RELEASE OF BACTERICIDAL PERMEABILITY-INCREASING PROTEIN IN EXPERIMENTAL ENDOTOXEMIA AND CLINICAL SEPSIS - ROLE OF TUMOR-NECROSIS-FACTOR/

Bactericidal/permeability-increasing protein (BPI) is contained within the azurophilic granules of neutrophils and is able to neutralize end otoxin and kill Gram-negative bacteria. TNF has been implicated as a m ediator of endotoxin-induced neutrophil degranulation. To assess the r ole of TNF in the elevated BPI levels during sepsis, the following stu dies were performed. 1) In 31 consecutive patients with sepsis syndrom e, plasma BPI levels were markedly elevated compared with those in hea lthy controls, but showed no correlation with simultaneously measured TNF concentrations. 2) In four healthy men, i.v. injection of recombin ant human TNF (50 mu g/m(2)) 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 conce ntrations of TNF and BPI. 4) Eight healthy chimpanzees were investigat ed after i.v, injection of endotoxin (4 ng/kg); four animals received endotoxin only, and four animals received an anti-TNF mAb simultaneous ly. Although anti-TNF completely prevented the endotoxin-induced appea rance of TNF activity, the rise in BPI levels remained unaltered. Thes e results suggest that TNF is not critical for the release of BPI from neutrophils during experimental endotoxemia or clinical sepsis.