Advertisement

Inflammation of the Fetal Ovine Skin Following in utero Exposure to Ureaplasma parvum

Abstract

There is increasing evidence linking in utero infection and inflammation to preterm birth. Many commensal urogenital tract microorganisms, including the Mycoplasmas and Ureaplasmas, are commonly detected in association with preterm birth. Using an ovine model of sterile fetal inflammation, we demonstrated previously that the fetal skin generates a robust inflammatory response following in utero exposure to lipopolysaccharides from Escherichia coli. The fetal skin’s response to colonization of the amniotic fluid by viable microorganisms remains unstudied. We hypothesised that in utero infection with Ureaplasma parvum serovar 3 would induce a proinflammatory response in the fetal skin. We found that (1) cultured fetal keratinocytes (the primary cellular constituent of the epidermis) respond to U. parvum exposure in vitro by increasing the expression of the chemotactant monocyte chemoattractant protein 1 (MCP-1) but not interleukin 1β (IL-1β), IL-6, IL-8, or tumor necrosis factor-α (TNF-α); (2) the fetal skin’s response to 7 days of U. parvum exposure is characterized by elevated expression of MCP-1, TNF-α, and IL-10; and (3) the magnitude of inflammatory cytokine/chemokine expression in the fetal skin is dependent on the duration of U parvum exposure. These novel findings provide further support for the role of the fetal skin in the development of fetal inflammation and the preterm birth that may follow.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 510

This is the net price. Taxes to be calculated in checkout.

References

  1. 1.

    Janeway CA, Travers P, Walport M, Shlomchik M. Basic Concepts in Immunobiology. New York: Garland; 2001.

  2. 2.

    Liggins GC. Cervical ripening as an inflammatory reaction. In: Ellwood DA, Anderson ABM, eds. The Cervix in Pregnancy and Labour, Clinical and Biochemical Investigations. Edinburgh: Churchill Livingstone; 1981:1–9.

  3. 3.

    Sennstromm MB, Ekman G, Westergren-Thorsson G, et al. Human cervical ripening, an inflammatory process mediated by cytokines. Mol Hum Reprod. 2000;6(4):375–381.

  4. 4.

    Kramer BW, Joshi SN, Moss TJ, et al. Endotoxin-induced maturation of monocytes in preterm fetal sheep lung. Am J Physiol Lung Cell Mol Physiol. 2007;293(2):L345–L353.

  5. 5.

    Moss TJM, Knox CL, Kallapur SG, et al. Experimental amniotic fluid infection in sheep: Effects of Ureaplasma parvum serovars 3 and 6 on preterm or term fetal sheep. Am J Obstet. Gynecol. 2008;198(1):122.e121–122.e128.

  6. 6.

    Newnham JP, Shub A, Jobe AH, et al. The effects of intra-amniotic injection of periodontopathic lipopolysaccharides in sheep. Am J Obstet Gynecol. 2005;193(2):313–321.

  7. 7.

    Romero R, Espinoza J, Goncͧalves LF, Kusanovic JP, Friel L, Hassan S. The role of inflammation and infection in preterm birth. Semin Reprod Med. 2007;25(1):21–39.

  8. 8.

    Romero R, Mazor M, Brandt F, et al. Interleukin-1 alpha and interleukin-1 beta in preterm and term human parturition. Am J Reprod Immunol. 1992;27(3–4): 117–123.

  9. 9.

    Sadowsky DW, Adams KM, Gravett MG, Witkin SS, Novy MJ. Preterm labor is induced by intraamniotic infusions of interleukin-1 beta and tumor necrosis factor-alpha but not by interleukin-6 or interleukin-8 in a nonhuman primate model. Am J Obstet Gynecol. 2006;195(6):1578–1589.

  10. 10.

    Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol. 1998;179(1):194–202.

  11. 11.

    Romero R, Espinoza J, Goncalves LF, Kusanovic JP, Friel LA, Nien JK. Inflammation in preterm and term labour and delivery. Semin Fetal Neonatal Med. 2006;11(5):317–326.

  12. 12.

    Romero R, Espinoza J, Goncalves LF, Kusanovic JP, Friel L, Hassan S. The role of inflammation and infection in preterm birth. Semin Reprod Med. 2007;25(1):21–39.

  13. 13.

    Gomez R, Ghezzi F, Römern R, Yoon BH, Mazor M, Berry SM. Two thirds of human fetuses with microbial invasion of the amniotic cavity have a detectable systemic cytokine response before birth. Acta Diabetologica Latina. 1997;176(1 part II).

  14. 14.

    Gravett MG, Adams KM, Sadowsky DW, et al. Immunomodula-tors plus antibiotics delay preterm delivery after experimental intraamniotic infection in a nonhuman primate model. Am J Obstet Gynecol. 2007;197(5):518.e511–518.e518.

  15. 15.

    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.

  16. 16.

    Kemp MW, Saito M, Newnham JP, Nitsos I, Okamura K, Kallapur SG. Preterm birth, infection, and inflammation advances from the study of animal models Reprod Sci. 2010;17(7): 619–628.

  17. 17.

    Jobe AH, Newnham JP, Willet KE, et al. Endotoxin-induced lung maturation in preterm lambs is not mediated by Cortisol. Am J Respir Crit Care Med. 2000;162(5):1656–1661.

  18. 18.

    Kramer BW, Ikegami M, Moss TJ, Nitsos I, Newnham JP, Jobe AH. Endotoxin-induced chorioamnionitis modulates innate immunity of monocytes in preterm sheep. Am J Respir Crit Care Med. 2005;171(1):73–77.

  19. 19.

    Moss TJ, Nitsos I, Ikegami M, Jobe AH, Newnham JP. Experimental intrauterine Ureaplasma infection in sheep. Am J Obstet Gynecol. 2005;192(4):1179–1186.

  20. 20.

    Moss TJ, Nitsos I, Newnham JP, Ikegami M, Jobe AH. Chorioamnionitis induced by subchorionic endotoxin infusion in sheep. Am J Obstet Gynecol. 2003;189(6):1771–1776.

  21. 21.

    Sadowsky DW, Haluska GJ, Gravett MG, Witkin SS, Novy MJ. Indomethacin blocks interleukin 1beta-induced myometrial contractions in pregnant rhesus monkeys. Am J Obstet Gynecol. 2000;183(1):173–180.

  22. 22.

    Grigsby PL, Novy MJ, Waldorf KM, Sadowsky DW, Gravett MG. Choriodecidual inflammation: a harbinger of the preterm labor syndrome. Reprod Sci. 2010;17(1):85–94.

  23. 23.

    Hirsch E, Filipovich Y, Mahendroo M. Signaling via the type I IL-1 and TNF receptors is necessary for bacterially induced preterm labor in a murine model. Am J Obstet Gynecol. 2006;194(5):1334–1340.

  24. 24.

    Hirsch E, Muhle RA, Mussalli GM, Blanchard R. Bacterially induced preterm labor in the mouse does not require maternal interleukin-1 signaling Am J Obstet Gynecol. 2002;186(3): 523–530.

  25. 25.

    Kemp MW, Saito M, Nitsos I, Jobe A, Kallapur S, Newnham J. Exposure to in utero lipopolysaccharide induces inflammation in the fetal ovine skin. Reprod Sci.

  26. 26.

    Kim YM, Romero R, Chaiworapongsa T, Espinoza J, Mor G, Kim CJ. Dermatitis as a component of the fetal inflammatory response syndrome is associated with activation of Toll-like receptors in epidermal keratinocytes. Histopathology. 2006;49(5):506–514.

  27. 27.

    Cheah FC, Anderson TP, Darlow BA, Murdoch DR. Comparison of the mycoplasma duo test with PCR for detection of Ureaplasma species in endotracheal aspirates from premature infants. J Clin Microbiol. 2005;43(1):509–510.

  28. 28.

    Chang JS, Russell GC, Jann O, Glass EJ, Werling D, Haig DM. Molecular cloning and characterization of Toll-like receptors 1–10 in sheep. Vet Immunol Immunopathol. 2009;127(1-2):94–105.

  29. 29.

    Sow FB, Gallup JM, Meyerholz DK, Ackermann MR. Gene profiling studies in the neonatal ovine lung show enhancing effects of VEGF on the immune response. Develop Comp Immunol. 2009;33(6):761–771.

  30. 30.

    Bustin SA, Benes V, Garson JA, et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem. 2009;55(4):611–622.

  31. 31.

    Andrews WW, Goldenberg RL, Faye-Petersen O, Cliver S, Goepfert AR, Hauth JC. The Alabama Preterm Birth study: polymorphonuclear and mononuclear cell placental infiltrations, other markers of inflammation, and outcomes in 23- to 32-week preterm newborn infants. Am J Obstet Gynecol. 2006;195(3):803–808.

  32. 32.

    Goldenberg RL, Andrews WW, Faye-Petersen OM, Goepfert AR, Cliver SP, Hauth JC. The Alabama Preterm Birth Study: intrauterine infection and placental histologic findings in preterm births of males and females less than 32 weeks. Am J Obstet Gynecol. 2006;195(6):1533–1537.

  33. 33.

    Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. :Lancet. 2008;371(9606):75–84.

  34. 34.

    Goldenberg RL, Andrews WW, Goepfert AR, et al. The Alabama Preterm Birth Study: umbilical cord blood Ureaplasma urealyti-cum and Mycoplasma hominis cultures in very preterm newborn infants. Am J Obstet Gynecol. 2008;198(1):43 e41–e45.

  35. 35.

    Viscardi RM. Ureaplasma species: role in diseases of prematurity. Clin Perinatol. 2010;37(2):393–409.

  36. 36.

    Oh KJ, Lee SE, Jung H, Kim G, Romero R, Yoon BH. Detection of ureaplasmas by the polymerase chain reaction in the amniotic fluid of patients with cervical insufficiency. J Perinat Med. 2010;38(3):261–268.

  37. 37.

    Kasper DC, Mechtler TP, Reischer GH, et al. The bacterial load of Ureaplasma parvum in amniotic fluid is correlated with an increased intrauterine inflammatory response. Diagn Microbiol Infect Dis. 2010;67(2):117–121.

  38. 38.

    Oh KJ, Lee KA, Sohn YK, et al. Intraamniotic infection with genital mycoplasmas exhibits a more intense inflammatory response than intraamniotic infection with other microorganisms in patients with preterm premature rupture of membranes. Am J Obstet Gynecol. 2010;203(3):211.e211–211.e218.

  39. 39.

    Novy MJ, Duffy L, Axthelm MK, et al. Ureaplasma parvum or Mycoplasma hominis as sole pathogens cause chorioamnionitis, preterm delivery, and fetal pneumonia in rhesus macaques. Reprod Sci. 2009;16(1):56–70.

  40. 40.

    Moss TJM, Nitsos I, Ikegami M, Jobe AH, Newnham JP. Experimental intrauterine Ureaplasma infection in sheep. Am J Obstet Gynecol. 2005;192(4):1179–1186.

  41. 41.

    Miller LS, Modlin RL. Toll-like receptors in the skin Semin Immunopathol. 2007;29(1): 15–26.

  42. 42.

    Yadav A, Saini V, Arora S. MCP-1: chemoattractant with a role beyond immunity: a review. Clinica Chimica Acta. 2010;411(21–22):1570–1579.

  43. 43.

    Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res. 2009;29(6):313–325.

  44. 44.

    Kramer BW, Joshi SN, Moss TJM, et al. Endotoxin-induced maturation of monocytes in preterm fetal sheep lung. Am J Physiol—Lung Cell Mol Physiol. 2007;293(2):L345–L353.

  45. 45.

    Jones HE, Harris KA, Azizia M, et al. Differing prevalence and diversity of bacterial species in fetal membranes from very preterm and term labor. PLoS One. 2009;4(12):1–9.

Download references

Author information

Correspondence to Matthew W. Kemp PhD.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kemp, M.W., Saito, M., Kallapur, S.G. et al. Inflammation of the Fetal Ovine Skin Following in utero Exposure to Ureaplasma parvum. Reprod. Sci. 18, 1128–1137 (2011). https://doi.org/10.1177/1933719111408114

Download citation

Keywords

  • preterm birth
  • uterine infection
  • inflammation