Treatment with recombinant bactericidal/permeability-increasing protein to prevent endotoxin-induced mortality in bile duct-ligated rats.
BACKGROUND
Operation in patients with obstructive jaundice is associated with substantial morbidity because of increased susceptibility to endotoxin (lipopolysaccharide) and the inflammatory cascade. Different interventions to reduce endotoxemia and cytokine induction, and resulting complications, have been studied. Bactericidal/permeability-increasing protein (BPI) is a naturally occurring endotoxin-binding protein produced in neutrophils. It binds endotoxin, neutralizing the activity and inhibiting cytokine production by mononuclear cells. In experimental endotoxemia in animals and in healthy human volunteers, BPI has shown a protective effect. The aim of this study was to determine whether BPI could protect against increased endotoxin sensitivity in rats with obstructive jaundice and reduce endotoxin-induced mortality.


METHODS
Male Wistar rats were used. Intraperitoneal Escherichia coli 2mg/kg was given 1 week after sham operation or bile duct ligation (BDL). Three groups were studied: sham, BDL with placebo, and BDL with 5 mg/kg recombinant BPI21.


RESULTS
BDL rats were jaundiced (mean bilirubin 186 micromol/L; no difference between BDL rats without or with BPI). Bilirubin remained less than 1 micromol/L in sham-operated rats (p = 0.002). Endotoxin levels were 3.4pg/mL in sham controls and 3.1 pg/mL in BDL rats before administration of lipopolysaccharide (p = NS). Two hours after administration, levels were 615.4ng/mL in placebo BDL rats and 10 times less in BPI-treated BDL rats, at 60.2ng/mL (p=0.03). The same trend was found at 6 hours. At 24 hours, mortality was 1 of 6 in sham-operated rats (15%) versus 8 of 11 in untreated BDL rats (75%). BPI intervention reduced the death rate to 1 of 12 BDL rats (8%) (p = 0.003).


CONCLUSIONS
Intraperitoneal recombinant BPI21 in rats having BDL reduced endotoxin-induced mortality from 75% to 8%, a death rate comparable to that in nonjaundiced rats. BPI could be an interesting perioperative treatment in clinical obstructive jaundice.
Kimmings
A N
AN
Department of Surgery, Center for Hemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Academic Medical Center, Amsterdam, The Netherlands.
van Deventer
S J
SJ
Obertop
H
H
Gouma
D J
DJ
D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D002779:Cholestasis / Q000188:drug therapy*; D019446:Endotoxemia / Q000517:prevention & control*; D004926:Escherichia coli; D007249:Inflammation / Q000517:prevention & control; D008026:Ligation; D008297:Male; D008565:Membrane Proteins / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000627:therapeutic use
D008565:Membrane Proteins; D011994:Recombinant Proteins; C025357:endotoxin binding proteins