EFFECT OF ANTITUMOR NECROSIS FACTOR-ALPHA ON LEUKOCYTE ADHESION IN THE LIVER AFTER HEMORRHAGIC-SHOCK - AN INTRAVITAL MICROSCOPIC STUDY IN THE RAT

Tumor necrosis factor (TNF) plays a well known role during the develop ment of multiple organ failure, in part due to its role for the expres sion of adhesion molecules on endothelial cells, thereby contributing to inflammatory reactions. The purpose of this study was to investigat e the effects of TNF on leukocyte-endothelial interactions in the live r as a key organ during the systemic inflammatory response syndrome. I n Sprague-Dawley rats (n = 6/group) hemorrhagic shock was induced by r eduction of the mean arterial blood pressure (MAP) to 40 mmHg for 45 m in; resuscitation was initiated by retransfusion of shed blood (60%) a nd Ringer's lactate. At 1 and 5 h after resuscitation, intravital micr oscopy of the liver was performed after injection of acridine orange a s marker of leukocytes in sham-control animals and in shock animals pr etreated with anti-TNF monoclonal antibody (2 mg/kg b.w. TN3; Celltech , Slough, UK) or NaCl .9% 2 h prior to shock induction, respectively. At constant systemic hemodynamic conditions in all groups (e.g., norma l MAP), sinusoidal diameters and sinusoidal blood flow were comparably decreased to approximately 75% of control values in all shock groups. Significant differences were observed particularly in respect to perm anent adherent leukocytes with 31.8 +/- 4.7% in the shock/NaCl group a nd 20.7 +/- 2.6% (mean +/- S.E., p < .05) in the shock/TN3 group 5 h a fter resuscitation following hemorrhagic shock. Consistently higher ad hesion rates were observed in the portal regions compared to pericentr al regions of the liver lobules. Moreover, elevated TNF plasma levels 5 h after onset of resuscitation in the shock/NaCl group (534 +/- 354 pg/mL) were significantly reduced by anti-TNF pretreatment in the shoc k/TN3 group (47 +/- 16 pg/mL, p < .05). The results of the study indic ate that TNF plays an important role for regulation of intrahepatic le ukocyte adhesion after hemorrhagic shock in the rat. Attenuation of TN F-induced leukocyte adhesion in the liver may reduce liver dysfunction or dysregulation after hemorrhagic shock.