Hepcidin, an Iron Regulatory Hormone of Innate Immunity, is Differentially Expressed in Premature Fetuses with Early-Onset Neonatal Sepsis.

OBJECTIVE: Hepcidin, a mediator of innate immunity, binds the iron exporter ferroportin, leading to functional hypoferremia through intracellular iron sequestration. We explored hepcidin-ferroportin interactions in neonates clinically diagnosed with early-onset neonatal sepsis (EONS). STUDY DESIGN: Hepcidin and interleukin (IL)-6 were quantified by enzyme-linked immunosorbent assay (ELISA) in 92 paired cord blood-maternal blood samples in the following groups: "Yes" EONS (n = 41, gestational age [GA] 29 ± 1 weeks) and "No" EONS (n = 51, GA 26 ± 1 weeks). Placental hepcidin and ferroportin expression were evaluated by immunohistochemistry and real-time-polymerase chain reaction (RT-PCR). Liver hepcidin and ferroportin expression patterns were ascertained in autopsy specimens of neonates (n = 8) who died secondary to culture-proven sepsis. RESULTS: Cord blood hepcidin was significantly elevated (GA corrected, p = 0.018) and was positively correlated with IL-6 (r = 0.379, p = 0.001) in EONS. Hepcidin localized at syncytiotrophoblast and fetal vascular endothelium. Placental ferroportin, but not hepcidin mRNA correlated with cord blood hepcidin levels (r = 0.46, p = 0.039) and funisitis severity (r = 0.50, p = 0.018). Newborns who died from sepsis (n = 4) had higher hepatic hepcidin and iron sequestration, but lower ferroportin staining than those who died of nonsepsis causes (n = 4). CONCLUSION: Premature fetuses with EONS have elevated circulating hepcidin, likely related to lower placenta and liver ferroportin expression. Fetal hepcidin-ferroportin interaction appears to play a role in EONS pathophysiology independent of maternal response to intrauterine inflammation.

Evidence for participation of neutrophil gelatinase-associated lipocalin/matrix metalloproteinase-9 (NGAL•MMP-9) complex in the inflammatory response to infection in pregnancies complicated by preterm birth.

PROBLEM: Neutrophil gelatinase-associated lipocalin (NGAL) is expressed in neutrophils and involved in innate immunity by sequestering iron. NGAL's ability to complex with matrix metalloproteinase-9 (MMP-9) and extend its gelatinolytic activity led us to investigate its role in pregnancies complicated by preterm birth (PTB) and intra-amniotic infection/inflammation (IAI). METHOD OF STUDY: We assayed the amniotic fluid (AF) levels of NGAL and MMP-9 in 308 women that had a clinically indicated amniocentesis and a normal pregnancy outcome or PTB. qRT-PCR was employed to determine NGAL mRNA expression of placental villous trophoblast and amniochorion. Immunohistochemistry was used for cellular localization. RESULTS: AF NGAL levels were gestational age-regulated. Women with IAI and PTB had significantly higher levels of NGAL, MMP-9 and NGAL•MMP-9 complex. CONCLUSION: The amniochorion is a source of NGAL and similarly to other inflammatory conditions, this protein may augment the collagenolytic effect of MMP-9 and modulate host-microbe interactions in pregnancies complicated by IAI.