Therapeutic Trial of Reconstituted Human High Density Upoprotein in a Dog Model of Gram-Negative Septic Shock

Quezado, Zenaide M.N.; Hoffman, William D.; Banks, Steve; Ailing, David W.; Koev, C A; Danner, R L; Elin, Ronald J.; Hosseini, Jeanette M.; Bacher, John; Parker, Todd; Levine, Daniel M.; Rubin, Albert L.; Natanson, Charles

doi:10.1097/00003246-199304001-00192

Cited by 18 publications

(27 citation statements)

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“…Without further separation, the protein:lipid ratio chosen yields a mixture of particles containing 2, 3 and 4 apoA-1 molecules per particle. Mean diameters of 12.6 and 17.7 nm for the two major particle populations are in the same range as published previously for discoidal complexes [58,59], Several studies have been published which suggest that rHDL may be useful for the prevention or the treatment of gram-negative septic shock [7,8,[60][61][62]. The mecha nism (s) of action have not yet been defined in detail, but one important element seems to be the binding of LPS to rHDL, thereby inhibiting the activity of LPS.…”

Section: Lca T Activationsupporting

confidence: 80%

Production and Characterization of a Reconstituted High Density Lipoprotein for Therapeutic Applications

Lerch¹,

Förtsch²,

Hodler³

et al. 1996

Vox Sanguinis

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A method is described for the large scale preparation of reconstituted high density lipoproteins (rHDL) suitable for therapeutic use. Apolipoprotein A-I (apoA-I) was isolated from precipitates obtained by cold ethanol fractionation of human plasma. This process includes several steps for virus removal and virus inactivation, among them pasteurization. Reconstitution of lipoprotein particles was performed by cholate dialysis using soybean phosphatidylcholine as the lipid source. An apoA-I:lipid ratio of 1:150 (mol.mol) was obtained. Redissolved rHDLs were disc-shaped particles resembling nascent HDL, as assessed by electron microscopy. The method was optimized for low content of free apoA-I protein as well as the low concentration of free lipid. The product was stabilized by lyophilization in the presence of sucrose. In vitro studies show potential effects in the prevention of gram-negative septic shock and in the inhibition of atherosclerosis.

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Section: Lca T Activationsupporting

confidence: 80%

Production and Characterization of a Reconstituted High Density Lipoprotein for Therapeutic Applications

Lerch¹,

Förtsch²,

Hodler³

et al. 1996

Vox Sanguinis

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“…76 Single or multiple injections of sHDL proved effective in animal models of human atherosclerosis, 46,47,78 postangioplasty restenosis, 72 arterial thrombosis, 55 myocardial ischemiareperfusion injury, 33 and hemorrhagic and septic shock. 41,79 If such sHDLs will be effective also in the clinical setting, a simple approach to the acute treatment of vascular diseases could soon become available.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Protection by High-Density Lipoproteins

Calabresi

Gomaraschi

Franceschini

2003

ATVB

223

140

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Abstract-There are several potential mechanisms by which HDLs protect against the development of vascular disease.One relates to the unique ability of these lipoproteins to remove cholesterol from the arterial wall. Another is the ability of HDL to prevent and eventually correct endothelial dysfunction, a key variable in the pathogenesis of atherosclerosis and its complications. HDLs help maintain endothelial integrity, facilitate vascular relaxation, inhibit blood cell adhesion to vascular endothelium, reduce platelet aggregability and coagulation, and may favor fibrinolysis. These functions of HDLs complement their activity in arterial cholesterol removal by providing an excellent rationale for favorably influencing pathological processes underlying a variety of clinical conditions, such as accelerated atherosclerosis, acute coronary syndromes, and restenosis after coronary angioplasty, through a chronic or acute elevation of plasma HDL concentration. Key Words: high-density lipoproteins Ⅲ endothelium Ⅲ endothelial dysfunction Ⅲ atherosclerosis H uman HDLs are a heterogeneous class of lipoproteins of high density (1.063 to 1.21 g/mL) and small diameter (5 to 17 nm). Most HDL particles contain apolipoprotein A-I (apoA-I) as the major protein component. Several other proteins, including apolipoprotein (apo) A-II, apoCs, apoE, minor apolipoproteins, lecithin:cholesterol acyltransferase (LCAT), paraoxonase (PON), and platelet-activating factor acetylhydrolase (PAF-AH), are associated with HDL and impart significant physiological functions. The plasma concentration of HDL is routinely quantified as HDL cholesterol (HDL-C). However, differences in lipid and protein composition characterize several major and minor HDL particle subpopulations, which differ in density, size, shape, and surface charge. 1 Although the physiological significance of these different particles is mostly undefined, some of them display peculiar functional properties, at least in vitro. [2][3][4] Several prospective epidemiological studies provided overwhelming evidence that a low plasma HDL-C is a major, independent risk factor for the development of an acute coronary event. 5 Studies in patients with rare disorders of HDL metabolism and in genetically modified animal models support a causal relationship between low HDL and development of atherosclerotic vascular disease. The atheroprotective activity of HDL is often explained by the unique ability of these lipoproteins to remove cholesterol from peripheral tissues, including the arterial wall, and transport it to the liver The present review will focus on the effects of HDL on vascular endothelium and will discuss how the in vitro evidence from cell-culture studies translates into in vivo HDL-mediated endothelial protection, which may be relevant in the development and prevention of vascular disease. Endothelial Dysfunction and Cardiovascular DiseaseTraditionally, the endothelium has been considered an inert component of the vessel wall. During the past 2 decades it has become evident that t...

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“…34 Infusing HDL has also been protective in some animal models. 35 When LPS binds to monocytes in the presence of 90% human serum, approximately 20% of it is quickly internalized whereas the remainder is released ('effluxed') from the cell surface over an hour or so. sCD14 in the serum transfers most of the released LPS to lipoproteins.…”

Section: Soluble Proteins That Bind Lps or Lipid Amentioning

confidence: 99%

Detoxifying endotoxin: time, place and person

Munford¹

2005

J. Endotoxin Res.

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Animals that cannot sense endotoxin may die if they are infected by Gram-negative bacteria. Animals that sense endotoxin and respond too vigorously may also die, victims of their own inflammatory reactions. The outcome of Gram-negative bacterial infection is thus determined not only by an individual's ability to sense endotoxin and respond to its presence, but also by numerous phenomena that inactivate endotoxin and/or prevent harmful reactions to it. Endotoxin sensing requires the MD-2/TLR4 recognition complex and occurs principally in local tissues and the liver. This review highlights the known detoxification mechanisms, which include: (i) proteins that facilitate LPS sequestration by plasma lipoproteins, prevent interactions between the bioactive lipid A moiety and MD-2/TLR4, or promote cellular uptake via non-signaling pathway(s); (ii) enzymes that deacylate or dephosphorylate lipid A; (iii) mechanisms that remove LPS and Gram-negative bacteria from the bloodstream; and (iv) neuroendocrine adaptations that modulate LPS-induced mediator production or neutralize pro-inflammatory molecules in the circulation. In general, the mechanisms for sensing and detoxifying endotoxin seem to be compartmentalized (local versus systemic), dynamic, and variable between individuals. They may have evolved to confine infection and inflammation to extravascular sites of infection while preventing harmful systemic reactions. Integration of endotoxin sensing and detoxification is essential for successful host defense.

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Therapeutic Trial of Reconstituted Human High Density Upoprotein in a Dog Model of Gram-Negative Septic Shock

Cited by 18 publications

References 0 publications

Production and Characterization of a Reconstituted High Density Lipoprotein for Therapeutic Applications

Production and Characterization of a Reconstituted High Density Lipoprotein for Therapeutic Applications

Endothelial Protection by High-Density Lipoproteins

Detoxifying endotoxin: time, place and person

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