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Related Collections Phagocytes Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 September 2002, Vol. 100, No. 5, pp. 1869-1877 PHAGOCYTES Essential role of the C5a receptor in E coli-induced oxidative burst and phagocytosis revealed by a novel lepirudin-based human whole blood model of inflammation Tom Eirik Mollnes, Ole-Lars Brekke, Michael Fung, Hilde Fure, Dorte Christiansen, Grethe Bergseth, Vibeke Videm, Knut Tore Lappegård, Jörg Köhl, and John D. Lambris From the Institute of Immunology, The National Hospital, University of Oslo, Norway; Department of Immunology and Transfusion Medicine, Department of Clinical Chemistry, and Medical Department, Nordland Central Hospital and University of Tromsø; Department of Immunology and Transfusion Medicine, Institute of Laboratory Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Institute of Medical Microbiology, Medical School, Hannover, Germany; Tanox, Houston, TX; and Laboratory of Protein Chemistry, Department of Pathology and Laboratory Medicine, University of Pennsylvania, PA. Complement plays an essential role in inflammation and tissue damage. However, it is largely unknown to what extent the system acts as a primary inducer of secondary mediator systems in the inflammatory network of human whole blood. Here we describe a novel in vitro model using the thrombin-specific hirudin analog lepirudin as anticoagulant, which, in contrast to heparin, did not interfere with complement activation. The model was used to study the role of complement in Escherichia coli-induced inflammatory responses. Granulocyte and monocyte oxidative burst was complement dependent as it was reduced by 85% and 70%, respectively, by the CD3 binding peptide compstatin. A similar reduction was found by inhibition of C5, C5a, and C5a receptor (C5aR). Furthermore, anti-CR3 antibodies were as efficient as the C5aR antagonist in reducing granulocyte oxidative burst, whereas blocking CD14 or C3aR had no effect. Up-regulation of granulocyte CR3 was virtually abolished by a C5aR antagonist. Opsonization and phagocytosis was completely inhibited by blocking of C5aR or CR3, whereas blocking of the FcRs (CD16, CD32, CD64) had no effect. In contrast to oxidative burst and phagocytosis, cytokine secretion was largely complement independent. Thus, anti-CD14 abolished tumor necrosis factor-, interleukin-6 (IL-6), and IL-10 secretion, whereas IL-8 was equally inhibited by anti-CD14 and compstatin. In conclusion, the present model is particularly useful for studying complement as part of the inflammatory network. The results emphasize a crucial role for C5a-C5aR interaction in E coli-induced up-regulation of CR3 and the subsequent oxidative burst and phagocytosis. Complement inhibition may have therapeutic implications in oxidative burst-induced tissue damage. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. T. Lappegard, D. Christiansen, A. Pharo, E. B. Thorgersen, B. C. Hellerud, J. Lindstad, E. W. Nielsen, G. Bergseth, D. Fadnes, T. G. Abrahamsen, et al. 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