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(The FASEB Journal. 2002;16:1567-1574.)
© 2002 FASEB

Protection of innate immunity by C5aR antagonist in septic mice

MARKUS S. HUBER-LANG, NIELS C. RIEDEMAN, J. VIDYA SARMA, ELLEN M. YOUNKIN, STEPHANIE R. McGUIRE, INES J. LAUDES, KRISTINA T. LU, REN-FENG GUO, THOMAS A. NEFF, VAISHALEE A. PADGAONKAR, JOHN D. LAMBRIS*, L. SPRUCE*, D. MASTELLOS*, FIRAS S. ZETOUNE and PETER A. WARD1

Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; and
* Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

1Correspondence: Department of Pathology, The University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, MI 48109-0602, USA. E-mail:pward{at}umich.edu

Innate immune functions are known to be compromised during sepsis, often with lethal consequences. There is also evidence in rats that sepsis is associated with excessive complement activation and generation of the potent anaphylatoxin C5a. In the presence of a cyclic peptide antagonist (C5aRa) to the C5a receptor (C5aR), the binding of murine 125I-C5a to murine neutrophils was reduced, the in vitro chemotactic responses of mouse neutrophils to mouse C5a were markedly diminished, the acquired defect in hydrogen peroxide (H2O2) production of C5a-exposed neutrophils was reversed, and the lung permeability index (extravascular leakage of albumin) in mice after intrapulmonary deposition of IgG immune complexes was markedly diminished. Mice that developed sepsis after cecal ligation/puncture (CLP) and were treated with C5aRa had greatly improved survival rates. These data suggest that C5aRa interferes with neutrophil responses to C5a, preventing C5a-induced compromise of innate immunity during sepsis, with greatly improved survival rates after CLP.—Huber-Lang, M. S., Riedeman, N. C., Sarma, J. V., Younkin, E. M., McGuire, S. R., Laudes, I. J., Lu, K. T., Guo, R.-F., Neff, T. A., Padgaonkar, V. A., Lambris, J. D., Spruce, L., Mastellos, D., Zetoune, F. S., Ward, P. A. Protection of innate immunity by C5aR antagonist in septic mice.


Key Words: sepsis • neutrophil • oxidative burst • blood clearance




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