Expression and Antimicrobial Function of Bactericidal Permeability-Increasing Protein in Cystic Fibrosis Patients

Abstract

In cystic fibrosis (CF), the condition limiting the prognosis of affected children is the chronic obstructive lung disease accompanied by chronic and persistent infection with mostly mucoid strains of Pseudomonas aeruginosa. The majority of CF patients have antineutrophil cytoplasmic antibodies (ANCA) primarily directed against the bactericidal permeability-increasing protein (BPI) potentially interfering with antimicrobial effects of BPI. We analyzed the expression of BPI in the airways of patients with CF. In their sputum samples or bronchoalveolar lavage specimens, nearly all patients expressed BPI mRNA and protein, which were mainly products of neutrophil granulocytes as revealed by intracellular staining and subsequent flow cytometry. Repeated measurements revealed consistent individual BPI expression levels during several months quantitatively correlating with interleukin-8. In vitro, P. aeruginosa isolates from CF patients initiated the rapid release of BPI occurring independently of protein de novo syntheses. Furthermore, purified natural BPI as well as a 27-mer BPI-derived peptide displayed antimicrobial activity against even patient-derived mucoid P. aeruginosa strains and bacteria resistant against all antibiotics tested. 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.

Murine Bactericidal/Permeability-Increasing Protein Inhibits the Endotoxic Activity of Lipopolysaccharide and Gram-Negative Bacteria

“…For human BPI, we recently demonstrated a strong and uniform antibacterial activity against various strains of P. aeruginosa that differed in their susceptibility to antibiotics (26). As expected, at concentrations of 10 g/ml human BPI, we observed a strong antibacterial activity.…”

The role for neutrophil extracellular traps in cystic fibrosis autoimmunity

“…functional BPI has been associated with decreased clearance of the mucoid strain of P. aeruginosa, which leads to biofilm formation and obstructed respiratory function (16). Furthermore, anti-BPI autoantibodies have been shown to neutralize the bactericidal and opsonic activity of BPI (63,64).…”

“…BPI (~55 kDa) is an antimicrobial peptide stored in azurophilic granules of neutrophils that is required for efficient clearance of gram-negative bacteria (16,17). However, there is little understanding of the etiopathogenic role of this autoimmunity in CF.…”

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

“…It is, however, conceivable that BPI could impair vascular access of GNB by inhibiting neo-angiogenesis in settings where chronic neutrophilic inflammation prevails, e.g. in inflammatory bowel diseases or cystic fibrosis [77,79,109,110].…”