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* Center for Experimental and Molecular Medicine,
Department of Anesthesiology,
Center for Infection and Immunity Amsterdam, and
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and
¶ CombinatoRx, Boston, MA 02118
The effects of steroids on the outcome of sepsis are dose dependent. Low doses appear to be beneficial, but high doses do not improve outcome for reasons that are insufficiently understood. The effects of steroids on systemic inflammation as a function of dose have not previously been studied in humans. To determine the effects of increasing doses of prednisolone on inflammation and coagulation in humans exposed to LPS, 32 healthy males received prednisolone orally at doses of 0, 3, 10, or 30 mg (n = 8 per group) at 2 h before i.v. injection of Escherichia coli LPS (4 ng/kg). Prednisolone dose-dependently inhibited the LPS-induced release of cytokines (TNF-
and IL-6) and chemokines (IL-8 and MCP-1), while enhancing the release of the anti-inflammatory cytokine IL-10. Prednisolone attenuated neutrophil activation (plasma elastase levels) and endothelial cell activation (von Willebrand factor). Most remarkably, prednisolone did not inhibit LPS-induced coagulation activation, measured by plasma concentrations of thrombin-antithrombin complexes, prothrombin fragment F1+2, and soluble tissue factor. In addition, activation of the fibrinolytic pathway (tissue-type plasminogen activator and plasmin-2-antiplasmin complexes) was dose-dependently enhanced by prednisolone. These data indicate that prednisolone dose-dependently and differentially influences the systemic activation of different host response pathways during human endotoxemia.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by research funding from CombinatoRx (to T.v.d.P.).
2 Address correspondence and reprint requests to Dr. Martijn D. de Kruif, Center for Experimental and Molecular Medicine, Academic Medical Center, Room G2-132, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail address: m.d.dekruif{at}amc.uva.nl
3 Abbreviations used in this paper: CRP, C-reactive protein; IL-1RA, IL-1R antagonist; vWF, von Willebrand factor; TAT, thrombin-antithrombin; TATc, TAT complex; tPA, tissue-type plasminogen activator; PAP, plasmin-2-antiplasmin; PAPc, PAP complex; PAI-1, plasminogen activator inhibitor type 1.
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