Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bacterial lipopolysaccharide (LPS) stimulates the production and release of endogenous mediators [e.g., tumor necrosis factor (TNF), interleukins-1 and -6 (IL-1 and IL-6), and Platelet Activating Factor [PAF] responsible for the pathophysiologic changes and the mortality associated with sepsis. We recently demonstrated that lysozyme (LZM) bound to LPS (LZM-LPS complex) suppresses LPS-induced tumor necrosis factor-alpha (TNF-alpha) production in vivo. In the present study, we investigated the effect of LZM-LPS complex formation on LPS-induced IL-6 production, both in vitro and in vivo. With the addition of LZM-LPS complex, TNF-alpha and IL-6 release was significantly reduced compared with that by LPS in a dose-dependent manner in mouse macrophage-like cells, RAW264.7. IL-6 production in serum by LPS in carrageenan (CAR)-primed mice peaked at 2 hr following injection. LZM-LPS and LZM-Escherichia coli cell complex (as 1 microgram of LPS per mouse) released significantly reduced concentrations of IL-6 in serum (P < 0.01 and P < 0.001 versus CAR-pretreated LPS- or cell-injected mice). These results emphasize the important role of LZM in vivo in the neutralization of endotoxin. However, in the case of IL-6, by administration of a lethal dose of LPS (as 100 micrograms of LPS per mouse), the IL-6 level was reduced by LZM, but a significant concentration of IL-6 was still released; although the TNF- alpha concentration was negligible in this experimental condition. Thus, it is suggested that LZM might regulate the systemic inflammation induced during Gram-negative bacterial infections by inhibiting the release of cytokines in serum.
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PMID:Lysozyme regulates LPS-induced interleukin-6 release in mice. 762 57

Platelet Activating Factor (PAF) is a D-glycerol derived phosopholipid which is a potent endogenous mediator of inflammation. PAF is synthesized and released by a variety of cell types and elicits its biological activity by interacting with specific G-protein coupled receptors found on platelets, neutrophils, and other inflammatory cells. The physiological consequences of the interaction on PAF with its receptor include an increase in vascular permeability, hypotension, bronchoconstriction, and platelet and neutrophil aggregation. These biological effects are consistent with the concept that PAF is involved in a number of inflammatory diseases such as septic shock and asthma (Arimura A., 1998). Given the potent pathophysiological effects of PAF, a great deal of effort has been focused on the discovery of agents which block the action of PAF at its receptor. Within the past 10 years, a wide range of structures have been identified as PAF antagonists. These include not only PAF analogs, but also antagonists derived form natural product as well as non-lipid synthetic compounds. Several theories have been proposed to unify these diverse structural classes, but sophisticated molecular models of the receptor have not been widely employed (Braquet P., 1987). The discovery of new PAF antagonists has relied heavily on traditional medicinal chemistry approaches. A number of PAF antagonists have advanced to clinical evaluation. While several early compounds demonstrated efficacy in animal models of asthma they have failed to provide benefit for this condition in man. The current generation of potent antagonists are being evaluated as therapies for sepsis, pancreatitis and other disorders (Braquet C., 1991).
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PMID:Platelet Activating Factor antagonists. 1641 13