SDZ MRL 953, A Novel Synthetic Lipid a Analogue, Induces Tolerance to the Lethal Effects of Endotoxin and Enhances Nonspecific Immunity
Despite the availability of potent antimicrobials, shock due to Gram-negative rod sepsis remains an important clinical concern in immunosuppressed patients. Current strategies for treating septic shock by removal of endotoxin (lipopolysaccharides [LPS]) or putative mediators have only been partially...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
1992-01-01
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| Series: | Canadian Journal of Infectious Diseases |
| Online Access: | http://dx.doi.org/10.1155/1992/591894 |
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| Summary: | Despite the availability of potent antimicrobials, shock due to Gram-negative
rod sepsis remains an important clinical concern in immunosuppressed patients. Current strategies for
treating septic shock by removal of endotoxin (lipopolysaccharides [LPS]) or putative mediators have only
been partially effective. An attractive alternative appears to be the induction of hyporesponsiveness to LPS
by synthetic lipid A analogues. SDZ MRL 953, a novel prototype of lipid A analogues. was examined for its
ability to induce early-phase tolerance against experimental endotoxemia in mice following single or
multiple administrations 2, 24, or 72 h before challenge. The analogue protected mice against a lethal dose
of LPS or infections in a time- and dose-dependent manner. Maximum effects were observed in animals
pretreated with SDZ MRL 953 on three consecutive days before the LPS challenge or microbial inoculation.
To examine the mechanisms involved, peritoneal macrophages from the tolerant mice were monitored ex
v1vo for the release of tumour necrosis factor (TNF) and killing of an isolate of Escherichia coli. It was found
that macrophages from endotoxin-tolerant mice produced only a fraction of the TNF released by cells from
control groups in response to LPS. However, the killing of E coli by the macrophages was enhanced. In
conclusion, SDZ MRL 953 may have a prophylactic potential in reducing the risk of endotoxic shock in
traumatized or in myelosuppressed patients. |
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| ISSN: | 1180-2332 |