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http://jem.rupress.org/content/182/1/267.abstract
http://jem.rupress.org/content/182/1/267.full.pdf+html
July 1, 1995 // JEM vol. 182 no. 1 267-272
Triglyceride-rich
lipoproteins prevent septic death in rats.
T E Read, C Grunfeld, Z L Kumwenda, M C Calhoun, J P Kane, K R Feingold, and J H Rapp Triglyceride-rich lipoproteins
bind and inactive bacterial endotoxin in
vitro and prevent death when given before a lethal dose of endotoxin in
animals. However, lipoproteins have not yet been demonstrated to improve
survival in polymicrobial gram-negative sepsis. We therefore tested the ability
of triglyceride-rich lipoproteins to prevent death after cecal ligation and
puncture (CLP) in rats. Animals were given bolus infusions of either
chylomicrons (1 g triglyceride/kg per 4 h) or an equal volume of saline for 28
h after CLP. Chylomicron infusions significantly improved survival (measured at
96 h) compared with saline controls (80 vs 27%, P < or = 0.03). Chylomicron
infusions also reduced serum levels of endotoxin, measured 90 min (26 +/- 3 vs
136 +/- 51 pg/ml, mean +/- SEM, P < or = 0.03) and 6 h (121 +/- 54 vs 1,026
+/- 459 pg/ml, P < or = 0.05) after CLP. The reduction in serum endotoxin
correlated with a reduction in serum tumor necrosis factor, measured 6 h after
CLP (0 +/- 0 vs 58 +/- 24 pg/ml, P < or = 0.03), suggesting that
chylomicrons improve survival in this model by limiting macrophage exposure to
endotoxin and thereby reducing secretion of inflammatory cytokines. Infusions
of a synthetic triglyceride-rich lipid emulsion (Intralipid; KabiVitrum, Inc.,
Alameda, CA) (1 g triglyceride/kg) also significantly improved survival
compared with saline controls (71 vs 27%, P < or = 0.03). These data
demonstrate that triglyceride-rich lipoproteins can protect animals from lethal
polymicrobial gram-negative sepsis. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ http://iai.asm.org/content/57/7/2237.short
Inhibition
of endotoxin-induced activation of human monocytes by human
lipoproteins.
W A Flegel,
A Wölpl,
D N Männel and
H Northof
Toxicity of lipopolysaccharide (LPS) (endotoxin) is, to a large extent,
mediated by the activation of monocytes/macrophages and subsequent release of
monokines, such as interleukin-1 (IL-1) and tumor necrosis factor alpha
(TNF-alpha). It is known that LPS binds
readily to serum lipoproteins and that
LPS-lipoprotein complexes are less toxic than unbound LPS. Here we present
data analyzing the impact of the LPS-serum interaction at the cellular level.
By measuring IL-1 TNF-alpha, and IL-6, the interaction of different LPSs or
lipid A with human serum could be shown to prevent the activation of human
monocytes. The amounts of LPS inactivated by normal human serum did not exceed
10 ng/ml. The LPS-inactivating capacity of serum was shown to be a function of
the lipoproteins. Other serum components, such as naturally occurring anti-LPS
immunoglobulin G, complement, or nutritive lipids, had no significant influence
in our system. Our experiments suggest that serum lipoproteins control
endotoxin-induced monocyte activation and monokine release.
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
http://cid.oxfordjournals.org/content/41/Supplement_7/S498.abstract
Triglyceride-Rich Lipoproteins
as
Agents of Innate Immunity
Abstract
Bacterial
endotoxin
(i.e., lipopolysaccharide [LPS]) elicits dramatic responses in the host,
including elevated plasma lipid levels due to increased synthesis and secretion
of triglyceride-rich lipoproteins by the liver and inhibition of lipoprotein
lipase. This cytokine-induced hyperlipoproteinemia, clinically termed the
“lipemia of sepsis,” was customarily thought to involve the mobilization of
lipid stores to fuel the host response to infection. However, because
lipoproteins can also bind and neutralize LPS, we have long postulated that
triglyceride-rich lipoproteins (very-low-density lipoproteins and chylomicrons)
are also components of an innate, nonadaptive host immune response to
infection. Recent research demonstrates
the capacity of lipoproteins to bind LPS, protect against LPS-induced toxicity,
and modulate the overall host response to this bacterial toxin.
Thematic review series: The Pathogenesis of Atherosclerosis.
Effects of
infection and inflammation on lipid and lipoprotein metabolism mechanisms and
consequences to the host
ABSTRACT
Infection
and inflammation induce the acute-phase response (APR), leading to multiple alterations
in
lipid and lipoprotein metabolism. Plasma triglyceride levels increase from
increased VLDL secretion as a result of adipose tissue lipolysis, increased de
novo hepatic fatty acid synthesis, and suppression of fatty acid oxidation.
With more severe infection, VLDL clearance decreases secondary to decreased
lipoprotein lipase and apolipoprotein E in VLDL. In rodents, hypercholesterolemia
occurs attributable to increased
hepatic cholesterol synthesis and decreased LDL clearance, conversion of
cholesterol to bile acids, and secretion of cholesterol into the bile. Marked
alterations in proteins important in HDL metabolism lead to decreased reverse
cholesterol transport and increased cholesterol delivery to immune cells.
Oxidation of LDL and VLDL increases, whereas HDL becomes a proinflammatory
molecule. Lipoproteins become enriched in ceramide, glucosylceramide, and
sphingomyelin, enhancing uptake by macrophages. Thus, many of the changes in
lipoproteins are proatherogenic. The molecular mechanisms underlying the
decrease in many of the proteins during the APR involve coordinated decreases
in several nuclear hormone receptors, including peroxisome
proliferator-activated receptor, liver X receptor, farnesoid X receptor, and
retinoid X receptor.
APR-induced
alterations initially protect the host from the harmful effects of bacteria, viruses,
and
parasites. However, if prolonged, these changes in the structure and
function of lipoproteins will contribute to atherogenesis [Just like firemen
contribute to water damage
in a building].
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
LPS
is lipopolysaccharide binding protein The protein encoded by this gene is involved in the acute-phase
immunologic response to gram-negative bacterial infections. Gram-negative
bacteria contain a glycolipid, lipopolysaccharide (LPS), on their outer cell
wall. Together with bactericidal
permeability-increasing protein (BPI), the encoded
protein binds LPS and interacts with the CD14
receptor, probably playing a role in regulating LPS-dependent monocyte
responses. Studies in mice suggest that the encoded protein is necessary for
the rapid acute-phase response to LPS but not for the clearance of LPS from
circulation.. Wiki.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC199173/
FULL Posted at http://healthfully.org/rja/id1.html
LPS-binding protein circulates
in association with
apoB-containing lipoproteins and enhances endotoxin-LDL/VLDL interaction
Abstract
LPS-binding protein (LBP) and serum lipoproteins cooperate in reducing the
toxic properties of LPS. In the present study, we demonstrate that
LBP circulates in association with LDL and VLDL in healthy persons. ApoB was
found to account at least in part for the interaction of LBP with LDL and VLDL.
Although LBP interacted with purified apoA-I in vitro, no association of LBP
with apoA-I or HDL was found in serum. Consistent with the observed association
of LBP with LDL and VLDL, these lipoproteins also were demonstrated to be the
predominant LPS-binding lipoproteins. Most interestingly, the association of
LBP with LDL and VLDL strongly enhanced the capacity of these lipoproteins to
bind LPS. Because this function of LBP is of utmost importance during infection,
the association of LBP and LPS with lipoproteins was also studied in serum from
septic patients. In septic serum containing high LBP levels and a markedly
altered lipoprotein spectrum, most of the LBP is associated with LDL and VLDL, although some LBP appeared to circulate
free from lipoproteins. Also in this
serum, LPS was found to bind predominantly to LDL and VLDL. The observed
binding of LBP and LPS to LDL and VLDL, as well as the LBP-dependent
incorporation of LPS into these lipoproteins, emphasizes a crucial role for
circulating LBP-LDL/VLDL complexes in
the scavenging of LPS.
Body of articles selected by
JK
“This
initiation of cellular responses is essential for the host defense against
bacterial infections,,,, LPS is detoxified in the circulation by incorporation
into lipoproteins (reviewed in ref. 1…
Evidence for a physiological role for LBP in inflammation is supported by
studies that demonstrate enhanced mortality and uncontrolled multiplication and
spread of bacteria in LBP knockout mice compared with wild-type mice after
intraperitoneal administration of bacteria (11)…. We consider that the physical association of LBP with these
lipoproteins may be important for the cooperation of LBP and lipoproteins in
the detoxification of endotoxin…. Because
it is firmly established that LDL and VLDL are critical in the survival of
infection with gram-negative bacteria (19) and that circulating levels of these lipoproteins are
relatively high during inflammation compared with HDL levels, the present study
was undertaken to investigate whether LBP associates with LDL and VLDL. To this
end, the distribution of LBP among lipoproteins was studied in serum of healthy
and septic persons. Subsequently, we investigated the effect of the association
of LBP with lipoproteins and apolipoproteins on the LPS-binding capacity…. The
beneficial role for LDL in the host defense against bacteria is supported by a
study that demonstrates that LDL-receptor–deficient mice with elevated
circulating LDL concentrations are protected against lethal endotoxemia and
severe infections with gram-negative micro-organisms (19). … Overall, the data of this study suggest that LBP is a
cofactor of circulating LDL and VLDL, which facilitates the uptake of endotoxin
by these lipoproteins. This implies an important role for LBP/LDL and VLDL
complexes in the defense against bacteria and endotoxin.”
11. Jack RS, et al. Lipopolysaccharide-binding protein is required
to combat a murine gram-negative bacterial infection. Nature. 1997;389:742–745. [PubMed]
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