Download PDF
J Pediatr Infect Dis 2017; 12(03): 176-183
DOI: 10.1055/s-0037-1603206
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Can Recombinant Granulocyte Colony Stimulating Factor Modulate Inflammatory Response in Extreme Low Gestational Age Newborns?: Effect of rhG-CSF on Cytokines in ELGAN

Prabhakar Kocherlokata
1   Department of Pediatrics, St Luke's Cornwall Hospital, Newburgh, New York, NY, United States
,
Mary Crow
2   Department of Medicine, Hospital for Special Surgery, New York, New York, NY, United States
,
Radhakrihna Vakkalanka
3   Genes, Cognition, and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, United States
,
Edmund F. La Gamma
4   Department of Pediatrics, Division of Newborn Medicine, The Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center, New York Medical College, Valhalla, New York, NY, United States
› Author Affiliations
Further Information

Publication History

08 December 2016

26 December 2016

Publication Date:
30 May 2017 (online)

    Permissions and Reprints

Abstract

Background Elevated levels of cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) are common in critically ill neonates, and may contribute to organ-based injury during acute illness contributing to neurodevelopmental delay. In both animals and human adults, recombinant human granulocyte-colony stimulating factor (rhG-CSF) is associated with a reduction in TNF-α blood levels.

Objective We aim to determine whether rhG-CSF treatment affects the blood levels of proinflammatory cytokines, TNF-α and IL-6 or the anti-inflammatory cytokine, IL-10 in extremely-low-gestational age neonates (ELGANs) compared with conventional medical management.

Methods The study included three groups of ELGANs between 2 and 4 days of age as subjects. Control group (n = 5); treated, nonseptic group (n = 10); and treated, septic group (n = 5) neonates were treated with conventional measures. In addition, the test subjects were treated with 10 μg/kg/d of rhG-CSF intravenously for 3 consecutive days. The levels of TNF-α, IL-6, and IL-10 were measured before and 24 hours after completion of the study.

Results The average TNF-α levels increased after birth in control subjects but did not rise in rhG-CSF treated subjects. A nonsignificant decrease of IL-6 and IL-10 blood levels was noted in all the subjects independent of the drug treatment.

Conclusion The use of rhG-CSF is associated with lower TNF-α levels in ELGANs.

Speculation During critical illness or sepsis, rhG-CSF may have unanticipated benefits as a drug that can elevate neutrophil number and function in neonates while simultaneously limiting collateral injury due to TNF-α.

Keywords

human recombinant granulocyte colony stimulating factor (rhG-CSF) - interleukin-6 - interleukin-10 - tumor necrosis factor-α - extremely-low-gestational age neonate

Note

This work was presented in part at the Pediatric Academic Society Meeting in New Orleans, Louisiana, LA, United States by Kocherlakota, P; Vakkalanka, R; Crow MK; and La Gamma, EF: Effect of human granulocyte colony stimulating factor (rhG-CSF) on cytokines in VLBW neonates. Ped. Res. 44(4): A1044, 1998.


Contributors' Statement

Prabhakar Kocherlakota, MD contributed to the design, acquired data, performed the initial analysis, drafted the manuscript, and approved the final manuscript as submitted.


Mary Crow, MD supervised the analysis, reviewed the initial manuscript, and approved the final manuscript as submitted.


Edmund La Gamma, MD conceptualized and designed the study, designed the data collection instruments, drafted the initial manuscript, and approved the final manuscript as submitted.


 

  • References

  • 1 Lieschke GJ, Burgess AW. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (1). N Engl J Med 1992; 327 (01) 28-35
    CrossrefPubMedGoogle Scholar
  • 2 Roberts AW. G-CSF: a key regulator of neutrophil production, but that's not all!. Growth Factors 2005; 23 (01) 33-41
    CrossrefPubMedGoogle Scholar
  • 3 Dale DC. Potential role of colony-stimulating factors in the prevention and treatment of infectious diseases. Clin Infect Dis 1994; 18 (Suppl. 02) S180-S188
    CrossrefPubMedGoogle Scholar
  • 4 Franzke A. The role of G-CSF in adaptive immunity. Cytokine Growth Factor Rev 2006; 17 (04) 235-244
    CrossrefPubMedGoogle Scholar
  • 5 La Gamma EF, Alpan O, Kocherlakota P. Effect of granulocyte colony-stimulating factor on preeclampsia-associated neonatal neutropenia. J Pediatr 1995; 126 (03) 457-459
    CrossrefPubMedGoogle Scholar
  • 6 Kocherlakota P, La Gamma EF, Breen C, Fleit C, Golightly M. Effects of rhG-CSF on neutrophil Fcy and complement receptors in ventilated very low birth weight human neonates. In: Bellanti JA, Bracci R, Prindull G, Xanthou M. , eds. Neonatal Hematology and Immunology III. New York: Elsevier Science B.V; 1997: 39-48
    Google Scholar
  • 7 Ahmad M, Fleit HB, Golightly MG, La Gamma EF. In vivo effect of recombinant human granulocyte colony-stimulating factor on phagocytic function and oxidative burst activity in septic neutropenic neonates. Biol Neonate 2004; 86 (01) 48-54
    CrossrefPubMedGoogle Scholar
  • 8 Drossou-Agakidou V, Kanakoudi-Tsakalidou F, Sarafidis K. , et al. Administration of recombinant human granulocyte-colony stimulating factor to septic neonates induces neutrophilia and enhances the neutrophil respiratory burst and β2 integrin expression. Results of a randomized controlled trial. Eur J Pediatr 1998; 157 (07) 583-588
    CrossrefPubMedGoogle Scholar
  • 9 Kocherlakota P, La Gamma EF. Human granulocyte colony-stimulating factor may improve outcome attributable to neonatal sepsis complicated by neutropenia. Pediatrics 1997; 100 (01) E6
    PubMedGoogle Scholar
  • 10 Gillan ER, Christensen RD, Suen Y, Ellis R, van de Ven C, Cairo MS. A randomized, placebo-controlled trial of recombinant human granulocyte colony-stimulating factor administration in newborn infants with presumed sepsis: significant induction of peripheral and bone marrow neutrophilia. Blood 1994; 84 (05) 1427-1433
    CrossrefPubMedGoogle Scholar
  • 11 Russell AR, Davies EG, Ball SE, Gordon-Smith E. Granulocyte colony stimulating factor treatment for neonatal neutropenia. Arch Dis Child Fetal Neonatal Ed 1995; 72 (01) F53-F54
    CrossrefPubMedGoogle Scholar
  • 12 La Gamma EF, Welch W, Jeffs R. A multicenter, double-blind, randomized, placebo-controlled safety & efficacy study of filgrastim (rhG-CSF) in the treatment of late-onset neonatal sepsis. Pediatr Res 2000; 47 (04) A2421
    PubMedGoogle Scholar
  • 13 Armstrong-Wells J, Donnelly M, Post MD, Manco-Johnson MJ, Winn VD, Sébire G. Inflammatory predictors of neurologic disability after preterm premature rupture of membranes. Am J Obstet Gynecol 2015; 212 (02) 212.e1-212.e9
    CrossrefPubMedGoogle Scholar
  • 14 Dammann O, O'Shea TM. Cytokines and perinatal brain damage. Clin Perinatol 2008; 35 (04) 643-663 , v
    CrossrefPubMedGoogle Scholar
  • 15 Nelson KB, Grether JK, Dambrosia JM. , et al. Neonatal cytokines and cerebral palsy in very preterm infants. Pediatr Res 2003; 53 (04) 600-607
    CrossrefPubMedGoogle Scholar
  • 16 Schultz C, Temming P, Bucsky P, Göpel W, Strunk T, Härtel C. Immature anti-inflammatory response in neonates. Clin Exp Immunol 2004; 135 (01) 130-136
    CrossrefPubMedGoogle Scholar
  • 17 Christensen RD. Neutrophil kinetics in the fetus and neonate. Am J Pediatr Hematol Oncol 1989; 11 (02) 215-223
    PubMedGoogle Scholar
  • 18 Hong DK, Wilson CB. Developmental immunology and role of host defenses in neonatal susceptibility to infection. In: Wilson CB, Nizet V, Maldonado YA, Remington JS. , and Klein JO. , eds. Remington and Klein Infectious Diseases of the Fetus & Newborn Infant. Eighth edition. Philadelphia, PA: Publishers Elsevier Saunders; 2016. (04): 81-188
    Google Scholar
  • 19 Hill HR. Biochemical, structural, and functional abnormalities of polymorphonuclear leukocytes in the neonate. Pediatr Res 1987; 22 (04) 375-382
    CrossrefPubMedGoogle Scholar
  • 20 Kilpatrick LE, Harris MC. Cytokines and inflammatory response in fetus and neonate. In: Pollin RA, Fox WW. and Abman SH. , eds. Fetal and neonatal Physiology. Philadelphia: Publisher Saunders; 2011: 1652-1671
    CrossrefGoogle Scholar
  • 21 Dammann O, Phillips TM, Allred EN. , et al; ELGAN STUDY INVESTIGATORS. Mediators of fetal inflammation in extremely low gestational age newborns. Cytokine 2001; 13 (04) 234-239
    CrossrefPubMedGoogle Scholar
  • 22 Lusyati S, Hulzebos CV, Zandvoort J, Sauer PJ. Levels of 25 cytokines in the first seven days of life in newborn infants. BMC Res Notes 2013; 6: 547
    CrossrefPubMedGoogle Scholar
  • 23 Kotiranta-Ainamo A, Rautonen J, Rautonen N. Imbalanced cytokine secretion in newborns. Biol Neonate 2004; 85 (01) 55-60
    CrossrefPubMedGoogle Scholar
  • 24 Ryan RM, Ahmed Q, Lakshminrusimha S. Inflammatory mediators in the immunobiology of bronchopulmonary dysplasia. Clin Rev Allergy Immunol 2008; 34 (02) 174-190
    CrossrefPubMedGoogle Scholar
  • 25 Kuban KC, O'Shea TM, Allred EN. , et al; ELGAN Study Investigators. Systemic inflammation and cerebral palsy risk in extremely preterm infants. J Child Neurol 2014; 29 (12) 1692-1698
    CrossrefPubMedGoogle Scholar
  • 26 Bhatia AM, Stoll BJ, Cismowski MJ, Hamrick SE. Cytokine levels in the preterm infant with neonatal intestinal injury. Am J Perinatol 2014; 31 (06) 489-496
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Harris MC, D'Angio CT, Gallagher PR, Kaufman D, Evans J, Kilpatrick L. Cytokine elaboration in critically ill infants with bacterial sepsis, necrotizing entercolitis, or sepsis syndrome: correlation with clinical parameters of inflammation and mortality. J Pediatr 2005; 147 (04) 462-468
    CrossrefPubMedGoogle Scholar
  • 28 Atici A, Satar M, Cetíner S, Yaman A. Serum tumor necrosis factor-alpha in neonatal sepsis. Am J Perinatol 1997; 14 (07) 401-404
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Chiesa C, Pacifico L, Natale F, Hofer N, Osborn JF, Resch B. Fetal and early neonatal interleukin-6 response. Cytokine 2015; 76 (01) 1-12
    CrossrefPubMedGoogle Scholar
  • 30 Kurt AN, Aygun AD, Godekmerdan A, Kurt A, Dogan Y, Yilmaz E. Serum IL-1beta, IL-6, IL-8, and TNF-alpha levels in early diagnosis and management of neonatal sepsis. Mediators Inflamm 2007; 2007: 31397
    PubMedGoogle Scholar
  • 31 Berner R, Niemeyer CM, Leititis JU. , et al. Plasma levels and gene expression of granulocyte colony-stimulating factor, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-8, and soluble intercellular adhesion molecule-1 in neonatal early onset sepsis. Pediatr Res 1998; 44 (04) 469-477
    CrossrefPubMedGoogle Scholar
  • 32 Sugitharini V, Prema A, Berla Thangam E. Inflammatory mediators of systemic inflammation in neonatal sepsis. Inflamm Res 2013; 62 (12) 1025-1034
    CrossrefPubMedGoogle Scholar
  • 33 Edelson MB, Bagwell CE, Rozycki HJ. Circulating pro- and counterinflammatory cytokine levels and severity in necrotizing enterocolitis. Pediatrics 1999; 103 (4 Pt 1): 766-771
    CrossrefPubMedGoogle Scholar
  • 34 Martin CR, Bellomy M, Allred EN, Fichorova RN, Leviton A. Systemic inflammation associated with severe intestinal injury in extremely low gestational age newborns. Fetal Pediatr Pathol 2013; 32 (03) 222-234
    CrossrefPubMedGoogle Scholar
  • 35 Sabat R, Grütz G, Warszawska K. , et al. Biology of interleukin-10. Cytokine Growth Factor Rev 2010; 21 (05) 331-344
    CrossrefPubMedGoogle Scholar
  • 36 Azizia M, Lloyd J, Allen M, Klein N, Peebles D. Immune status in very preterm neonates. Pediatrics 2012; 129 (04) e967-e974
    CrossrefPubMedGoogle Scholar
  • 37 Miura E, Procianoy RS, Bittar C. , et al. A randomized, double-masked, placebo-controlled trial of recombinant granulocyte colony-stimulating factor administration to preterm infants with the clinical diagnosis of early-onset sepsis. Pediatrics 2001; 107 (01) 30-35
    CrossrefPubMedGoogle Scholar
  • 38 Kücüködük S, Sezer T, Yildiran A, Albayrak D. Randomized, double-blinded, placebo-controlled trial of early administration of recombinant human granulocyte colony-stimulating factor to non-neutropenic preterm newborns between 33 and 36 weeks with presumed sepsis. Scand J Infect Dis 2002; 34 (12) 893-897
    CrossrefPubMedGoogle Scholar
  • 39 Simmonds A, La Gamma EF. Addressing the “New” NEC: Part I: rediscovering the basics. Indian J Pediatr 2006; 73 (11) 1011-1018
    CrossrefPubMedGoogle Scholar
  • 40 Boneberg EM, Hartung T. Molecular aspects of anti-inflammatory action of G-CSF. Inflamm Res 2002; 51 (03) 119-128
    CrossrefPubMedGoogle Scholar
  • 41 Ishikawa K, Tanaka H, Matsuoka T, Shimazu T, Yoshioka T, Sugimoto H. Recombinant human granulocyte colony-stimulating factor attenuates inflammatory responses in septic patients with neutropenia. J Trauma 1998; 44 (06) 1047-1054 , discussion 1054–1055
    CrossrefPubMedGoogle Scholar
  • 42 Hartung T, Döcke WD, Gantner F. , et al. Effect of granulocyte colony-stimulating factor treatment on ex vivo blood cytokine response in human volunteers. Blood 1995; 85 (09) 2482-2489
    CrossrefPubMedGoogle Scholar
  • 43 Takala A, Pettilä V, Takkunen O, Rintala E, Kautiainen H, Repo H. Granulocyte colony-stimulating factor therapy and systemic inflammation in critically ill patients. Inflamm Res 2005; 54 (04) 180-185
    CrossrefPubMedGoogle Scholar
  • 44 Barak Y, Leibovitz E, Mogilner B. , et al. The in vivo effect of recombinant human granulocyte-colony stimulating factor in neutropenic neonates with sepsis. Eur J Pediatr 1997; 156 (08) 643-646
    CrossrefPubMedGoogle Scholar
  • 45 Martins A, Han J, Kim SO. The multifaceted effects of granulocyte colony-stimulating factor in immunomodulation and potential roles in intestinal immune homeostasis. IUBMB Life 2010; 62 (08) 611-617
    CrossrefPubMedGoogle Scholar
  • 46 Molloy EJ, O'Neill AJ, Grantham JJ. , et al. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor have differential effects on neonatal and adult neutrophil survival and function. Pediatr Res 2005; 57 (06) 806-812
    CrossrefPubMedGoogle Scholar
  • 47 Ahmad M, Kocherlakota P, Niu J. , et al. Does granulocyte colony stimulating factor (rhG-CSF) treatment of premature infants affect the incidence of BPD and neutrophil recruitment to the lungs?. Pediatr Res 1998; 44: A942
    CrossrefPubMedGoogle Scholar
  • 48 Lawlor KE, Campbell IK, Metcalf D. , et al. Critical role for granulocyte colony-stimulating factor in inflammatory arthritis. Proc Natl Acad Sci U S A 2004; 101 (31) 11398-11403
    CrossrefPubMedGoogle Scholar
  • 49 Vrtovec B, Haddad F, Pham M. , et al. Granulocyte colony-stimulating factor therapy is associated with a reduced incidence of acute rejection episodes or allograft vasculopathy in heart transplant recipients. Transplant Proc 2013; 45 (06) 2406-2409
    CrossrefPubMedGoogle Scholar
  • 50 Zoso A, Serafini P, Lanzoni G. , et al. GCSF and Exenatide Might Be Associated with Increased LongTerm Survival of Allogeneic Pancreatic Islet Grafts. PLoS One 2016; 11 (06) e0157245
    CrossrefPubMedGoogle Scholar