Effect of age on second messenger generation in neutrophils.
Effect of age on second messenger generation in neutrophils.
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DOI：
10.1182/blood.v78.5.1347.1347
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发表时间：
1991-09
期刊：
影响因子：
20.3
通讯作者：
D. Lipschitz;K. Udupa;S. Indelicato;M. Das
中科院分区：
文献类型：
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作者：
D. Lipschitz;K. Udupa;S. Indelicato;M. Das
在趋化肽甲酰基-蛋氨酸-亮基苯基丙氨酸（FMLP）刺激下，健康老年供者的中性粒细胞产生的二酰基甘油（DAG）和肌醇三磷酸（IP3）明显少于年轻供者的中性粒细胞。信号转导的缺陷发生在IP3和DAG生成的邻近点，因为如果绕过中间的信号转导步骤，通过亚刺激剂量（1.62 nmol/L）的肉豆蔻酸酯（PMA），通过离子载体升高的细胞质钙，或使用刺激剂量的PMA (1.62 mumol/L)， fmlp诱导的超氧化物生成的减少就会得到纠正。FMLP受体数量和亲和力不受衰老影响。在FMLP激活时，与年轻志愿者相比，老年志愿者的中性粒细胞在磷脂酰肌醇（PI）、磷脂酰肌醇4-单磷酸（PIP）和磷脂酰肌醇4,5-二磷酸（PIP2）浓度方面表现出更大、更持久的下降。这表明随着年龄的增长，负责产生IP3和DAG的代谢活性前体池减少。相反，衰老对磷脂酸（PA）的产生几乎没有影响，而磷脂酸最近被认为是NADPH氧化酶的主要激活剂。这可以解释为什么IP3和DAG产生的减少没有伴随着超氧化物产生的相应减少，老年中性粒细胞的超氧化物产生仅比年轻中性粒细胞低17%。因此，衰老与至关重要的磷酸肌苷浓度降低有关，导致产生关键第二信使的能力下降。尽管衰老的中性粒细胞在很大程度上能够补偿信号转导的减少，但其储备能力受到损害，使其特别容易受到外部损伤，也会损害功能。
Neutrophils from healthy elderly donors generate significantly less diacylglycerol (DAG) and inositol triphosphate (IP3) than neutrophils from young donors, following stimulation by the chemotactic peptide, formyl-methionyl-leucylphenylalanine (FMLP). The defect in signal transduction occurred at a point proximal to the generation of IP3 and DAG, since the reduction in FMLP-induced superoxide generation was corrected if the intervening signal transduction steps were bypassed, either by priming with a substimulatory dose (1.62 nmol/L) of phorbol myristate acetate (PMA), by ionophore elevation of cytosolic calcium, or by using a stimulatory dose of PMA (1.62 mumol/L). FMLP receptor number and affinity were unaffected by aging. On FMLP activation, neutrophils from old, as compared with young, volunteers showed significantly greater and more long-lasting decreases in the concentrations of phosphatidylinositol (PI), phosphatidylinositol 4-monophosphate (PIP), and phosphatidylinositol 4,5-bisphosphate (PIP2). This indicates a reduction with age in the metabolically active precursor pools responsible for the generation of IP3 and DAG. In contrast, aging had little effect on the production of phosphatidic acid (PA), which has recently been suggested to serve as a major activator of the NADPH oxidase. This may explain why the decrease in IP3 and DAG production was not accompanied by a comparable decrement in superoxide generation, which was only 17% lower in the old than in young donor neutrophils. Thus, aging is associated with reductions in the concentration of critically important phosphoinositides, resulting in diminution in the ability to produce key second messengers. Although the aged neutrophil is largely able to compensate for the decrements in signal transduction, its reserve capacity is compromised, making it particularly vulnerable to external insults that also impair function.