Treatment with recombinant bactericidal/permeability-increasing protein toprevent endotoxin-induced mortality in bile duct-ligated rats

Background: Operation in patients with obstructive jaundice is associated w ith 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 b inds endotoxin, neutralizing the activity and inhibiting cytokine productio n by mononuclear cells. In experimental endotoxemia in animals and in healt hy human volunteers, BPI has shown a protective effect; The aim of this stu dy was to determine whether BPI could protect against increased endotoxin s ensitivity in rats with obstructive jaundice and reduce endotoxin-induced m ortality. Study Design: Male Wistar rats were used. Intraperitoneal Escherichia coli 2 mg/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 rec ombinant BPI21. Results: BDL rats were jaundiced (mean bilirubin 186 mu mol/L; no differenc e between BDL rats without or with BPI). Bilirubin remained less than 1 mu mol/L in sham-operated rats (p = 0.002). Endotoxin levels were 3.4 pg/mL in sham controls and 3.1 pg/mL in BDL rats before administration of-lipopolys accharide (p=NS) Two hours after administration, levels were 615.4 ng/mL in placebo BDL rats and 10 times less in BPI-treated BDL rats, at 60.2 ng/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 (7 5%). 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 e ndotoxin-induced mortality from 75% to 8%, a death rate comparable to that in nonjaundiced rats. BPI could be an interesting perioperative treatment i n clinical obstructive jaundice. (J Am Coil Surg 1999;189:374-379. (C) 1999 by the American College of Surgeons).