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Infection and Immunity, April 2000, p. 2301-2308, Vol. 68, No. 4
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-
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

and
) 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.
*
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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