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Clinical and Diagnostic Laboratory Immunology, January 2005, p. 60-67, Vol. 12, No. 1
1071-412X/05/$08.00+0     doi:10.1128/CDLI.12.1.60-67.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Acute Inflammatory Response to Endotoxin in Mice and Humans

Shannon Copeland,¹ H. Shaw Warren,² Stephen F. Lowry,³ Steve E. Calvano,³ Daniel Remick,^1* and the Inflammation and the Host Response to Injury Investigators

Department of Pathology, University of Michigan, Ann Arbor, Michigan,¹ Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts,² Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey³

Received 25 June 2004/ Returned for modification 10 August 2004/ Accepted 6 October 2004

Endotoxin injection has been widely used to study the acute inflammatory response. In this study, we directly compared the inflammatory responses to endotoxin in mice and humans. Escherichia coli type O113 endotoxin was prepared under identical conditions, verified to be of equal biological potency, and used for both mice and humans. The dose of endotoxin needed to induce an interleukin-6 (IL-6) concentration in plasma of 1,000 pg/ml 2 h after injection was 2 ng/kg of body weight in humans and 500 ng/kg in mice. Healthy adult volunteers were injected intravenously with endotoxin, and male C57BL/6 mice (n = 4 to 12) were injected intraperitoneally with endotoxin. Physiological, hematological, and cytokine responses were determined. Endotoxin induced a rapid physiological response in humans (fever, tachycardia, and slight hypotension) but not in mice. Both mice and humans exhibited lymphopenia with a nadir at 4 h and recovery by 24 h. The levels of tumor necrosis factor (TNF) and IL-6 in plasma peaked at 2 h and returned to baseline levels by 4 to 6 h. IL-1 receptor antagonist RA and TNF soluble receptor I were upregulated in both mice and humans but were upregulated more strongly in humans. Mice produced greater levels of CXC chemokines, and both mice and humans exhibited peak production at 2 h. These studies demonstrate that although differences exist and a higher endotoxin challenge is necessary in mice, there are several similarities in the inflammatory response to endotoxin in mice and humans.

Contributing members of the Inflammation and the Host Response to Injury Investigators are listed in Acknowledgments.