This Article Order Full text via Infotrieve 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 Smedegard, G. Articles by Hugli, T. E. Search for Related Content PubMed PubMed Citation Articles by Smedegard, G. Articles by Hugli, T. E.

American Journal of Pathology, Vol 135, 489-497, Copyright © 1989 by American Society for Investigative Pathology

REGULAR ARTICLES

Endotoxin-induced shock in the rat. A role for C5a

G Smedegard, LX Cui and TE Hugli
Department of Inflammation Research, Pharmacia AB, Uppsala, Sweden.

Administration of endotoxin from gram-negative bacteria to rats results in systemic hypotension, an increased hematocrit, and decreased numbers of circulating leukocytes (polymorphonuclear), monocytes, and platelets. These potentially lethal physiologic changes may be partially attributed to complement activation and generation of anaphylatoxins by the endotoxin (LPS). We demonstrated an elevation in the plasma levels of both C3a and C5a in LPS-treated rats. Injection of 5 micrograms C5ades Arg (rat) into rats produced effects similar to those induced by LPS, including decreased mean arterial pressure (systemic hypotension) and decreased numbers of circulating polymorphonuclear leukocytes, monocytes, and platelets. Unlike the response to LPS, C5a did not increase the hematocrit, indicating little effect on vascular permeability at the doses used. When LPS-treated animals were pretreated with F(ab')2 fragments of rabbit anti-rat C5a, no changes were measured in the circulating cell counts compared with LPS alone; however a significant improvement in the mean arterial pressure and a decrease in hematocrit was observed. We conclude that LPS-induced (septic) shock in the rat may result, in part, from the effects of complement activation and particularly from the generation of C5a. The influence of C5a on the LPS effect in the rat appears to enhance both the hypotensive (mean arterial pressure) and vascular permeability (hematocrit) responses. These results appear to support and confirm earlier observations that anti-human C5a increased survival in a septic-shock monkey model by eliminating circulating C5a and presumably thereby reducing the effects of endotoxin on blood pressure. Our results demonstrate that C5a plays a significant role in the hemodynamic changes associated with endotoxin-induced shock. Neutralization of C5a with specific antibodies may reduce the hypotensive response to endotoxin sufficiently to prevent lethal septic shock both in animals and in man.

This article has been cited by other articles:

				S. N. Patel, J. Berghout, F. E. Lovegrove, K. Ayi, A. Conroy, L. Serghides, G. Min-oo, D. C. Gowda, J. V. Sarma, D. Rittirsch, et al. C5 deficiency and C5a or C5aR blockade protects against cerebral malaria J. Exp. Med., May 12, 2008; 205(5): 1133 - 1143. [Abstract] [Full Text] [PDF]

				R.-F. Guo, L. Sun, H. Gao, K. X. Shi, D. Rittirsch, V. J. Sarma, F. S. Zetoune, and P. A. Ward In vivo regulation of neutrophil apoptosis by C5a during sepsis J. Leukoc. Biol., December 1, 2006; 80(6): 1575 - 1583. [Abstract] [Full Text] [PDF]

				A. D. Niederbichler, L. M. Hoesel, M. V. Westfall, H. Gao, K. R. Ipaktchi, L. Sun, F. S. Zetoune, G. L. Su, S. Arbabi, J. V. Sarma, et al. An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction J. Exp. Med., January 23, 2006; 203(1): 53 - 61. [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]

				R. D. Fannin, J. T. Auman, M. E. Bruno, S. O. Sieber, S. M. Ward, C. J. Tucker, B. A. Merrick, and R. S. Paules Differential gene expression profiling in whole blood during acute systemic inflammation in lipopolysaccharide-treated rats Physiol Genomics, March 21, 2005; 21(1): 92 - 104. [Abstract] [Full Text] [PDF]

				F. B. M. Ibrahim, S. J. Pang, and A. J. Melendez Anaphylatoxin Signaling in Human Neutrophils: A KEY ROLE FOR SPHINGOSINE KINASE J. Biol. Chem., October 22, 2004; 279(43): 44802 - 44811. [Abstract] [Full Text] [PDF]

				A. J. Melendez and F. B. M. Ibrahim Antisense Knockdown of Sphingosine Kinase 1 in Human Macrophages Inhibits C5a Receptor-Dependent Signal Transduction, Ca2+ Signals, Enzyme Release, Cytokine Production, and Chemotaxis J. Immunol., August 1, 2004; 173(3): 1596 - 1603. [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]

				N. C. Riedemann, T. A. Neff, R.-F. Guo, K. D. Bernacki, I. J. Laudes, J. V. Sarma, J. D. Lambris, and P. A. Ward Protective Effects of IL-6 Blockade in Sepsis Are Linked to Reduced C5a Receptor Expression J. Immunol., January 1, 2003; 170(1): 503 - 507. [Abstract] [Full Text] [PDF]

				J. Kildsgaard, T. J. Hollmann, K. W. Matthews, K. Bian, F. Murad, and R. A. Wetsel Cutting Edge: Targeted Disruption of the C3a Receptor Gene Demonstrates a Novel Protective Anti-Inflammatory Role for C3a in Endotoxin-Shock J. Immunol., November 15, 2000; 165(10): 5406 - 5409. [Abstract] [Full Text] [PDF]

				A. J. Strachan, T. M. Woodruff, G. Haaima, D. P. Fairlie, and S. M. Taylor A New Small Molecule C5a Receptor Antagonist Inhibits the Reverse-Passive Arthus Reaction and Endotoxic Shock in Rats J. Immunol., June 15, 2000; 164(12): 6560 - 6565. [Abstract] [Full Text] [PDF]

				T. Heller, M. Hennecke, U. Baumann, J. E. Gessner, A. Meyer zu Vilsendorf, M. Baensch, F. Boulay, A. Kola, A. Klos, W. Bautsch, et al. Selection of a C5a Receptor Antagonist from Phage Libraries Attenuating the Inflammatory Response in Immune Complex Disease and Ischemia/Reperfusion Injury J. Immunol., July 15, 1999; 163(2): 985 - 994. [Abstract] [Full Text] [PDF]

				M. Mizuno, K. Nishikawa, N. Okada, S. Matsuo, K. Ito, and H. Okada Inhibition of a Membrane Complement Regulatory Protein by a Monoclonal Antibody Induces Acute Lethal Shock in Rats Primed with Lipopolysaccharide J. Immunol., May 1, 1999; 162(9): 5477 - 5482. [Abstract] [Full Text] [PDF]

				M. S. Mulligan, R. L. Warner, C. W. Rittershaus, L. J. Thomas, U. S. Ryan, K. E. Foreman, L. D. Crouch, G. O. Till, and P. A. Ward Endothelial Targeting and Enhanced Antiinflammatory Effects of Complement Inhibitors Possessing Sialyl Lewisx Moieties J. Immunol., April 15, 1999; 162(8): 4952 - 4959. [Abstract] [Full Text] [PDF]

				B. J. Czermak, M. Breckwoldt, Z. B. Ravage, M. Huber-Lang, H. Schmal, N. M. Bless, H. P. Friedl, and P. A. Ward Mechanisms of Enhanced Lung Injury during Sepsis Am. J. Pathol., April 1, 1999; 154(4): 1057 - 1065. [Abstract] [Full Text] [PDF]

				E. J. Hindmarsh and R. M. Marks Complement Activation Occurs on Subendothelial Extracellular Matrix In Vitro and Is Initiated by Retraction or Removal of Overlying Endothelial Cells J. Immunol., June 15, 1998; 160(12): 6128 - 6136. [Abstract] [Full Text] [PDF]