Skip to main content

Increased nitric oxide production by neutrophils in early stage of Kawasaki disease

European Journal of Pediatrics volume 168, pages 1037–1041 (2009)Cite this article

Abstract

Recent observations suggested that nitric oxide (NO) has a role in triggering the early endothelial dysfunction in Kawasaki disease (KD). We investigated the amount of NO in conjunction with reactive oxygen species (ROS) produced by neutrophils in children with acute KD by a newly developed flow cytometric analysis. Forty children with acute KD (n = 14), non-KD febrile disease (n = 14), and afebrile control (n = 12) were enrolled (age, 3 to 88 months). Neutrophils in KD produced significantly higher amount of NO compared to others (p < 0.05). With regard to ROS, significant increase was not only found in KD but also in non-KD febrile children (p < 0.05 and p < 0.01, respectively). In KD patients, the amount of NO produced by neutrophils decreased after immunoglobulin (IVIG) treatment, while there was no significant change in ROS production. The amount of NO in KD patients also correlated well with the days from the onset. One patient who developed coronary arterial lesion showed the highest value of NO. In conclusion, neutrophils in acute KD generate both NO and ROS considerably, while NO production is exclusive in the early stage of KD before IVIG treatment. Abnormal immune system in KD might be characterized by an overproduction of NO, whereas the role of NO in endothelial damage remains to be elucidated.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3

References

  1. Adewuya O, Irie Y, Bian K, Onigu-Otite E, Murad F (2003) Mechanism of vasculitis and aneurysms in Kawasaki disease: role of nitric oxide. Nitric Oxide 8:15–25

    PubMed  Article  CAS  Google Scholar 

  2. Anggard E (1994) Nitric oxide: mediator, murderer, and medicine. Lancet 343:199–1206

    Google Scholar 

  3. Burns JC (2007) The riddle of Kawasaki disease. N Engl J Med 356:659–661

    PubMed  Article  CAS  Google Scholar 

  4. Burns JC, Glodé MP (2004) Kawasaki syndrome. Lancet 364:533–544

    PubMed  Article  Google Scholar 

  5. Cheung YF, Huang GY, Chen SB et al (2008) Inflammatory gene polymorphisms and susceptibility to Kawasaki disease and its arterial sequelae. Pediatrics 122:e608–e614

    PubMed  Article  Google Scholar 

  6. Cheung YF, O K, Tam SC, Siow YL (2005) Induction of MCP1, CCR2, and iNOS expression in THP-1 macrophages by serum of children late after Kawasaki disease. Pediatr Res 58:1306–1310

    PubMed  Article  CAS  Google Scholar 

  7. Fang FC (2004) Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nat Rev Microbiol 2:820–832

    PubMed  Article  CAS  Google Scholar 

  8. Hamamichi Y, Ichida F, Xianyi Yu et al (2001) Neutrophils and mononuclear cells express vascular endothelial growth factor in acute Kawasaki disease. Pediatr Res 49:74–80

    PubMed  Article  CAS  Google Scholar 

  9. Hobbs MR, Udhayakumar V, Levesque MC et al (2002) A new NOS2 promoter polymorphism associated with increased nitric oxide production and protection from severe malaria in Tanzanian and Kenyan children. Lancet 360:1468–1475

    PubMed  Article  CAS  Google Scholar 

  10. Ikemoto Y, Teraguchi M, Ono A, Kino M, Yoshimura K, Kobayashi Y (2003) Serial changes of plasma nitrate in the acute phase of Kawasaki disease. Pediatr Int 45:421–425

    PubMed  Article  CAS  Google Scholar 

  11. Kojima H, Nakatsubo N, Kikuchi K et al (1998) Detection and imaging of nitric oxide with novel fluorescent indicators: diaminofluoresceins. Anal Chem 70:2446–2453

    PubMed  Article  CAS  Google Scholar 

  12. Kroncke KD, Fehsel K, Kolb-Bachofen V (1998) Inducible nitric oxide synthase in human diseases. Clin Exp Immunol 113:147–156

    PubMed  Article  CAS  Google Scholar 

  13. Matsubara T, Ichiyama T, Furukawa S (2005) Immunological profile of peripheral blood lymphocytes and monocytes/macrophages in Kawasaki disease. Clin Exp Immunol 141:381–387

    PubMed  Article  CAS  Google Scholar 

  14. Nathan C, Xie Q (1994) Nitric oxide synthase: roles, tolls, and controls. Cell 78:915–918

    PubMed  Article  CAS  Google Scholar 

  15. Onouchi Y, Gunji T, Burns JC et al (2008) ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nat Genet 40:35–42

    PubMed  Article  CAS  Google Scholar 

  16. Research Committee on Kawasaki disease (1984) Report of subcommittee on standardization of diagnostic criteria and reporting of coronary artery lesions in Kawasaki disease. Ministry of Health and Welfare, Tokyo

    Google Scholar 

  17. Sato S, Tsukahara H, Ohta N, Todoroki Y, Nishida K, Mayumi M (2004) Endothelial dysfunction in Kawasaki disease: focus on nitric oxide. Pediatr Int 46:114

    PubMed  Article  Google Scholar 

  18. Setsukinai K, Urano Y, Kakinuma K, Majima HJ, Nagano T (2003) Development of novel fluorescence probes that can reliably detect reactive oxygen species and distinguish specific species. J Biol Chem 278:3170–3175

    PubMed  Article  CAS  Google Scholar 

  19. Takahashi K, Oharaseki T, Naoe S, Wakayama M, Yokouchi Y (2005) Neutrophilic involvement in the damage to coronary arteries in acute stage of Kawasaki disease. Pediatr Int 47:305–310

    PubMed  Article  Google Scholar 

  20. Terai M, Jibiki T, Harada A et al (1999) Dramatic decrease of circulating levels of monocyte chemoattractant protein-1 in Kawasaki disease after gamma globulin treatment. J Leukoc Biol 65:566–572

    PubMed  CAS  Google Scholar 

  21. Tsuji S, Taniuchi S, Hasui M, Yamamoto A, Kobayashi Y (2002) Increased nitric oxide production by neutrophils from patients with chronic granulomatous disease on trimethoprim-sulfamethoxazole. Nitric Oxide 7:283–288

    PubMed  Article  CAS  Google Scholar 

  22. Wang CL, Wu YT, Lee CJ, Liu HC, Huang LT, Yang KD (2002) Decreased nitric oxide production after intravenous immunoglobulin treatment in patients with Kawasaki disease. J Pediat 141:560–565

    PubMed  Article  CAS  Google Scholar 

  23. Yu X, Hirono KI, Ichida F et al (2004) Enhanced iNOS expression in leukocytes and circulating endothelial cells is associated with the progression of coronary artery lesions in acute Kawasaki disease. Pediatr Res 55:688–694

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgment

We are indebted to Dr. Urano and Dr. Nagano (Laboratory of Chemistry and Biology, Graduate School of Pharmaceutical Sciences, The University of Tokyo) for their kindly providing hydroxyphenyl fluorescence (HPF).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Affiliations

  1. Department of Pediatrics, Kansai Medical University, 2-3-1 Shin-machi, Hirakata-shi, Osaka, 573-1191, Japan

    Ken Yoshimura, Kimiko Tatsumi, Anna Iharada, Shoji Tsuji, Ai Tateiwa, Masayuki Teraguchi, Hirotaro Ogino & Kazunari Kaneko

Authors
  1. Ken Yoshimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kimiko Tatsumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Iharada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shoji Tsuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ai Tateiwa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masayuki Teraguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hirotaro Ogino
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kazunari Kaneko
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kazunari Kaneko.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yoshimura, K., Tatsumi, K., Iharada, A. et al. Increased nitric oxide production by neutrophils in early stage of Kawasaki disease. Eur J Pediatr 168, 1037–1041 (2009). https://doi.org/10.1007/s00431-008-0872-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-008-0872-1

Keywords

  • Kawasaki disease
  • Nitric oxide
  • Reactive oxygen species
  • Endothelial dysfunction