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Infection and Immunity, April 2000, p. 2301-2308, Vol. 68, No. 4
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Differential Host Inflammatory Responses to Viable Versus Antibiotic-Killed Bacteria in Experimental Microbial Sepsis

Richard Silverstein,^1,* John G. Wood,² Qiao Xue,^1,3 Mari Norimatsu,^3, David L. Horn,^4, and David C. Morrison^3,5,6

Departments of Biochemistry and Molecular Biology,¹ Molecular and Integrative Physiology,² and Microbiology, Molecular Genetics, and Immunology,³ University of Kansas Medical Center, Kansas City, Kansas 66160; U.S. Human Health Division, Merck & Co., Inc., West Point, Pennsylvania 19486⁴; Departments of Basic Medical Sciences and Anesthesiology, School of Medicine, University of Missouri at Kansas City, Kansas City, Missouri 64108⁵; and Office of Medical Research Administration, Saint Luke's Hospital, Kansas City, Missouri 64111⁶

Received 11 October 1999/Returned for modification 30 November 1999/Accepted 28 December 1999

Staphylococcus aureus killed during imipenem or ceftazidime chemotherapy in mice elicited an early release of tumor necrosis factor alpha (TNF-) into the systemic circulation. This response was coincident in time with an increase in leukocyte-endothelium adhesive interactions in the microvasculature. Equivalent responses were not observed without the antibiotic treatment (imipenem or ceftazidime). Protective efficacy of the same antibiotic treatment was markedly diminished in D-galactosamine-treated mice compared to controls; e.g., it dropped from 2,000-fold to 70-fold with 4 mg of imipenem per kg given at the time of challenge. Nevertheless, protection was quantitatively restored upon concurrent administration of neutralizing anti-TNF- antibody or 4 mg of dexamethasone per kg to these TNF--hypersensitive mice. Importantly, protection afforded by dexamethasone was not seen when the animals were challenged with viable organisms but without the concurrent administration of antibiotic. An early TNF- response could also be demonstrated upon challenge with Escherichia coli, but in this instance, neither the timing nor the magnitude of that response was influenced by treatment with these antibiotics. We conclude from these studies that the inflammatory response to viable versus killed bacteria may differ markedly depending on the particular bacterium, host sensitivity to TNF-, and possibly the Gram stain classification.

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^* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160. Phone: (913) 588-6954. Fax: (913) 588-7440. E-mail: rsilvers{at}kumc.edu.

Present address: Institute for Animal Health, Compton Laboratory, Compton, Newbury, Berkshire RG20 7NN, United Kingdom.

Present address: Bristol-Myers Squibb, Oncology/Immunology, Princeton, NJ 08543.

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Infection and Immunity, April 2000, p. 2301-2308, Vol. 68, No. 4
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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