Mechanisms of Endotoxin Tolerance with Special Reference to Man

Greisman, Sheldon E.; Hornick, Richard B.

doi:10.1093/infdis/128.supplement_1.s265

Cited by 83 publications

(36 citation statements)

References 31 publications

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“…The current study demonstrates unequivocally that LPS administration to male human volunteers depresses hepatic cytochrome P450-mediated drug metabolism. Decreased clearances of all three drugs used in this study were (31). However, because septic patients are probably exposed to much higher concentrations of LPS and suffer multisystem organ failure from these doses, it is likely that the decreases in P450-mediated metabolism reported in the volunteers are an underestimation of what occurs clinically.…”

Section: Discussionmentioning

confidence: 72%

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Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism.

Shedlofsky¹,

Israel²,

McClain³

et al. 1994

J. Clin. Invest.

198

114

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In experimental animals, injection of gram-negative endotoxin (LPS) decreases hepatic cytochrome P450-mediated drug metabolism. To evaluate this phenomenon in a human model of gram-negative sepsis, LPS was administered on two consecutive days to healthy male volunteers during which time a cocktail of antipyrine (AP-250 mg), hexobarbital (HB-500 mg), and theophylline (TH-150 mg) was ingested and the apparent oral clearance of each drug determined. Each subject had a control drug clearance study with saline injections. In the first experiment, six subjects received the drug cocktail 0.5 h after the first dose of LPS. In the second experiment, another six subjects received the drug cocktail 0.5 h after the second dose of LPS. In both experiments, LPS caused the expected physiologic responses of inflammation including fever with increases in serum concentrations of TNFa, IL-113, IL-6, and acute phase reactants. In the first experiment, only minor decreases in clearances of the probe drugs were observed (7-12%). However in the second experiment, marked decreases in the clearances of AP (35, 95% CI 18-48%), HB (27, 95% CI 14-34%), and TH (22, 95% CI 12-32%) were seen. The decreases in AP clearance correlated with initial peak values of TNFat (r = 0.82) and IL-6 (r = 0.86). These data show that in humans the inflammatory response to even a very low dose of LPS significantly decreases hepatic cytochrome P450-mediated drug metabolism and this effect evolves over a 24-h period. It is likely that septic patients with much higher exposures to LPS have more profound inhibition of drug metabolism. (J.

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Section: Discussionmentioning

confidence: 72%

“…In EXP 1, (Table II) there did not appear to be any significant blunting of the response to the second LPS dose, a phenomenon referred to as "endotoxin tolerance" (31). In EXP 2, in which the drug cocktail was given 0.5 h after the second LPS dose, there did appear to be marked blunting of the TNF and IL-6 responses (Figs.…”

Section: Discussionmentioning

confidence: 93%

Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism.

Shedlofsky¹,

Israel²,

McClain³

et al. 1994

J. Clin. Invest.

198

114

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“…and pyrogenic tolerance is assessed at serial intervals thereafter, the refractory and immune mechanisms become apparent as temporally distinct early and late phases of tolerance (13,23). When endotoxin is administered repetitively at daily (or more closely spaced) intervals, pyrogenic tolerance increases as the refractory and immlune states appear to become sutperimiiposed (26 The defect in the late phase of tolerance in man was such that to produce equivalent impairment in volunteers with intact spleens the immunizing doses of endotoxin had to be reduced to levels extrapolated to fall between 1/10 and 1/100 of those used in the splenectomized volunteers. The impairment of late-phase tolerance developed concomitantly with the impaired capacity to produce circulating antiendotoxin antibodies.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of endotoxin tolerance. The role of the spleen.

Greisman¹,

Young²,

Workman³

et al. 1975

J. Clin. Invest.

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A B S T R A C T Splenectomy markedly impaired the production of circulating anti-endotoxin antibodies during the initial 10 days after i.v. administration of a Boivin preparation of Escherichia coli endotoxin (ET) lated to fall between 1/10 and 1/100 of those used in the splenectomized subjects. The impairment of latephase pyrogenic tolerance after splenectomy appeared to be the result of the concomitant suppression of antiendotoxin antibody production rather than the loss of splenic reticuloendothelium required to clear and inactivate the ET. This was evidenced by: (a) the significant retardation in appearance of humoral factors in the splenectomized rabbits capable of transferring high levels of specific tolerance; (b) the inability to impair the late phase of tolerance in human volunteers with intact spleens until the immunizing doses of endotoxin were reduced to levels that virtually eliminated circulating anti-endotoxin antibody production; (c) the unimpaired development of tolerance in partially hepatectomized rabbits lacking more functional reticuloendothelium than splenectomized animals, but capable of normal anti-endotoxin antibody synthesis.

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“…LPS will cause coagulation of platelets (Frank,May & Kane,I973), and such coagulation has been suggested as the cause of the deveIopment of the fibrosing granulomata characteristic of FLD (Kochman, Martin, Bureau & Dubois de Montreynaud, 1972). Of particular interest is the pyrogenic and rigor activity of LPS in man (Greisman & Hornick, 1973), as both conditions are frequently associated with FLD.…”

Section: R Hollingdale Discussionmentioning

confidence: 99%

Isolation of Lipopolysaccharide from the Walls of Micropolyspora Faeni: Chemical Composition and Serological Reactivity

Hollingdale¹

1975

Journal of General Microbiology

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Extraction of mycelium or walls of Micropolyspora faeni with cold or hot aqueous phenol yielded a lipopolysaccharide consisting of lipid A, phosphate, galactose, arabinose, glucose, glucosamine, and a dideoxy sugar. Extraction with trichloroacetic acid (TCA) yielded an incomplete molecule lacking lipid A. Part of an 0-chain was secreted into the culture medium. Phenol and TCA extracts gave three lines of precipitation with human serum from cases of farmer's lung disease, and one of these was given by the culture medium polysaccharide. Serologically-reactive sugars were arabinose, galactose and glucose. The lipopolysaccharide fixed on to red cells which agglutinated in the presence of specific antibody and lysed on the addition of complement. The lipopolysaccharide appeared to elicit mainly IgM antibodies in animals, but IgM and IgG antibodies in humans.

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Mechanisms of Endotoxin Tolerance with Special Reference to Man

Cited by 83 publications

References 31 publications

Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism.

Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism.

Mechanisms of endotoxin tolerance. The role of the spleen.

Isolation of Lipopolysaccharide from the Walls of Micropolyspora Faeni: Chemical Composition and Serological Reactivity

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