Antiinflammatory effects of reconstituted high-density lipoprotein during human endotoxemia

High-density lipoprotein (HDL) has been found to neutralize LPS activity in vitro and in animals in vivo. We sought to determine the effects of reconstituted HDL (rHDL) on LPS responsiveness in humans in a double-blind, randomized, placebo-controlled, cross-over study. rHDL, given as a 4-h infusion...

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Published in:	The Journal of experimental medicine Vol. 184; no. 5; p. 1601
Main Authors:	Pajkrt, D, Doran, J E, Koster, F, Lerch, P G, Arnet, B, van der Poll, T, ten Cate, J W, van Deventer, S J
Format:	Journal Article
Language:	English
Published:	United States 01.11.1996
Subjects:	Adult Antigens, CD Apolipoprotein A-I - metabolism Apolipoprotein A-I - therapeutic use Cholesterol - metabolism Cholesterol - therapeutic use Cross-Over Studies Double-Blind Method Endotoxemia - drug therapy Endotoxins - metabolism Granulocytes Humans Inflammation - drug therapy Infusions, Intravenous Interleukin-6 - blood Interleukin-8 - blood Leukocyte Count Lipopolysaccharides - metabolism Lipoproteins, HDL - metabolism Lipoproteins, HDL - therapeutic use Male Monocytes Nausea Pain Phosphatidylcholines - metabolism Phosphatidylcholines - therapeutic use Placebos Shivering Time Factors Tumor Necrosis Factor-alpha - analysis Vomiting
ISSN:	0022-1007
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Abstract	High-density lipoprotein (HDL) has been found to neutralize LPS activity in vitro and in animals in vivo. We sought to determine the effects of reconstituted HDL (rHDL) on LPS responsiveness in humans in a double-blind, randomized, placebo-controlled, cross-over study. rHDL, given as a 4-h infusion at 40 mg/kg starting 3.5 h before endotoxin challenge (4 ng/kg), reduced flu-like symptoms during endotoxemia, but did not influence the febrile response. rHDL potently reduced the endotoxin-induced release of TNF, IL-6, and IL-8, while only modestly attenuating the secretion of proinflammatory cytokine inhibitors IL-1ra, soluble TNF receptors and IL-10. In addition, rHDL attenuated LPS-induced changes in leukocyte counts and the enhanced expression of CD11b/CD18 on granulocytes. Importantly, rHDL infusion per se, before LPS administration, was associated with a downregulation of CD14, the main LPS receptor, on monocytes. This effect was biologically relevant, since monocytes isolated from rHDL-treated whole blood showed reduced expression of CD14 and diminished TNF production upon stimulation with LPS. These results suggest that rHDL may inhibit LPS effects in humans in vivo not only by binding and neutralizing LPS but also by reducing CD14 expression on monocytes.
AbstractList	High-density lipoprotein (HDL) has been found to neutralize LPS activity in vitro and in animals in vivo. We sought to determine the effects of reconstituted HDL (rHDL) on LPS responsiveness in humans in a double-blind, randomized, placebo-controlled, cross-over study. rHDL, given as a 4-h infusion at 40 mg/kg starting 3.5 h before endotoxin challenge (4 ng/kg), reduced flu-like symptoms during endotoxemia, but did not influence the febrile response. rHDL potently reduced the endotoxin-induced release of TNF, IL-6, and IL-8, while only modestly attenuating the secretion of proinflammatory cytokine inhibitors IL-1ra, soluble TNF receptors and IL-10. In addition, rHDL attenuated LPS-induced changes in leukocyte counts and the enhanced expression of CD11b/CD18 on granulocytes. Importantly, rHDL infusion per se, before LPS administration, was associated with a downregulation of CD14, the main LPS receptor, on monocytes. This effect was biologically relevant, since monocytes isolated from rHDL-treated whole blood showed reduced expression of CD14 and diminished TNF production upon stimulation with LPS. These results suggest that rHDL may inhibit LPS effects in humans in vivo not only by binding and neutralizing LPS but also by reducing CD14 expression on monocytes.High-density lipoprotein (HDL) has been found to neutralize LPS activity in vitro and in animals in vivo. We sought to determine the effects of reconstituted HDL (rHDL) on LPS responsiveness in humans in a double-blind, randomized, placebo-controlled, cross-over study. rHDL, given as a 4-h infusion at 40 mg/kg starting 3.5 h before endotoxin challenge (4 ng/kg), reduced flu-like symptoms during endotoxemia, but did not influence the febrile response. rHDL potently reduced the endotoxin-induced release of TNF, IL-6, and IL-8, while only modestly attenuating the secretion of proinflammatory cytokine inhibitors IL-1ra, soluble TNF receptors and IL-10. In addition, rHDL attenuated LPS-induced changes in leukocyte counts and the enhanced expression of CD11b/CD18 on granulocytes. Importantly, rHDL infusion per se, before LPS administration, was associated with a downregulation of CD14, the main LPS receptor, on monocytes. This effect was biologically relevant, since monocytes isolated from rHDL-treated whole blood showed reduced expression of CD14 and diminished TNF production upon stimulation with LPS. These results suggest that rHDL may inhibit LPS effects in humans in vivo not only by binding and neutralizing LPS but also by reducing CD14 expression on monocytes. High-density lipoprotein (HDL) has been found to neutralize LPS activity in vitro and in animals in vivo. We sought to determine the effects of reconstituted HDL (rHDL) on LPS responsiveness in humans in a double-blind, randomized, placebo-controlled, cross-over study. rHDL, given as a 4-h infusion at 40 mg/kg starting 3.5 h before endotoxin challenge (4 ng/kg), reduced flu-like symptoms during endotoxemia, but did not influence the febrile response. rHDL potently reduced the endotoxin-induced release of TNF, IL-6, and IL-8, while only modestly attenuating the secretion of proinflammatory cytokine inhibitors IL-1ra, soluble TNF receptors and IL-10. In addition, rHDL attenuated LPS-induced changes in leukocyte counts and the enhanced expression of CD11b/CD18 on granulocytes. Importantly, rHDL infusion per se, before LPS administration, was associated with a downregulation of CD14, the main LPS receptor, on monocytes. This effect was biologically relevant, since monocytes isolated from rHDL-treated whole blood showed reduced expression of CD14 and diminished TNF production upon stimulation with LPS. These results suggest that rHDL may inhibit LPS effects in humans in vivo not only by binding and neutralizing LPS but also by reducing CD14 expression on monocytes.
Author	ten Cate, J W Koster, F Lerch, P G Doran, J E Pajkrt, D van der Poll, T van Deventer, S J Arnet, B
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BackLink	https://www.ncbi.nlm.nih.gov/pubmed/8920850$$D View this record in MEDLINE/PubMed
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PublicationTitle	The Journal of experimental medicine
PublicationTitleAlternate	J Exp Med
PublicationYear	1996
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Snippet	High-density lipoprotein (HDL) has been found to neutralize LPS activity in vitro and in animals in vivo. We sought to determine the effects of reconstituted...
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SubjectTerms	Adult Antigens, CD Apolipoprotein A-I - metabolism Apolipoprotein A-I - therapeutic use Cholesterol - metabolism Cholesterol - therapeutic use Cross-Over Studies Double-Blind Method Endotoxemia - drug therapy Endotoxins - metabolism Granulocytes Humans Inflammation - drug therapy Infusions, Intravenous Interleukin-6 - blood Interleukin-8 - blood Leukocyte Count Lipopolysaccharides - metabolism Lipoproteins, HDL - metabolism Lipoproteins, HDL - therapeutic use Male Monocytes Nausea Pain Phosphatidylcholines - metabolism Phosphatidylcholines - therapeutic use Placebos Shivering Time Factors Tumor Necrosis Factor-alpha - analysis Vomiting
Title	Antiinflammatory effects of reconstituted high-density lipoprotein during human endotoxemia
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Volume	184
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