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

Personal Author(s) : Henricson,Beth E

Full Text :

Report Date : 24 Jun 1992

Pagination or Media Count : 241

Abstract : Gram negative sepsis is increasing in frequency at present due to an increased number of patients at risk. Chemotherapy, A TT'S 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.

Descriptors :   Endotoxins , gram negative bacteria , lipopolysaccharides , Sepsis , cytokines , receptor sites (physiology) , cells (biology) , macrophages , toxicity , mice , antibodies , assaying , interactions , proteins , gene expression

Distribution Statement : APPROVED FOR PUBLIC RELEASE