Outside-in? Acute fetal systemic inflammation in very preterm chronically catheterized sheep fetuses is not driven by cells in the fetal blood

Matthew W Kemp, Timothy J Molloy, Haruo Usuda, Eleanor Woodward, Yuichiro Miura, Matthew S Payne, Demelza J Ireland, Alan H Jobe, Suhas G Kallapur, Sarah J Stock, Owen B Spiller, John P Newnham, Masatoshi Saito

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: The preterm birth syndrome (delivery before 37 weeks' gestation) is a major contributor to the global burden of perinatal morbidity and mortality. The aetiology of preterm birth is complex, multifactorial, and likely dependent, at least in part, on the gestational age of the fetus. Intrauterine infection is frequent in preterm deliveries occurring before 32 weeks' gestation; understanding how the fetus responds to pro-inflammatory insult will be an important step towards early preterm birth prevention. However, animal studies of infection and inflammation in prematurity commonly use older fetuses possessing comparatively mature immune systems.

OBJECTIVE: Aiming to characterise acute fetal responses to microbial agonist at a clinically-relevant gestation, we used 92d gestational age fetuses (62% of term) to develop a chronically catheterized sheep model of very preterm pregnancy. We hypothesised that any acute fetal systemic inflammatory responses would be driven by signalling from the tissues exposed to E. coli lipopolysaccharide introduced into the amniotic fluid.

STUDY DESIGN: 18 ewes carrying a single fetus at 92d gestation had recovery surgery to place fetal tracheal, jugular, and intraamniotic catheters. Animals were recovered for 24h before being administered either: intraamniotic E.coli lipopolysaccharide (LPS; n=9); or sterile saline (n=9). Samples were collected for 48h before euthanasia and necroscopy. Fetal inflammatory responses were characterised by microarray analysis, quantitative PCR and ELISA.

RESULTS: Intraamniotic LPS reached the distal trachea within 2h. LPS increased tracheal fluid interleukin-8 within 2h and generated a robust inflammatory response characterised by interleukin-6 signalling pathway activation, up-regulation of cell proliferation, but no increases in inflammatory mediator expression in cord blood RNA.

CONCLUSIONS: In very preterm sheep fetuses, LPS: i) stimulates inflammation in the fetal lung and fetal skin; and ii) stimulates a systemic inflammatory response that is not generated by fetal blood cells. These data argue for amniotic fuid-exposed tissues playing key role in driving acute fetal and intrauterine inflammatory responses.

Original languageEnglish
JournalAmerican Journal of Obstetrics and Gynecology
Volume214
Issue number2
Early online date25 Sep 2015
DOIs
Publication statusPublished - Feb 2016

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