Sites of tissue binding and uptake in vivo of bacterial lipopolysaccharide-high density lipoprotein complexes: studies in the rat and squirrel monkey.

Munford, Robert S.; Andersen, John M.

doi:10.1172/jci110404

Cited by 94 publications

(67 citation statements)

References 26 publications

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“…The cholesterol ester-rich LDL and HDL also have been shown to decrease endotoxin-induced toxicity in rodents ( 15,18,20,38). The complexing ofendotoxin to these cholesterol ester-rich lipoproteins may also redirect their fate (39). As demonstrated here, when chylomicrons increase the amount of endotoxin delivered to the hepatocyte, there is a concomitant decrease in plasma TNF levels, a cytokine that is a known mediator of endotoxic shock (30,31 ).…”

Section: Discussionmentioning

confidence: 74%

Chylomicrons alter the fate of endotoxin, decreasing tumor necrosis factor release and preventing death.

Harris

Grünfeld²,

Feingold³

et al. 1993

J. Clin. Invest.

197

179

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The hypertriglyceridemia of infection was traditionally thought to represent the mobilization of substrate to fuel the body's response to the infectious challenge. However, we have previously shown that triglyceride-rich lipoproteins can protect against endotoxin-induced lethality. The current studies examine the mechanism by which this protection occurs. Rats infused with a lethal dose of endotoxin preincubated with chylomicrons had a reduced mortality compared with rats infused with endotoxin alone (15 vs. 76%, P < 0.001). Preincubation with chylomicrons increased the rate of clearance of endotoxin from plasma and doubled the amount of endotoxin cleared by the liver (30±1 vs. 14±2% of the total infused radiolabel, P < 0.001). In addition, autoradiographic studies showed that chylomicrons directed more of the endotoxin to hepatocytes and away from hepatic macrophages. Rats infused with endotoxin plus chylomicrons also showed reduced peak serum levels of tumor necrosis factor as compared with controls (14.2±3.3 vs. 44.9±9.5 ng/ml, mean±SEM, P = 0.014). In separate experiments, chylomicrons (1,000 mg triglyceride/kg) or saline were infused 10 min before the infusion of endotoxin. Chylomicron pretreatment resulted in a reduced mortality compared with rats infused with endotoxin alone (22 vs. 78%, P < 0.005). Therefore, chylomicrons can protect against endotoxin-induced lethality with and without preincubation with endotoxin. The mechanism by which chylomicrons protect against endotoxin appears to involve the shunting of endotoxin to hepatocytes and away from macrophages, thereby decreasing macrophage activation and the secretion of cytokines. (J. Clin. Invest. 1993. 91:1028-1034.) Key words: lipoproteins * triglycerides * lipopolysaccharide * cytokines * liver mediate the acute phase response, a change in the hepatic synthetic program with increased production of acute phase proteins that aid host defense (4-7). The host response to infection also includes cytokine-mediated changes in intermediary metabolism such as hypertriglyceridemia (8,9), which is due to both increases in hepatic triglyceride-rich lipoprotein synthesis (10, 11 ) and decreases in lipoprotein lipase-mediated lipoprotein clearance ( 12, 13).The increased production of triglyceride-rich lipoproteins by the liver is now postulated to be a part of the acute phase response, as lipoproteins serve not only as a potential source of metabolic fuel ( 14) but also as direct participants in the protective process. All lipoproteins, including cholesterol-rich HDL (15)(16)(17)(18)(19)(20) and and triglyceride-rich VLDL and chylomicrons ( 19,20), have been shown to bind endotoxin, subsequently reducing its toxic properties. Recent data from our laboratory has demonstrated a dose-dependent increase in mouse survival when varying concentrations of either VLDL or chylomicrons were incubated with a lethal dose of Escherichia coli endotoxin before its intraperitoneal injection (20). In addition, we found that in normal humans triglyceride-rich lipoprotei...

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Section: Discussionmentioning

confidence: 74%

Chylomicrons alter the fate of endotoxin, decreasing tumor necrosis factor release and preventing death.

Harris

Grünfeld²,

Feingold³

et al. 1993

J. Clin. Invest.

197

179

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“…The metabolic fate of LPS was shown to be strongly affected by complex formation with chylomicrons. Whereas the association of LPS with high density lipoprotein (HDL) 3 decreases its clearance from the circulation (3,4), chylomicrons enhance the plasma clearance and hepatic uptake of LPS, with shunting of LPS to hepatocytes and away from hepatic macrophages (2,5). Harris et al (6) recently presented data indicating that both the low density lipoprotein (LDL) receptor and LDL receptor-related protein participate in the rapid internalization of chylomicron-bound LPS by hepatocytes.…”

mentioning

confidence: 99%

Lipopolysaccharide (LPS)-Binding Protein Mediates LPS Detoxification by Chylomicrons

Vreugdenhil

Rousseau

Hartung

et al. 2003

The Journal of Immunology

186

132

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Chylomicrons have been shown to protect against endotoxin-induced lethality. LPS-binding protein (LBP) is involved in the inactivation of bacterial toxin by lipoproteins. The current study examined the interaction among LBP, chylomicrons, and bacterial toxin. LBP was demonstrated to associate with chylomicrons and enhance the amount of LPS binding to chylomicrons in a dose-dependent fashion. In addition, LBP accelerated LPS binding to chylomicrons. This LBP-induced interaction of LPS with chylomicrons prevented endotoxin toxicity, as demonstrated by reduced cytokine secretion by PBMC. When postprandial circulating concentrations of chylomicrons were compared with circulating levels of low density lipoprotein, very low density lipoprotein, and high density lipoprotein, chylomicrons exceeded the other lipoproteins in LPS-inactivating capacity. Furthermore, highly purified lipoteichoic acid, an immunostimulatory component of Gram-positive bacteria, was detoxified by incubation with LBP and chylomicrons. In conclusion, our results indicate that LBP associates with chylomicrons and enables chylomicrons to rapidly bind bacterial toxin, thereby preventing cell activation. Besides a role in the detoxification of bacterial toxin present in the circulation, we believe that LBP-chylomicron complexes may be part of a local defense mechanism of the intestine against translocated bacterial toxin.

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“…Whereas LPS recognition benefits the host by sensing the presence of bacteria and mobilizing defense mechanisms, an exaggerated response to LPS may contribute to the harmful sequelae of severe sepsis, which include coagulation disorders, organ failure, shock, and death. The host, therefore, has numerous mechanisms that down-regulate responses to LPS and remove it from the circulation and tissues (1)(2)(3)(4)(5)(6)(7).…”

mentioning

confidence: 99%

Lipopolysaccharide (LPS)-binding Protein Inhibits Responses to Cell-bound LPS

Thompson

Tobias

Viriyakosol

et al. 2003

Journal of Biological Chemistry

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Lipopolysaccharide (LPS)-binding protein (LBP) is an acute phase reactant that may play a dual role in vivo,both potentiating and decreasing cell responses to bacterial LPS. Whereas low concentrations of LBP potentiate cell stimulation by transferring LPS to CD14, high LBP concentrations inhibit cell responses to LPS. One inhibitory mechanism involves the ability of LBP to neutralize LPS by transferring it to plasma lipoproteins, whereas other inhibitory mechanisms, such as the one described here, do not require exogenous lipoproteins. Here we show that LBP can inhibit monocyte responses to LPS that has already bound to membrane-bound CD14 (mCD14) on the cell surface. LBP caused rapid dissociation of LPS from mCD14 as measured by the ability of LBP to inhibit cross-linking of a radioiodinated, photoactivatable LPS derivative to mCD14. Whereas LBP removed up to 75% of the mCD14-bound LPS in 10 min, this was not accompanied by extensive release of the LPS from the cells. The cross-linking data suggest that much of the LPS that remained bound to the cells was associated with LBP. The ability of LBP to inhibit cell responses could not be explained by its effect on LPS internalization, because LBP did not significantly increase the internalization of the cell-bound LPS. In cell-free LPS cross-linking experiments, LBP inhibited the transfer of LPS from soluble CD14 to soluble MD-2. Our data support the hypothesis that LBP can inhibit cell responses to LPS by inhibiting LPS transfer from mCD14 to the Toll-like receptor 4-MD-2 signaling receptor.Lipopolysaccharide (LPS 1 ; endotoxin), an abundant component of the outer membrane of Gram-negative bacteria, is one of the most potent of the known bacterial agonists in animal host cells. Whereas LPS recognition benefits the host by sensing the presence of bacteria and mobilizing defense mechanisms, an exaggerated response to LPS may contribute to the harmful sequelae of severe sepsis, which include coagulation disorders, organ failure, shock, and death. The host, therefore, has numerous mechanisms that down-regulate responses to LPS and remove it from the circulation and tissues (1-7).The potency of LPS is due to the sensitivity of the host recognition system, which requires the Toll-like receptor 4 (Tlr4) (8) signaling receptor. At least three LPS-binding proteins (LBP (9), CD14 (10), and MD-2 (11)) are required for sensitive Tlr4-mediated LPS recognition. Plasma LBP potentiates LPS recognition by transferring it from bacterial membranes (6) to CD14 (12, 13), which is expressed as a glycosylphosphatidylinositol-anchored protein on the surfaces of myeloid lineage cells (mCD14) and as an anchorless plasma protein, soluble CD14 (sCD14) (14, 15). CD14 presents LPS to Tlr4, presumably by transferring the LPS to MD-2, an accessory protein that is constitutively associated with the extracellular domain of Tlr4 (16). MD-2 binds LPS with high affinity (17), and it is required for Tlr4 signaling (11). Although normal expression of the Tlr4 and MD-2 are too low for direct measurements...

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Sites of tissue binding and uptake in vivo of bacterial lipopolysaccharide-high density lipoprotein complexes: studies in the rat and squirrel monkey.

Cited by 94 publications

References 26 publications

Chylomicrons alter the fate of endotoxin, decreasing tumor necrosis factor release and preventing death.

Chylomicrons alter the fate of endotoxin, decreasing tumor necrosis factor release and preventing death.

Lipopolysaccharide (LPS)-Binding Protein Mediates LPS Detoxification by Chylomicrons

Lipopolysaccharide (LPS)-binding Protein Inhibits Responses to Cell-bound LPS

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