Reproductive Sciences

, Volume 18, Issue 11, pp 1071–1079 | Cite as

Expression of Coagulation-Related Protein Genes During LPS-Induced Preterm Delivery in the Pregnant Mouse

  • Mark PhillippeEmail author
  • Allaire K. Diamond
  • Leigh M. Sweet
  • Karen H. Oppenheimer
  • Diana F. Bradley
Original Articles


Preterm delivery (PTD) has been associated with inflammation along with activation of the coagulation pathway. These studies sought to characterize the expression of several coagulation pathway genes including plasminogen activator inhibitor 1 (PAI-1), tissue factor (TF), protease-activated receptor 1 (Par1), protease-activated receptor 2 (Par2), fibrinogen-like protein 2 (Fgl2), and thrombomodulin (TM) during lipopolysaccharide (LPS)-induced PTD in day 15 pregnant CD-1 mice. Western blot studies confirmed protein expression for PAI-1, Par1, Par2, Fgl2, and TM in the mouse uterus. Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) confirmed increased PAI-1 messenger RNA (mRNA) in the uteri, lung, kidney, and liver tissues at 2 to 6 hours after LPS injection. In contrast, TF expression significantly decreased by 12 hours in uterine tissue; whereas, its expression was unchanged in the other maternal tissues. The uterine mRNA for Par1, Par2, Fgl2, and TM remained stable. In summary, these studies have confirmed expression of coagulation pathway genes within the pregnant uterus; some of which are modulated during LPS-induced PTD.


plasminogen activator inhibitor 1 tissue factor lipopolysaccharide preterm delivery CD-1 mouse 


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  1. 1.
    Callaghan WM, MacDorman MF, Rasmussen SA, Qin C, Lackritz EM. The contribution of preterm birth to infant mortality rates in the United States. Pediatrics. 2006;118(4):1566–1573.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Petrou S. The economic consequences of preterm birth during the first 10 years of life. Bjog. 2005;112(suppl 1): 10–15.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Hirsch E, Wang H. The molecular pathophysiology of bacterially induced preterm labor: insights from the murine model. J Soc Gynecol Investig. 2005;12(3):145–155.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Elovitz MA, Wang Z, Chien EK, Rychlik DF, Phillippe M. A new model for inflammation-induced preterm birth: the role of platelet-activating factor and Toll-like receptor-4. Am J Pathol. 2003;163(5):2103–2111.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Tornblom SA, Klimaviciute A, Bystrom B, Chromek M, Brauner A, Ekman-Ordeberg G. Non-infected preterm parturition is related to increased concentrations of IL-6, IL-8 and MCP-1 in human cervix. Reprod Biol Endocrinol. 2005;3:39.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Gravett MG, Hitti J, Hess DL, Eschenbach DA. Intrauterine infection and preterm delivery: evidence for activation of the fetal hypothalamic-pituitary-adrenal axis. Am J Obstet Gynecol. 2000;182(6):1404–1413.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Gravett MG, Witkin SS, Haluska GJ, Edwards JL, Cook MJ, Novy MJ. An experimental model for intraamniotic infection and preterm labor in rhesus monkeys. Am J Obstet Gynecol. 1994;171(6):1660–1667.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Leslie KK, Lee SL, Woodcock SM, et al. Acute intrauterine infection results in an imbalance between pro- and anti-inflammatory cytokines in the pregnant rabbit. Am J Reprod Immunol. 2000;43(5):305–311.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Mussalli GM, Brunnert SR, Hirsch E. Preterm delivery in mice with renal abscess. Obstet Gynecol. 2000;95(3):453–456.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Renckens R, Pater JM, van der Poll T. Plasminogen activator inhibitor type-1-deficient mice have an enhanced IFN-gamma response to lipopolysaccharide and staphylococcal enterotoxin B. J Immunol. 2006;177(11):8171–8176.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Thibeault I, Laflamme N, Rivest S. Regulation of the gene encoding the monocyte chemoattractant protein 1 (MCP-1) in the mouse and rat brain in response to circulating LPS and proinflammatory cytokines J Comp Neurol. 2001;434(4): 461–477.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Sun S, Zhang H, Xue B, et al. Protective effect of glutathione against lipopolysaccharide-induced inflammation and mortality in rats. Inflamm Res. 2006;55(11):504–510.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Morello S, Vellecco V, Roviezzo F, et al. A protective role for proteinase activated receptor 2 in airways of lipopolysaccharide-treated rats. Biochem Pharmacol. 2005;71(1–2):223–230.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Steiner AA, Li S, Llanos QJ, Blatteis CM. Differential inhibition by nimesulide of the early and late phases of intravenous- and intracerebroventricular-LPS-induced fever in guinea pigs. Neuroimmunomodulation. 2001 ;9(5):263–275.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Kabaroff LC, Rodriguez A, Quinton M, Boermans H, Karrow NA. Assessment of the ovine acute phase response and hepatic gene expression in response to Escherichia coli endotoxin. Vet Immunol Immunopathol. 2006;113(1–2): 113–124.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Maris NA, de Vos AF, Bresser P, et al. Activation of coagulation and inhibition of fibrinolysis in the lung after inhalation of lipopolysaccharide by healthy volunteers. Thromb Haemost. 2005;93(6):1036–1040.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Salminen A, Paananen R, Vuolteenaho R, et al. Maternal endotoxin-induced preterm birth in mice: fetal responses in tolllike receptors, collectins, and cytokines. Pediatr Res. 2008;63(3):280–286.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Diamond AK, Sweet LM, Oppenheimer KH, Bradley DF, Phillippe M. Modulation of monocyte chemotactic protein-1 expression during lipopolysaccharide-induced preterm delivery in the pregnant mouse. Reprod Sci. 2007;14(6):548–559.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Chaouat G. Synergy of lipopolysaccharide and inflammatory cytokines in murine pregnancy: alloimmunization prevents abortion but does not affect the induction of preterm delivery. Cell Immunol. 1994;157(2):328–340.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Mitsuhashi Y, Otsuki K, Yoda A, Shimizu Y, Saito H, Yanaihara T. Effect of lactoferrin on lipopolysaccharide (LPS) induced preterm delivery in mice. Acta Obstet Gynecol Scand. 2000;79(5):355–358.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Esmon CT. The interactions between inflammation and coagulation. Br J Haematol. 2005;131(4):417–430.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Strukova S. Blood coagulation-dependent inflammation. Coagulation-dependent inflammation and inflammation-dependent thrombosis. Front Biosci. 2006;11:59–80.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Levi M, Keller TT, van Gorp E, ten Cate H. Infection and inflammation and the coagulation system Cardiovasc Res. 2003;60(1): 26–39.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Biemond BJ, Levi M, Ten Cate H, et al. Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades Clin Sci (Lond). 1995;88(5): 587–594.Google Scholar
  25. 25.
    van Deventer SJ, Buller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood. 1990;76(12):2520–2526.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Dellas C, Loskutoff DJ. Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease. Thromb Haemost. 2005;93(4):631–640.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Chu AJ. Tissue factor mediates inflammation Arch Biochem Biophys. 2005;440(2): 123–132.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Phillippe M, Bradley DF, Phillippe K, Engle D. Tissue prothrom-binase activity in myometrium from timed-pregnant rats. J Soc Gynecol Investig. 2006;13(7):477–482.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Pawlinski R, Mackman N. Tissue factor, coagulation proteases, and protease-activated receptors in endotoxemia and sepsis. Crit Care Med. 2004;32(5 suppl):S293–S297.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Zeerleder S, Schroeder V, Hack CE, Kohler HP, Wuillemin WA. TAFI and PAI-1 levels in human sepsis Thromb Res. 2006;118(2): 205–212.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Deng G, Curriden SA, Wang S, Rosenberg S, Loskutoff DJ. Is plasminogen activator inhibitor-1 the molecular switch that governs urokinase receptor-mediated cell adhesion and release? J Cell Biol. 1996;134(6):1563–1571.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Tanjung MT, Siddik HD, Hariman H, Koh SC. Coagulation and fibrinolysis in preeclampsia and neonates. Clin Appl Thromb Hemost. 2005;11(4):467–473.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Coolman M, de Groot CJ, Steegers EA, et al. Concentrations of plasminogen activators and their inhibitors in blood preconcep-tionally, during and after pregnancy. Eur J Obstet Gynecol Reprod Biol. 2006;128(1–2):22–28.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Kruithof EK, Tran-Thang C, Gudinchet A, et al. Fibrinolysis in pregnancy: a study of plasminogen activator inhibitors. Blood. 1987;69(2):460–466.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Glueck CJ, Kupferminc MJ, Fontaine RN, Wang P, Weksler BB, Eldor A. Genetic hypofibrinolysis in complicated pregnancies. Obstet Gynecol. 2001;97(1):44–48.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Elovitz MA, Baron J, Phillippe M. The role of thrombin in preterm parturition. Am J Obstet Gynecol. 2001;185(5):1059–1063.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Chaiworapongsa T, Espinoza J, Yoshimatsu J, et al. Activation of coagulation system in preterm labor and preterm premature rupture of membranes J Matern Fetal Neonatal Med. 2002;11(6): 368–373.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Rosen T, Kuczynski E, O’Neill LM, Funai EF, Lockwood CJ. Plasma levels of thrombin-antithrombin complexes predict preterm premature rupture of the fetal membranes. J Matern Fetal Med. 2001;10(5):297–300.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Chien EK, Sweet L, Phillippe M, et al. Protease-activated receptor isoform expression in pregnant and nonpregnant rat myometrial tissue. J Soc Gynecol Investig. 2003;10(8):460–468.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Fidel PI Jr, Romero R, Maymon E, Hertelendy F. Bacteria-induced or bacterial product-induced preterm parturition in mice and rabbits is preceded by a significant fall in serum progesterone concentrations. J Matern Fetal Med. 1998;7(5):222–226.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Elovitz M, Wang Z. Medroxyprogesterone acetate, but not progesterone, protects against inflammation-induced parturition and intrauterine fetal demise Am J Obstet Gynecol. 2004;190(3): 693–701.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Hirsch E, Muhle R. Intrauterine bacterial inoculation induces labor in the mouse by mechanisms other than progesterone withdrawal Biol Reprod. 2002;67(4): 1337–1341.PubMedPubMedCentralGoogle Scholar

Copyright information

© Society for Reproductive Investigation 2011

Authors and Affiliations

  • Mark Phillippe
    • 1
    Email author
  • Allaire K. Diamond
    • 1
  • Leigh M. Sweet
    • 1
  • Karen H. Oppenheimer
    • 1
  • Diana F. Bradley
  1. 1.Department of Obstetrics, Gynecology and Reproductive Sciences, College of MedicineUniversity of VermontBurlingtonUSA

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