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Published online before print October 4, 2005

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(Journal of Leukocyte Biology. 2005;78:1356-1365.)
© 2005 by Society for Leukocyte Biology

Local anesthetics inhibit priming of neutrophils by lipopolysaccharide for enhanced release of superoxide: suppression of cytochrome b₅₅₈ expression by disparate mechanisms

Akio Jinnouchi^*, Yoshitomi Aida^*,1, Kohji Nozoe^*, Katsumasa Maeda^* and Michael J. Pabst

^* Section of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, Fukuoka, Japan; and
Dental Research Center and Department of Molecular Sciences, The University of Tennessee, Memphis

¹ Correspondence: Section of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 Japan. E-mail: yaida{at}dent.kyushu-u.ac.jp

Local anesthetics have anti-inflammatory effects in vivo and inhibit neutrophil functions in vitro, but how these agents act on neutrophils remains unclear. Phagocytosis and bactericidal activity of neutrophils are enhanced by exposure to bacterial components such as lipopolysaccharide (LPS); this process is termed priming, which for enhanced release of superoxide (O₂^–) causes mobilization of intracellular granules that contain cytochrome b₅₅₈, a component of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. We studied whether local anesthetics affected LPS priming for enhanced release of O₂^– in response to triggering by the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP), and we investigated which element in the LPS signaling pathway might be the target of local anesthetics. Neutrophils were incubated with 10 ng/ml LPS and 1% plasma ± local anesthetics, washed, and triggered with fMLP. Local anesthetics all inhibited LPS priming, and 50% inhibition was at 0.1 mM tetracaine, 0.5 mM bupivacaine, 3.0 mM lidocaine, or 4.0 mM procaine. Local anesthetics inhibited LPS-induced mobilization of specific granules and secretory vesicles. Local anesthetics inhibited LPS-induced up-regulation of cytochrome b₅₅₈ but not LPS-induced translocation of p47^phox. Inhibition of priming by local anesthetics was reversed by washing and incubating for 5 min. Tetracaine alone, but not the other local anesthetics, inhibited LPS activation of p38 mitogen-activated protein kinase (MAPK) and MAPK kinase 3 (kinases in the LPS signaling pathway). The p38 MAPK inhibitors SB203580 and PD169316 also blocked LPS priming. Thus, tetracaine and the other local anesthetics inhibit by disparate mechanisms, but all the local anesthetics impaired up-regulation of cytochrome b₅₅₈ and all impaired priming of NADPH oxidase by LPS.

Key Words: mitogen-activated protein kinase kinase • p38 mitogen-activated protein kinase • NADPH oxidase • tetracaine • fMLP • granule mobilization

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