ANTIBACTERIAL ACTIVITY OF HUMAN NEUTROPHIL DEFENSINS IN EXPERIMENTAL INFECTIONS IN MICE IS ACCOMPANIED BY INCREASED LEUKOCYTE ACCUMULATION

Neutrophil defensins (or human neutrophil peptides-HNP) are major cons tituents of the azurophilic granules of human neutrophils and have bee n shown to display broad-spectrum antimicrobial activity. Other activi ties of these defensins, which are released from stimulated neutrophil s, include cytotoxic, stimulatory, and chemotactic activities toward a variety of target cells. We studied the potential use of HNP-1 for an tibacterial therapy of experimental bacterial infections in mice. In e xperimental peritoneal Klebsiella pneumoniae infections in mice, HNP-1 injection was shown to markedly reduce bacterial numbers in the infec ted peritoneal cavity 24 h after infection. This antibacterial effect was found to be associated with an increased influx of macrophages, gr anulocytes, and lymphocytes into the peritoneal cavity. These leukocyt es appeared to be a requirement for the antibacterial effect, since in leukocytopenic mice administration of HNP-1 did not display antibacte rial activity. HNP-1 treatment also reduced bacterial numbers in exper imental K. pneumoniae or Staphylococcus aureus thigh muscle infections . In this model, radiolabeled HNP-1 was found to accumulate at the sit e of infection, whereas most of the injected HNP-1 was rapidly removed from the circulation via renal excretion. These results demonstrate t hat 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.