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The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Oct 15;102(8):1583–1590. doi: 10.1172/JCI3664

Antibacterial activity of human neutrophil defensins in experimental infections in mice is accompanied by increased leukocyte accumulation.

M M Welling 1, P S Hiemstra 1, M T van den Barselaar 1, A Paulusma-Annema 1, P H Nibbering 1, E K Pauwels 1, W Calame 1
PMCID: PMC509009  PMID: 9788972

Abstract

Neutrophil defensins (or human neutrophil peptides-HNP) are major constituents of the azurophilic granules of human neutrophils and have been shown to display broad-spectrum antimicrobial activity. Other activities of these defensins, which are released from stimulated neutrophils, include cytotoxic, stimulatory, and chemotactic activities toward a variety of target cells. We studied the potential use of HNP-1 for antibacterial therapy of experimental bacterial infections in mice. In experimental peritoneal Klebsiella pneumoniae infections in mice, HNP-1 injection was shown to markedly reduce bacterial numbers in the infected peritoneal cavity 24 h after infection. This antibacterial effect was found to be associated with an increased influx of macrophages, granulocytes, and lymphocytes into the peritoneal cavity. These leukocytes appeared to be a requirement for the antibacterial effect, since in leukocytopenic mice administration of HNP-1 did not display antibacterial activity. HNP-1 treatment also reduced bacterial numbers in experimental K. pneumoniae or Staphylococcus aureus thigh muscle infections. In this model, radiolabeled HNP-1 was found to accumulate at the site of infection, whereas most of the injected HNP-1 was rapidly removed from the circulation via renal excretion. These results demonstrate that neutrophil defensins display marked in vivo antibacterial activity in experimental infections in mice and that this activity appears to be mediated, at least in part, by local leukocyte accumulation.

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Selected References

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  1. Bals R., Goldman M. J., Wilson J. M. Mouse beta-defensin 1 is a salt-sensitive antimicrobial peptide present in epithelia of the lung and urogenital tract. Infect Immun. 1998 Mar;66(3):1225–1232. doi: 10.1128/iai.66.3.1225-1232.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Becker W. The contribution of nuclear medicine to the patient with infection. Eur J Nucl Med. 1995 Oct;22(10):1195–1211. doi: 10.1007/BF00800606. [DOI] [PubMed] [Google Scholar]
  3. Calame W., Feitsma H. I., Ensing G. J., Arndt J. W., van Furth R., Pauwels E. K. Binding of 99mTc-labelled polyclonal human immunoglobulin to bacteria as a mechanism for scintigraphic detection of infection. Eur J Nucl Med. 1991;18(6):396–400. doi: 10.1007/BF02258430. [DOI] [PubMed] [Google Scholar]
  4. Calame W., Feitsma H. I., Ensing G. J., Goedemans W. T., Camps J. A., van Furth R., Pauwels E. K. Detection of a local staphylococcal infection in mice with technetium-99m-labeled polyclonal human immunoglobulin. J Nucl Med. 1991 Mar;32(3):468–474. [PubMed] [Google Scholar]
  5. Calame W., Welling M., Feitsma H. I., Goedemans W. T., Pauwels E. K. Contribution of phagocytic cells and bacteria to the accumulation of technetium-99m labelled polyclonal human immunoglobulin at sites of inflammation. Eur J Nucl Med. 1995 Jul;22(7):638–644. doi: 10.1007/BF01254565. [DOI] [PubMed] [Google Scholar]
  6. Chertov O., Michiel D. F., Xu L., Wang J. M., Tani K., Murphy W. J., Longo D. L., Taub D. D., Oppenheim J. J. Identification of defensin-1, defensin-2, and CAP37/azurocidin as T-cell chemoattractant proteins released from interleukin-8-stimulated neutrophils. J Biol Chem. 1996 Feb 9;271(6):2935–2940. doi: 10.1074/jbc.271.6.2935. [DOI] [PubMed] [Google Scholar]
  7. Daher K. A., Selsted M. E., Lehrer R. I. Direct inactivation of viruses by human granulocyte defensins. J Virol. 1986 Dec;60(3):1068–1074. doi: 10.1128/jvi.60.3.1068-1074.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Deakin A. M., Payne A. N., Whittle B. J., Moncada S. The modulation of IL-6 and TNF-alpha release by nitric oxide following stimulation of J774 cells with LPS and IFN-gamma. Cytokine. 1995 Jul;7(5):408–416. doi: 10.1006/cyto.1995.0056. [DOI] [PubMed] [Google Scholar]
  9. Eisenhauer P. B., Lehrer R. I. Mouse neutrophils lack defensins. Infect Immun. 1992 Aug;60(8):3446–3447. doi: 10.1128/iai.60.8.3446-3447.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ganz T., Selsted M. E., Lehrer R. I. Defensins. Eur J Haematol. 1990 Jan;44(1):1–8. doi: 10.1111/j.1600-0609.1990.tb00339.x. [DOI] [PubMed] [Google Scholar]
  11. Ganz T., Selsted M. E., Szklarek D., Harwig S. S., Daher K., Bainton D. F., Lehrer R. I. Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest. 1985 Oct;76(4):1427–1435. doi: 10.1172/JCI112120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gerber A. U., Brugger H. P., Feller C., Stritzko T., Stalder B. Antibiotic therapy of infections due to Pseudomonas aeruginosa in normal and granulocytopenic mice: comparison of murine and human pharmacokinetics. J Infect Dis. 1986 Jan;153(1):90–97. doi: 10.1093/infdis/153.1.90. [DOI] [PubMed] [Google Scholar]
  13. Hancock R. E. Peptide antibiotics. Lancet. 1997 Feb 8;349(9049):418–422. doi: 10.1016/S0140-6736(97)80051-7. [DOI] [PubMed] [Google Scholar]
  14. Ihi T., Nakazato M., Mukae H., Matsukura S. Elevated concentrations of human neutrophil peptides in plasma, blood, and body fluids from patients with infections. Clin Infect Dis. 1997 Nov;25(5):1134–1140. doi: 10.1086/516075. [DOI] [PubMed] [Google Scholar]
  15. Kunst M. W., Mattie H. Cefazolin and cephradine: relationship between antibacterial activity in vitro and in mice experimentally infected with Escherichia coli. J Infect Dis. 1978 Apr;137(4):391–402. doi: 10.1093/infdis/137.4.391. [DOI] [PubMed] [Google Scholar]
  16. Lehrer R. I., Barton A., Daher K. A., Harwig S. S., Ganz T., Selsted M. E. Interaction of human defensins with Escherichia coli. Mechanism of bactericidal activity. J Clin Invest. 1989 Aug;84(2):553–561. doi: 10.1172/JCI114198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lehrer R. I., Lichtenstein A. K., Ganz T. Defensins: antimicrobial and cytotoxic peptides of mammalian cells. Annu Rev Immunol. 1993;11:105–128. doi: 10.1146/annurev.iy.11.040193.000541. [DOI] [PubMed] [Google Scholar]
  18. Nakajima Y., Alvarez-Bravo J., Cho J., Homma K., Kanegasaki S., Natori S. Chemotherapeutic activity of synthetic antimicrobial peptides: correlation between chemotherapeutic activity and neutrophil-activating activity. FEBS Lett. 1997 Sep 22;415(1):64–66. doi: 10.1016/s0014-5793(97)01101-0. [DOI] [PubMed] [Google Scholar]
  19. Panyutich A. V., Panyutich E. A., Krapivin V. A., Baturevich E. A., Ganz T. Plasma defensin concentrations are elevated in patients with septicemia or bacterial meningitis. J Lab Clin Med. 1993 Aug;122(2):202–207. [PubMed] [Google Scholar]
  20. Pauwels E. K., Welling M. M., Feitsma R. I., Atsma D. E., Nieuwenhuizen W. The labeling of proteins and LDL with 99mTc: a new direct method employing KBH4 and stannous chloride. Nucl Med Biol. 1993 Oct;20(7):825–833. doi: 10.1016/0969-8051(93)90148-n. [DOI] [PubMed] [Google Scholar]
  21. Pohlman T. H., Stanness K. A., Beatty P. G., Ochs H. D., Harlan J. M. An endothelial cell surface factor(s) induced in vitro by lipopolysaccharide, interleukin 1, and tumor necrosis factor-alpha increases neutrophil adherence by a CDw18-dependent mechanism. J Immunol. 1986 Jun 15;136(12):4548–4553. [PubMed] [Google Scholar]
  22. Stolk J., Camps J., Feitsma H. I., Hermans J., Dijkman J. H., Pauwels E. K. Pulmonary deposition and disappearance of aerosolised secretory leucocyte protease inhibitor. Thorax. 1995 Jun;50(6):645–650. doi: 10.1136/thx.50.6.645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Territo M. C., Ganz T., Selsted M. E., Lehrer R. Monocyte-chemotactic activity of defensins from human neutrophils. J Clin Invest. 1989 Dec;84(6):2017–2020. doi: 10.1172/JCI114394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. van Waarde D., Hulsing-Hesselink E., Sandkuyl L. A., van Furth R. Humoral regulation of monocytopoiesis during the early phase of an inflammatory reaction caused by particulate substances. Blood. 1977 Jul;50(1):141–154. [PubMed] [Google Scholar]

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