SA of mesometrial triangle. The percentages of fibrinoid (A), trophoblast (B) and VSMC (C) of total SA contour length were determined. Corresponding concentrations of anti-IgG served as non-specific controls (D).Data are mean ± SEM, 2–3 SAs measured from 1–2 implantation sites per rat, N = 10 rats per group. **P<0.01 vs. saline-treated pregnant group. Magnification 200 ×. Bar 100 μm.

Mentions: Trophoblast invasion and trophoblast-mediated SA remodeling in the mesometrial triangle were assessed (Fig 3). PAS staining revealed decreased deposition of fibrinoid in the SA of the LPS-treated pregnant group compared with that in the control pregnant group (Fig 3A). Specifically, cytokeratin staining revealed that the LPS-treated pregnant group was significantly less prone to trophoblast invasion of SA than the control pregnant group (Fig 3B). However, significantly more of the SA contour was occupied by α-SMA-positive VSMCs in the LPS-treated pregnant group (Fig 3C). Hence, LPS administration to rats in early pregnancy undermined trophoblast invasion and SA remodeling.


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)

Trophoblast invasion and SA remodeling in different pregnant groups.Representative PAS staining of fibrinoid (solid arrows), cytokeratin staining of trophoblast invasion (solid arrowheads), and α-SMA staining of VSMC (hollow arrows) in the SA of mesometrial triangle. The percentages of fibrinoid (A), trophoblast (B) and VSMC (C) of total SA contour length were determined. Corresponding concentrations of anti-IgG served as non-specific controls (D).Data are mean ± SEM, 2–3 SAs measured from 1–2 implantation sites per rat, N = 10 rats per group. **P<0.01 vs. saline-treated pregnant group. Magnification 200 ×. Bar 100 μm.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0124001.g003: Trophoblast invasion and SA remodeling in different pregnant groups.Representative PAS staining of fibrinoid (solid arrows), cytokeratin staining of trophoblast invasion (solid arrowheads), and α-SMA staining of VSMC (hollow arrows) in the SA of mesometrial triangle. The percentages of fibrinoid (A), trophoblast (B) and VSMC (C) of total SA contour length were determined. Corresponding concentrations of anti-IgG served as non-specific controls (D).Data are mean ± SEM, 2–3 SAs measured from 1–2 implantation sites per rat, N = 10 rats per group. **P<0.01 vs. saline-treated pregnant group. Magnification 200 ×. Bar 100 μm.
Mentions: Trophoblast invasion and trophoblast-mediated SA remodeling in the mesometrial triangle were assessed (Fig 3). PAS staining revealed decreased deposition of fibrinoid in the SA of the LPS-treated pregnant group compared with that in the control pregnant group (Fig 3A). Specifically, cytokeratin staining revealed that the LPS-treated pregnant group was significantly less prone to trophoblast invasion of SA than the control pregnant group (Fig 3B). However, significantly more of the SA contour was occupied by α-SMA-positive VSMCs in the LPS-treated pregnant group (Fig 3C). Hence, LPS administration to rats in early pregnancy undermined trophoblast invasion and SA remodeling.

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