title: Corticosteroids inhibit complement-induced granulocyte aggregation. A possible mechanism for their efficacy in shock states.
abstract: Granulocyte (PMN) aggregation and embolization may underlie complement (C)-mediated organ dysfunction in such syndromes as hemodialysis neutropenia and Purtscher's ischem;c retinopathy. Because of clinical and pathologic parallels, we have further suggested a role for this phenomenon in the genesis of the adult respiratory distress syndrome (ARDS). Because corticosteroids are commonly used in immune diseases, and have particularly been claimed efficacious in shock and ARDS, we tested the capability of methylprednisolone (MP), hydrocortisone (HC), and dexamethasone (DEX) to inhibit PMN aggregation. Aggregation engendered in vitro by zymosan-activated plasma (ZAP) was inhibited by MP and HC at concentrations approximating plasma levels achieved with the large bolus (30 mg/kg i.v) therapy advocated in shock states; DEX was almost without effect. Using intravital fluorescence microscopy, we observed PMN aggregation and embolization in the mesenteric vessels of rats given intra-arterial infusions of ZAP; this was also prevented by pretreatment with 30 mg/kg MP. Steroid inhibition of aggregation seemed not to involve disruption of receptor function, because aggregation induced by alternative agents, n-formyl-Met-Leu-Phe and the ionophore A23187, was also inhibited by MP. Moreover, corticosteroid inhibition of PMN prostaglandin synthesis is also an unlikely explanation for our results, since aspirin and ibuprofen failed to block aggregation and arachidonic acid neither effected aggregation itself nor ameliorated the steroid effect. Our studies provide a plausible rationale for the empiric observation that high-dose corticosteroids may benefit patients with syndromes associated with microvascular leukostasis.
mesh_terms: D002449:Cell Aggregation / Q000187:drug effects; D003165:Complement System Proteins / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology*; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D008775:Methylprednisolone / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D012769:Shock / Q000503:physiopathology*
chemical_list: D003907:Dexamethasone; D003165:Complement System Proteins; D006854:Hydrocortisone; D008775:Methylprednisolone