Polymyxin B agonist capture therapy for intrauterine inflammation: Proof-of-principle in a fetal ovine model

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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 a 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.

Original languageEnglish
Pages (from-to)623-631
Number of pages9
JournalReproductive Sciences
Volume21
Issue number5
DOIs
Publication statusPublished - 2014 May

Keywords

  • agonist
  • fetus
  • infection
  • inflammation
  • preterm birth
  • sheep

ASJC Scopus subject areas

  • Obstetrics and Gynaecology

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  • Cite this

    Saito, M., Payne, M. S., Miura, Y., Ireland, D. J., Stock, S., Kallapur, S. G., Kannan, P. S., Newnham, J. P., Kramer, B. W., Jobe, A. H., Keelan, J. A., & Kemp, M. W. (2014). Polymyxin B agonist capture therapy for intrauterine inflammation: Proof-of-principle in a fetal ovine model. Reproductive Sciences, 21(5), 623-631. https://doi.org/10.1177/1933719113508820