Fetal skin as a pro-inflammatory organ: Evidence from a primate model of chorioamnionitis.

Paranthaman Senthamarai Kannan,Matthew W Kemp,Alan H Jobe,Suhas G Kallapur,Suppawat Boonkasidecha,Colette Kanellopoulos-Langevin

doi:10.1371/journal.pone.0184938

Abstract

BackgroundIntrauterine infection is a primary cause of preterm birth and fetal injury. The pro-inflammatory role of the fetal skin in the setting of intrauterine infection remains poorly characterized. Whether or not inflammation of the fetal skin occurs in primates remains unstudied. Accordingly, we hypothesized that: i) the fetal primate skin would mount a pro-inflammatory response to preterm birth associated pro-inflammatory agents (lipopolysaccharides from Escherichia coli, live Ureaplasma parvum, interleukin-1β) and; ii) that inhibiting interleukin-1 signaling would decrease the skin inflammatory response.MethodsRhesus macaques with singleton pregnancies received intraamniotic injections of either sterile saline (control) or one of three pro-inflammatory agonists: E. coli lipopolysaccharides, interluekin-1β or live U. parvum under ultrasound guidance. A fourth group of animals received both E. coli lipopolysaccharide and interleukin-1 signaling inhibitor interleukin-1 receptor antagonist (Anakinra) prior to delivery. Animals were surgically delivered at approximately 130 days’ gestational age.ResultsIntraamniotic lipopolysaccharide caused an inflammatory skin response characterized by increases in interluekin-1β,-6 and -8 mRNA at 16 hours. There was a modest inflammatory response to U. parvum, but interleukin-1β alone caused no inflammatory response in the fetal skin. Intraamniotic Anakinra treatment of lipopolysaccharide-exposed animals significantly reduced skin inflammation.ConclusionsIntraamniotic lipopolysaccharide and U. parvum were associated with modest increases in the expression of inflammatory mediators in primate fetal skin. Although administration of Interleukin-1β alone did not elicit an inflammatory response, lipopolysaccharide-driven skin inflammation was decreased following intraamniotic Anakinra therapy. These findings provide support for the role of the fetal skin in the development of the fetal inflammatory response.

Highlights

Preterm birth is implicated in more than 1 million perinatal deaths worldwide each year [1]
Administration of Interleukin-1β alone did not elicit an inflammatory response, lipopolysaccharide-driven skin inflammation was decreased following intraamniotic Anakinra therapy. These findings provide support for the role of the fetal skin in the development of the fetal inflammatory response
Using sheep models of chorioamnionitis induced by the intraamniotic (IA) administration of E.coli lipopolysaccharide (LPS) or live Ureaplasma parvum (UP) we reported that the fetal skin responded with increased inflammatory cells and cytokine expression in the dermis [11,12,13]

Summary

Introduction

Preterm birth (delivery before 37 weeks’ gestation) is implicated in more than 1 million perinatal deaths worldwide each year [1]. Fetal and intrauterine inflammation cause preterm labor, and the presence of a systemic fetal inflammatory response at delivery is associated with increased risk of adverse neonatal respiratory and central nervous system outcomes [2]. Identifying the gestational tissues responsible for generating intrauterine inflammation is an important step in advancing both our understanding of the aetiology of preterm birth and in the development of potential anti-inflammatory interventions. The pro-inflammatory role of the fetal skin in the setting of intrauterine infection remains poorly characterized. We hypothesized that: i) the fetal primate skin would mount a pro-inflammatory response to preterm birth associated pro-inflammatory agents (lipopolysaccharides from Escherichia coli, live Ureaplasma parvum, interleukin-1β) and; ii) that inhibiting interleukin-1 signaling would decrease the skin inflammatory response

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Results

Conclusion