HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Strachan, A. J. Articles by Taylor, S. M. Search for Related Content PubMed PubMed Citation Articles by Strachan, A. J. Articles by Taylor, S. M.

A New Small Molecule C5a Receptor Antagonist Inhibits the Reverse-Passive Arthus Reaction and Endotoxic Shock in Rats¹

Anna J. Strachan^*, Trent M. Woodruff^*, Gerald Haaima, David P. Fairlie and Stephen M. Taylor^2,*

^* Department of Physiology and Pharmacology, and Drug, Design and Development Centre, University of Queensland, St. Lucia, Australia

C5a is implicated as a pathogenic factor in a wide range of immunoinflammatory diseases, including sepsis and immune complex disease. Agents that antagonize the effects of C5a could be useful in these diseases. We have developed some novel C5a antagonists and have determined the acute anti-inflammatory properties of a new small molecule C5a receptor antagonist against C5a- and LPS-induced neutrophil adhesion and cytokine expression, as well as against some hallmarks of the reverse Arthus reaction in rats. We found that a single i.v. dose (1 mg/kg) of this antagonist inhibited both C5a- and LPS-induced neutropenia and elevated levels of circulating TNF-, as well as polymorphonuclear leukocyte migration, increased TNF- levels and vascular leakage at the site of immune complex deposition. These results indicate potent anti-inflammatory activities of a new C5a receptor antagonist and provide more evidence for a key early role for C5a in sepsis and the reverse Arthus reaction. The results support a role for antagonists of C5a receptors in the therapeutic intervention of immunoinflammatory disease states such as sepsis and immune complex disease.

This article has been cited by other articles:

				M. R. Maurya and S. Subramaniam A Kinetic Model for Calcium Dynamics in RAW 264.7 Cells: 1. Mechanisms, Parameters, and Subpopulational Variability Biophys. J., August 1, 2007; 93(3): 709 - 728. [Abstract] [Full Text] [PDF]

				G. Girardi, D. Yarilin, J. M. Thurman, V. M. Holers, and J. E. Salmon Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction J. Exp. Med., September 4, 2006; 203(9): 2165 - 2175. [Abstract] [Full Text] [PDF]

				J. J. Alexander, A. Jacob, L. Bao, R. L. Macdonald, and R. J. Quigg Complement-Dependent Apoptosis and Inflammatory Gene Changes in Murine Lupus Cerebritis J. Immunol., December 15, 2005; 175(12): 8312 - 8319. [Abstract] [Full Text] [PDF]

				T. M. Woodruff, S. Pollitt, L. M. Proctor, S. Z. Stocks, H. D. Manthey, H. M. Williams, I. B. Mahadevan, I. A. Shiels, and S. M. Taylor Increased Potency of a Novel Complement Factor 5a Receptor Antagonist in a Rat Model of Inflammatory Bowel Disease J. Pharmacol. Exp. Ther., August 1, 2005; 314(2): 811 - 817. [Abstract] [Full Text] [PDF]

				L. P. Vlasenko and A. J. Melendez A Critical Role for Sphingosine Kinase in Anaphylatoxin-Induced Neutropenia, Peritonitis, and Cytokine Production in Vivo J. Immunol., May 15, 2005; 174(10): 6456 - 6461. [Abstract] [Full Text] [PDF]

				A. H. J. Kim, I. D. Dimitriou, M. C. H. Holland, D. Mastellos, Y. M. Mueller, J. D. Altman, J. D. Lambris, and P. D. Katsikis Complement C5a Receptor Is Essential for the Optimal Generation of Antiviral CD8+ T Cell Responses J. Immunol., August 15, 2004; 173(4): 2524 - 2529. [Abstract] [Full Text] [PDF]

				D. R. March, L. M. Proctor, M. J. Stoermer, R. Sbaglia, G. Abbenante, R. C. Reid, T. M. Woodruff, K. Wadi, N. Paczkowski, J. D. A. Tyndall, et al. Potent Cyclic Antagonists of the Complement C5a Receptor on Human Polymorphonuclear Leukocytes. Relationships between Structures and Activity Mol. Pharmacol., April 1, 2004; 65(4): 868 - 879. [Abstract] [Full Text]

				M. Otto, H. Hawlisch, P. N. Monk, M. Muller, A. Klos, C. L. Karp, and J. Kohl C5a Mutants Are Potent Antagonists of the C5a Receptor (CD88) and of C5L2: POSITION 69 IS THE LOCUS THAT DETERMINES AGONISM OR ANTAGONISM J. Biol. Chem., January 2, 2004; 279(1): 142 - 151. [Abstract] [Full Text] [PDF]

				N. C. Riedemann, R.-F. Guo, and P. A. Ward A key role of C5a/C5aR activation for the development of sepsis J. Leukoc. Biol., December 1, 2003; 74(6): 966 - 970. [Abstract] [Full Text]

				T. M. Woodruff, T. V. Arumugam, I. A. Shiels, R. C. Reid, D. P. Fairlie, and S. M. Taylor A Potent Human C5a Receptor Antagonist Protects against Disease Pathology in a Rat Model of Inflammatory Bowel Disease J. Immunol., November 15, 2003; 171(10): 5514 - 5520. [Abstract] [Full Text] [PDF]

				T. Sprong, P. Brandtzaeg, M. Fung, A. M. Pharo, E. A. Hoiby, T. E. Michaelsen, A. Aase, J. W. M. van der Meer, M. van Deuren, and T. E. Mollnes Inhibition of C5a-induced inflammation with preserved C5b-9-mediated bactericidal activity in a human whole blood model of meningococcal sepsis Blood, November 15, 2003; 102(10): 3702 - 3710. [Abstract] [Full Text] [PDF]

				J. M. Inal, B. Schneider, M. Armanini, and J. A. Schifferli A Peptide Derived from the Parasite Receptor, Complement C2 Receptor Inhibitor Trispanning, Suppresses Immune Complex-Mediated Inflammation in Mice J. Immunol., April 15, 2003; 170(8): 4310 - 4317. [Abstract] [Full Text] [PDF]

				H. Sumichika, K. Sakata, N. Sato, S. Takeshita, S. Ishibuchi, M. Nakamura, T. Kamahori, S. Ehara, K. Itoh, T. Ohtsuka, et al. Identification of a Potent and Orally Active Non-peptide C5a Receptor Antagonist J. Biol. Chem., December 13, 2002; 277(51): 49403 - 49407. [Abstract] [Full Text] [PDF]

				M. S. HUBER-LANG, N. C. RIEDEMAN, J. V. SARMA, E. M. YOUNKIN, S. R. McGUIRE, I. J. LAUDES, K. T. LU, R.-F. GUO, T. A. NEFF, V. A. PADGAONKAR, et al. Protection of innate immunity by C5aR antagonist in septic mice FASEB J, October 1, 2002; 16(12): 1567 - 1574. [Abstract] [Full Text] [PDF]

				T. E. Mollnes, O.-L. Brekke, M. Fung, H. Fure, D. Christiansen, G. Bergseth, V. Videm, K. T. Lappegard, J. Kohl, and J. D. Lambris 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 Blood, August 13, 2002; 100(5): 1869 - 1877. [Abstract] [Full Text] [PDF]

				D. Mastellos, J. C. Papadimitriou, S. Franchini, P. A. Tsonis, and J. D. Lambris A Novel Role of Complement: Mice Deficient in the Fifth Component of Complement (C5) Exhibit Impaired Liver Regeneration J. Immunol., February 15, 2001; 166(4): 2479 - 2486. [Abstract] [Full Text] [PDF]

				M. Huber-Lang, V. J. Sarma, K. T. Lu, S. R. McGuire, V. A. Padgaonkar, R.-F. Guo, E. M. Younkin, R. G. Kunkel, J. Ding, R. Erickson, et al. Role of C5a in Multiorgan Failure During Sepsis J. Immunol., January 15, 2001; 166(2): 1193 - 1199. [Abstract] [Full Text] [PDF]