title: Antibacterial activity of human neutrophil defensins in experimental infections in mice is accompanied by increased leukocyte accumulation.
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.
authors.affiliation: Department of Radiology, Division of Nuclear Medicine, Leiden University Medical Center, Leiden, The Netherlands. welling@rullf2.medfac.leidenuniv.nl
authors.forename: M M
authors.initials: MM
authors.lastname: Welling
authors.forename: P S
authors.initials: PS
authors.lastname: Hiemstra
authors.forename: M T
authors.initials: MT
authors.lastname: van den Barselaar
authors.forename: A
authors.initials: A
authors.lastname: Paulusma-Annema
authors.forename: P H
authors.initials: PH
authors.lastname: Nibbering
authors.forename: E K
authors.initials: EK
authors.lastname: Pauwels
authors.forename: W
authors.initials: W
authors.lastname: Calame
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D023082:Defensins; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy*; D007711:Klebsiella pneumoniae; D008297:Male; D051379:Mice; D009135:Muscular Diseases / Q000188:drug therapy; D010532:Peritoneal Diseases / Q000188:drug therapy; D011506:Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013848:Thigh; D014018:Tissue Distribution; D023084:alpha-Defensins
chemical_list: D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D023082:Defensins; D011506:Proteins; D023084:alpha-Defensins; C406413:human neutrophil peptide 1