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Inflammatory mediators of systemic inflammation in neonatal sepsis

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Abstract

Objective and design

Sepsis refers to severe systemic inflammation in response to invading pathogens. To understand the molecular events that initiate the systemic inflammatory response, various inflammatory mediators were analyzed in neonatal sepsis samples and compared with normal samples.

Materials and methods

We initially measured the levels of the various classical inflammatory mediators such as acute phase proteins [C-reactive protein (CRP) and procalcitonin (PCT)], granule-associated mediators (NE, MPO and NO), proinflammatory cytokines [tumour necrosis factor-α (TNFα), IL-1β and IL-6), antiinflammatory cytokines (IL-10 and IL-13) and chemokines [IL-8 and monocyte chemotactic protein (MCP-1)] and novel cytokines (IL-12/IL-23p40, IL-21 and IL-23) using ELISA. We also used the human inflammation antibody array membrane to profile the inflammatory proteins that are involved in neonatal sepsis.

Results

There were significantly higher levels of CRP (5.4 ± 0.70 mg/L), PCT (1.500 ± 0.2400 μg/L); NE (499.2 ± 22.01 μg/L), NO (54.22 ± 3.131 μM/L); TNFα (396.6 ± 37.40 pg/mL), IL-1β (445.3 ± 34.25 pg/mL), IL-6 (320.9 ± 43.38 pg/mL); IL-8 (429.5 ± 64.08 pg/mL) MCP-1 (626.25 ± 88.91 pg/mL), IL-10 (81.80 ± 9.45 pg/mL), IL-12/IL-23p40 (30.25 ± 0.6 pg/mL), IL-21 (8,263.3 ± 526.8 pg/mL) and IL-23 (6,083 ± 781.3 pg/mL) in neonates with sepsis compared to normal. The levels of MPO (21.20 ± 3.099 ng/mL) were downregulated, whereas there was no change in IL-13 (188.7 ± 10.63 pg/mL) levels in septic neonates when compared with normal. Using the human inflammation antibody array membrane, we detected the presence of 17 inflammatory proteins such as IL-3, IL6R, IL12p40, IL-16, TNFα, TNFβ, TNF R1, chemokines I-309, IP-10 (IFN-γ inducible protein 10), MCP-1, MCP-2, MIP 1β (macrophage inflammatory protein), MIP-1δ, eotaxin-2, growth factors TGFβ1 (transforming growth factor beta), PDGF (platelet derived growth factor), and cell adhesion molecule ICAM-1 (intracellular adhesion molecule) that were upregulated whereas RANTES which was downregulated in neonatal sepsis.

Conclusion

The simultaneous secretion and release of multiple mediators such as proinflammatory cytokines and chemokines, cell adhesion molecules, and growth factors were found to be involved in the initiation of systemic inflammation in neonatal sepsis. Therefore, measuring the concentration of multiple mediators may help in the early detection of neonatal sepsis and help to avoid unnecessary antibiotic treatment.

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References

  1. Kenzel S, Henneke L. The innate immune system and its relevance to neonatal sepsis. Curr Opin Infect Dis. 2006;19(3):264–70.

    Article  PubMed  CAS  Google Scholar 

  2. Cloberty JP, Stark R, Eichenwald E. Manual of neonatal care. Chap 49, 7th ed. Lippincott Williams and Wilkins; 1998.

  3. Pertova A, Metha R. Dysfunction of innate immunity and associated pathology in neonates. Indian J Pediatr. 2007;74:185–91.

    Article  Google Scholar 

  4. Dasari P, Zola H, Nicholson IC. Expression of toll-like receptors by neonatal leukocytes. Pediatr Allergy Immunol. 2011;22(2):221–8.

    Article  PubMed  Google Scholar 

  5. Medzhitov R, Janeway CA Jr. Innate immunity: the virtues of a nonclonal system of recognition. Cell. 1997;91:295–8.

    Article  PubMed  CAS  Google Scholar 

  6. Hotoura E, Giapros V, Kostoula A, Spirou P, Andronikou S. Tracking changes of lymphocyte subsets and pre-inflammatory mediators in full-term neonates with suspected or documented infection. Scand J Immunol. 2011;73(3):250–5.

    Article  PubMed  CAS  Google Scholar 

  7. Santana RC, Garcia MF, Reyes D, Gonzalez G, Dominguez C, Domenech E. Role of cytokines (interleukin-1beta, 6, 8, tumour necrosis factor-alpha, and soluble receptor of interleukin-2) and C-reactive protein in the diagnosis of neonatal sepsis. Acta Paediatr. 2003;92(2):221–7.

    Google Scholar 

  8. Abdelhamid AE, Chuang SL, Hayes P, Fell JM. In vitro cow’s milk protein-specific inflammatory and regulatory cytokine responses in preterm infants with necrotizing enterocolitis and sepsis. Pediatr Res. 2011;69(2):165–9.

    Article  PubMed  CAS  Google Scholar 

  9. Mokart D, Merlin M, Sannini A, Brun JP, Delpero JR, Houvenaeghel G, Moutardier V, Blache JL. Procalcitonin, interleukin 6 and systemic inflammatory response syndrome (SIRS): early markers of postoperative sepsis after major surgery. Br J Anaesth. 2005;94(6):767–73.

    Article  PubMed  CAS  Google Scholar 

  10. Weinberg GA, D’Angio CT. The search for new diagnostic tests for neonatal sepsis. J Pediatr. 2009;155(5):763–4.

    Article  PubMed  Google Scholar 

  11. Riedemann NC, Goo RF, Ward PA. Novel strategies for the treatment of sepsis. Nat Med. 2003;9:517–20.

    Article  PubMed  CAS  Google Scholar 

  12. Aziz M, Jacob A, Yang WL, Matsuda A, Wang P. Current trends in inflammatory and immunomodulatory mediators in sepsis. J Leukoc Biol. 2013. doi:10.1189/jlb.0912437.

    PubMed  Google Scholar 

  13. Miller E. Phagocytosis in the newborn infant. J Ped. 1969;74:255.

    Article  CAS  Google Scholar 

  14. Baltimore R, Huie SM, Meek JI, Schuchat A, Brien KLO. Early-onset neonatal sepsis in the era of group B Streptococcal prevention. J Pediatr. 2001;108:1094–8.

    Article  CAS  Google Scholar 

  15. Baltimore RS. Perinatal bacterial and fungal infections. In: Jenson HB, Baltimore RS, editors. Ped Inf Dis. Prin Prac. 2nd ed. Philadelphia: WB Saunders Co; 2002. p. 1119–34.

  16. Dollner H, Vatten L, Austgulen R. Early diagnostic markers for neonatal sepsis: comparing C-reactive protein, interleukin-6, soluble tumour necrosis factor receptors and soluble adhesion molecules. J Clin Epidemiol. 2001;54:1251.

    Article  PubMed  CAS  Google Scholar 

  17. Chiesa C, Natale F, Pascone R, Osborn JF, Pacifico L, Bonci E, De Curtis M. C reactive protein and procalcitonin: reference intervals for preterm and term newborns during the early neonatal period. Clin Chimica Acta. 2011;412:1053–9.

    Article  CAS  Google Scholar 

  18. Manroe BL, Weinberg AG, Rosenfeld CR, Browne R. The neonatal blood count in health and disease. I. Reference values for neutrophils cells. J Ped. 1979;95(1):89–98.

    Article  CAS  Google Scholar 

  19. Tsaka T, Herkner KR. Polymorphonuclear elastase in neonatal sepsis. Clin Chim Acta. 1990;193:103–12.

    Article  PubMed  CAS  Google Scholar 

  20. Henson PM. The immunologic release of constituents from neutrophil leukocytes. I. The role of antibody and complement on nonphagocytosable surfaces or phagocytosable particles. J Immunol. 1971;107:1535.

    PubMed  CAS  Google Scholar 

  21. Ohlsson K, Olsson AS. Immunoreactive granulocyte elastase in human serum. Hoppe-Seyler’s Z Physiol Chem. 1978;359:1531.

    Article  PubMed  CAS  Google Scholar 

  22. Terregino C, Lopez B, Karras D, Killian A, Arnold G. Endogenous mediators in emergency department patients with presumed sepsis: are levels associated with progression to severe sepsis and death. Ann Emerg Med. 2000;35:26–34.

    Article  PubMed  CAS  Google Scholar 

  23. Shi YH, Li C, Shen J, Wang S, Qin R, Pan LJ. Plasma nitric oxide level in newborn infants with sepsis. J Ped. 1993;123:436–8.

    Article  Google Scholar 

  24. Spack LP, Griffith HO. Measurement of total plasma nitrite and nitrate in pediatric patients with the systemic inflammatory response syndrome. Crit Care Med. 1997;25:1071–8.

    Article  PubMed  CAS  Google Scholar 

  25. Martin H, Olander B, Norman M. Reactive hyperemia and interleukin 6, interleukin 8, and tumor necrosis factor-α in the diagnosis of early-onset neonatal sepsis. Pediatrics. 2001;108:1–6.

    Article  Google Scholar 

  26. Urbonas V, Eidukaite A, Tamuliene I. Increased interleukin-10 levels correlate with bacteremia and sepsis in febrile neutropenia pediatric oncology patients. Cytokine. 2012;57:313–5.

    Article  PubMed  CAS  Google Scholar 

  27. Takahashi N, Uehara R, Kobayashi M, Yada Y, Koike Y, Kawamata R, Odaka J, Honma Y, Momoi MY. Cytokine profiles of seventeen cytokines, growth factors and chemokines in cord blood and its relation to perinatal clinical findings. Cytokine. 2010;49:331–7.

    Article  PubMed  CAS  Google Scholar 

  28. Caoa YZ, Tua YY, Chen X, Wang BL, Zhong YX, Liu MH. Protective effect of ulinastatin against murine models of sepsis: inhibition of TNF and IL-6 and augmentation of IL-10 and IL-13. Exp Toxicol Pathol. 2012;64(6):543–7.

    Article  Google Scholar 

  29. Schelonka RL, Maheshwari A, Carlo WA, Taylor S, Hansen NI, Schendel DE, Thorsen P, Skogstrand K, Hougaard DM, Higgins RD, NICHD Neonatal Research Network. T cell cytokines and the risk of blood stream infection in extremely low birth weight infants. Cytokine. 2011;53:249–55.

    Article  PubMed  CAS  Google Scholar 

  30. Ng PC, Li K, Leung TF, Wong RP, Li G, Chui KM, Wong E, Cheng FW, Fok TF. Early prediction of sepsis-induced disseminated intravascular coagulation with interleukin-10, interleukin-6, and RANTES in preterm infants. Clin Chem. 2006;52(6):1181–9.

    Article  PubMed  CAS  Google Scholar 

  31. Mera S, Tatulescu D, Cismaru C, Bondor C, Slavcovici A, Zanc V, et al. Multiplex cytokine profiling in patients with sepsis. Apmis. 2011;119(2):155–63.

    Article  PubMed  CAS  Google Scholar 

  32. Andaluz-Ojeda D, Bobillo F, Iglesias V, Almansa R, Rico L, Gandía F, Resino S, Tamayo E, de Lejarazu RO, Bermejo-Martin JF. A combined score of pro- and anti inflammatory interleukins improves mortality prediction in severe sepsis. Cytokine. 2012;57(3):332–6.

    Article  PubMed  CAS  Google Scholar 

  33. Harlan JM. Leukocyte–endothelial interactions. Blood. 1985;65:513–25.

    PubMed  CAS  Google Scholar 

  34. Manoura A, Gourgiotis D, Galanakis E, Matalliotakis E, Hatzidaki E, Korakaki E, Saitakis E, Marmarinos AS, Giannakopoulou C. Circulating concentrations of α- and β-chemokines in neonatal sepsis. Int J Infect Dis. 2010;14(9):e806–9.

    Article  PubMed  CAS  Google Scholar 

  35. Wu YH, Chuang SY, Hong WC, Lai YJ, Chang YL, Pang JH. In vivo and in vitro inhibitory effects of a traditional Chinese formulation on LPS-stimulated leukocyte–endothelial cell adhesion and VCAM-1 gene expression. J Ethnopharmacol. 2012;140(1):55–63.

    Article  PubMed  Google Scholar 

  36. Cheon H, Yu SJ, Yoo DH, Chae IJ, Song GG, Sohn J. Increased expression of pro-inflammatory cytokines and metalloproteinase-1 by TGFbeta1 in synovial fibroblasts from rheumatoid arthritis and normal individuals. Clin Exp Immunol. 2002;127:547–52.

    Article  PubMed  CAS  Google Scholar 

  37. Edwards DR, Leco KJ, Beaudry PP, Atadja PW, Veillette C, Riabowol KT. Differential effects of transforming growth factor-beta 1 on the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in young and old human fibroblasts. Exp Gerontol. 1996;31:207–23.

    Article  PubMed  CAS  Google Scholar 

  38. Fava RA, Olsen NJ, Postlethwaite AE, Broadley KN, Davidson JM, Nanney LB, et al. Transforming growth factor beta 1(TGFbeta 1) induced neutrophil recruitment to synovial tissues: implications for TGFbeta-driven synovial inflammation and hyperplasia. J Exp Med. 1991;173(5):1121–32.

    Article  PubMed  CAS  Google Scholar 

  39. Ramsay PL, O’Brian Smith E, Hegemier S, et al. Early clinical markers for the development of bronchopulmonary dysplasia: soluble E-Selectin and ICAM-1. Pediatrics. 1998;102:927.

    Article  PubMed  CAS  Google Scholar 

  40. Endo S, Inada K, Kasai T, et al. Levels of soluble adhesion molecules and cytokines in patients with septic multiple organ failure. J Inflamm. 1995;46:212.

    PubMed  CAS  Google Scholar 

  41. Xanthou M, Fotopoulos S, Mouchtouri A, et al. Inflammatory mediators in perinatal asphyxia and infection. Acta Paediatr Suppl. 2002;91:92.

    Article  PubMed  CAS  Google Scholar 

  42. Ramnath RD, Ng SW, Guglielmotti A, Bhatia M. Role of MCP-1 in endotoxemia and sepsis. Int Immunopharmacol. 2008;8:810–8.

    Article  PubMed  CAS  Google Scholar 

  43. Bozza FA, Salluh JI, Japiassu AM, Soares M, Assis EF, Gomes RN, Bozza MT, Castro-Faria-Neto HC, Bozza PT. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care. 2007;11(2):R49.

    Article  PubMed  Google Scholar 

  44. Kantar M, Kültürsay N, Kütükçüler N, Akisü M, Cetingül N, Caglayan S. Plasma concentrations of granulocyte-macrophage colony-stimulating factor and interleukin-6 in septic and healthy preterms. Eur J Pediatr. 2000;159:156–7.

    Article  PubMed  CAS  Google Scholar 

  45. Magudumana O, Ballot DE, Cooper PA, et al. Serial interleukin 6 measurements in the early diagnosis of neonatal sepsis. J Trop Pediatr. 2000;46:267–71.

    Article  PubMed  CAS  Google Scholar 

  46. Yannam GR, Gutti T, Poluektova LY. IL-23 in infections, inflammation, autoimmunity and cancer: possible role in HIV-1 and AIDS. J Neuroimmune Pharmacol. 2012;7:95–112.

    Article  PubMed  Google Scholar 

  47. Louis S, Dutertre C-A, Vimeux L, Fery L, Henno L, Diocou S, Kahi S, Deveau C, Meyer L, Goujard C, Hosmalin A. IL-23 and IL-12p70 production by monocytes and dendritic cells in primary HIV-1 infection. J Leukoc Biol. 2010;. doi:10.1189/jlb.1009684.

    PubMed  Google Scholar 

  48. Kollmann TR, Crabtree J, Rein-Weston A, Blimkie D, Thommai F, Wang XY, Lavoie PM, Furlong J, Fortuno ES 3rd, Hajjar AM, Hawkins NR, Self SG, Wilson CB. Neonatal innate TLR-mediated responses are distinct from those of adults. J Immunol. 2009;183(11):7150–60.

    Article  PubMed  CAS  Google Scholar 

  49. Bozza FA, Salluh JI, Japiassu AM, Soares M, Assis EF, Gomes RN, et al. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care. 2007;11:R49.

    Article  PubMed  Google Scholar 

  50. Nakano N, Nishiyama C, Kanada S, Niwa Y, Shimokawa N, Ushio H, Nishiyama M, Okumura K, Ogawa H. Involvement of mast cells in IL-12/23 p40 production is essential for survival from polymicrobial infections. Blood. 2007;109:4846–55.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study is supported by the grant from Department of Biotechnology (DBT), Government of India (No. BT/PR12666/BRB/10/723/2009). The authors are thankful to SRM University for their support. Authors are also thankful to staffs of SRM hospital and CMC hospital, Chengalpet for assistance in sample collection.

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Authors and Affiliations

  1. Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur, Chennai, 603203, Tamil Nadu, India

    V. Sugitharini & E. Berla Thangam

  2. Department of Pediatrics, SRM Medical College Hospital and Research Centre, Kattankulathur, Chennai, 603203, India

    A. Prema

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  1. V. Sugitharini
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Correspondence to E. Berla Thangam.

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Responsible Editor: Artur Bauhofer.

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Sugitharini, V., Prema, A. & Berla Thangam, E. Inflammatory mediators of systemic inflammation in neonatal sepsis. Inflamm. Res. 62, 1025–1034 (2013). https://doi.org/10.1007/s00011-013-0661-9

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