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Accession Number:
AD1011103
Title:
Analysis of the Cellular and Molecular Mechanisms Which Underlie Sensitivity to Bacterial Endotoxin and Early Tolerance
Descriptive Note:
Technical Report
Corporate Author:
Uniformed Services University Of The Health Sciences Bethesda United States
Report Date:
1992-06-24
Pagination or Media Count:
241.0
Abstract:
Gram negative sepsis is increasing in frequency at present due to an increased number of patients at risk. Chemotherapy, A TTS related immune suppression, and complicated surgical interventions predispose already compromised patients to intractable infection. Gram negative bacterial endotoxin lipopolysaccharide or LPS is a causative factor in septic shock. LPS can elicit both toxic and beneficial effects, which have been suggested to be cytokine-mediated. The phenomenon of early endotoxin tolerance, which is induced by sublethal exposure to LPS, results in a transient period of hyporesponsiveness that is most profound at three to four days alter exposure, and is marked by reduced cytokine production alter a challenge exposure to LPS. Early endotoxin tolerance is also inducible by the non toxic LPS derivative monophosphoryllipid A, although a larger dose is required to induce a level of tolerance equivalent to that induced by LPS. Equivalent tolerance-inducing doses of LPS and MPL were compared for their ability to induce several cytokines. Although LPS- and MPL-induced colony stimulating factor CSF activity was comparable for doses 01 LPS and MPL that elicited an equivalent state of early endotoxin tolerance, levels of tumor necrosis factor lNF,Interleukin-6, Interleukin-l, and interferon were significantly lower in MPL-injected mice. These results suggest that the lowered toxicity of MPL may be related to its elicitation of significantly lower levels of potentially toxic intermediaries. Administration of a recombinant Interleukin-l receptor antagonist protein to mice was found to inhibit induction of colony stimulating factor, as well as induction of early endotoxin tolerance, by LPS. LPS-induced hypoglycemia was also significantly reversed by recombinant Interleukin-1 receptor antagonist. These findings provide direct evidence that Interleukin-l and Tumor Necrosis Factor are intermediates in these lipopolysaccharide-induced phenomena.
Distribution Statement:
APPROVED FOR PUBLIC RELEASE
