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* Center for Experimental and Molecular Medicine and
Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria;
Department of Internal Medicine 1, Medical University of Vienna, Vienna, Austria; and
¶ Cardiovascular Research Center and Department of Pharmacology, University of Virginia, Charlottesville, VA 22908
Oxidized phospholipids that are generated during inflammation exert anti-inflammatory properties and prevent death during murine endotoxemia. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) inhibits the interaction of LPS with LPS-binding protein and CD14. In this study, we determined the functional properties of OxPAPC and potential interference with CD14 during abdominal sepsis caused by Escherichia coli. Administration of OxPAPC rendered mice highly susceptible to E. coli peritonitis, as indicated by an accelerated mortality and enhanced bacterial outgrowth and dissemination. CD14–/– mice also displayed increased mortality and bacterial outgrowth and OxPAPC did not further impair host defense in these animals. The mechanisms by which OxPAPC and CD14 deficiency impaired the immune response differed: whereas CD14–/– mice demonstrated a strongly reduced recruitment of phagocytes to the site of the infection, OxPAPC did not influence the influx of inflammatory cells but strongly diminished the phagocytosing capacity of neutrophils and macrophages by a CD14-independent mechanism. Furthermore, OxPAPC potently inhibited uptake of fluorospheres as well as receptor-mediated endocytosis and fluid-phase pinocytosis. These data suggest that oxidized phospholipids such as produced during inflammatory reactions may contribute to mortality during Gram-negative sepsis in vivo via impairment of the phagocytic properties of professional phagocytes.
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 in part supported by the Austrian Fonds zur Förderung der Wissenschafllichen Forschung Grant P18232-B11 (to S.K.).
2 Address correspondence and reprint requests to Dr. Sylvia Knapp, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Department of Internal Medicine 1, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. E-mail address: sknapp{at}cemm.oeaw.ac.at or sylvia.knapp{at}meduniwien.ac.at
3 Abbreviations used in this paper: LBP, LPS-binding protein; WT, wild type; OxPAPC, oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; KC, keratinocyte-derived chemokine; LY, Lucifer yellow; SR, scavenger receptor; DMPC, dimyristoylphosphatodylcholine; OxPL, oxidized phospholipid; PLF, peritoneal lavage fluid; PM, peritoneal macrophage; PMN, polymorphonuclear cell.
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