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

Harris, Hobart W.; Grünfeld, Carl; Feingold, Kenneth R.; Read, Thomas E.; Kane, John P.; Jones, Alison; Eichbaum, E B; Bland, G F; Rapp, Joseph H.

doi:10.1172/jci116259

Cited by 197 publications

(190 citation statements)

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“…are destroyed extracellularly or when antibiotics are present, neutralization of LPS by plasma (lipo)proteins may be most important in detoxification. Such complexing is viewed as an important step in the delivery of LPS to the liver and its subsequent disposal (24,(27)(28)(29). At extravascular sites where lipoprotein-mediated clearance is less prominent, delivery of shed LPS to MNC and subsequent deacylation may be more important.…”

Section: Discussionmentioning

confidence: 99%

Deacylation of Lipopolysaccharide in Whole Escherichia coli during Destruction by Cellular and Extracellular Components of a Rabbit Peritoneal Inflammatory Exudate

Katz¹,

Weinrauch²,

Munford³

et al. 1999

Journal of Biological Chemistry

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Deacylation of purified lipopolysaccharides (LPS)markedly reduces its toxicity toward mammals. However, the biological significance of LPS deacylation during infection of the mammalian host is uncertain, particularly because the ability of acyloxyacyl hydrolase, the leukocyte enzyme that deacylates purified LPS, to attack LPS residing in the bacterial cell envelope has not been established. We recently showed that the cellular and extracellular components of a rabbit sterile inflammatory exudate are capable of extensive and selective removal of secondary acyl chains from purified LPS. We now report that LPS as a constituent of the bacterial envelope is also subject to deacylation in the same inflammatory setting. Using Escherichia coli LCD25, a strain that exclusively incorporates radiolabeled acetate into fatty acids, we quantitated LPS deacylation as the loss of radiolabeled secondary (laurate and myristate) and primary fatty acids (3-hydroxymyristate) from the LPS backbone. Isolated mononuclear cells and neutrophils removed 50% and 20 -30%, respectively, of the secondary acyl chains of the LPS of ingested whole bacteria. When bacteria were killed extracellularly during incubation with ascitic fluid, no LPS deacylation occurred. In this setting, the addition of neutrophils had no effect, but addition of mononuclear cells resulted in removal of >40% of the secondary acyl chains by 20 h. Deacylation of LPS was always restricted to the secondary acyl chains. Thus, in an inflammatory exudate, primarily in mononuclear phagocytes, the LPS in whole bacteria undergoes substantial and selective acyloxyacyl hydrolase-like deacylation, both after phagocytosis of intact bacteria and after uptake of LPS shed from extracellularly killed bacteria. This study demonstrates for the first time that the destruction of Gram-negative bacteria by a mammalian host is not restricted to degradation of phospholipids, protein, and RNA, but also includes extensive deacylation of the envelope LPS.The prominent role ascribed to LPS 1 in evoking beneficial as well as harmful mammalian host responses to invading Gramnegative bacteria has prompted intense scrutiny of host recognition, detoxification, and elimination of this bacterial product. Underacylated and underphosphorylated biosynthetic precursors and chemically synthesized analogs of lipid A (the endotoxic part of LPS) possess greatly diminished endotoxic activity and can act as antagonists in human cell bioassays (1, 2). Mammalian enzyme systems capable of removing acyl and phosphate groups from lipid A may therefore play an important role in host defense against Gram-negative bacteria and their LPS. Thus far, only one mammalian enzyme, acyloxyacyl hydrolase, has been shown to deacylate LPS (3, 4).We recently showed that both the cells and extracellular fluid of a sterile inflammatory exudate actively deacylate purified LPS ex vivo in an acyloxyacyl hydrolase-like fashion (5). It has been much more difficult to analyze LPS breakdown products when the LPS is presented in intact bacteria...

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Section: Discussionmentioning

confidence: 99%

Deacylation of Lipopolysaccharide in Whole Escherichia coli during Destruction by Cellular and Extracellular Components of a Rabbit Peritoneal Inflammatory Exudate

Katz¹,

Weinrauch²,

Munford³

et al. 1999

Journal of Biological Chemistry

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“…Conversely, binding of LPS to lipoproteins facilitates delivery of LPS to hepatocytes for detoxifi cation, which if insuffi cient may lead to increased mononuclear cell activation 65 . Lipoproteins, especially HDL, bind to and neutralize lipopolysaccharide (LPS).…”

Section: Clinical Consequences Of Hypocholesterolemiamentioning

confidence: 99%

Hypocholesterolemia in Clinically Serious Conditions - Review

Vyroubal¹,

Chiarla²,

Giovannini³

et al. 2008

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background:Cholesterol is an essential component of cell membranes, precursor of steroids, biliary acids and other components of serious importance in live organism. Cholesterol synthesis is a complicated and energy-demanding process. Real daily need of cholesterol and mechanisms of decline cholesterol levels in critical ill are unknown. During stressful situations a signifi cant hypocholesterolaemia may be found. Hypocholesterolemia has been known for a number of years to be a signifi cant prognostic indicator of increased morbidity and mortality connected with a whole spectrum of pathological conditions. The aim of article is the elucidation of the role and importance of hypocholesterolaemia during the intensive care. . Methods and Results:We examined studies that are engaged in problems of hypocholesterolemia in critically ill. Very low levels of total as well as LDL cholesterol are most frequently found in serious polytrauma, after extensive surgery, in serious infections, in protracted hypovolemic shock. It is still not clear whether hypocholesterolemia refl ects only a serious metabolic disorder, which results from a life-threatening condition, or whether it has an active role in evolution and outcome.Conclusions: Hypocholesterolemia is commonly observed in critically ill patients. Nevertheless, it is not known whether it is a secondary manifestation of disease, or whether it actively contributes to deterioration of the disease. Although the contribution of hypocholesterolemia to mortality is modest compared with known risk factors such as increased severity of illness and the development of nosocomial infection, low serum lipid concentrations represent a potential therapeutic target in sepsis.

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“…esides a crucial role in the transport of dietary lipids, chylomicrons appear to reinforce the host defense against LPS, a major constituent of the outer membrane of Gram-negative bacteria (1,2). LPS provokes an inflammatory response in the infected host by virtue of its ability to bind membrane factors present on the surface of macrophages and other cells essential to host defense.…”

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confidence: 99%

“…Once the response to Gram-negative bacteria is initiated, there is a need to inactivate and eliminate LPS to minimize potential deleterious effects of an unregulated response. Circulating chylomicrons were previously demonstrated to be potent inhibitors of LPS activity in vivo and to prevent endotoxininduced mortality (1,2). The metabolic fate of LPS was shown to be strongly affected by complex formation with chylomicrons.…”

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

Cited by 197 publications

References 50 publications

Deacylation of Lipopolysaccharide in Whole Escherichia coli during Destruction by Cellular and Extracellular Components of a Rabbit Peritoneal Inflammatory Exudate

Deacylation of Lipopolysaccharide in Whole Escherichia coli during Destruction by Cellular and Extracellular Components of a Rabbit Peritoneal Inflammatory Exudate

Hypocholesterolemia in Clinically Serious Conditions - Review

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

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