Neutrophil-induced liver injury during endotoxemia is was shown in models of endotoxin shock, 3 hemorrhagic dependent on the adhesion molecules Mac-1 (CD11b/ shock, 4 and hepatic ischemia-reperfusion injury. 5 CD18) on neutrophils and its counterreceptor on endo-Upregulation of the b 2 integrin Mac-1 (CD11b/CD18) thelial cells and hepatocytes, intercellular adhesion moleon circulating neutrophils was shown during reperfucule 1 (ICAM-1). To investigate a potential release of a sion after hepatic ischemia 6 and after endotoxin injecsoluble form of ICAM-1 (sICAM-1), animals received 100 tion. 7,8 The expression of Mac-1 on circulating neutromg/kg Salmonella abortus equi endotoxin alone or in comphils during endotoxemia is similar to Mac-1 bination with 700 mg/kg galactosamine. In endotoxin-senexpression on neutrophils accumulated in the liver. 9 sitive mice (C3Heb/FeJ), injection of endotoxin did not Monoclonal antibodies to Mac-1 or CD18 effectively cause liver injury but induced a time-dependent increase protected against reperfusion injury 6,10 or endotoxinof sICAM-1 in serum (300%) and in bile (615%) without affecting bile flow. In galactosamine/endotoxin-treated induced hepatic failure. 3,10 The counterreceptor for b 2 animals, which developed liver injury, the increase in integrins, intercellular adhesion molecule 1 (ICAMboth compartments was only 97% and 104%, respectively. 1), 11 is constitutively expressed on endothelial cells. 8,[12][13][14] In either case, the increase in sICAM-1 concentrations ICAM-1 messenger RNA (mRNA) and protein expresparalleled the enhanced ICAM-1 expression in the liver. sion on hepatocytes and endothelial cells is increased The endotoxin-resistant strain (C3H/HeJ) did not show during ischemia-reperfusion 12 and endotoxemia. 8,14 elevated sICAM-1 levels in serum or bile after endotoxin ICAM-1 antibodies were also highly effective in reducadministration. In contrast, the intravenous injection of ing the neutrophil-dependent injury in the liver. 8,12 murine tumor necrosis factor a (TNF-a), interleukin-1a
These experimental data support the hypothesis that (IL-1a) or IL-1b (13-23 mg/kg) into endotoxin-resistant mice induced a 225% to 364% increase in serum sICAM-1 adhesion molecules are essential for inflammatory liver and a 370% elevation of the biliary efflux of sICAM-1, injury.
again independent of changes in bile flow. These data
Consistent with these findings in animal models, a indicate that cytokines are major inducers of sICAM-1 substantial upregulation of ICAM-1 was reported in formation during endotoxemia in vivo. The described exinflammatory liver disease states in humans, including perimental model can be used to investigate the role of viral hepatitis, 14-16 alcoholic hepatitis, 14 primary biliary sICAM-1 in the pathophysiology of inflammatory liver cirrhosis, 14,17 primary sclerosing cholangitis, 17 and allodisease. (HEPATOLOGY 1996;23:530-536.) graft rejection. [18][19][20] In addition to the membrane-bound Adhesion molecules are important for neutrophil loform of ICAM-1, a second, circulating form of this adhecalization at the site of inflammation. 1,2 Substantial sion molecule was described in human serum. 21,22 This neutrophil accumulation in the liver and a role for soluble ICAM-1 (sICAM-1) molecule appears to contain these phagocytes in the pathophysiology of liver injury most of the extracellular portion of the membranebound form. 22 Subsequent investigations indicated that plasma levels of sICAM-1 are elevated in most inflam-Abbreviations: ICAM-1, intercellular adhesion molecule 1; mRNA, messenger RNA; sICAM-1, soluble ICAM-1; PBS, phosphate-buffered saline; TNF-a, matory liver diseases in humans. [23][24][25][26] The hypothesis tumor necrosis factor a; IL-1, interleukin-1.
that most of the sICAM-1 in serum under these condi-From the 1 Cardiovascular Pharmacology and 2 Drug Development Toxicoltions is derived from liver cells is supported by the