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Am J Perinatol 2018; 35(09): 865-872
DOI: 10.1055/s-0038-1626711
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

Sammy M. Tabbah
1   Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio
,
Catalin S. Buhimschi
1   Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio
,
Katherine Rodewald-Millen
1   Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio
,
Christopher R. Pierson
2   Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio
3   Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio
4   Department of Biomedical Education and Anatomy, The Ohio State University College of Medicine, Columbus, Ohio
,
Vineet Bhandari
5   Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania
,
Philip Samuels
1   Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio
,
Irina A. Buhimschi
6   Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
7   Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio
› Author Affiliations Funding This work was supported by grants from National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) R01HD062007 (C.S.B. and I.A.B.) and R01HD047321 (I.A.B.). In addition, the Division of Maternal Fetal Medicine of The Ohio State University College of Medicine and The Center for Perinatal Research of The Research Institute at Nationwide Children's Hospital participated with funds allocated for MFM fellow research projects. The funding sources had no involvement in study design, interpretation of data, writing of the report, or decision to submit the paper for publication.
Further Information

Publication History

19 December 2017

29 December 2017

Publication Date:
02 February 2018 (online)

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Abstract

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.

Keywords

chorioamnionitis - funisitis - placenta - cord blood
 

  • References

  • 1 Lasocki S, Gaillard T, Rineau E. Iron is essential for living!. Crit Care 2014; 18 (06) 678
    CrossrefPubMedGoogle Scholar
  • 2 Zhang C. Essential functions of iron-requiring proteins in DNA replication, repair and cell cycle control. Protein Cell 2014; 5 (10) 750-760
    CrossrefPubMedGoogle Scholar
  • 3 Unger EL, Bianco LE, Jones BC, Allen RP, Earley CJ. Low brain iron effects and reversibility on striatal dopamine dynamics. Exp Neurol 2014; 261: 462-468
    CrossrefPubMedGoogle Scholar
  • 4 Guo S, Frazer DM, Anderson GJ. Iron homeostasis: transport, metabolism, and regulation. Curr Opin Clin Nutr Metab Care 2016; 19 (04) 276-281
    CrossrefPubMedGoogle Scholar
  • 5 Andrews SC, Robinson AK, Rodríguez-Quiñones F. Bacterial iron homeostasis. FEMS Microbiol Rev 2003; 27 (2-3): 215-237
    CrossrefPubMedGoogle Scholar
  • 6 Parrow NL, Fleming RE, Minnick MF. Sequestration and scavenging of iron in infection. Infect Immun 2013; 81 (10) 3503-3514
    CrossrefPubMedGoogle Scholar
  • 7 Zhang X, Rovin BH. Beyond anemia: hepcidin, monocytes and inflammation. Biol Chem 2013; 394 (02) 231-238
    PubMedGoogle Scholar
  • 8 Drakesmith H, Prentice AM. Hepcidin and the iron-infection axis. Science 2012; 338 (6108): 768-772
    CrossrefPubMedGoogle Scholar
  • 9 Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001; 276 (11) 7806-7810
    CrossrefPubMedGoogle Scholar
  • 10 Pigeon C, Ilyin G, Courselaud B. , et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 2001; 276 (11) 7811-7819
    CrossrefPubMedGoogle Scholar
  • 11 Nicolas G, Chauvet C, Viatte L. , et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002; 110 (07) 1037-1044
    CrossrefPubMedGoogle Scholar
  • 12 Nemeth E, Rivera S, Gabayan V. , et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004; 113 (09) 1271-1276
    CrossrefPubMedGoogle Scholar
  • 13 Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005; 352 (10) 1011-1023
    CrossrefPubMedGoogle Scholar
  • 14 Gambling L, Lang C, McArdle HJ. Fetal regulation of iron transport during pregnancy. Am J Clin Nutr 2011; 94 (6, Suppl) 1903S-1907S
    CrossrefPubMedGoogle Scholar
  • 15 Buhimschi IA, Buhimschi CS. Proteomics/diagnosis of chorioamnionitis and of relationships with the fetal exposome. Semin Fetal Neonatal Med 2012; 17 (01) 36-45
    CrossrefPubMedGoogle Scholar
  • 16 Cizmeci MN, Kara S, Kanburoglu MK, Simavli S, Duvan CI, Tatli MM. Detection of cord blood hepcidin levels as a biomarker for early-onset neonatal sepsis. Med Hypotheses 2014; 82 (03) 310-312
    CrossrefPubMedGoogle Scholar
  • 17 Wu TW, Tabangin M, Kusano R, Ma Y, Ridsdale R, Akinbi H. The utility of serum hepcidin as a biomarker for late-onset neonatal sepsis. J Pediatr 2013; 162 (01) 67-71
    CrossrefPubMedGoogle Scholar
  • 18 Hadlock FP, Deter RL, Harrist RB, Park SK. Computer assisted analysis of fetal age in the third trimester using multiple fetal growth parameters. J Clin Ultrasound 1983; 11 (06) 313-316
    CrossrefPubMedGoogle Scholar
  • 19 Bhandari V, Wang C, Rinder C, Rinder H. Hematologic profile of sepsis in neonates: neutrophil CD64 as a diagnostic marker. Pediatrics 2008; 121 (01) 129-134
    Google Scholar
  • 20 Buhimschi CS, Buhimschi IA, Abdel-Razeq S. , et al. Proteomic biomarkers of intra-amniotic inflammation: relationship with funisitis and early-onset sepsis in the premature neonate. Pediatr Res 2007; 61 (03) 318-324
    CrossrefPubMedGoogle Scholar
  • 21 Garry D, Figueroa R, Aguero-Rosenfeld M, Martinez E, Visintainer P, Tejani N. A comparison of rapid amniotic fluid markers in the prediction of microbial invasion of the uterine cavity and preterm delivery. Am J Obstet Gynecol 1996; 175 (05) 1336-1341
    CrossrefPubMedGoogle Scholar
  • 22 Edwards RK, Clark P, Locksmith Gregory J, Duff P. Performance characteristics of putative tests for subclinical chorioamnionitis. Infect Dis Obstet Gynecol 2001; 9 (04) 209-214
    CrossrefPubMedGoogle Scholar
  • 23 Naeye RL. Disorders of the placenta and decidua. In: Naeye RL. , ed. Disorder of the Placenta, Fetus and Neonate: Diagnosis and Clinical Significance. St. Louis: Mosby; 1992: 118-247
    Google Scholar
  • 24 Salafia CM, Weigl C, Silberman L. The prevalence and distribution of acute placental inflammation in uncomplicated term pregnancies. Obstet Gynecol 1989; 73 (3 Pt 1): 383-389
    PubMedGoogle Scholar
  • 25 Meguro R, Asano Y, Iwatsuki H, Shoumura K. Perfusion-Perls and -Turnbull methods supplemented by DAB intensification for nonheme iron histochemistry: demonstration of the superior sensitivity of the methods in the liver, spleen, and stomach of the rat. Histochem Cell Biol 2003; 120 (01) 73-82
    CrossrefPubMedGoogle Scholar
  • 26 Zhang AS, Xiong S, Tsukamoto H, Enns CA. Localization of iron metabolism-related mRNAs in rat liver indicate that HFE is expressed predominantly in hepatocytes. Blood 2004; 103 (04) 1509-1514
    CrossrefPubMedGoogle Scholar
  • 27 Strauss RG. Anaemia of prematurity: pathophysiology and treatment. Blood Rev 2010; 24 (06) 221-225
    CrossrefPubMedGoogle Scholar
  • 28 Müller KF, Lorenz L, Poets CF, Westerman M, Franz AR. Hepcidin concentrations in serum and urine correlate with iron homeostasis in preterm infants. J Pediatr 2012; 160 (06) 949-953
    CrossrefPubMedGoogle Scholar
  • 29 Lozoff B, Beard J, Connor J, Barbara F, Georgieff M, Schallert T. Long-lasting neural and behavioral effects of iron deficiency in infancy. Nutr Rev 2006; 64 (5 Pt 2): S34-S43
    CrossrefPubMedGoogle Scholar
  • 30 Steinmacher J, Pohlandt F, Bode H, Sander S, Kron M, Franz AR. Randomized trial of early versus late enteral iron supplementation in infants with a birth weight of less than 1301 grams: neurocognitive development at 5.3 years' corrected age. Pediatrics 2007; 120 (03) 538-546
    CrossrefPubMedGoogle Scholar
  • 31 Dulay AT, Buhimschi IA, Zhao G. , et al. Compartmentalization of acute phase reactants interleukin-6, C-reactive protein and procalcitonin as biomarkers of intra-amniotic infection and chorioamnionitis. Cytokine 2015; 76 (02) 236-243
    CrossrefPubMedGoogle Scholar