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Polymyxin B Agonist Capture Therapy for Intrauterine Inflammation: Proof-of-Principle in a Fetal Ovine Model

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Abstract

Intrauterine infection is a leading cause of preterm birth (PTB), most notably in deliveries occurring before 32 weeks gestation. Preterm infants exposed to intrauterine inflammation are more likely to have a host of neurological, respiratory, gastrointestinal, and visual pathologies. Preventing preterm delivery and protecting the fetus from injury is thus likely to require treatment of both intrauterine infection and inflammation. Polymyxin B (PMXB) is a cationic peptide antibiotic that binds Escherichia coli lipopolysaccharides (LPS) and prevents inflammatory activation. We hypothesized that intraamniotic administration of PMXB would selectively inhibit LPS-driven inflammation, serving as a proof-of-principle for targeted agonist capture therapy as a treatment for PTB and fetal injury. In vitro studies with primary fetal ovine keratinocytes demonstrated a significant and sustained reduction in tumor necrosis factor α and interleukin 8 messenger RNA expression after treatment with PMXB and LPS, relative to cells treated with LPS alone. In vivo studies with fetal sheep demonstrated a significant reduction in proinflammatory cytokines in the amniotic fluid and fetal lung (but not fetal skin or chorioamnion) in LPS + PMXB-treated animals, relative to those treated with LPS alone. These data are consistent with a partial resolution of LPS-driven intrauterine inflammation. They suggest the potential for agonist capture as a conceptual means of resolving the proparturition inflammation caused by infection of the amniotic cavity.

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References

  1. March of Dimes P, Save the Children, WHO. Born Too Soon: The Gobal Action Report on Preterm Birth. Geneva: World Health Organization; 2012.

    Google Scholar 

  2. Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012;379(9832): 2162–2172.

    Article  PubMed  Google Scholar 

  3. Newnham JP, Sahota DS, Zhang CY, et al. Preterm birth rates in Chinese women in China, Hong Kong and Australia—the price of Westernisation. Aust N Z J Obstet Gynaecol. 2011;51(5):426–431.

    Article  PubMed  Google Scholar 

  4. Petrou S, Eddama O, Mangham L. A structured review of the recent literature on the economic consequences of preterm birth. Arch Dis Child Fetal Neonatal Ed. 2011;96(3):F225–F232.

    Article  PubMed  Google Scholar 

  5. Lawn JE, Cousens S, Zupan J, Lancet Neonatal Survival Steering Team. 4 Million neonatal deaths: when? Where? Why? Lancet. 2005;365(9462):891–900.

    Article  PubMed  Google Scholar 

  6. Tracy SK, Tracy MB, Dean J, Laws P, Sullivan E. Spontaneous preterm birth of liveborn infants in women at low risk in Australia over 10 years: a population-based study. BJOG. 2007;114(6): 731–735.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bastek JA, Gomez LM, Elovitz MA. The role of inflammation and infection in preterm birth. Clin Perinatol. 2011;38(3): 385–406.

    Article  PubMed  Google Scholar 

  9. Fawke J. Neurological outcomes following preterm birth. Semin Fetal Neonatal Med. 2007;12(5):374–382.

    Article  PubMed  Google Scholar 

  10. McAdams RM, Juul SE. Cerebral palsy: prevalence, predictability, and parental counseling. Neo Rev. 2011;12(10):e564–e574.

    Google Scholar 

  11. Romero R, Espinoza J, Kusanovic JP, et al. The preterm parturition syndrome. BJOG. 2006;113(suppl 3):17–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shatrov JG, Birch SCM, Lam LT, Quinlivan JA, McIntyre S, Mendz GL. Chorioamnionitis and cerebral palsy: a meta-analysis. Obstet Gynecol. 2010;116(2 pt 1):387–392.

    Article  PubMed  Google Scholar 

  13. Vermeulen GM, Bruinse HW, de Vries LS. Perinatal risk factors for adverse neurodevelopmental outcome after spontaneous preterm birth. Eur J Obstet Gynecol Reprod Biol. 2001;99(2): 207–212.

    Article  CAS  PubMed  Google Scholar 

  14. Wood NS, Costeloe K, Gibson AT, et al. The EPICure study: associations and entecedents of neurological and developmental disability at the 30 months of age following extremely preterm birth. Arch Dis Childh Fetal Neonatal Ed. 2005;90(2):F134–F140.

    Article  CAS  Google Scholar 

  15. Jobe AH. Effects of chorioamnionitis on the fetal lung. Clin Perinatol. 2012;39(3):441–457.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Smith GCS, Pell JP, Dobbie R. Risk of sudden infant death syndrome and week of gestation of term birth. Pediatrics. 2003; 111(6 pt 1):1367–1371.

    Article  PubMed  Google Scholar 

  17. Yang S, Platt RW, Kramer MS. Variation in child cognitive ability by week of gestation among healthy term births. Am J Epidemiol. 2010;171(4):399–406.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Mangham LJ, Petrou S, Doyle LW, Draper ES, Marlow N. The cost of preterm birth throughout childhood in England and Wales. Pediatrics. 2009;123(2):e312–e327.

    Article  PubMed  Google Scholar 

  19. Agrawal V, Hirsch E. Intrauterine infection and preterm labor. Semin Fetal Neonatal Med. 2012;17(1):12–19.

    Article  PubMed  Google Scholar 

  20. Gotsch F, Romero R, Kusanovic JP, et al. The fetal inflammatory response syndrome. Clin Obstet Gynecol. 2007;50(3):652–683.

    Article  PubMed  Google Scholar 

  21. Keelan JA. Pharmacological inhibition of inflammatory pathways for the prevention of preterm birth. J Reprod Immunol. 2011; 88(2):176–184.

    Article  CAS  PubMed  Google Scholar 

  22. Rinaldi SF, Hutchinson JL, Rossi AG, Norman JE. Anti-inflammatory mediators as physiological and pharmacological regulators of parturition. Expert Rev Clin Immunol. 2011; 7(5): 675–696.

    Article  CAS  PubMed  Google Scholar 

  23. Hayden MS, West AP, Ghosh S. NF-κB and the immune response. Oncogene. 2006;25(51):6758–6780.

    Article  CAS  PubMed  Google Scholar 

  24. Jiang YJ, Lu B, Crumrine D, Man MQ, Elias PM, Feingold KR. IL-1α accelerates stratum corneum formation and improves permeability barrier homeostasis during murine fetal development. J Dermatol Sci. 2009;54(2):88–98.

    Article  CAS  PubMed  Google Scholar 

  25. Jiang YJ, Lu B, Crumrine D, Elias PM, Feingold KR. IL-6 Stimulates but is not essential for stratum corneum formation and permeability barrier development during gestation. Exp Dermatol. 2010;19(8):e31–e36.

    Article  PubMed  Google Scholar 

  26. Kemp MW, Saito M, Nitsos I, Jobe AH, Kallapur SG, Newnham JP. Exposure to in utero lipopolysaccharide induces inflammation in the fetal ovine skin. Reprod Sci. 2010;18(1):88–98.

    Article  PubMed  CAS  Google Scholar 

  27. 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):e8205.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Coyne CP, Fenwick BW. Inhibition of lipopolysaccharide-induced macrophage tumor necrosis factor-α synthesis by polymyxin B sulfate. Am J Veterinary Res. 1993;54(2):305–314.

    CAS  Google Scholar 

  29. Stokes DC, Shenep JL, Fishman M, Hildner WK, Bysani GK, Rufus K. Polymyxin B prevents lipopolysaccharide-induced release of tumor necrosis factor-α from alveolar macrophages. J Infect Dis. 1989;160(1):52–57.

    Article  CAS  PubMed  Google Scholar 

  30. Coyne CP, Moritz JT, Fenwick BW. Inhibition of lipopolysaccharide-induced TNF-α production by semisynthetic polymyxin-B conjugated dextran. Biotechnol Ther. 1994;5(3–4):137–162.

    PubMed  Google Scholar 

  31. Jaber BL, Barrett TW, Cendoroglo Neto M, Sundaram S, King AJ, Pereira BJ. Removal of cytokine inducing substances by polymyxin-B immobilized polystyrene-derivative fibers during in vitro hemoperfusion of 10% human plasma containing Staphy-lococcus aureus challenge. ASAIO J. 1998;44(1):48–53.

    Article  CAS  PubMed  Google Scholar 

  32. Barton MH. Use of Polymyxin B for treatment of endotoxemia in horses. Comp Cont Educ Pract 2000;22(11):1056.

    Google Scholar 

  33. Iwagaki A, Porro M, Pollack M. Influence of synthetic antiendotoxin peptides on lipopolysaccharide (LPS) recognition and LPS-induced proinflammatory cytokine responses by cells expressing membrane-bound CD14. Infect Immum. 2000;68(3):1655–1663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kemp MW, Saito M, Kallapur SG, et al. Inflammation of the fetal ovine skin following in utero exposure to ureaplasma parvum. Reprod Sci. 2011;18(11):1128–1137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kemp MW, Senthamarai Kannan P, Saito M, et al. Selective exposure of the fetal lung and skin/amnion (but not gastrointestinal tract) to LPS elicits acute systemic inflammation in fetal sheep. PLoS One. 2013;8(5):e63355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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.

    Article  CAS  PubMed  Google Scholar 

  37. Zhang L, Saito M, Jobe A, et al. Intra-amniotic administration of E. coli lipopolysaccharides causes sustained inflammation of the fetal skin in sheep. Reprod Sci. 2012;19(11):1181–1189.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Burd I, Balakrishnan B, Kannan S. Models of fetal brain injury, intrauterine inflammation, and preterm birth. Am J Reprod Immunol. 2012;67(4):287–294.

    Article  CAS  PubMed  Google Scholar 

  39. Wolfs TGAM, Buurman WA, Zoer B, et al. Endotoxin induced chorioamnionitis prevents intestinal development during gestation in fetal sheep. PLoS One. 2009;4(6):e5837.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Vlassaks E, Gavilanes AWD, et al. Antenatal exposure to chorioamnionitis affects lipid metabolism in 7-week-old sheep. J Dev Orig Health Dis. 2012;3(2):103.

    Article  CAS  PubMed  Google Scholar 

  41. 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.

    Google Scholar 

  42. Bo Hyun Y, Jong Kwan J, Romero R, et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1β, and tumor necrosis factor-α), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol. 1997;177(1):19–26.

    Article  Google Scholar 

  43. Burd I, Bentz AI, Chai J, et al. Inflammation-induced preterm birth alters neuronal morphology in the mouse fetal brain. J Neu-rosci Res. 2010;88(9):1872–1881.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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.

    Article  CAS  PubMed  Google Scholar 

  45. Kramer BW, Moss TJ, Willet KE, et al. Dose and time response after intraamniotic endotoxin in preterm lambs. Am J Respir Crit Care Med. 2001;164(6):982–988.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  47. Kramer BW, Kramer S, Ikegami M, Jobe AH. Injury, inflammation, and remodeling in fetal sheep lung after intra-amniotic endotoxin. Am J Physiol Lung Cell Mol Physiol. 2002;283(2): L452–L459.

    Article  CAS  PubMed  Google Scholar 

  48. Kallapur SG, Willet KE, Jobe AH, Ikegami M, Bachurski CJ. Intra-amniotic endotoxin: Chorioamnionitis precedes lung maturation in preterm lambs. Am J Physiol Lung Cell Mol Physiol. 2001;280(3):L527–L536.

    Article  CAS  PubMed  Google Scholar 

  49. Davies JK, Shikes RH, Sze CI, et al. Histologic inflammation in the maternal and fetal compartments in a rabbit model of acute intra-amniotic infection. Am J Obstet Gynecol. 2000;183(5): 1088–1093.

    Article  CAS  PubMed  Google Scholar 

  50. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Newnham JP, Kallapur SG, Kramer BW, et al. Betamethasone effects on chorioamnionitis induced by intra-amniotic endotoxin in sheep. Am J Obstet Gynecol. 2003;189(5):1458–1466.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. School of Women’s and Infants’ Health, The University of Western Australia, 6009, Perth, Western, Australia

    Masatoshi Saito PhD, Matthew S. Payne PhD, Yuichiro Miura PhD, Demelza J. Ireland PhD, Sarah Stock PhD, Suhas G. Kallapur MD, John P. Newnham MD, Boris W. Kramer PhD, Alan H. Jobe PhD, Jeffrey A. Keelan PhD & Matthew W. Kemp PhD

  2. Division of Perinatal Medicine, Tohoku University Hospital, Sendai, Japan

    Masatoshi Saito PhD

  3. Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Centre, University of Cincinnati School of Medicine, Cincinnati, OH, USA

    Suhas G. Kallapur MD, Paranthaman S. Kannan PhD & Alan H. Jobe PhD

  4. Department of Paediatrics, School of Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands

    Boris W. Kramer PhD

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  1. Masatoshi Saito PhD
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  2. Matthew S. Payne PhD
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  3. Yuichiro Miura PhD
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  6. Suhas G. Kallapur MD
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Correspondence to Matthew W. Kemp PhD.

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Saito, M., Payne, M.S., Miura, Y. et al. Polymyxin B Agonist Capture Therapy for Intrauterine Inflammation: Proof-of-Principle in a Fetal Ovine Model. Reprod. Sci. 21, 623–631 (2014). https://doi.org/10.1177/1933719113508820

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  • DOI: https://doi.org/10.1177/1933719113508820

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