Disease relevance of BPI

• BPI may attenuate the local inflammatory response and the systemic toxicity of endotoxin release during gram-negative infections [1].
• Under optimal conditions for potentiation, fewer than 100 BPI molecules were required to kill a single E. coli J5 bacterium [2].
• Human bactericidal/permeability-increasing protein (BPI) from neutrophils and a recombinant amino-terminal fragment, rBPI23, bind to and are cytotoxic for gram-negative bacteria both in vitro and ex vivo in plasma or whole blood [2].
• Due to its inhibitory activity for various LPS, BPI has therapeutic potential in endotoxic shock [3].
• Whole blood was collected in EDTA from 28 undialyzed patients with chronic renal failure (undialyzed CRF), 36 patients on chronic HD (HD) and 15 healthy controls, and plasma levels of LBP and BPI were measured by a sandwich ELISA [4] .

High impact information on BPI

• We designed a multistage study in the genetically isolated population of the Central Valley of Costa Rica to identify genes that promote susceptibility to severe BP (termed BPI), and screened the genome ot two Costa Rican BPI pedigrees (McInnes et al., submitted) [5] .
• The bactericidal/permeability-increasing protein (BPI) of polymorphonuclear leukocytes (PMN) is a potent cytotoxin, specific for Gram-negative bacteria, that also inhibits endotoxin activity by neutralizing isolated bacterial lipopolysaccharides (LPS) [6].
• This activity is weak relative to holo-BPI and the 25 kD N-terminal fragment in the Limulus and PMN-priming assay, but is comparable for inhibition of TNF production in whole blood [6].
• Holo-BPI and the 25 kD fragment have similar neutralizing potency (in nanomolar range) in all assays toward "smooth" LPS from Escherichia coli O111:B4 and O55:B5 (possessing long chain polysaccharide or O-antigen), and "deep rough" LPS from Salmonella minnesota Re595 mutant (possessing no O-antigen) [6].

Chemical compound and disease context of BPI

• LBP also potentiated BPI-mediated permeabilization of the E. coli outer membrane to actinomycin D by about 100-fold but had no permeabilizing activity of its own [2].
• The protein products of this gene cluster are predicted to be structural homologues of the human lipopolysaccharide binding proteins, lipopolysaccharide binding-protein (LBP) and bacterial permeability-increasing protein (BPI), which are known mediators of host defense against Gram-negative bacteria [7].
• Heat treatment of normal sera to 56 degrees C for 30 min, a common procedure for the inactivation of viruses, e.g. HIV, reveals the presence of antibodies to neutrophil cytoplasm antigens (ANCA), as detected by indirect immunofluorescence on ethanol-fixed human neutrophils and by antigen-specific ELISA for BPI [8].
• Thus, BPI and an even more potent NH2-terminal fragment may protect against Gram-negative bacteria in the host by blocking bacterial proliferation as well as endotoxin-mediated effects, not only as components of the intracellular antibacterial arsenal of the neutrophil, but also as potentially therapeutic extracellular agents [9].
• Thus, killing of ingested E. coli S15 by human as well as rabbit PMN does not require O2 and appears to be BPI-mediated [10].

Biological context of BPI

• The LBP gene spans approximately 28.5 kb and is composed of 14 exons while the 31.5-kb-long BPI gene is composed of 15 exons [11].
• A cluster of related genes whose products show structural identity with bactericidal permeability-increasing protein (BPI) has been identified in the genomes of both mice (on chromosome 2) and humans (on chromosome 20) [12].
• In this study the influences of LBP and BPI, two proteins with opposite effects, but with considerable sequence homology, on LPS-induced mononuclear phagocytic cell cytokine release was studied [13].
• LPS induces the phosphorylation of a number of proteins in a dose and time-dependent manner, however, the pattern of LPS-induced phosphorylation was not reduced by either LBP or BPI under conditions that result in selective TNF-alpha inhibition [14].
• Our aim was to investigate the role of the amino-and carboxy-terminal domains of BPI and LBP for sorting and storage in myeloid cells after transfection of cDNA to two rodent hematopoietic cell lines [15].

Anatomical context of BPI

• BPI concentrations were directly correlated with the quantity of neutrophils within clinical samples (rs = 0.81, p < 0.0001) [1].
• The bactericidal/permeability-increasing protein (BPI) inhibits the lipopolysaccharide (LPS)-mediated activation of monocytes [3].
• We have demonstrated that, unlike the human monocyte response to LPS, both LBP and BPI inhibited LPS-stimulated TNF-alpha production in mouse peritoneal macrophages [14].
• The carboxy-terminal domain of BPI promotes bacterial attachment to phagocytes, whereas the corresponding domain of LBP delivers lipopolysaccharide to monocytes/macrophages [15].
• Deletion of the carboxy-terminal half of BPI resulted in storage followed by degradation while the reciprocal deletion of the amino-terminal half led to retention in the endoplasmic reticulum for proteasomal degradation [15].

Associations of BPI with chemical compounds

• We have previously shown that human bactericidal/permeability-increasing protein (BPI) is able to inhibit serum-dependent lipopolysaccharide (LPS)-mediated activation of human monocytes and neutrophils in vitro, and to counteract the lethal effects of LPS challenge in vivo [16].
• We studied circulating BPI across categories of glucose tolerance [17].
• In parallel to improved insulin sensitivity, plasma BPI significantly increased in the metformin group but not in the placebo group [17].
• There was no correlation between serum creatinine and plasma levels of either LBP or BPI [4].
• Overall differences in charge and electrostatic potential between BPI and LBP suggest that BPI's bactericidal activity is related to the high positive charge of its NH2-terminal domain [18].

Physical interactions of BPI

• BPI inhibited the binding of poly(M) to monocytes in the presence of LBP, LBP-sCD14, or 10% human serum [19].
• Finally, flow cytometry analysis was used to determine whether BPI incubation with THP-1 cells affects the surface expression of the lipopolysaccharide-binding protein-lipopolysaccharide receptor CD14 [20].
• These artificial fusions retain BPI functions such as lipopolysaccharide (LPS) binding and protein-protein interactions that are not observed with native CETP [21].
• In contrast, myeloperoxidase binding to E. coli is strongly inhibited by BPI [22].

Regulatory relationships of BPI

• We further demonstrate that purified recombinant human BPI can inhibit LBP-mediated LPS binding to cells and their subsequent activation [16].
• BPI and LBP(N)-BPI(C) promote apparently CD14-independent LPS association to monocytes without cell activation [23].
• Thus, BPI that is functionally active against mucoid P. aeruginosa strains is expressed in the airways of CF patients but may be hampered by autoantibodies, resulting in chronic infection [24] .
• Added BPI in nanomolar concentrations killed each of three encapsulated strains of E. coli and in closely parallel fashion inhibited tumor necrosis factor (TNF) release [9].

Other interactions of BPI

• The neutrophil granular protein bactericidal/permeability-increasing protein (BPI) competes with LBP for endotoxin binding and functions as a molecular antagonist of LBP-endotoxin interactions [1].
• Recently, the crystal structure of one of the members of the gene family, bactericidal permeability increasing protein, was solved, providing potential insights into the mechanisms of action of CETP and PLTP [25].
• In the present study, we used the crystallographic data available for BPI to build a three-dimensional model for PLTP [26].
• CONCLUSION: BPI and cathepsin G are the major antigenic targets of ANCA seen in patients with SSc [27].
• Patients with antibodies to BPI had lower skin score, whereas no patient with antibodies to MPO had renal disease [27].

Analytical, diagnostic and therapeutic context of BPI

• No significant differences were found between both groups for BPI and IL-6 levels in the early reperfusion period [28].
• In immunoblotting, bands corresponding to lactoferrin and BPI were recognised in 44% and 22% of ReA sera [29].
• In subjects with glucose intolerance, BPI was also linked to BMI, waist-to-hip ratio, and age- and BMI-adjusted insulin sensitivity [17].
• The recent characterization of lipopolysaccharide binding protein (LBP) and bactericidal/permeability increasing factor (BPI) have provided the opportunity to examine the natural factors that regulate cytokine production in response to endotoxin in patients on hemodialysis (HD) [4].
• A model of human LBP derived from the BPI structure provides a rational basis for future experiments, such as site-directed mutagenesis and inhibitor design [18].

References