Release of bactericidal/permeability-increasing protein in experimental endotoxemia and clinical sepsis. Role of tumor necrosis factor.

Bactericidal/permeability-increasing protein (BP]) is contained within the azurophilic granules of neutrophils and is able to neutralize endotoxin and kill Gram-negative bacteria. TNF has been implicated as a mediator of endotoxin-induced neutrophil degranulation. To assess the role of TNF in the elevated BPI levels during sepsis, the following studies were performed. 1) In 31 consecutive patients with sepsis syndrome, plasma BPI levels were markedly elevated compared with those in healthy controls, but showed no correlation with simultaneously measured TNF concentrations. 2) In four healthy men, i.v. injection of recombinant human TNF (50 microg/m2) induced a rapid rise in plasma BPI levels. 3) In eight normal subjects, i.v. administration of Escherichia coli endotoxin (4 ng/kg) elicited subsequent increases in the plasma concentrations of TNF and BPI. 4) Eight healthy chimpanzees were investigated after i.v. injection of endotoxin (4 ng/kg); four animals received endotoxin only, and four animals received an anti-TNF mAb simultaneously. Although anti-TNF completely prevented the endotoxin-induced appearance of TNF activity, the rise in BPI levels remained unaltered. These results suggest that TNF is not critical for the release of BPI from neutrophils during experimental endotoxemia or clinical sepsis.