The bactericidal/permeability increasing protein of neutrophils is a potent antibacterial and anti-endotoxin agent in vitro and in vivo.
The Bactericidal/Permeability Increasing protein (BPI) is a major constituent of the azurophilic granules of human and rabbit polymorphonuclear leukocytes (PMN). The cDNA of the highly conserved protein has been isolated from man, rabbit and cow. The ca. 50 kDa BPI and a ca. 25 kDa bioactive N-terminal fragment are cytotoxic only for Gram-negative bacteria (GNB). This target-cell specificity reflects the strong attraction of the highly cationic protein for the negatively charged lipopolysaccharides (LPS) in the bacterial envelope. Native and recombinant (r) holo-BPI and the N-terminal fragment (rBPI-23) bind with high affinity (apparent Kd 1-10 nM) to all forms of isolated LPS so far examined, and inhibit the numerous biological effects of LPS in vitro (including in whole blood ex vivo) as well as in animals. Under the same conditions the antibacterial activities of holo-BPI and rBPI-23 against GNB with rough chemotype LPS are the same, but against serum-resistant and smooth chemotype GNB rBPI-23 is up to 30-fold more potent than holo-BPI. Holo-BPI and rBPI-23 protect mice, rats and rabbits against lethal cytotoxic effects of LPS and in some cases against lethal inoculations with live GNB.
Department of Medicine, New York University Medical Center, NY 10016.
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P
Elsbach
J
J
Weiss
M
M
Doerfler
C
C
Shu
F
F
Kohn
W S
WS
Ammons
A H
AH
Kung
K K
KK
Meszaros
J B
JB
Parent
D000818:Animals; D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides; D001770:Blood Bactericidal Activity; D001798:Blood Proteins / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology*; D002417:Cattle; D016207:Cytokines / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D004731:Endotoxins / Q000037:antagonists & inhibitors*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D008565:Membrane Proteins; D051379:Mice; D008970:Molecular Weight; D009504:Neutrophils / Q000502:physiology*; D011817:Rabbits; D051381:Rats
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D016207:Cytokines; D018076:DNA, Complementary; D004731:Endotoxins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C021623:bactericidal permeability increasing protein