Molecular mechanisms of leukocytes activation by heavy metals : Free radical generation system

为从信号转导的角度解决金属烟雾热的发病机制，通过监测超氧化物的释放，探讨重金属(主要是锌)诱导肺泡巨噬细胞和中性粒细胞活化，进而激活金属螯合剂的机制。锌化合物产生超氧阴离子自由基的效率由高到低依次为：硫酸锌(ZnSO4)、氧化锌(氧化锌)和氢氧化锌(氢氧化锌)。三种锌化合物的信号转导机制各不相同。硫酸锌中的锌离子对过氧化氢有刺激作用。过氧化氢的产生不是超氧化物，不依赖于钙离子，对蛋白激酶C的依赖性较小。提示锌离子对中性粒细胞的激活可能依赖于未知的信号转导途径。氧化锌在没有细胞外钙的情况下刺激中性粒细胞，GSH的刺激作用增强(一种启动效应)。因此，有人建议…进一步推测，氧化锌可能通过与酪氨酸蛋白激酶密切相关的受体刺激中性粒细胞产生超氧化物。另一方面，氢氧化锌通过细胞外液中钙离子内流和蛋白激酶C的激活来刺激中性粒细胞。氢氧化锌激活中性粒细胞的主要机制可能依赖于吞噬作用。这些结果表明，锌化合物的微小分子变化可能与吞噬细胞的识别有关。氢氧化锌刺激中性粒细胞减少了同一细胞释放的NO。这一现象可能是由于NO与超氧化物或NO与氢氧化锌相互作用的结果。在氢氧化锌刺激下，细胞膜表面无LAF-1表达。抗LAF-1的单抗不能抑制氢氧化锌对中性粒细胞的激活作用，镉和二乙基二硫代氨基甲酸酯金属螯合剂对中性粒细胞的激活也有抑制作用，Gd对激活的吞噬细胞也有抑制作用。较少

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 … More 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