Preliminary evaluation of recombinant amino-terminal fragment of human bactericidal/permeability-increasing protein in children with severe meningococcal sepsis

Giroir, Brett P.; Quint, P.; Barton, Phil; Kirsch, E; Kitchen, Louann; Goldstein, Brahm; Nelson, Betty J.; Wedel, Nancy; Carroll, Stephen F.; Scannon, Patrick J.

doi:10.1016/s0140-6736(97)06468-4

Cited by 184 publications

(104 citation statements)

References 26 publications

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“…In brief summary, in a variety of animal models, recombinant human BPI (rBPI) and its amino-terminal derivate (rBPI 21 ), were protective against lethal and sub-lethal challenges with Gram-negative bacteria and endotoxin [11,[58][59][60][61]. Subsequent studies in humans, including in meningococcal sepsis, also showed a significant protective effect of BPI [12][13][14][15][61][62][63][64], although not yet sufficient to lead to an approved clinical application. However, these studies strongly suggested that BPI could act in vivo and help resolve GNB infection and endotoxin-induced inflammation.…”

Section: Bpi Actions During Host: Gnb Interactionsmentioning

confidence: 99%

“…In contrast to many of the clinical trials in which rBPI 21 was continuously infused to maintain functionally significant plasma levels and the target was systemic endotoxin and/or GNB [14,15,64], early interactions of BPI with GNB and endotoxin during natural infections are much more likely to occur in tissue, outside of the bloodstream [3]. Typically, the critical initial event in invasive GNB infections is the crossing of epithelial barriers by the microorganism, particularly those of the skin, lungs, the gastrointestinal and urogenital tracts, and the subsequent exposure of underlying host tissue to the microbe and its products ( Figure 3, [3]).…”

Section: Bpi Actions During Host: Gnb Interactionsmentioning

confidence: 99%

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The bactericidal/permeability-increasing protein (BPI) in infection and inflammatory disease

Schultz

Weiss

2007

Clinica Chimica Acta

114

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Gram-negative bacteria (GNB) and their endotoxin present a constant environmental challenge. Endotoxins can potently signal mobilization of host defenses against invading GNB but also potentially induce severe pathophysiology, necessitating controlled initiation and resolution of endotoxin-induced inflammation to maintain host integrity. The bactericidal/permeability-increasing protein (BPI) is a pluripotent protein expressed, in humans, mainly neutrophils. BPI exhibits strong anti-microbial activity against GNB and potent endotoxin-neutralizing activity. BPI mobilized with neutrophils in response to invading GNB can promote intracellular and extracellular bacterial killing, endotoxin neutralization and clearance, and delivery of GNB outer membrane antigens to dendritic cells. Tissue expression by dermal fibroblasts and epithelia could further amplify local levels of BPI and local interaction with GNB and endotoxin, helping to constrain local tissue infection and inflammation and prevent systemic infection and systemic inflammation. This review article focuses on the structural and functional properties of BPI with respect to its contribution to host defense during GNB infections and endotoxin-induced inflammation and the genesis of auto-antibodies against BPI that can blunt BPI activity and potentially contribute to chronic inflammatory disease.

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Section: Bpi Actions During Host: Gnb Interactionsmentioning

confidence: 99%

Section: Bpi Actions During Host: Gnb Interactionsmentioning

confidence: 99%

The bactericidal/permeability-increasing protein (BPI) in infection and inflammatory disease

Schultz

Weiss

2007

Clinica Chimica Acta

114

View full text Add to dashboard Cite

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“…Von der Mohlen et al could show that BPI has a significant protective effect in meningococcal sepsis [35]. Several phase I and II studies have dealt with the pharmacokinetics and possible indications of a recombinant fragment of bactericidal/permeability increasing protein [36][37][38], but have not yet led to an approved clinical application.…”

Section: Human Bactericidal/permeability-increasing Protein (Bpi)mentioning

confidence: 99%

Human antimicrobial proteins in ear wax

Schwaab

Gurr

Neumann

et al. 2011

Eur J Clin Microbiol Infect Dis

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Introduction Antimicrobial peptides (AMP)Generally speaking surfaces like the skin or the oral mucosa are protected by several factors including the adaptive and innate immune systems against invading bacteria and fungi. The antimicrobial mucosal shield of the human airways has been subject of several studies and is well investigated [1][2][3]. A growing number of different human antimicrobial peptides (AMP) have been described which are produced e. g. by surface epithelial cells or by neutrophil granulocytes. The AMPs have a broad, but not identical spectrum of antimicrobial activity against bacteria, virus or fungi. A synergistic and additive effect of different AMPs has been reported [4]. In addition to their antimicrobial charactics, AMPs play a major part in inflammation, immune activation, and wound healing [5][6][7]. Some of the well described AMPs are subject to this study and therefore will be further described. The human ß-Defensins (hBD)The family of human ß-Defensins (hBD) is named after their beta-sheet structure which is stabilised by intramolecular disulfide bonds. Human ß-Defensin 1 (hBD1) was first isolated from hemofiltrate [8] and is expressed in epithelial cells of the urinary, respiratory tract and in keratinocytes [9][10]. It has a strong antimicrobial effect on Gram-negative bacteria [11][12]. Human ß-Defensin 2 (hBD2) is an inducible (by Escherichia coli, Pseudomonas aeruginosa, Helicobacter pylori, Lipoprotienacid, Candida albicans, TumorNecrosis-Factor-α, Interleucine1-ß) peptide [13][14][15] with a strong antimicrobial effect on Escherichia coli, Pseudomonas aeruginosa and Candida albicans, and a relatively weak effect on Staphylococcus aureus [13]. The human ß-Defensin 3 (hBD3) can be induced by tumor necrosis factor α and contact with Pseudmonas aeruginosa or Staphalyococcus aureus e. g. in keratinocytes [16]. HBD3 has antimicrobial activity against Staphylococcus aureus, including Methicillin restistant Staphylococcus aureus (MRSA), Streptococcus pyogenes, Pseudomonas aeruginosa, Escherichia coli, Vancomycin-resistant Enterococcus faecium, Candida albicans and Haemophilus influenza [9; 12; 17]. Human LL-37 (LL-37)LL-37 is the 37-amino acid long C-terminus and the antimicrobial active component of the human Cathelicidin antimicrobial peptide 18 (hCAP-18). It is expressed in leukocytes (monocytes, neutrophiles, T-cells, B-cells), epithelial cells (skin, gastrointestinal and respiratory tract) and secreted into wound and airway surface fluid [18][19][20][21]. LL-37 alone and in combination with other AMPs is bactericidal against a broad spectrum of [21][22][23]. Apart from the antimicrobial activity LL-37 plays a role in angiogenesis, cancer development, neutralisation of bacterial lipopolysaccharide and is chemotactic for human monocytes, neutrophils and CD 4 T-lymphocytes [24-26.]. Human Secretory Leucoprotease Inhibitor (hSLPI)hSLPI is a 11.7-kDa heavy protein which is expressed in macrophages, neutrophils and epithelial cells [27-28.].The antimicrobial activity against Gram-negativ...

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“…54 This first clinical administration of rBPI 21 occurred in an open-label, dose-escalation, multicenter trial in which 26 children (aged 1 to 18 years) with meningococcemia received standard treatment plus intravenous rBPI 21 . 55 Meningococcemia is characterized by massive levels of bacteria and their endotoxins in the blood, triggering an inflammatory cascade that can lead to death within hours or leave survivors with serious permanent damage, such as amputations or neurological damage. Because bacteria and endotoxins have a central role in the development of meningococcemia, they present the main target of therapeutic interventions.…”

Section: Clinical Studiesmentioning

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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Preliminary evaluation of recombinant amino-terminal fragment of human bactericidal/permeability-increasing protein in children with severe meningococcal sepsis

Cited by 184 publications

References 26 publications

The bactericidal/permeability-increasing protein (BPI) in infection and inflammatory disease

The bactericidal/permeability-increasing protein (BPI) in infection and inflammatory disease

Human antimicrobial proteins in ear wax

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

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