Kupffer cell blockade, tumour necrosis factor secretion and survival following endotoxin challenge in experimental biliary obstruction

Background: Gram-negative sepsis and its sequelae frequently complicate inv asive procedures in patients with obstructive jaundice. In response to endo toxin, Kupffer cells secrete tumour necrosis factor (TNF), a pivotal early mediator of sepsis. An investigation was carried out into the specific role of Kupffer cell TNF secretion following endotoxin challenge in obstructive jaundice. Methods: Survival following intraperitoneal administration of endotoxin (2. 0, 0.02 and 0.0002 mg per 100 g) was determined in rats following bile duct ligation (BDL) or sham operation. Plasma TNF concentration was quantified following endotoxin administration (0.0002 mg per 100 g) at 1, 2 and 6 h. S ubsequently, the effect of Kupffer cell blockade by gadolinium chloride on survival and plasma TNF concentration was assessed. Results: Jaundiced animals showed a significantly increased mortality rate following intraperitoneal injection of endotoxin 2.0 mg per 100 g (BDL 100 per cent versus sham 0 per cent) and 0.02 mg per 100 g (BDL 70 per cent ver sus sham 0 per cent; P = 0.002, Fisher's exact test). Median plasma TNF con centration was significantly greater in jaundiced animals Ih after endotoxi n administration (BDL 943 (interquartile range (i.q.r.) 211-3900) pg/ml ver sus sham 64 (i.q.r. 47-127)pg/ml; P = 0.002, Mann-Whitney U test). Kupffer cell blockade with gadolinium chloride increased the survival rate followin g endotoxin administration in BDL animals (BDL-GdCl3 100 per cent versus BD L-saline 40 per cent; P = 0.0003, Fisher's exact test) and decreased median plasma levels of TNF (BDL-GdCl3 88 (i.q.r. 0-1065) pg/ml versus BDL-saline 16 550 (1255-29 360) pg/ml; P = 0.002, Mann-Whitney U test). Conclusion: Kupffer cell blockade improved survival and suppressed systemic TNF activity after endotoxin challenge. In obstructive jaundice, hypersecr etion of TNF by Kupffer cells may supplement systemic cytokine production a nd be responsible for significant complications.