Analysis of the Cellular and Molecular Mechanisms Which Underlie Sensitivity to Bacterial Endotoxin and Early Tolerance
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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 24, 1992
- Accession Number
- AD1011103
Entities
People
- Beth E. Henricson
Organizations
- Uniformed Services University of the Health Sciences