Corticosteroids block binding of chemotactic peptide to its receptor on granulocytes and cause disaggregation of granulocyte aggregates in vitro.
Corticosteroids block binding of chemotactic peptide to its receptor on granulocytes and cause disaggregation of granulocyte aggregates in vitro.
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皮质类固醇阻断趋化肽与其粒细胞受体的结合，并在体外引起粒细胞聚集体解聚。
DOI：
10.1172/jci110228
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发表时间：
1981
期刊：
影响因子：
--
通讯作者：
August,JT
中科院分区：
文献类型：
--
作者：
Skubitz,KM;Craddock,PR;Hammerschmidt,DE;August,JT
最近提出抑制补体介导的粒细胞聚集是休克状态下大剂量皮质类固醇的作用机制。假设这种抑制可能是通过改变受体功能的影响，我们研究了甲基强的松龙（MP），氢化可的松（HC），地塞米松（DEX）的合成趋化因子f-甲硫氨酸-亮氨酸-苯丙氨酸（FMLP）的结合的程度和动力学的影响，其特定的受体在粒细胞表面。在与30 mg/kg静脉推注治疗达到的血浆水平平行的皮质类固醇浓度下观察到结合的剂量依赖性抑制;效力顺序为MP大于HC大于DEX。受体数量不受类固醇暴露的影响，但类固醇影响FMLP-受体相互作用的缔合速率常数降低（0.2 mg/ml MP为35% N），导致受体-配体亲和力降低。解离动力学，检查冷追逐实验，未改变的皮质类固醇。此外，除了先前报道的对聚集的抑制外，发现聚集的粒细胞在加入皮质类固醇后解聚;效力的顺序再次是MP大于HC大于DEX，需要约2-3 mg/ml的MP浓度来实现完全解聚。我们的结论是，皮质类固醇激素可以取代FMLP从粒细胞表面通过减缓协会，同时允许解离进行;受体FMLP相互作用的动力学改变可以解释抑制粒细胞聚集和粒细胞解聚。如果这些观察结果也适用于生理刺激（如C5 adesarginine，其在聚集、抑制和解聚方面的行为相似），则这种动力学变化可能对极高剂量皮质类固醇（如在休克中给药）的临床效应很重要。
Inhibition of complement-mediated granulocyte aggregation has recently been proposed as a mechanism of action of high-dose corticosteroids in shock states. Postulating that such inhibition might be effected through alteration of receptors function, we examined the effect of methylprednisolone (MP), hydrocortisone (HC), and dexamethasone (DEX) on the extent and kinetics of binding of the synthetic chemotaxin f-methionine-leucine-phenylalanine (FMLP) to its specific receptor on the granulocyte surface. Dose-dependent inhibition of binding was observed at corticosteroid concentrations paralleling plasma levels achieved with 30 mg/kg intravenous bolus therapy; the order of potency was MP greater than HC greater than DEX. Receptor number was unaffected by steroid exposure, but the steroids effected a decrease in association rate constant for the FMLP-receptor interaction (35% of N for 0.2 mg/ml MP), leading to decreased receptor-ligand affinity. Dissociation kinetics, as examined by cold-chase experiments, were unaltered by the corticosteroids. Furthermore, in addition to the inhibition of aggregation previously reported, aggregated granulocytes were found to disaggregate upon addition of corticosteroids; the order of potency was again MP greater than HC greater than DEX, with an MP concentration of approximately 2-3 mg/ml required to effect complete disaggregation. We conclude that corticosteroids can displace FMLP from the granulocyte surface by slowing association while allowing dissociation to proceed; altered kinetics of receptor-FMLP interaction may explain both the inhibition of granulocyte aggregation and granulocyte disaggregation. If these observations also hold for physiologic stimuli (such as C5adesarginine, which behaves similarly with respect to aggregation, inhibition, and disaggregation), such kinetic changes may be important in the clinical effects of very high-dose corticosteroids such as are administered in shock.