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Altered expression of Notch signaling, Tlr receptors, and surfactant protein expression after prostaglandin inhibition may be associated with the delayed labor in LPS-induced mice

  • Reproductive Physiology and Disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

This study aims to investigate whether indomethacin (IND) delays preterm birth by regulating the Notch pathway, Tlr receptors, and Sp-A in the placenta in lipopolysaccharide (LPS)-induced preterm labor (PTL) model.

Methods

CD-1 mice were distributed to the pregnant control (PC), Sham, PBS, IND (2 mg/kg; i.p.), LPS (25 μg/100 μl; intrauterine), and LPS + IND groups. The injections were performed on day 14.5 of pregnancy. Placentae were collected on day 15.5 of pregnancy, and immunohistochemical analyzes were performed. Differences in staining intensities between the Cox-1, Notch-1 (N1), Dll-1, Jagged-2 (Jag-2), Tlr-2, and Tlr-4 proteins were compared.

Results

Preterm labor rates were 100% and 66% (preterm delivery delayed 5 h) in the LPS and LPS + IND groups, respectively. In LPS-treated mice, a general morphological deterioration was observed in the placenta. Total placental mid-sagittal measurement was significantly reduced in the LPS-treated group, while it was similar to the PC group in the LPS + IND group. Cox-1 expression in the LZ increased, and Sp-A expression decreased after LPS injection, and IND administration diminished this increase. N1 expression increased in the labyrinth zone (LZ) and the junctional zone (JZ). Dll-1 and Jag-2 expression increased in the JZ after LPS injection (p < 0.0001). IND administration diminished Tlr-2 expression in the LZ and Tlr-4 expression in the JZ after LPS injection.

Conclusion

In conclusion, PG (prostaglandin) inhibition may alter Notch signaling, Tlr, and Sp-A protein expression and may be associated with delayed labor in LPS-induced mice.

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Data availability

All data will be provided by the corresponding author upon request.

References

  1. Furuya M, et al. Pathophysiology of placentation abnormalities in pregnancy-induced hypertension. Vasc Health Risk Manag. 2008;4(6):1301–13.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Maltepe E, Fisher SJ. Placenta: the forgotten organ. Annu Rev Cell Dev Biol. 2015;31:523–52.

    Article  CAS  PubMed  Google Scholar 

  3. Fisher SJ. The placenta dilemma. Semin Reprod Med. 2000;18(3):321–6.

    Article  CAS  PubMed  Google Scholar 

  4. Isaac SM, et al. In: Anne Croy B, et al., editors. Anatomy of the mouse placenta throughout gestation, in the guide to investigation of mouse pregnancy: Academic Press; 2014. p. 69–74.

    Chapter  Google Scholar 

  5. Azevedo Portilho N, Pelajo-Machado M. Mechanism of hematopoiesis and vasculogenesis in mouse placenta. Placenta. 2018;69:140–5.

    Article  CAS  PubMed  Google Scholar 

  6. Azevedo Portilho N, et al. Localization of transient immature hematopoietic cells to two distinct, potential niches in the developing mouse placenta. Placenta. 2016;47:1–11.

    Article  CAS  PubMed  Google Scholar 

  7. Hu D, Cross JC. Development and function of trophoblast giant cells in the rodent placenta. Int J Dev Biol. 2010;54(2-3):341–54.

    Article  CAS  PubMed  Google Scholar 

  8. Simmons DG, Fortier AL, Cross JC. Diverse subtypes and developmental origins of trophoblast giant cells in the mouse placenta. Dev Biol. 2007;304(2):567–78.

    Article  CAS  PubMed  Google Scholar 

  9. Hemberger M, Hanna CW, Dean W. Mechanisms of early placental development in mouse and humans. Nat Rev Genet. 2020;21(1):27–43.

    Article  CAS  PubMed  Google Scholar 

  10. Bolon B. In: Anne Croy B, et al., editors. Pathology analysis of the placenta, in The guide to investigation of mouse pregnancy: Elsevier Inc.; 2014. p. 175–88.

    Chapter  Google Scholar 

  11. De Falco M, et al. Expression and distribution of notch protein members in human placenta throughout pregnancy. Placenta. 2007;28(2-3):118–26.

    Article  PubMed  CAS  Google Scholar 

  12. Hunkapiller NM, et al. A role for Notch signaling in trophoblast endovascular invasion and in the pathogenesis of pre-eclampsia. Development. 2011;138(14):2987–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gasperowicz M, Otto F. The notch signalling pathway in the development of the mouse placenta. Placenta. 2008;29(8):651–9.

    Article  CAS  PubMed  Google Scholar 

  14. Zhao WX, Lin JH. Notch signaling pathway and human placenta. Int J Med Sci. 2012;9(6):447–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Walker L, et al. The notch receptor and its ligands are selectively expressed during hematopoietic development in the mouse. Stem Cells. 2001;19(6):543–52.

    Article  CAS  PubMed  Google Scholar 

  16. Gasperowicz M, Rai A, Cross JC. Spatiotemporal expression of Notch receptors and ligands in developing mouse placenta. Gene Expr Patterns. 2013;13(7):249–54.

    Article  CAS  PubMed  Google Scholar 

  17. Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006;7(9):678–89.

    Article  CAS  PubMed  Google Scholar 

  18. Keewan E, Naser SA. The role of notch signaling in macrophages during inflammation and infection: implication in rheumatoid arthritis? Cells. 2020;9(1).

  19. Shang Y, Smith S, Hu X. Role of Notch signaling in regulating innate immunity and inflammation in health and disease. Protein Cell. 2016;7(3):159–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Agrawal V, et al. Role of Notch signaling during lipopolysaccharide-induced preterm labor. J Leukoc Biol. 2016;100(2):261–74.

    Article  CAS  PubMed  Google Scholar 

  21. Bollapragada S, et al. Term labor is associated with a core inflammatory response in human fetal membranes, myometrium, and cervix. Am J Obstet Gynecol. 2009;200(1):104–e1-11.

    PubMed  Google Scholar 

  22. Boyle AK, et al. Preterm birth: inflammation, fetal injury and treatment strategies. J Reprod Immunol. 2017;119:62–6.

    Article  PubMed  Google Scholar 

  23. Eloundou SN, et al. Placental malperfusion in response to intrauterine inflammation and its connection to fetal sequelae. PLoS One. 2019;14(4):e0214951.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Renaud SJ, et al. Spontaneous pregnancy loss mediated by abnormal maternal inflammation in rats is linked to deficient uteroplacental perfusion. J Immunol. 2011;186(3):1799–808.

    Article  CAS  PubMed  Google Scholar 

  25. Timmons BC, et al. Prostaglandins are essential for cervical ripening in LPS-mediated preterm birth but not term or antiprogestin-driven preterm ripening. Endocrinology. 2014;155(1):287–98.

    Article  PubMed  CAS  Google Scholar 

  26. Rankin JG. A role for prostaglandins in the regulation of the placental blood flows. Prostaglandins. 1976;11(2):343–53.

    Article  CAS  PubMed  Google Scholar 

  27. Rhind SG, et al. Indomethacin inhibits circulating PGE2 and reverses postexercise suppression of natural killer cell activity. Am J Phys. 1999;276(5):R1496–505.

    CAS  Google Scholar 

  28. Snegovskikh VV, et al. Surfactant protein-A (SP-A) selectively inhibits prostaglandin F2alpha (PGF2alpha) production in term decidua: implications for the onset of labor. J Clin Endocrinol Metab. 2011;96(4):E624–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wright JR. Immunoregulatory functions of surfactant proteins. Nat Rev Immunol. 2005;5(1):58–68.

    Article  CAS  PubMed  Google Scholar 

  30. Agrawal V, et al. Surfactant protein (SP)-A suppresses preterm delivery and inflammation via TLR2. PLoS One. 2013;8(5):e63990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sones JL, Davisson RL. Preeclampsia, of mice and women. Physiol Genomics. 2016;48(8):565–72.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Zhang YH, et al. Modulators of the balance between M1 and M2 macrophages during pregnancy. Front Immunol. 2017;8:120.

    PubMed  PubMed Central  Google Scholar 

  33. Altshuler G, et al. Premature onset of labor, neonatal patent ductus arteriosus, and prostaglandin synthetase antagonists--a rat model of a human problem. Am J Obstet Gynecol. 1979;135(2):261–5.

    Article  CAS  PubMed  Google Scholar 

  34. Lai JH, et al. A randomized trial comparing the efficacy of single-dose and double-dose administration of rectal indomethacin in preventing post-endoscopic retrograde cholangiopancreatography pancreatitis. Medicine (Baltimore). 2019;98(20):e15742.

    Article  Google Scholar 

  35. Huang H, et al. Sensitivity of mice to lipopolysaccharide is increased by a high saturated fat and cholesterol diet. J Inflamm (Lond). 2007;4:22.

    Article  CAS  Google Scholar 

  36. Grigsby PL, et al. Fetal responses to maternal and intra-amniotic lipopolysaccharide administration in sheep. Biol Reprod. 2003;68(5):1695–702.

    Article  CAS  PubMed  Google Scholar 

  37. Kim HS, et al. Endotoxin-neutralizing antimicrobial proteins of the human placenta. J Immunol. 2002;168(5):2356–64.

    Article  CAS  PubMed  Google Scholar 

  38. Xue H, et al. Indomethacin inhibits PGE2, regulates inflammatory response, participates in adipogenesis regulation, and improves success rate of fat transplantation in C57/B6 mice. Trop J Pharm Res. 2019;18(11):2313–8.

    Google Scholar 

  39. Charlier C, Michaux C. Dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) as a new strategy to provide safer non-steroidal anti-inflammatory drugs. Eur J Med Chem. 2003;38(7-8):645–59.

    Article  CAS  PubMed  Google Scholar 

  40. Gross G, et al. Inhibition of cyclooxygenase-2 prevents inflammation-mediated preterm labor in the mouse. Am J Phys Regul Integr Comp Phys. 2000;278(6):R1415–23.

    CAS  Google Scholar 

  41. Gross GA, et al. Opposing actions of prostaglandins and oxytocin determine the onset of murine labor. Proc Natl Acad Sci U S A. 1998;95(20):11875–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Benedito R, et al. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell. 2009;137(6):1124–35.

    Article  CAS  PubMed  Google Scholar 

  43. Blanco R, Gerhardt H. VEGF and Notch in tip and stalk cell selection. Cold Spring Harb Perspect Med. 2013;3(1):a006569.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Boareto M, et al. Jagged mediates differences in normal and tumor angiogenesis by affecting tip-stalk fate decision. Proc Natl Acad Sci U S A. 2015;112(29):E3836–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tunster SJ, et al. Placental glycogen stores and fetal growth: insights from genetic mouse models. Reproduction. 2020;159(6):R213–35.

    Article  CAS  PubMed  Google Scholar 

  46. Kim W, et al. Notch signaling in pancreatic endocrine cell and diabetes. Biochem Biophys Res Commun. 2010;392(3):247–51.

    Article  CAS  PubMed  Google Scholar 

  47. Moco NP, et al. Gene expression and protein localization of TLR-1, -2, -4 and -6 in amniochorion membranes of pregnancies complicated by histologic chorioamnionitis. Eur J Obstet Gynecol Reprod Biol. 2013;171(1):12–7.

    Article  CAS  PubMed  Google Scholar 

  48. Kim YM, et al. Toll-like receptor-2 and -4 in the chorioamniotic membranes in spontaneous labor at term and in preterm parturition that are associated with chorioamnionitis. Am J Obstet Gynecol. 2004;191(4):1346–55.

    Article  CAS  PubMed  Google Scholar 

  49. Jing X, et al. Toll-like receptor 2/4 inhibitors can reduce preterm birth in mice. J Int Med Res. 2020;48(10):300060520933795.

    Article  CAS  PubMed  Google Scholar 

  50. Henning LN, et al. Pulmonary surfactant protein A regulates TLR expression and activity in human macrophages. J Immunol. 2008;180(12):7847–58.

    Article  CAS  PubMed  Google Scholar 

  51. Borron P, et al. Surfactant-associated protein A inhibits LPS-induced cytokine and nitric oxide production in vivo. Am J Phys Lung Cell Mol Phys. 2000;278(4):L840–7.

    CAS  Google Scholar 

  52. LeVine AM, Whitsett JA. Pulmonary collectins and innate host defense of the lung. Microbes Infect. 2001;3(2):161–6.

    Article  CAS  PubMed  Google Scholar 

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Funding

SA was funded by the Scientific and Technological Research Council of Turkey with International Research Fellowship 2214-A Programme for PhD students grant (1059B141700505-2214/A. The study represents a part of the PhD thesis of SA.

Author information

Authors and Affiliations

  1. Department of Histology and Embryology, School of Medicine, Alanya Alaaddin Keykubat University, Alanya, Turkey

    Sema Avci

  2. Department of Histology and Embryology, School of Medicine, Akdeniz University, Antalya, Turkey

    Nilay Kuscu, Begum Durkut, Leyla Kilinc & Ismail Ustunel

  3. Department of Histology and Embryology, School of Medicine, Koc University, Istanbul, Turkey

    Ciler Celik-Ozenci

  4. Koç University Research Center for Translational Medicine (KUTTAM), Koc University, Istanbul, Turkey

    Ciler Celik-Ozenci

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  1. Sema Avci
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  2. Nilay Kuscu
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  4. Leyla Kilinc
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  6. Ciler Celik-Ozenci
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Contributions

SA designed the study, performed the experimental procedures, analyzed the data, and drafted the manuscript. NK, BD, and LK assisted SA during experiments, surgical procedures, and data generation. IU acted as a consultant during the execution of the project. CCO contributed to the data analysis and drafting of the article.

Corresponding author

Correspondence to Ciler Celik-Ozenci.

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Ethics approval

The Animal Research Ethical Committee approved the experimental protocol of Akdeniz University by protocol number 1201/2020.10.008. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.

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All authors have read and accepted the content of the article; all authors have their consent to participate in the study.

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The authors declare no competing interests.

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Part of the study has been presented as a poster presentation at the 77th American Society for Reproductive Medicine Scientific Congress that has been held in Baltimore in person and on-demand between 17–20 October 2021.

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Avci, S., Kuscu, N., Durkut, B. et al. Altered expression of Notch signaling, Tlr receptors, and surfactant protein expression after prostaglandin inhibition may be associated with the delayed labor in LPS-induced mice. J Assist Reprod Genet 39, 1531–1544 (2022). https://doi.org/10.1007/s10815-022-02515-y

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  • DOI: https://doi.org/10.1007/s10815-022-02515-y

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