Inhibition of endotoxin-induced activation of the coagulation and fibrinolytic pathways using a recombinant endotoxin-binding protein (rBPI23)

Möhlen, M. A. M. Von Der; Deventer, S. J. H. Van; Levi, Marcel; Ende, B. Van Den; Wedel, Nancy; Nelson, Betty J.; Friedmann, Nadav; Cate, J. W. Ten

doi:10.1182/blood.v85.12.3437.bloodjournal85123437

Cited by 41 publications

(21 citation statements)

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“…In multiple animal models of gram-negative sepsis and/or endotoxemia, administration of BPI congeners is associated with improved outcome (26). Recombinant NH 2 -terminal proteins derived from BPI have demonstrated potent antiendotoxic activity in phase II/III trials (27)(28)(29). BPI has been demonstrated to improve hyperglycemia and other metabolic events after lipopolysaccharide administration in animal models (30).…”

Section: Discussionmentioning

confidence: 99%

Natural Antibiotics and Insulin Sensitivity: The Role of Bactericidal/Permeability-Increasing Protein

Gubern¹

2006

Diabetes

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The innate immune system can immediately respond to microorganism intrusion by helping to prevent further invasion. Bactericidal/permeability-increasing protein (BPI) is a major constituent of neutrophils that possesses anti-inflammatory properties. Inflammation is increasingly recognized as a component of the metabolic syndrome. We hypothesized that the production of BPI could be linked to insulin sensitivity and glucose tolerance. We studied circulating BPI across categories of glucose tolerance. We also studied whether these cross-sectional associations were of functional importance. For this reason, we investigated circulating bioactive lipopolysaccharide and the effects of changing insulin action-after treatment with an insulin sensitizer (metformin)-on circulating BPI in subjects with glucose intolerance. Finally, we tested whether a 3'-untranslated region (UTR) BPI polymorphism led to differences in BPI and insulin action among nondiabetic subjects. Age- and BMI-adjusted circulating BPI was significantly lower among patients with type 2 diabetes. Circulating BPI correlated negatively with fasting and postload glucose and insulin concentrations. In subjects with glucose intolerance, BPI was also linked to BMI, waist-to-hip ratio, and age- and BMI-adjusted insulin sensitivity. Bioactive lipopolysaccharide was negatively correlated with circulating BPI (r = -0.57, P < 0.0001) and positively with plasma lipopolysaccharide-binding protein (r = 0.54, P = 0.002). In parallel to improved insulin sensitivity, plasma BPI significantly increased in the metformin group but not in the placebo group. A 3'-UTR BPI polymorphism was simultaneously associated with plasma BPI concentration, waist-to-hip ratio, fasting and postload insulin concentration, fasting plasma triglycerides, and insulin sensitivity. These findings suggest that this component of the innate immune system is associated with metabolic pathways.

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Section: Discussionmentioning

confidence: 99%

Natural Antibiotics and Insulin Sensitivity: The Role of Bactericidal/Permeability-Increasing Protein

Gubern¹

2006

Diabetes

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“…Among these is BPI, the first endogenous antibiotic that has been tested in humans and that already has shown promise in clinical trials [12]. Particularly encouraging is the demonstration that short-term administration of rBPI 21 (a recombinant amino-terminal 21-kDa BPI derivative) to both normal individuals [58,59,61] and to seriously ill patients [12] has raised no safety issues. Moreover, evidence has been obtained that BPI may act synergistically with a range of antibiotics, including some to which the target bacteria are resistant [unpublished observations].…”

Section: Discussionmentioning

confidence: 99%

“…Recombinant amino-terminal fragments (such as rBPI 21 ), alone or in combination with conventional antibiotics, have been shown to protect experimental animals against lethal doses of bacterial inocula and isolated LPS [5]. Subsequent phase I and II trials in humans have shown that BPI is neither toxic nor immunogenic in normal individuals [58,59] and in seriously ill patients [12]. Phase II trials have been or are being conducted in patients after hemorrhagic trauma, partial hepatectomy, with serious peritoneal infections, and in cystic fibrosis, all conditions in which GNB and their endotoxin are known to appear in the circulating blood and to contribute to morbidity and mortality [60].…”

Section: Evidence That Administered Bpi (And Derivatives) Protects Anmentioning

confidence: 99%

The bactericidal/permeability-increasing protein (BPI) in antibacterial host defense

Elsbach

1998

Journal of Leukocyte Biology

173

150

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The bactericidal/permeability-increasing protein (BPI) is a 456-residue cationic protein produced only by precursors of polymorphonuclear leukocytes (PMN) and is stored in the primary granules of these cells. The potent (nM) cytotoxicity of BPI is limited to gram-negative bacteria (GNB), reflecting the high affinity (<10 nM) of BPI for bacterial lipopolysaccharides (LPS). The biological effects of isolated BPI are linked to complex formation with LPS. Binding of BPI to live bacteria via LPS causes immediate growth arrest. Actual killing coincides with later damage to the inner membrane. Complex formation of BPI with cell-associated or cell-free LPS inhibits all LPS-induced host cell responses. BPI-blocking antibodies abolish the potent activity of whole PMN lysates and inflammatory fluids against BPI-sensitive GNB. The antibacterial and the anti-endotoxin activities of BPI are fully expressed by the amino terminal half of the molecule. These properties of BPI have prompted preclinical and subsequent clinical testing of recombinant amino-terminal fragments of BPI. In animals, human BPI protein products protect against lethal injections of isolated LPS and inocula of GNB. Phase I trials in healthy human volunteers and multiple Phase I/II clinical trials have been completed or are in progress (severe pediatric meningococcemia, hemorrhagic trauma, partial hepatectomy, severe peritoneal infections, and cystic fibrosis) and two phase III trials (meningococcemia and hemorrhagic trauma) have been initiated. In none of >900 normal and severely ill individuals have issues of safety or immunogenicity been encountered. Preliminary evidence points to overall benefit in BPI-treated patients. These results suggest that BPI may have a place in the treatment of life-threatening infections and conditions associated with bacteremia and endotoxemia.

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“…48 The early endotoxin-induced leukopenia was blunted, and neutrophil degranulation, measured by circulating levels of elastase-␣ 1antitrypsin complexes and lactoferrin, was largely prevented by rBPI 23 . 48 In similar settings, rBPI 23 treatment reduced the activation of fibrinolytic and coagulation systems 49 and attenuated the potentially deleterious circulatory effects of endotoxins. 50…”

Section: Studies Of Human Volunteersmentioning

confidence: 99%

Potential applications of N-terminal recombinant fragments of bactericidal/permeability-increasing protein in liver surgery

et al. 1999

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Bactericidal/permeability-increasing protein (BPI) was first isolated by Elsbach and Weiss in 1978. 1,2 It is a natural host-defense protein of 55 kd found in the azurophilic granules of human neutrophils, which are important in the host defense against infections. The protein was named after one of its first discovered properties, the potential to kill bacteria by increasing the permeability of their cell walls. 1,2 This ability to kill bacteria has led to further studies of the functions of BPI, from which researchers have discovered several potentially useful properties. In this article, we first give a brief review of the most important in vitro and in vivo studies showing the functions and properties of BPI and then focus on the potential applications of one of the more stable recombinant BPIs, rBPI 21 , in the field of liver surgery and transplantation. The Main Effects of BPI Antibacterial ActionBPI shows antimicrobial activity against a wide range of gram-negative bacteria. 1-3 The cell envelope of gram-negative bacteria consists of the cytoplasmic membrane, peptidoglycan layer, and an additional barrier, the outer membrane, which is strictly asymmetric with respect to its lipid composition. The outer leaflet of this membrane is composed mainly of lipopolysaccharides (LPS; endotoxins). LPS consists of an oligosaccharide or polysaccharide and a covalently linked glycolipid component (lipid A) that anchors the LPS in the outer membrane. 4 The selectivity of BPI against gram-negative bacteria has been attributed to the strong attraction of BPI for this LPS in the bacterial envelope, especially the high affinity for its lipid A component. 5,6 It has become evident that the LPS structure primarily determines bacterial sensitivity. Strains bearing LPS with short polysaccharide chains in their outer membrane are the most sensitive. Long polysaccharide chains sterically hinder the access of BPI to the binding sites in the inner core and the lipid A regions of LPS, thereby reducing the affinity of BPI for the envelope LPS, necessitating higher ambient BPI concentrations to achieve the required amount of bound BPI to produce its biological effects. 3,6,7 The cytotoxic effect of BPI on gram-negative bacteria can be divided into two stages. When BPI binds to the outer membrane, several immediate effects are manifest, including arrest of bacterial growth, discrete changes in the permeability of the outer membrane, and selective activation of several envelope enzymes, which degrade phospholipids and peptidoglycans. These changes are evident despite preservation of the functional integrity of the biochemical machinery in the nongrowing bacteria. In fact, certain manipulations result in repair of the envelope alterations and resumption of growth, therefore indicating that the initial effects of BPI are not directly bactericidal. 2,8 However, when this process is continued, alterations of the cytoplasmic membrane are produced, resulting in an impairment of the energy metabolism that leads to an irreversible growth arre...

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Inhibition of endotoxin-induced activation of the coagulation and fibrinolytic pathways using a recombinant endotoxin-binding protein (rBPI23)

Cited by 41 publications

References 0 publications

Natural Antibiotics and Insulin Sensitivity: The Role of Bactericidal/Permeability-Increasing Protein

Natural Antibiotics and Insulin Sensitivity: The Role of Bactericidal/Permeability-Increasing Protein

The bactericidal/permeability-increasing protein (BPI) in antibacterial host defense

Potential applications of N-terminal recombinant fragments of bactericidal/permeability-increasing protein in liver surgery

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