1995 Fiscal Year Final Research Report Summary
Molecular mechanisms of leukocytes activation by heavy metals : Free radical generation system
| Project/Area Number |
05454228
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Public health/Health science
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| Research Institution | Kanazawa University (1995)
Yamaguchi University (1993-1994) |
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Principal Investigator |
OGINO Keiki Kanazawa University, School of Medicine, Professor, 医学部, 教授 (70204104)
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| Co-Investigator(Kenkyū-buntansha) |
ISHIYAMA Hironobu Tokushima Research Institute Otsuka Pharmaceutical Co., Ltd., Researcher, 徳島研究所, 研究員
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| Project Period (FY) |
1993 – 1995
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| Keywords | Zinc fume fever / Superoxide / Neutrophil / Macrophage / Intracellular signal transduction pathway / Calcium / Protein kinase C / Tyrosine protein kinase |
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| Research Abstract |
The mechanisms of activation of alveolar macrophages and neutrophils induced by heavy metals, mainly zinc, and then metal chelator were investigated by monitoring the release of superoxide in order to resolve the pathogenesis of metal fume fever from a view point of signal transduction. The effciency of superoxide radical production by zinc compounds was ranked in order as zinc sulfate (ZnSO4) <<zinc oxide (ZnO) <zinc hydroxide (Zn(OH)2). The mechanisms of the signal transduction of three zinc compounds varied with each other. Zinc ions from zinc sulfate stimulated hydrogen peroxide. The hydrogen peroxide production was not superoxide, independent on calcium and less dependent on protein kinase C.It was suggested that the activation of neutrophils by zinc ions might be dependent on unknown signal transduction pathway. Zinc oxide stimulated neutrophils in the absence of extracellular calcium and the stimulation was enhanced by addition of GSH (a priming effect). Therefore, it was sugges
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ted that zinc oxide might stimulate superoxide production of neutrophils via receptors closely related with tyrosine protein kinase. On the other hand, zinc hydroxide stimulated neutrophils by the process of the influx of calcium from extracellular fluids and the activation of protein kinase C.The major mechanism of neutrophils activation by zinc hydroxide may be dependent on the phagocytosis. These results suggested that a subtle molecular change of zinc compounds might be contributed to the recognition of the phagocytes.
Stimulation of neutrophils by zinc hydroxide reduced NO release from the same cells. This phenomenon may result from the interaction with NO and superoxide or NO and zunc hydroxide. There was no expression of LAF-1 on the surface of cell membrane with the stimulation of zinc hydroxide. A monolonal antibody to LAF-1 did not suppress the activation of neutrophils by zinc hydroxide.
The activation of neutrophils by cadmium and a metal chelator of diethydithiocarbamate, and the suppression of activated phagocytes by gadolinium were also observed. Less
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