TUMOR-NECROSIS-FACTOR UP-REGULATES INTERCELLULAR-ADHESION MOLECULE-1,WHICH IS IMPORTANT IN THE NEUTROPHIL-DEPENDENT LUNG AND LIVER-INJURY ASSOCIATED WITH HEPATIC ISCHEMIA AND REPERFUSION IN THE RAT

Tumor necrosis factor (TNF) is released during hepatic ischemia/reperf usion (I/R) and plays an important role in the ensuing neutrophil-medi ated lung and liver injury. Since TNF is not a direct neutrophil chemo taxin, we hypothesized that TNF may up-regulate neutrophil adhesion mo lecules, specifically intercellular adhesion molecule-1 (ICAM-1), foll owing hepatic I/R, and that this molecule then plays an important role in tissue neutrophil influx. Rats underwent 90 min of lobar hepatic i schemia with reperfusion. Pulmonary and hepatic ICAM-1 expression were assessed by reverse transcription-polymerase chain reaction, Western blot analysis, and immunohistochemical staining. Increases in hepatic ICAM-1 were demonstrated within 1 h of reperfusion, while increases in pulmonary ICAM-1 were not seen until 6 h of reperfusion, Next, rats w ere treated with anti-TNF antibody or control antibody without TNF neu tralizing properties prior to hepatic I/R. Pretreatment with anti-TNF antibody significantly decreased pulmonary and hepatic ICAM-1 expressi on after hepatic I/R, We next investigated the effects of pretreatment with anti-ICAM-1 antibodies an the lung and liver injury that follows hepatic I/R. Lung injury was assessed by changes in pulmonary capilla ry permeability as estimated by extravasation of Evans Blue dye and pu lmonary neutrophil influx as measured by lung myeloperoxidase levels. Liver injury was assessed by hepatic neutrophil morphometrics and plas ma liver enzymes (alanine aminotransferase). Pretreatment with anti-IC AM-1 antibodies significantly decreased pulmonary capillary permeabili ty, pulmonary myeloperoxidase, hepatic neutrophil influx, and plasma a lanine aminotransferase, as compared to animals pretreated with contro l antibody. These data suggest that TNF is a proximal trigger far pulm onary and hepatic ICAM-1 up-regulation following hepatic ischemia with reperfusion, and that ICAM-1 is important for pulmonary and hepatic n eutrophil influx, with the resultant tissue injury, following hepatic I/R.