Abstracts
1997 Digestive Disease Week

Hepatic Kupffer cell blockade reduces mortality in acute hemorrhagic pancreatitis in mice.

B Gloor, KE Todd, JS Lane, MPN Lewis, HA Reber. Departments of Surgery, UCLA School of Medicine and Sepulveda VAMC, Los Angeles, CA.

We hypothesize that inflammatory cytokines derived from the liver may cause distant organ failure and death in severe acute pancreatitis (AP). To test this, we determined the effects of Kupffer cell (KC) blockade on the mortality rate and severity of inflammation in AP. Methods: 30 mice were divided into 3 groups. Gadolinium chloride (Gd), which blocks KC activity, was given at the start of the study and again after 36 hr. Group 1 received only Gd (1mg/100g IV), and regular chow. Groups 2 and 3 were fed a choline deficient, ethionine supplemented (CDE) diet for 72 hr, to induce a lethal pancreatitis. Group 2 received IV saline; Group 3 received Gd. After 72 hr, serum TNF-alpha, IL1ß, IL6 and 10 were measured by ELISA, neutrophil infiltration in the lung was determined by myeloperoxidase (MPO) assay, and histologic severity of AP was scored (0-16; normal to most abnormal) in a blinded fashion by 2 investigators. In a 2nd study, the mortality rate of CDE AP was determined in saline and Gd treated groups of 50 mice each. Results:

  Cytokines                Group 1      Group 2        Group 3
  - TNFlpha (pg/ml)    4.6 ± 2      605 ± 188      361 ± 86 #
  - IL 1ß     (pg/ml)     10 ± 6.7   1159 ± 209      592 ± 112 #
  - IL 6      (pg/ml)     43 ± 8.3    794 ± 531      481 ± 321 #
  - IL 10     (pg/ml)     58 ± 18    1423 ± 1203     597 ± 424 #
  Histologic score       0.6 ± 0.2    9.8 ± 1.7     10.5 ± 1.4 °
  Mortality (10 day)         -          86.3 %          52% *
  MPO lung (U/mg)        613 ± 58    1678 ± 226      953 ± 114 **
  Serum-Amylase          2987±567    23090±2380     20930±1577 °
  (U/l)
* p<0.001; ** p<0.01; # p<0.05; ° NS vs Group 2 (Values are mean ± SEM).

Conclusions: KC blockade decreased mortality, lung neutrophil accumulation, and serum cytokines. The fact that the degree of local pancreatic inflammation was unchanged supports the hypothesis that mortality is a function of secondary release of hepatic cytokines. It suggests new strategies for clinical treatment.