Abstract
Inhibition of complement-mediated granulocyte aggregation has recently been proposed as a mechanism of action of high-dose corticosteroids in shock states. Such inhibition may be effected through alteration of receptor function. Methylprednisolone inhibits binding of the synthetic chemotaxin f-methionine-leucine-phenylalanine (FMLP) to its surface receptor on granulocytes in a dose-dependent manner by slowing the association rate of the FMLP-receptor interaction without altering receptor number. Because the half-life of high-dose methylprednisolone in vivo is short, we examined the reversibility of its effects on granulocyte aggregation and receptor function; both effects were readily reversed by washing. Furthermore, methylprednisolone, at concentrations that profoundly inhibited the granulocyte aggregation response to FMLP, allowed the occurrence of FMLP-receptor down- regulation and granulocyte desensitization to further stimulation by FMLP. We conclude that methylprednisolone at concentrations that inhibit granulocyte aggregation can slow the rate of the FMLP-receptor interaction while simultaneously allowing receptor down-regulation and granulocyte desensitization to proceed. Transient blockade of granulocyte function with concomitant desensitization and receptor down- regulation may be important in the clinical effects of very high-dose corticosteroids such as are administered in shock and could partially explain how drugs with such short half-lives administered intermittently could exert a beneficial effect in shock states. Similar observations may hold for other physiologic stimuli.
