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 journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)623-31
Number of pages9
JournalReproductive Sciences
Volume21
Issue number5
DOIs
Publication statusPublished - May 2014

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