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JAC Advance Access published online on September 6, 2002
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkf160
© 2002 by The British Society for Antimicrobial Chemotherapy
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© 2002 The British Society for Antimicrobial Chemotherapy

Original Paper

Priming by grepafloxacin on respiratory burst of human neutrophils: its possible mechanism

Masayuki Niwa 1*, Yutaka Kanamori 2, Koichi Hotta 2, Hiroyuki Matsuno 2, Osamu Kozawa 2, Sadaki Fujimoto 3, Toshihiko Uematsu 2

1 Medical Education Development Center, Gifu University School of Medicine, 40-Tsukasamachi, Gifu 500-8705; Department of Pharmacology, Gifu University School of Medicine, 40-Tsukasamachi, Gifu 500-8705
2 Department of Pharmacology, Gifu University School of Medicine, 40-Tsukasamachi, Gifu 500-8705
3 Department of Environmental Biochemistry, Kyoto Pharmaceutical University, Nakauchi-cho 5, Yamashina-ku, Kyoto 607-8414, Japan

* Corresponding author. E-mail: mniwa{at}cc.gifu-u.ac.jp.

Received 1 May 2002 ; revised 16 June 2002 ; accepted 21 June 2002

Abstract

Grepafloxacin is a broad-spectrum fluoroquinolone derivative that has good tissue penetration. We demonstrated that grepafloxacin showed a priming effect on neutrophil respiratory burst, triggered by either a chemotactic factor N-formyl-methionyl-leucyl-phenylalanine (fMLP) or leukotriene B4 (LTB4), but not by the phorbol ester phorbol 12-myristate 13-acetate (PMA). The priming effect of grepafloxacin on fMLP-stimulated superoxide generation by human neutrophils correlated with the penetration of grepafloxacin into cells. Removal of extracellular grepafloxacin did not inhibit the priming effect on fMLP-stimulated superoxide generation. Furthermore, grepafloxacin induced the translocation of p47-phox and p67-phox to the membrane fraction of neutrophils, whereas tyrosine phosphorylation was hardly observed in neutrophils exposed to grepafloxacin. The priming effect of grepafloxacin on superoxide generation from neutrophils was not inhibited by treatment with pertussis toxin, a protein-tyrosine kinase inhibitor (ST-638) or a protein kinase C inhibitor (calphostin C), or chelation of extracellular calcium. Grepafloxacin did not change the fMLP receptor-binding properties. Taken together, these findings suggest that grepafloxacin evokes a priming effect on neutrophil superoxide generation intracellularly through the translocation of p47-phox and even p67-phox protein to the membrane fractions. GTP binding protein, protein-tyrosine phosphorylation and protein kinase C activation are not involved in the priming effect.

Keywords: free radicals, fluoroquinolone antimicrobial agents, grepafloxacin, human neutrophils, p47-phox
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