RELEASE OF SOLUBLE INTERCELLULAR-ADHESION MOLECULE-1 INTO BILE AND SERUM IN MURINE ENDOTOXIN-SHOCK

Neutrophil-induced liver injury during endotoxemia is dependent on the adhesion molecules Mac-1 (CD11b/CD18) on neutrophils and its counterr eceptor on endothelial cells and hepatocytes, intercellular adhesion m olecule 1 (ICAM-1). To investigate a potential release of a soluble fo rm of ICAM-1 (sICAM-1), animals received 100 mu g/kg Salmonella abortu s equi endotoxin alone or in combination with 700 mg/kg galactosamine. In endotoxin-sensitive mice (C3Heb/FeJ), injection of endotoxin did n ot cause liver injury but induced a time-dependent increase of sICAM-1 in serum (300%) and in bile (615%) without affecting bile now. In gal actosamine/endotoxin-treated animals, which developed liver injury, th e increase in both compartments was only 97% and 104%, respectively, L n either case, the increase in sICAM-1 concentrations paralleled the e nhanced ICAM-1 expression in the Liver. The endotoxin-resistant strain (C3H/HeJ) did not show elevated sICAM-1 levels in serum or bile after endotoxin administration, In contrast, the intravenous injection of m urine tumor necrosis factor alpha (TNF-alpha), interleukin-la (IL-1 al pha) or IL-1 beta (13-23 mu g/kg) into endotoxin-resistant mice induce d a 225% to 364% increase in serum sICAM-1 and a 370% elevation of the biliary efflux of sICAM-1, again independent of changes in bile now, These data indicate that cytokines are major inducers of sICAM-1 forma tion during endotoxemia in vivo. The described experimental model can be used to investigate the role of sICAM-1 in the pathophysiology of i nflammatory liver disease.