Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Analysis of fatal sensitivity to 0.2 microgram of S. enteritidis lipopolysaccharide in cycloheximide-treated mice identified two independent lethal elements. First, an absolute requirement for steroid supplementation to ensure survival suggests a crucial role for cycloheximide-mediated inhibition of steroidogenesis. The second factor is the development of virtually total bilateral renal cortical necrosis, itself a consequence of glomerular capillary occlusion with fibrin-like material. The survival of cycloheximide and endotoxin-challenged mice requires both hydrocortisone treatment and defibrination with ancrod. Cycloheximide and a smaller dose of endotoxin (0.1 microgram per mouse) is also fatal, but here steroid deficiency is not a crucial factor, protection being conferred by ancrod defibrination alone.
 ...
PMID:Factors involved in the fatal susceptibility to submicrogram doses of endotoxin in cycloheximide-treated mice. 264 18

Evidence suggests that components of the coagulation system contribute to the pathogenesis of liver injury after exposure to lipopolysaccharide (LPS) from gram-negative bacteria. Although the mechanism by which the coagulation system mediates liver injury remains unknown, it has been proposed that the conversion of fibrinogen to insoluble fibrin and consequent deposition in liver microvasculature may contribute to the development of liver injury. The purpose of this study was to test the hypothesis that the coagulation system contributes to LPS hepatotoxicity by a mechanism which is dependent on circulating fibrinogen. A marked reduction in plasma fibrinogen concentration occurred in rats after LPS exposure. The decrease in circulating fibrinogen, which marked activation of the coagulation cascade: 1) occurred at doses of LPS that caused liver injury; 2) was temporally associated with the onset of liver injury; and 3) was attenuated by pretreatment with heparin or warfarin under conditions which afforded protection against liver injury. Pretreatment with either pentoxifylline or antiserum to tumor necrosis factor-alpha, both of which protect against LPS hepatotoxicity, also attenuated the LPS-induced decrease in circulating fibrinogen. Polymorphonuclear leukocyte (neutrophil) depletion protected against liver injury after administration of either a small (2 mg/kg) or a large (8 mg/kg) dose of LPS and attenuated the decrease in circulating fibrinogen albeit to a lesser degree after the larger LPS dose. Depletion of circulating fibrinogen with ancrod did not afford protection against LPS hepatotoxicity. These results suggest that the coagulation system contributes to the pathogenesis of LPS-induced liver injury, but it does so by a mechanism which is independent of circulating fibrinogen.
 ...
PMID:The coagulation system, but not circulating fibrinogen, contributes to liver injury in rats exposed to lipopolysaccharide from gram-negative bacteria. 781 64

Previous results demonstrated that rats given Escherichia coli lipopolysaccharide (LPS; 4 mg/kg, i.v.) experience hepatocellular necrosis that begins within 4 hr and that prior treatment with anticoagulants (e.g., heparin) which target thrombin prevents the liver injury. In this study, hepatocellular injury, as marked by increased plasma alanine aminotransferase (ALT) activity and histologic changes, was prevented when heparin or hirudin was administered to rats shortly before the onset of injury. These results suggest that thrombin is a critical mediator that acts distally in the series of inflammatory events that culminates in hepatocellular damage. To explore further this hypothesis, livers isolated from rats 2 hr after LPS administration were perfused with various media. Perfusion of livers with medium comprising diluted blood from heparin-treated donors resulted in no release of ALT activity. By contrast, perfusion with similar medium anticoagulated with ancrod, which prevents clotting by depleting fibrinogen but does not inhibit thrombin, resulted in hepatocellular injury evidenced as a time-dependent appearance of ALT activity in the medium. Moreover, when livers from rats treated 2 hr previously with LPS were perfused with buffer to which thrombin had been added, injury resulted. No injury resulted when thrombin was omitted from the buffer or when livers from saline-treated rats were used. These results indicate that thrombin is a critical and distal mediator of LPS-induced liver damage and contributes to hepatocellular injury through a mechanism that is independent of clot formation. Furthermore, inflammatory events triggered by LPS exposure are a prerequisite for thrombin-induced injury.
 ...
PMID:Thrombin is a distal mediator of lipopolysaccharide-induced liver injury in the rat. 890 62

Tumour necrosis factor (TNF) is known to have procoagulant activity, and platelet depletion is a feature of TNF-mediated systemic inflammatory responses. The aim of this study was to investigate the role of fibrinogen consumption in the development of TNF-mediated systemic inflammatory responses and in the associated depletion of platelets. Three murine models of TNF-mediated systemic inflammatory responses were examined: the systemic toxicity reactions (STR) induced by TNF or lipopolysaccharide (LPS) and severe malaria (SM), a prominently neurological complication of Plasmodium berghei ANKA infection in susceptible mice. There was an acceleration in the consumption of fibrinogen during TNF-STR but not during LPS-STR or SM. However, a concomitant reduction in platelet count was found in all conditions. Mice preliminarily depleted in fibrinogen by treatment with ancrod, an enzyme that specifically degrades fibrinogen, showed no protection against mortality during TNF- or LPS-STR or SM, although they were protected against tissue damage during a modification of the classical local Shwartzman reaction. During TNF- and LPS-STR platelets were even lower in ancrod-treated than control mice and during SM they were not significantly different. This study shows that fibrinogen consumption, although accelerated by the direct injection of TNF, is not necessary for the development of TNF-mediated systemic inflammatory responses in mice, at variance with local pathology, and does not contribute to the associated depletion of platelets.
 ...
PMID:Mortality and platelet depletion occur independently of fibrinogen consumption in murine models of tumour necrosis factor-mediated systemic inflammatory responses. 961 77