Skubitz K M, Craddock P R, Hammerschmidt D E, August J T
J Clin Invest. 1981 Jul;68(1):13-20. doi: 10.1172/jci110228.
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.
最近有人提出，抑制补体介导的粒细胞聚集是大剂量皮质类固醇在休克状态下的一种作用机制。假设这种抑制可能是通过改变受体功能来实现的，我们研究了甲泼尼龙（MP）、氢化可的松（HC）和地塞米松（DEX）对合成趋化因子f-甲硫氨酸-亮氨酸-苯丙氨酸（FMLP）与其在粒细胞表面的特异性受体结合程度和动力学的影响。在与30mg/kg静脉推注治疗所达到的血浆水平相当的皮质类固醇浓度下，观察到了剂量依赖性的结合抑制；效力顺序为MP＞HC＞DEX。受体数量不受类固醇暴露的影响，但类固醇导致FMLP-受体相互作用的结合速率常数降低（0.2mg/ml MP时为正常的35%），导致受体-配体亲和力下降。通过冷追踪实验检测的解离动力学不受皮质类固醇的影响。此外，除了先前报道的对聚集的抑制作用外，还发现加入皮质类固醇后聚集的粒细胞会解聚；效力顺序再次为MP＞HC＞DEX，大约需要2-3mg/ml的MP浓度才能实现完全解聚。我们得出结论，皮质类固醇可以通过减缓结合同时允许解离进行，从而将FMLP从粒细胞表面置换下来；受体-FMLP相互作用动力学的改变可能解释了粒细胞聚集的抑制和解聚现象。如果这些观察结果也适用于生理刺激（如C5adesarginine，其在聚集、抑制和解聚方面表现相似），那么这种动力学变化可能在休克时使用的非常高剂量皮质类固醇的临床效果中起重要作用。
