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  • Title: Disruption of the C5a receptor gene increases resistance to acute Gram-negative bacteremia and endotoxic shock: opposing roles of C3a and C5a.
    Author: Hollmann TJ, Mueller-Ortiz SL, Braun MC, Wetsel RA.
    Journal: Mol Immunol; 2008 Apr; 45(7):1907-15. PubMed ID: 18063050.
    Abstract:
    The host response to intravascular, Gram-negative bacteria includes profound immunologic, hematologic and physiologic changes. Numerous host defense mechanisms are activated by Gram-negative bacteria, including the complement system. Activation of the complement system leads to cleavage of C5 with subsequent generation of the C5a anaphylatoxin peptide. C5a mediates potent, proinflammatory activities by binding to the C5a receptor (C5aR, CD88). In this study, we report the targeted disruption of the murine C5aR gene (C5aR-/- mice) and define the role of the C5aR in a model of Gram-negative bacteremia. Following an intravenous infusion of heat-killed Escherichia coli, the C5aR-/- mice were completely protected from the mortality suffered by their wild-type littermates (P<0.001). The C5aR-/- mice were also significantly (P=0.008) more resistant to mortality following an intravenous infusion of purified E. coli endotoxin compared to the wild-type littermates. In addition, the C5aR-/- mice were resistant to the thrombocytopenia and hemoconcentration observed in wild-type animals. Lethality in the wild-type mice was reversed by pre-treatment with either the histamine antagonist diphenhydramine or triprolidine. The wild-type littermates were also rescued following pre-treatment with the basophil and mast cell-stabilizing agent - cromolyn sodium. Collectively, these data demonstrate that not only is the absence of the C5aR protective in E. coli bacteremia, but that C5aR-dependent histamine release plays a major role in shock induced by Gram-negative septicemia. Moreover, they provide additional in vivo evidence that C3a and C5a have divergent biological functions in Gram-negative bacteremia and shock.
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