Polymyxin B agonist capture therapy for intrauterine inflammation: proof-of-principle in a fetal ovine model.
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.
1School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia.
Masatoshi
M
Saito
Matthew S
MS
Payne
Yuichiro
Y
Miura
Demelza J
DJ
Ireland
Sarah
S
Stock
Suhas G
SG
Kallapur
Paranthaman S
PS
Kannan
John P
JP
Newnham
Boris W
BW
Kramer
Alan H
AH
Jobe
Jeffrey A
JA
Keelan
Matthew W
MW
Kemp
D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005315:Fetal Diseases / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D011112:Polymyxin B / Q000008:administration & dosage*; D011247:Pregnancy; D011897:Random Allocation; D012756:Sheep; D014599:Uterus / Q000187:drug effects* / Q000473:pathology*
D008070:Lipopolysaccharides; D011112:Polymyxin B
agonist; fetus; infection; inflammation; preterm birth; sheep