Bactericidal/permeability-increasing protein protects vascular endothelial cells from lipopolysaccharide-induced activation and injury.
Bactericidal/permeability-increasing protein (BPI), a human neutrophil granule protein, has been shown to bind lipopolysaccharide (LPS) and neutralize LPS-mediated cytokine production in adherent monocytes and the whole-blood system. In this study we investigated the ability of recombinant human BPI (rBPI) to inhibit LPS-induced vascular endothelial cell (EC) injury and activation. rBPI inhibited significantly both rough and smooth LPS-mediated injury for cultured bovine brain microvessel ECs, as measured by lactic dehydrogenase release, and blocked the LPS-induced interleukin-6 (IL-6) release from human umbilical vein ECs in a dose-dependent manner. BPI was able to inhibit LPS-mediated EC injury or activation whether it was added before or at the same time with LPS, but delaying the time of addition of rBPI resulted only in a partial inhibition. BPI also inhibited LPS-induced tumor necrosis factor alpha, IL-1 beta, and IL-6 release from human whole blood. This inhibition of tumor necrosis factor alpha, IL-1 beta, and IL-6 release from whole blood was maximal when BPI was premixed with LPS before addition to blood and was partial when BPI was added simultaneously with LPS, but no inhibition was observed when the addition of rBPI was delayed for 5 min. These findings suggest that rBPI is a potent inhibitor of LPS-mediated responses in ECs and whole blood and underscore the potential use of BPI in treatment or prevention of endotoxic shock. In contrast, the anti-lipid A monoclonal antibodies HA-1A and E5 were ineffective in inhibiting LPS-mediated EC injury and activation as well as LPS-induced cytokine release in whole blood.
Arditi
M
M
Division of Infectious Diseases, Children's Hospital Los Angeles, University of Southern California School of Medicine 90027.
Zhou
J
J
Huang
S H
SH
Luckett
P M
PM
Marra
M N
MN
Kim
K S
KS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D023181:Antimicrobial Cationic Peptides; D001770:Blood Bactericidal Activity; D001798:Blood Proteins / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008565:Membrane Proteins; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000911:Antibodies, Monoclonal; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C021623:bactericidal permeability increasing protein