Acute Inflammatory Response to Endotoxin in Mice and Humans

Abstract

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 ϳ1,000 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.Administration of specific pathogens has proven to be a powerful tool for investigating the host's inflammatory response. Infusion of endotoxin, a cell wall component of gramnegative bacteria, is a well-established model for studying the acute inflammatory response (11,17,35). The murine endotoxin model has provided basic information resulting in dramatic improvements in understanding the inflammatory response. As a specific example, injecting endotoxin into mice led to the discovery of tumor necrosis factor (TNF) (6). Further investigation of this critical mediator of inflammation demonstrated that TNF also played a role in chronic inflammatory conditions, such as arthritis and inflammatory bowel disease. At this time, TNF inhibitors are therapies for the treatment of patients with rheumatoid arthritis (32) and Crohn's disease (23) approved by the Food and Drug Administration.Complementary studies of endotoxin administration in humans are often limited due to the risk of toxicity. On the basis of the pyrogenic response to endotoxin, humans are considered the most sensitive of all models to the effects of endotoxin (38). Despite the differences in sensitivity, the human model is useful in measuring the responses that are common to the acute inflammatory response and those responses that are specific to the endotoxin (17). Linking the murine and human models into one definitive comparison proves to be more difficult, if not impossible. A recent review article has highlighted the differences between murine and human imm...

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